Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[NH2:5].[Br:12]Br.[OH-].[Na+]>CC(O)=O.C(Cl)(Cl)Cl>[Br:12][C:6]1[CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]([F:1])=[CH:3][C:4]=1[NH2:5]
Reactant: BrBr
Reactant: Nc1ccc([N+](=O)[O-])c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Nc1cc(F)c([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To a mixture of 3-fluoro-4-nitroaniline (6.5 g, 42.2 mmol) in AcOH (80 mL) and chloroform (25 mL) was added dropwise Br2 (2.15 mL, 42.2 mmol) at 0° C. After addition, the resulting mixture was stirred at room temperature for 2 h and then poured into ice water. The mixture was basified with aqueous NaOH (10%) to pH˜8.0-9.0 under cooling and then extracted with EtOAc (50 mL×3). The combined organic layers were washed with water (80 mL×2) and brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to give 2-bromo-5-fluoro-4-nitroaniline (9 g, 90%). 1H-NMR (400 MHz, DMSO-d5) δ 8.26 (d, J=8.0, Hz, 1H), 7.07 (brs, 2H), 6.62 (d, J=9.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4](Cl)[N:3]=1.[NH2:25][C@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:25][C@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N
Reactant: COc1ccc(CN2Cc3c(F)c(Cl)nc(Cl)c3C2=O)c(OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(CN2Cc3c(F)c(N[C@H]4CCCC[C@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Yield: 20.5 %

Procedure:
To a mixture of 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (200 mg, 0.539 mmol) and tert-butyl (1R,2S)-2-aminocyclohexylcarbamate (173 mg, 0.808 mmol) in ACN (5 mL) was added N,N-diisopropylethylamine (0.141 mL, 0.808 mmol). The reaction mixture was heated in a sealed vial at 100° C. for several hours after which additional amine (0.5 eq) was added. The mixture was heated overnight and the solvent was subsequently removed in vacuo. The residue was dispersed in DMSO and MeOH (1/1) and the resulting mixture was filtered. The filtrate was purified via preparative HPLC. The fractions were collected and dried in vacuo to give the title compound as a tan solid (60.7 mg, 21%). [M+H] calc'd for C27H34ClFN4O5, 550; found, 550
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([Cl:11])[CH:3]=1.S(Cl)([Cl:14])=O>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:14])=[O:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Br)cc1Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Br)cc1Cl
Temperature: 75 °C
Reaction time: 16 h

Procedure:
To a mixture of 15 g of 4-bromo-2-chlorobenzoic acid in 25 ml DMF is added 10 ml thionyl chloride at room temperature and the reaction mixture is stirred for 16 h at 75° C. Excess of thionyl chloride is removed under reduced pressure to give 4-bromo-2-chlorobenzoyl chloride as crude material that is used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]([CH2:4]Cl)=[CH2:3].[C:6]1(=[O:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C1(C)C=CC=CC=1>[Zn].C(O)(=O)C>[Cl:1][C:2](=[CH2:3])[CH2:4][C:6]1([OH:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C=C(Cl)CCl
Reactant: O=C1CCCCC1
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C=C(Cl)CC1(O)CCCCC1
Yield: 99 %

Procedure:
56.53 Grams of 2,3-dichloro-1-propene were added dropwise to a mixture of 25.00 g of cyclohexanone, 75 g of toluene, 100 g of 5% acetic acid and 34.35 g of zinc powder at 45° C., and then the mixture was allowed to react at the same temperature for 3 hours. After the reaction was completed zinc-derived insolubles were filtered off, and the resultant filtrate was subjected to separation. The organic phase was washed with a 7% sodium carbonate aqueous solution and dried over sodium sulfate. The desiccant was filtered off, and then the toluene was distilled off under reduced pressure to give 44.05 g of 1-(2'-chloroallyl)-1-cyclohexanol. The results were as follows.
Reaction SMILES: Cl[CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17](=[O:19])[CH3:18])=[CH:11][CH:10]=1)[C:3]([O:5]CC)=O.[NH2:20][C:21](N)=[S:22].S1(CCCC1)(=O)=[O:25].Cl>C(OCC)(=O)C.O.COCCO>[O:19]=[C:17]([CH3:18])[CH2:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH:2]2[S:22][C:21](=[O:25])[NH:20][C:3]2=[O:5])=[CH:14][CH:13]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC(C)=O)cc1
Reactant: O=S1(=O)CCCC1
Agent: Cl
Solvent: COCCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 90 °C

Procedure:
A mixture comprising 12 g of ethyl 2-chloro-3-[4-(2-oxopropoxy)phenyl]propionate [prepared as described in step (b) above], 5 g of thiourea and 30 ml of sulfolane was heated at 90° C. for 3 hours, and then 100 ml of ethylene glycol monomethyl ether were added to the mixture, which was then heated for a further 4 hours. At the end of this time, 40 ml of water and 20 ml of concentrated aqueous hydrochloric acid were added to the reaction mixture, and the resulting mixture was heated for 4.5 hours in an oil bath kept at 100° C. After this, the reaction mixture was mixed with water and ethyl acetate, and then the ethyl acetate layer was separated, washed with water and dried over anhydrous sodium sulfate; the solvent was then removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 3:2 to 2:3 by volume as the eluent, followed by crystallization from a mixture of ethyl acetate and hexane, to give 4.2 g of the title compound as crystals, melting at 158°-159° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:13].[Br:15]N1C(C)(C)C(=O)N(Br)C1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.CCCCCCC>C(OC)(=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:13][Br:15]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: COC(=O)c1c(C)cccc1[N+](=O)[O-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: COC(C)=O
Solvent: CCCCCCC
Product: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Temperature: 75 °C
Yield: 64.1 %

Procedure:
A mixture of 2-methyl-6-nitro-benzoic acid methyl ester (99 g, 508 mmol), 1,3-dibromo-5,5-dimethylhydantoin (DBH) (80 g, 279 mmol), in methyl acetate (600 mL) was heated at 78° C. for 40 minutes, while stirred with a mechanical stirrer. Then a solution of 2,2′-azobisisobutyro-nitrile (AlBN) (4.2 g, 25 mmol) in methyl acetate (80 mL) was added and heated at 75° C. for 11 hours. The mixture was allowed to cool to 15° C. and stirred for 2 hours to age the precipitate. The suspension was filtered, washed with 10° C. methyl acetate (2×50 mL) to give a brown filtrate. To the filtrate, was added heptane (500 mL). The solution was washed with 2% brine (2×500 mL) and water (2×500 mL). The organic layer was concentrated to about 2 volumes, added t-butyl methyl ether (300 mL), heated at 70° C. for 15 minutes, cooled the solution to 53° C. over one hour, seeded with the product (about 250 mg) at 45° C., then at 20˜25° C., while blowing nitrogen with a glass pipette overnight. The resulting suspension was filtered via a medium pore-sized funnel, washed with a pre-cooled 10° C. mixed solvent of heptane/MTBE (1/2 vol/vol) and suction dried in hood overnight to give 2-bromomethyl-6-nitro-benzoic acid methyl ester as an off-white solid (49 g, 35% yield). The solid was used in the next step without further purification.
Reaction SMILES: S([O-])([O:4][CH2:5][C:6]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:7])(=O)=O.[Na+].[CH2:24]([OH:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].O>C1(C)C=CC=CC=1>[CH2:9]([O:8][C:6]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:7])[C:5]([O:30][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:4])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCOC(C)(COS(=O)(=O)[O-])OCCCCCC
Reactant: CCCCCCO
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCOC(=O)C(C)(OCCCCCC)OCCCCCC
Yield: 84 %

Procedure:
To a solution of methyl pyruvate 1 (10.0 g, 98.0 mmol) in toluene (100 mL) is added 1-hexanol 2 (40.1 g, 392 mmol) and p-Ts0H (186 mg, 0.98 mmol). The mixture is heated to reflux for 10 hours with azeotropic removal of water from the reaction mixture. The reaction is quenched with saturated NaHCO3 (100 mL), and the reaction mixture is extracted with ethyl acetate (2×100 mL). The combined organic layers are washed with brine (100 mL) and dried over anhydrous sodium sulfate. The solvent is removed and the residue is purified by silica gel chromatography (1→10% ethyl acetate/hexane) to give hexyl 2,2-bis(hexyloxy)propanoate 3 (29.5 g, 84%) as a colorless oil: Rf (15% EtOAc/hexane)=0.53; IR (thin film, cm−1) 2956, 2930, 2860, 1746 (C═O), 1467, 1280, 1137, 1062. 1H NMR (600 MHz, CDCl3) δ 4.14 (t, J=7.2 Hz, 2H), 3.48 (ddd, J=9.0, 7.2, 6.6 Hz, 2H), 3.35 (ddd, J=9.0, 7.2, 6.6 Hz, 2H), 1.65-1.63 (m, 2H), 1.59-1.54 (m, 4H), 1.49 (s, 3H), 1.35-1.24 (m, 18H), 0.86 (t, J=7.2 Hz, 9H); 13C NMR (150 MHz, CDCl3) δ 170.2, 99.5, 65.4, 62.6, 31.7, 31.3, 29.7, 28.5, 25.8, 25.5, 22.6, 22.5, 21.9, 14.0, 13.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[NH:11][CH2:12][CH2:13][CH2:14][OH:15].[H][H]>[Ni].C(O)C>[NH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:11][CH2:12][CH2:13][CH2:14][OH:15]
Reactant: O=[N+]([O-])c1cccc(Cl)c1NCCCO
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1cccc(Cl)c1NCCCO
Yield: 20 %

Procedure:
A mixture of 115 parts of 3-[(2-chloro-6-nitrophenyl)amino]-1-propanol and 400 parts of ethanol is hydrogenated at normal pressure and at room temperature with 12 parts of a Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluant. The pure fractions are collected and the eluent is evaporated, yielding 20 parts (20%) of 3-[(2-amino-6-chlorophenyl)amino]-1-propanol as a residue.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].[C:17](OC)(=[O:22])[C:18]([O:20][CH3:21])=[O:19].Cl>C1COCC1>[C:1]1(/[CH:7]=[CH:8]\[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccccc1C=Cc1ccccc1
Reactant: COC(=O)C(=O)OC
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1ccccc1/C=C\c1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
A solution of the Grignard reagent prepared from part of the mixture of isomers of 1-phenyl-2-(2-bromophenyl)ethylene described above (5.58 g) and magnesium (0.63 g) in dry THF (20 ml) was added dropwise over 30 mins. to a stirred solution of dimethyl oxalate (5.06 g) in dry THF (40 ml) cooled to -15° C. The resulting mixture was stirred at about -15° C. for 30 minutes, then at room temperature for 1 hour, then poured into dilute hydrochloric acid and extracted with ether. The extracts were washed with water, dried, concentrated under reduced pressure, then chromatographed twice [(i) 30% ether in petrol; (ii) 20% hexane in dichloromethane] to give isomerically pure Z-methyl 2-(2'-phenylethenyl)phenylglyoxalate (1.76 g, 31% yield) as a yellow oil, 1H nmr (CDCl3) : delta 3.87 (3H, s), 6.78 (centre of 2 doublets, each 1 H, J 12Hz) p.p.m.
Reaction SMILES: [Cl-].[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:11][N:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][C:18]#[N:19].Cl>C(Cl)Cl>[C:2]([C:16]1[N:12]([CH3:11])[C:13]([CH2:17][C:18]#[N:19])=[CH:14][CH:15]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cn1cccc1CC#N
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Product: Cn1c(CC#N)ccc1C(=O)c1ccccc1
Temperature: 0 °C

Procedure:
To a chilled suspension of 9.7 g. (0.07 mole) of alumonum chloride in 45 ml. methylene chloride is added 9 ml. (0.07 mole) benzoyl chloride. The resulting solution is added dropwise to a solution of 1-methylpyrrole-2-acetonitrile in 30 ml. methylene chloride while cooling externally with an ammonium chloride ice bath (temperature below 5°C.). After the addition is complete, the reaction mixture is stirred at 0°C. for fifteen minutes and then poured into ice acidified with 3N hydrochloric acid. The acidic fraction is extracted three times with methylene chloride. The organic fractions are combined and washed consecutively with N,N-dimethyl-1,3-propanediamine and 3N hydrochloric acid. The organic solution is dried over anhydrous magnesium sulfate. The solvent is then evaporated off to yield an oily residue which is column chromatographed on neutral alumina using hexane, benzene and ethylacetate as successive solvents. The first few fractions having ultraviolet absorption in the 240-260 mμ range contain the desired product. These fractions are combined, the solvent evaporated off and the oily residue, when triturated with methanol, yields the crystalline product, 5-benzoyl-1-methylpyrrole-2-acetonitrile, m.p. 106°-108°C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)C(C)C)(C)C>C(O)CCC>[Br:8][C:4]1[N:3]=[C:2]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(Br)n2)CC1

Procedure:
A solution of 4 g (16.88 mmol) of 2,6-dibromopyridine, 3.14 g (16.88 mmol) of tert.butyl piperazine-1-carboxylate and 5.89 ml (33.77 mmol) of N,N-diisopropylethylamine in 30 ml of n-butanol is refluxed for eight hours. The solvent is then distilled off. Purification is by column chromatography on silica gel (eluant: cyclohexane/ethyl acetate=2:1).
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[CH2:6]([N:9](CC=C)[CH:10]=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[C:14]#[N:15])[CH:7]=[CH2:8].C(O)C>O>[C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[CH2:6]([NH:9][CH:10]=[CH:11][CH:12]=[C:13]([C:14]#[N:15])[C:16]#[N:17])[CH:7]=[CH2:8]
Reactant: C=CCN(C=CC=C(C#N)C#N)CC=C
Agent: C=CC(N)=O
Solvent: CCO
Solvent: O
Product: C=CCNC=CC=C(C#N)C#N

Procedure:
A solution of 120 g. of acrylamide and 114 g. of 3-diallylaminoallylidenemalononitrile (A) in 500 cc. of ethanol was refluxed. 3.2 g. of AZBN were added and the solution was refluxed for one hour under stirring. A solution of 104 g. of acrylamide, 800 cc. of ethanol and 3.2 g. of AZBN was added and the solution was refluxed for one hour under stirring. A solution of 88 g. of acrylamide, 400 cc. of ethanol and 2.4 g. of AZBN was added and refluxed for one hour. A solution of 72 g. of acrylamide, 400 cc. of ethanol and 1.6 g. of AZBN was added and the solution was refluxed for one hour. In conclusion a solution of 56 g. of acrylamide, 400 cc. of ethanol and 1.6 g. of AZBN was added and refluxed for 2 hours. The mixture was cooled, filtered, washed with ethanol and then with ethyl ether and vacuum dried at 50° C. 478 g. of a product containing about 9% aminoallylidenemalononitrile units in weight were obtained, the product solution at 6% in water diluted 1:2000 with water had an optical density of 0.76 at 382 nm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([OH:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.[CH2:22]=[C:23]([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([O:16][C:23]([CH3:25])([CH3:24])[CH3:22])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: C=C(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 98 %

Procedure:
A 100-ml flask was charged with 5 ml of toluene and 2.12 g (10 mmol) of 4′-methyl-2-biphenylcarboxylic acid, and they were vigorously stirred. To this mixture was added dropwise 0.18 ml (2 mmol) of phosphorus oxytrichloride, and isobutene gas (98 mmol) was introduced to the mixture at a flow rate of 1.2 liter/min for 2 minutes. The resulting mixture was stirred at room temperature for 6 hours. After having confirmed that almost all of the peaks ascribed to 4′-methyl-2-biphenylcarboxylic acid disappeared by HPLC, the reaction solution was washed with a 1.5 M aqueous sodium hydroxide. The reaction solution was dried over anhydrous magnesium sulfate, and then the mixture was concentrated by distilling off toluene by using a rotary evaporator, to give 2.63 g of tert-butyl 4′-methyl-2-biphenylcarboxylate as crystals (yield: 98% based on 4′-methyl-2-biphenylcarboxylic acid, purity by HPLC: 99.9%). Incidentally, the obtained compound had the same physical properties as those of the compound obtained in Example II-1.
Reaction SMILES: [CH:1](=[N:8][C:9]([CH3:24])([CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[C:10](OCC)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[CH2:1]([NH:8][C:9]([CH3:24])([CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[CH2:10][OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(CCOC1CCCCO1)N=Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(CO)(CCOC1CCCCO1)NCc1ccccc1
Yield: 92.1 %

Procedure:
A solution of ethyl 2-benzylideneamino-2-methyl-4-[(tetrahydro-2H-pyran-2-yl)oxy]butyrate (67C, 100.0 g, 0.3 mol) in THF (100 mL) was added slowly to a suspension of lithium aluminum hydride (Morton Thiokol, Inc.-Alfa Products, 22.77 g, 0.6 mol) rapidly stirred in dry THF (1 L) at such a rate to maintain a gentle reflux. After the addition was complete the mixture was refluxed for 4 h. The reaction mixture was cooled and treated successively with H2O (23 mL), 15N NaOH (23 mL) and H2O (45 mL). The solid was removed by filtration and washed with THF (200 mL). The organic layers were combined and concentrated by rotary evaporation to give 2-benzylamino-2-methyl-4-[(tetrahydro-2H-pyran-2-yl)oxy]butanol (81.1 g, 92.0%) as a thick oil which was used without further purification.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[N:11]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:10][C:9](=[O:20])[NH:8][C:5]2=[N:6][CH:7]=1.C[Sn](C)(C)[C:23]1[CH:24]=[CH:25][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[N:27][CH:28]=1>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:32][C:29]([C:26]1[N:27]=[CH:28][C:23]([C:2]2[N:3]=[C:4]3[N:11]([CH2:12][CH2:13][N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH2:10][C:9](=[O:20])[NH:8][C:5]3=[N:6][CH:7]=2)=[CH:24][CH:25]=1)([CH3:31])[CH3:30]
Reactant: CC(C)(O)c1ccc([Sn](C)(C)C)cn1
Reactant: O=C1CN(CCN2CCOCC2)c2nc(Br)cnc2N1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(O)c1ccc(-c2cnc3c(n2)N(CCN2CCOCC2)CC(=O)N3)cn1
Temperature: 100 °C
Yield: 27 %

Procedure:
6-Bromo-4-(2-morpholinoethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (0.228 g, 0.666 mmol) and 2-(5-(trimethylstannyl)pyridin-2-yl)propan-2-ol (0.220 g, 0.733 mmol) were combined in dimethylformamide (3 mL). Solution was purged with nitrogen gas followed by the addition of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane (0.109 g, 0.133 mmol). Solution was heated to 100° C. for 2 h. Solution was condensed under reduced pressure and the resulting oil purified via reverse-phase-preparative HPLC (5-60% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min) and desired fractions were loaded onto a Strata-XC ion exchange column. The column was washed successively with water, acetonitrile, methanol and 5% ammonium hydroxide in methanol. The product eluted with the 5% ammonium hydroxide in methanol and was concentrated under reduced pressure and dried to afford the title compound (0.070 g, 0.18 mmol, 26% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 11.33 (br. s., 1H), 9.05 (d, J=1.56 Hz, 1H), 8.27 (dd, J=8.59, 2.34 Hz, 1H), 8.06 (s, 1H), 7.72 (d, J=8.59 Hz, 1H), 5.27 (s, 1H), 4.29 (s, 2H), 3.71 (t, J=6.44 Hz, 2H), 3.54 (t, J=4.49 Hz, 4H), 2.62 (t, J=6.44 Hz, 2H), 2.40-2.48 (m, 4H), 1.46 (s, 6H); MS (ESI) m/z 399.2 [M+1]+; mp 239-241° C.
Reaction SMILES: [CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].Cl.[C:11]([OH:14])(=[O:13])[CH3:12].[OH-].[K+]>O>[CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3].[C:11]([O-:14])(=[O:13])[CH3:12]
Reactant: CC(=O)O
Reactant: CN(C)C(=N)N=C(N)N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(=O)[O-]
Product: CN(C)C(=N)NC(=N)N
Temperature: 30 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
20.0 g (1 equivalent) of metformin hydrochloride and 50 Ml of water, and then 10 Ml (1.45 equivalents) of glacial acetic acid were added to a reactor, and stirred for 2 hours at 30° C. to dissolve thoroughly. Then 10.2 g (1.5 equivalents) of aqueous solution of potassium hydroxide were added to the reaction solution. The resulting crystal was filtered and washed with acetone, and then dried at 60° C. to obtain 13.3 g of metformin acetate (yield: 58.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].C(Cl)(=O)C(Cl)=O.Cl.[NH:22]1[CH2:25][CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[N:22]1([C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:8]=2)=[O:13])[CH2:25][CH2:24][CH2:23]1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: C1CNC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1cc2nccc(Cl)c2s1)N1CCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.7 %

Procedure:
A 50 mL round bottom flask was charged with lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylate (0.500 g, 2.28 mmol), methylene chloride (15 ml), and 12 drops of DMF. Oxalyl chloride (0.298 ml, 3.42 mmol) was added dropwise, and the mixture was stirred at room temperature for 3 hours and concentrated to yield a tan solid. This was redissolved in methylene chloride (15 ml). Azetidine hydrochloride (0.426 g, 4.55 mmol) was added in one portion and Hunig's Base (1.59 ml, 9.11 mmol) was added dropwise. This mixture was stirred at room temperature overnight, then diluted with methylene chloride (15 mL) and washed with water (25 mL), sat. NaHCO3 (25 mL), and brine (25 mL). The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield azetidin-1-yl(7-chlorothieno[3,2-b]pyridin-2-yl)methanone (0.58 g, 100% yield) as a tan solid.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[C:13](=[O:16])([O-])[O-].[K+].[K+].[OH2:19]>CS(C)=O.O.[N+](C1C=C(C=CC=1)C([O-])=O)([O-])=O.[Na+].[Na+].[N+](C1C=C(C=CC=1)C([O-])=O)([O-])=O>[CH:6]1[C:7]([N+:10]([O-:11])=[O:19])=[CH:8][CH:9]=[C:13]([O:16][C:4]2[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=2)[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc([N+](=O)[O-])cc1
Reactant: O
Agent: O=C([O-])c1cccc([N+](=O)[O-])c1
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 8 h
Yield: 92 %

Procedure:
1,4-Dinitrobenzene (3.52 g, 20.5 mmol), potassium carbonate (1.38 g, 10 mmol), and sodium 3-nitrobenzoate hemihydrate (32 mg, 0.16 mmol) were heated in dimethylsulfoxide (8 mL) at about 100° C. for approximately 5.8 hours. The reaction was allowed to cool and was poured into water (20 mL). The reaction vessel was rinsed with an additional 10 mL of water and the rinses were combined. The combined aqueous suspensions were allowed to stand overnight. The solid was collected, washed with water, and dried to give 2.51 g (92% pure) of 4,4'-dinitrodiphenyl ether.