Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:10]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:9]1)C1C=CC=CC=1>[Pd]>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]1[CH2:21][CH2:22][CH2:23][CH3:24])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCCC[C@H]1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Agent: [Pd]
Product: CCCC[C@H]1CNCCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in Example 2, Step C, except using 4-benzyl-1-tert-butoxycarbonyl-2(S)-n-butylpiperazine (3.75 g, 11.3 mmol) and 10% palladium on carbon (0.80 g). The title compound was obtained as an oil (2.68 g). NMR (300 MHz, CDCl3) δ 4.08 (1H, br s), 3.90 (1H, d, J=12 Hz), 2.5-3.8 (6H, m), 1.80 (1H, m), 1.60 (1H, m), 1.46 (9H, s), 1.30 (4H, m),0.90 (3H, t, J=7 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2C(Cl)=CC(Cl)=C(Cl)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2CCCCC2)C2C=CC=C[C:31]=2[C:36]2[C:41](OC)=[CH:40][CH:39]=[CH:38][C:37]=2OC)CCCCC1.[F-].[K+].CB(O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:38]([CH3:39])=[CH:37][C:36]([CH3:31])=[C:41]([CH3:40])[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)c(Cl)cc2Cl)CC1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd+2]
Agent: CB(O)O
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: Cc1cc(C)c(N2CCN(C(=O)OC(C)(C)C)CC2)nc1C
Yield: 990.4 %

Procedure:
To a mixture of 2,3,5,6-tetrachloropyridine (10 g), 1-Boc-piperazine (8.6 g) and potassium carbonate (13 g) was added 2-butanone (140 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give 4-(3,5,6-trichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (17 g). To a mixture of 4-(3,5,6-trichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (17 g), palladium (II) acetate (516 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.9 g), potassium fluoride (24 g) and methylboronic acid (12 g) was added tetrahydrofuran (140 mL), and the mixture was refluxed for 8 hr. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (14 g). 4-(3,5,6-Trimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (14 g) was dissolved in chloroform (28 mL), 4N hydrogen chloride/ethyl acetate (25 mL) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (100 mL) was added, and the mixture was filtered to give the title compound (11 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH2:7][OH:8].[CH3:11][C:12]([CH3:14])=O.[OH-].[Na+].C(OCC)C>COC(OC)(C)C.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:12]([CH3:14])([CH3:11])[O:8][CH2:7][C:6]=2[CH:9]=1
Reactant: CC(C)=O
Reactant: OCc1cc(Br)ccc1O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)OC
Solvent: CCOCC
Product: CC1(C)OCc2cc(Br)ccc2O1
Reaction time: 18 h

Procedure:
To 5-bromo-2-hydroxybenzyl alcohol (93 g, 0.46 mol, available from Sigma-Aldrich) in 2.0 L of 2,2-dimethoxypropane was added 700 mL of acetone, followed by zinc chloride (170 g). After stirring for 18 hours, 1.0 M aqueous sodium hydroxide was added until the aqueous phase was basic. Diethyl ether (1.5 L) was added to the slurry and the organic phase was decanted into a separatory funnel. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as an oil.
Reaction SMILES: [OH:1][C:2]1([C:7]#[CH:8])[CH2:6][CH2:5][NH:4][CH2:3]1.[C:9]([C:12]1[CH:13]=[C:14](/[CH:17]=[C:18]2\[C:19](=[O:29])[NH:20][C:21]3[C:26]\2=[C:25](I)[C:24]([F:28])=[CH:23][CH:22]=3)[NH:15][CH:16]=1)(=[O:11])[CH3:10]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C.CCN(CC)CC>[C:9]([C:12]1[CH:13]=[C:14](/[CH:17]=[C:18]2\[C:19](=[O:29])[NH:20][C:21]3[C:26]\2=[C:25]([C:8]#[C:7][C:2]2([OH:1])[CH2:6][CH2:5][NH:4][CH2:3]2)[C:24]([F:28])=[CH:23][CH:22]=3)[NH:15][CH:16]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(I)c32)c1
Reactant: C#CC1(O)CCNC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(C#CC4(O)CCNC4)c32)c1

Procedure:
Using Method C above, rac-3-hydroxy-3-ethynyl-pyrrolidine (35.1 mg, 0.32 mmol) (Example 97C) was coupled with (Z)-3-[(4-acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (50 mg, 0.13 mmol) (see Example 90B) using (Ph3P)4Pd (15 mg) and Cul (3.0 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 85° C. for 5 h. (Yield 10 mg, 21%).
Reaction SMILES: Cl.[CH:2]([NH2:4])=[NH:3].CC[O-].[Na+].[CH3:9][O:10][CH:11]([C:16](OC)=[O:17])[C:12](OC)=[O:13].C(O)(=O)C>C(O)C>[CH3:9][O:10][C:11]1[C:12]([OH:13])=[N:3][CH:2]=[N:4][C:16]=1[OH:17]
Reactant: COC(=O)C(OC)C(=O)OC
Reactant: N=CN
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1c(O)ncnc1O
Temperature: 25 °C

Procedure:
5 g (6.2 mmoles) of formamidine hydrochloride is added at 0° C. and in small quantities into a single-necked flask containing 30 ml of absolute ethanol and 90 ml of a solution of sodium ethylate at a concentration of 1.7 mol/l in ethanol. Stirring is maintained at ambient temperature for about twenty minutes, then 8.5 ml of dimethyl methoxymalonate is added dropwise. Stirring is maintained for 16 hours. The reaction mixture is then acidified with pure acetic acid to a pH between 4 and 5, then concentrated to dryness in the presence of cyclohexane. After impasting the crude product obtained is chromatographed on silicagel eluting with a mixture of methylene chloride-methanol (85-15)and 2% water-acetic acid (1-1). 9.5 g of the expected product is obtained containing a small quantity of sodium acetate salts.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:22][N+:23](C)([CH3:25])[CH3:24].[Cl-].CN(C)CC(O)CO.CC(C)([O-])C.[K+]>C1(C)C(C)=CC=CC=1>[CH2:28]([O:27][CH:21]([CH2:20][O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH2:22][N:23]([CH3:25])[CH3:24])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCCCCC/C=C\CCCCCCCCOCC(C[N+](C)(C)C)OCCCCCCCC/C=C\CCCCCCCC
Agent: CC(C)(C)[O-]
Agent: CN(C)CC(O)CO
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: CCCCCCCC/C=C\CCCCCCCCOCC(CN(C)C)OCCCCCCCC/C=C\CCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
DOTMA may be prepared according to the following protocol: A mixture of 3-(dimethylamino)-l,2-propanediol (Aldrich; 1.19 g, 10 mmol), potassium tert-butoxide (3.36 g, 30 mmol), and oleyl ptoluenesulfonate (12.7 g, 30 mmol) in xylene (50 ml) was stirred at room temperature and reduced pressure (30 torr; 1 torr=133 Pa) for 30 min and then was heated to 50° C. with stirring for an additional 15 min. The reaction vessel was purged with nitrogen, and the mixture was heated to reflux (≈140° C.) for 3 hr. After cooling, the reaction mixture was diluted with hexane (100 ml), and the resulting solution was extracted with water (twice, 50 ml each). The organic layer was concentrated, and the residue was chromatographed over silica gel by elution with a mixture of hexane and diethyl ether (1:2) to afford the intermediate 2,3-dioleyloxyl(dimethylamino)propane as a colorless oil. Quaternization was carried out by condensation of methyl chloride (50 ml) into a Parr pressure apparatus cooled to -78° C. and containing this compound (10 g). The sealed vessel was heated behind a safety shield at 70° C. for 48 hr. After cooling to 0° C., the reaction vessel was opened, and the excess methyl chloride was allowed to evaporate under a stream of nitrogen in a well-ventilated hood. The crude residue was recrystallized from acetonitrile to afford DOTMA as an off-white solid, mp 35°-58° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH:11]([OH:14])[CH2:12][NH2:13].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=O.C([BH3-])#N.[Na+]>C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH:11]([OH:14])[CH2:12][NH:13][CH:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: NCC(O)C1COc2ccccc2O1
Reactant: O=C1CCCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: OC(CNC1CCNCC1)C1COc2ccccc2O1
Temperature: 25 °C

Procedure:
The [2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]amine prepared in Preparation A' (50 g) and piperidone (85 g) are dissolved in 500 ml of ethanol. Seventy-five grams of sodium cyanoborohydride is added, and the mixture is maintained at room temperature for 12 hours and cooled and evaporated. The product is recovered by adding aqueous ammonia to the residue and extracting with methylene chloride. Three 100 ml portions of methylene chloride are used which are combined, washed twice with 50 ml of water and evaporated to a semi-solid. Upon addition of ether, the product crystallizes and is recovered by filtration. The resulting crude mixture is boiled gently in 100 ml of diethyl ether and then evaporated to a residue and triturated with hexane to yield pure material, 4-{[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]amino}piperidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH2:10][CH:9]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][CH:3]=1.[O-]CC.[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:13][C:12](=[O:14])[NH:11][CH2:10][C@H:9]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CNC(=O)CC1c1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1CNC(=O)C[C@H]1c1ccc(F)cc1
Temperature: 90 °C

Procedure:
0.1 g of the cis/trans mixture of ethyl 4-(p-fluorophenyl)-6-oxo-3-piperidinecarboxylate obtained in Examples 4 to 6 was added to 10 mL of toluene, and 26 mg of sodium ethoxide was added. The reaction mixture was heated at 90° C. for 5 hours, then poured into ice water, and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to obtain 50 mg of ethyl trans-4-(p-fluorophenyl)-6-oxo-3-piperidinecarboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.N1(S(N)(=O)=O)CCNCC1.Cl.[F:36][C:37]1[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:44][S:45][C:46]1[N:51]=[C:50]([NH:52][S:53]([N:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)(=[O:55])=[O:54])[CH:49]=[C:48]([O:62][CH3:63])[N:47]=1.CN1CCOCC1>CN(C=O)C>[F:36][C:37]1[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:44][S:45][C:46]1[N:51]=[C:50]([NH:52][S:53]([N:56]2[CH2:57][CH2:58][N:59]([C:10](=[O:12])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:60][CH2:61]2)(=[O:54])=[O:55])[CH:49]=[C:48]([O:62][CH3:63])[N:47]=1
Reactant: COc1cc(NS(=O)(=O)N2CCNCC2)nc(SCc2cccc(F)c2F)n1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Cl
Agent: NS(=O)(=O)N1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: COc1cc(NS(=O)(=O)N2CCN(C(=O)CNC(=O)OC(C)(C)C)CC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(tert-butoxycarbonyl)glycine (0.11 g) in DMF (10 mL) was added 1,3-Dicyclohexycarbodiimide (0.14 g) and 1-hydroxybenzotriazole hydrate (94 mg). After stirring at room temperature for 1 h, a solution of N42-[[(2,3-Difluorophenyl)methyl]thio]-6-methoxypyrimidin-4-yl]piperazine-1-sulfonamide, hydrochloride salt (the product of step i, 0.27 g) and N-methylmorpholine (78 μL) in DMF (5 mL) was added dropwise and stirring continued at room temperature for 24 h. The mixture was filtered, rinsed with DCM and the filtrate evaporated. The crude material was purified by column chromatography on silica gel using EtOAc/isohexane (3:2) as eluent to give the subtitle compound as a foam. Yield: 0.24 g
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[O:10])[CH:6]=[CH:5][C:4]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][CH2:20]Cl>C(C1C=CC=CC=1)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[O:11][CH2:18][O:19][CH3:20])[CH:9]=[O:10]
Reactant: COCCl
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)c1ccccc1
Product: COCOc1ccc(C=O)cc1OC
Temperature: 25 °C
Yield: 53.1 %

Procedure:
To 14.0 g of vaniline and 51.0 g of potassium carbonate was added 280 ml of acetophenone, and chloromethyl methyl ether was further added and the mixture was refluxed for 1 hour. The reaction liquid was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. The reaction mixture was dissolved in ether, washed with water, shaken with a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was subjected to the column chromatography [230-400 mesh Kieselgel; eluting solvent=hexane/ethyl acetate (2/1)] to obtain 9.6 g (yield=53.1%) of 3-methoxy-4methoxymethoxybenzaldehyde.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1(C)C(C)=CC=CC=1.CCCCCC>[C:1]([O:9][CH2:10][CH3:11])(=[S:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1ccccc1
Solvent: Cc1ccccc1C
Solvent: CCCCCC
Product: CCOC(=S)c1ccccc1
Yield: 175.3 %

Procedure:
70 ml (0.487 mol) of ethyl benzoate were heated to reflux for 12 hours with 100 g (0.247 mol) of Lawesson reagent in 350 ml of xylene. After cooling to 20° the reaction mixture was diluted with 500 ml of hexane and filtered. The filtrate was flash-chromatographed on 1 kg of silica gel. Elution was carried out with hexane. The fractions which were pure according to the thin-layer chromatogram (eluent: toluene) were combined and evaporated under reduced pressure. There were obtained 72 g (89%) of O-ethyl thiobenzoate as a dark yellow evil-smelling oil which was used without further purification.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.S(Cl)(Cl)=O.[OH-].[Na+].Cl.[NH:25]1[CH2:28][CH:27]([OH:29])[CH2:26]1>COCCOC.O>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([N:25]3[CH2:28][CH:27]([OH:29])[CH2:26]3)=[O:17])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(O)CCOCCc1ccc2sccc2c1
Reactant: OC1CNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Solvent: O=S(Cl)Cl
Product: O=C(CCOCCc1ccc2sccc2c1)N1CC(O)C1
Temperature: 7.5 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
In 75 mL of 1,2-dimethoxyethane was dissolved 50.0 g of 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic acid. Thereto was added 26.1 g of thionyl chloride, which was then refluxed for 2 hours. After cooling, this reaction solution was dropwise added to a mixed solution of 125 mL of water, 20.0 g of sodium hydroxide and 25.2 g of 3-azetidinol hydrochloride at −5 to 10° C., which was then stirred at 0 to 15° C. for 30 minutes. Thereto was added 75 mL of water, which was heated to 40° C. and dissolved. After cooling, the precipitate was collected by filtration to provide 56.5 g of 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propionyl)azetidin-3-ol as white solid form.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12](O)[N:11]=[C:10]([CH3:15])[N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O.N>O>[Cl:18][C:12]1[CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=[C:10]([CH3:15])[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(O)cc(-c2ccc(F)cc2)n1
Agent: N
Solvent: O
Product: Cc1nc(Cl)cc(-c2ccc(F)cc2)n1

Procedure:
To 21 g of 4-(4-fluorophenyl)-6-hydroxy-2-methylpyrimidine was added 63 ml of phosphorus oxychloride and the mixture was refluxed for 1 hour. This reaction mixture was cooled, poured into iced water, and neutralized with 28% aqueous ammonia and the crystals that separated out were collected by filtration. The crystals were washed with water and dried to provide 21 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N+:11]([O-])=O)=[C:4]([NH2:14])[CH:3]=1.[H][H]>O>[NH2:1][C:2]1[CH:3]=[C:4]([NH2:14])[C:5]([NH2:11])=[CH:6][C:7]=1[NH2:8]
Reactant: [H][H]
Reactant: Nc1cc(N)c([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: O
Product: Nc1cc(N)c(N)cc1N

Procedure:
forming a slurry of the 1,3-diamino-4,6-dinitrobenzene with water, and contacting the slurry with hydrogen and a hydrogenation catalyst to hydrogenate the 1,3-diamino-4,6-dinitrobenzene and produce 1,2,4,5-tetraminobenzene;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:11][CH2:12][O:13][CH3:14])[CH3:10])=[CH:5][C:4]=1[NH:15][C:16]([NH2:18])=[S:17].BrBr>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]2[N:15]=[C:16]([NH2:18])[S:17][C:5]=2[C:6]([N:9]([CH2:11][CH2:12][O:13][CH3:14])[CH3:10])=[CH:7][CH:8]=1
Reactant: COCCN(C)c1ccc(OC)c(NC(N)=S)c1
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: COCCN(C)c1ccc(OC)c2nc(N)sc12
Temperature: 25 °C
Yield: 70.8 %

Procedure:
To a stirred solution of 1.40 g (5.20 mmol) {2-methoxy-5-[(2-methoxy-ethyl)-methyl-amino]-phenyl}-thiourea in 35 ml chloroform was added dropwise 0.27 ml (5.27 mmol) bromine and the reaction mixture heated at reflux for 18 hours. The mixture was then cooled to room temperature, poured slowly onto sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (ethyl acetate) afforded 984 mg (71%) 4-methoxy-N7-(2-methoxy-ethyl)-N7-methyl-benzothiazole-2,7-diamine as an orange crystalline solid. ES-MS m/e (%): 268 (M+H+, 100).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.CCOCC.O>[OH:1][C:2]1[CH:9]=[C:8]([O:10][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: N#Cc1ccc(O)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: N#Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1O
Temperature: 110 °C
Yield: 117.3 %

Procedure:
In a vial 2,4-dihydroxybenzonitrile (300 mg, 2.2 mmol), 2-chloro-5-nitropyridine (351.96 mg, 2.22 mmol) and K2CO3 (920 mg, 6.62 mmol) were dissolved in DMF (5 mL). The reaction was heated for 1 hour under microwave irradiations (Set Temperature: 110° C.). The reaction mixture was diluted with Et2O and water, acidified with aqueous 1N HCl until pH=2, the phases were separated and the organics were dried over Na2SO4. The solid was filtered out and the solvent was removed affording crude 2-hydroxy-4-[(5-nitro-2-pyridinyl)oxy]benzonitrile (664 mg) as a brown solid. To a solution of this crude in dry DMF (5 mL) potassium carbonate (460 mg, 3.33 mmol) and isopropyl bromide (313 μL, 3.33 mmol) were added and the reaction mixture was stirred overnight at 50° C. The reaction was diluted with brine (10 mL) and extracted with ethyl acetate (2×20 mL). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography on silica gel (SNAP 25 g) eluting from 100:0 to 75:25 cyclohexane/ethyl acetate affording the title compound (260 mg) as white solid.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][NH:11][CH:12]2[CH2:15][CH2:16][CH3:17])=[CH:7][CH:6]=1)([O-])=O>C(O)C>[ClH:1].[CH2:15]([CH:12]1[C:13]2[C:8](=[CH:7][CH:6]=[C:5]([NH2:2])[CH:14]=2)[CH2:9][CH2:10][NH:11]1)[CH2:16][CH3:17]
Reactant: CCCC1NCCc2ccc([N+](=O)[O-])cc21
Agent: Cl
Solvent: CCO
Product: CCCC1NCCc2ccc(N)cc21
Reaction time: 3 h
Yield: 64 %

Procedure:
To a suspension of 7-nitro-1-propyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.51 g, 9.78 mmol) in ethanol (150 ml) was added 10% Pd--C (0.3 g) and the reaction mixture was hydrogenated at 50 psi for 3 h. The solution was filtered and the filtrate was concentrated and absolute ethanol was added to help evaporate any excess water. The resulting solid was triturated with isopropanol (30 ml) to give the title compound (1.42 g, 64%) as an off-white solid, m.p. 192-4° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Br:4][C:5]1[CH:6]=[C:7](F)[CH:8]=[C:9]([Br:11])[CH:10]=1>CN(C)C=O>[Br:4][C:5]1[CH:6]=[C:7]([O:2][CH3:1])[CH:8]=[C:9]([Br:11])[CH:10]=1
Reactant: Fc1cc(Br)cc(Br)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.5 %

Procedure:
Sodium methoxide (4.5M solution in methanol, 8.80 ml, 41.0 mmol) was added dropwise to a stirred solution of 3,5-dibromofluorobenzene (5.00 g, 19.0 mmol, Aldrich) in N,N-dimethylformamide (95 ml) at 0° C. under a nitrogen atmosphere. The reaction was warmed to room temperature, stirred for 1 hour and then evaporated under reduced pressure. The residue was dissolved in diethyl ether and was washed with water (3×300 ml) and brine (300 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the title compound as a white solid (5.13 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:16])[C:6]([C:9]([O:11]C(C)(C)C)=[O:10])=[N:7][CH:8]=1)#[N:2].C(O)(C(F)(F)F)=O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH3:16])[C:6]([C:9]([OH:11])=[O:10])=[N:7][CH:8]=1)#[N:2]
Reactant: Cc1cc(C#N)cnc1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C#N)cnc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a solution of tert-butyl 5-cyano-3-methylpicolinate (synthesized according to procedure described in WO2012095521; 4.18 g, 19.15 mmol) in dichloromethane (96 ml) was added TFA (Aldrich, 148 ml, 1915 mmol). The reaction mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure and the residue was triturated with EtOAc. The yellow slurry was concentrated under reduced pressure. The residue was triturated with 30 mL of methyl tert-butyl ether (30 mL) and hexanes (50 mL) to yield 5-cyano-3-methylpicolinic acid (2.91 g, 17.95 mmol, 94% yield) as yellow solid. MS m/z=163.2 [M+H]+. Calculated for C8H6N2O2: 162.0