Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[NH2:16][C@@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]([NH2:25])=[O:24])[CH2:19][CH2:18]1>N1C=CC=CC=1>[CH3:13][N:12]([CH3:14])[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([NH:16][C@@H:17]2[CH2:22][CH2:21][C@H:20]([C:23]([NH2:25])=[O:24])[CH2:19][CH2:18]2)[N:11]=1
Reactant: NC(=O)[C@H]1CC[C@@H](N)CC1
Reactant: CN(C)c1nc(Cl)nc2ccccc12
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)c1nc(N[C@H]2CC[C@@H](C(N)=O)CC2)nc2ccccc12
Yield: 43.8 %

Procedure:
A solution of (2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in step B of example 1 (31.05 g, 150 mmol) and cis-4-amino-cyclohexanecarboxylic acid amide hydrochloride (26.7 g, 150 mmol) in pyridine (150 mL) was stirred at reflux for overnight. The reaction mixture was concentrated and residue was dissolve in CH2Cl2. The organic layer was washed with saturated aqueous NaHCO3 and the aqueous layer was extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, 2% to 10% 2 M NH3/MeOH in CH2Cl2) to give a slightly brown solid and the solid was recrystallized from CH2Cl2 to give cis-4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexanecarboxylic acid amide (20.6 g, 44%) as yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([NH:15][CH:16]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:17](OCC)=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].C[O-].[Na+]>CO>[CH2:35]([O:34][C:32]([CH2:31][N:30]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH2:23][CH2:22][CH:16]([NH:15][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:17]1=[O:18])=[O:33])[CH3:36]
Reactant: CCOC(=O)CNc1ccccc1CCC(NC(CCc1ccccc1)C(=O)OCC)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)CN1C(=O)C(NC(CCc2ccccc2)C(=O)OCC)CCc2ccccc21

Procedure:
A solution of ethyl 2-(1-ethoxycarbonyl-3-phenylpropylamino)-4-[o-(ethoxycarbonylmethylamino)phenyl]butyrate (5.6 g) in methanol (100 ml) is added to a solution of sodium methoxide in methanol [prepared from sodium (0.25 g) and methanol (50 ml)] with stirring under a nitrogen atmosphere. The reaction mixture is refluxed for 65 hours, then evaporated under reduced pressure. The residue is distributed between water (50 ml) and dichloromethane (200 ml). The aqueous solution is extracted with dichloromethane (200 ml) and the combined organic solutions washed with water (50 ml) and dried over potassium carbonate. Evaporation of the solvent gives as a mixture of isomers A and B of 1-ethoxycarbonylmethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, which is separated by chromatography on silica gel and converted to the individual maleate salts as described in example 10.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>CN(C)C=O>[O:25]1[CH2:26][CH2:27][N:22]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:23][CH2:24]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCOCC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed a solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv) in N,N-dimethylformamide (4 mL), morpholine (76.6 mg, 0.88 mmol, 2.00 equiv), DIEA (170.3 mg, 1.32 mmol, 3.00 equiv). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting solution was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 136.4 mg (86%) of methyl 3-morpholino-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([Cl:16])[C:7]=1[C:8]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=O.[CH3:23][NH:24][NH2:25]>C(O)C>[Cl:16][C:6]1[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:4][N:3]=[C:2]2[N:24]([CH3:23])[N:25]=[C:8]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[C:7]=12
Reactant: CNN
Reactant: O=C(c1cccnc1)c1c(Cl)nnc(-c2ccccc2)c1Cl
Solvent: CCO
Product: Cn1nc(-c2cccnc2)c2c(Cl)c(-c3ccccc3)nnc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 31.1 %

Procedure:
A mixture of (3,5-dichloro-6-phenyl-pyridazin-4-yl)-(3-pyridyl)methanone (100 mg, 0.3 mmol) and methyl hydrazine (19.5 mg, 0.42 mmol) in ethanol (1.5 mL) was stirred in a sealed tube at 60° C. for 3 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (silica gel, isohexane/ethyl acetate 9:1 to 8:2) yielding Compound 26 as a solid (30 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](I)[CH:12]=1>>[Cl:10][C:11]1[CH:12]=[C:13]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:14]=[CH:15][CH:16]=1
Reactant: Clc1cccc(I)c1
Reactant: c1ccc2[nH]ccc2c1
Product: Clc1cccc(-n2ccc3ccccc32)c1

Procedure:
Prepared by Procedure C and Scheme O using 1H-indole and 1-chloro-3-iodobenzene: ESMS m/e: 227.9 (M+H)+.
Reaction SMILES: [C:1]([C:7]([O:9][CH3:10])=[O:8])#[C:2][C:3]([O:5][CH3:6])=[O:4].[CH2:11]=[CH:12][C:13]([Cl:15])=[CH2:14]>>[Cl:15][C:13]1[CH2:14][C:1]([C:7]([O:9][CH3:10])=[O:8])=[C:2]([CH2:11][CH:12]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C#CC(=O)OC
Reactant: C=CC(=C)Cl
Product: COC(=O)C1=C(C(=O)OC)CC(Cl)=CC1
Yield: 100 %

Procedure:
Dimethyl acetylenedicarboxylate (6.3 g) and chloroprene (6.2 g) were heated at 50° C. for 25 hours. The reaction mixture was distilled under reduced pressure and the fraction boiling at 135° to 138° C. at 2.5 torr was collected. The thick oil weighed 4.6 g (100% yield based on unreacted dimethyl acetylenedicarboxylate).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([O-])(=O)C.[Na+].[Br:15]Br>C(O)(=O)C.[Fe]>[Br:15][C:3]1[C:2]([OH:1])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: BrBr
Reactant: O=Cc1cccc(O)c1
Agent: [Fe]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=Cc1cccc(O)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
The suspension of 3-hydroxybenzaldehyde (5 g, 0.04 mol), iron powder (172 mg, 3 mmol) and sodium acetate (6.72 g, 0.08 mol) in acetic acid (40 mL) was warmed until a clear solution was obtained and then cooled to room temperature. To this mixture was dropwise added a solution of bromine in glacial acetic acid (10 mL) over 15 min. After the addition, the reaction mixture was stirred for 2 h and then poured into ice-water. The resulting mixture was extracted with dichloromethane (3×50 mL). The combined extracts were dried over anhydrous Na2SO4 and concentrated. The residue was re-crystallized from dichloromethane to afford the product (2.3 g, yield 28%). 1H NMR (400 MHz, DMSO-d6 δ 10.30 (s, 1H), 7.54-7.51 (m, 1H), 7.39-7.35 (m, 1H), 7.31-7.27 (m, 1H), 5.90 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][C:5]1[C:13](C([O-])=O)=[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][N:7]2[N:6]=1.[ClH:18]>>[ClH:18].[N:6]1[N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[CH:13][C:5]=1[CH2:4][C:3]([OH:17])=[O:2]
Reactant: COC(=O)Cc1nn2c(c1C(=O)[O-])CCCC2
Agent: Cl
Product: O=C(O)Cc1cc2n(n1)CCCC2
Yield: 88 %

Procedure:
The crude 2-(2-methoxy-2-oxoethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxylate (39 mg, 0.16 mmol) was suspended in concentrated HCl (5 mL) and was heated at reflux for 2 hours. The reaction was cooled and concentrated in vacuo to afford the title compound (30 mg, 88%). The material was used directly without further purification. MS (ES+) 181.2 (M+H)+. Retention time: 1.26 min XBridge C18 4.6×50 mm 5 um, 5-100% acetonitrile:water (0.1% formic acid).
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH2:7][N:8]([CH2:32][CH2:33][O:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([N+:18]([O-:20])=[O:19])=[CH:11][C:10]=1[C:21]([NH:23][CH2:24][CH:25]1[CH2:29][O:28]C(C)(C)[O:26]1)=[O:22])(=[O:4])=[O:3].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:38][S:35]([O:34][CH2:33][CH2:32][N:8]([CH2:7][CH2:6][O:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([N+:18]([O-:20])=[O:19])=[CH:11][C:10]=1[C:21]([NH:23][CH2:24][CH:25]([OH:26])[CH2:29][OH:28])=[O:22])(=[O:36])=[O:37]
Reactant: CC1(C)OCC(CNC(=O)c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2N(CCOS(C)(=O)=O)CCOS(C)(=O)=O)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CS(=O)(=O)OCCN(CCOS(C)(=O)=O)c1c(C(=O)NCC(O)CO)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 73.5 %

Procedure:
A solution of 2-(2-({[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]amino}carbonyl){2-[(methylsulfonyl)oxy]ethyl}-4,6-dinitroanilino)ethyl methanesulfonate (13g) [Palmer et al., J. Med. Chem. 1997, 40, 1272] (5.0 mmol) in MeOH (200 mL) was treated with p-toluenesulfonic acid (0.2 g) at room temperature for 4 h. Most of the MeOH was then evaporated, and the residue was taken up in EtOAc (200 mL), washed with satd. NaHCO3 and brine, dried and concentrated. Chromatography of the product on silica gel, eluting with EtOAc/MeOH (20:1), gave 2-(2-{[(2,3-dihydroxypropyl)amino]carbonyl}{2-[(methylsulfonyl)oxy]ethyl}-4,6-dinitroanilino)ethyl methanesulfonate (13f) (2.0 g, 73%): as yellow foam;
Reaction SMILES: C([O:3][C:4]([C:6]1([C:10]2[CH:11]=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[C:13]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[C:14]([Cl:16])[CH:15]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5])C.O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:16][C:14]1[CH:15]=[C:10]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][CH2:9]2)[CH:11]=[C:12]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=2)[C:13]=1[O:17][CH2:18][C:19]([F:21])([F:22])[F:20]
Reactant: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C(F)(F)F)cc3)c2)CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C(F)(F)F)cc3)c2)CCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A mixture of ethyl-1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclo butane carboxylate (400 mg, 0.83 mmol) and lithium hydroxide monohydrate (0.2 g, 8.3 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10 ml) was stirred for 3 h at room temperature. Upon completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography to give 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclobutane carboxylic acid in 88% yield (0.21 g). 1H-NMR (CDCl3, 400 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.39 (s, 1H); 7.26 (s, 1H); 3.98 (q, 2H); 2.86 (m, 2H); 2.52 (m, 2H); 2.16 (m, 1H), 1.91 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([CH:8]2[CH2:13][C:12]([NH:14][NH:15]S(C3C=CC(C)=CC=3)(=O)=O)=[CH:11][C:10](=[O:26])[CH2:9]2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CO.Br[CH2:37][C:38](=O)[CH3:39]>COCCOC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([CH:8]2[CH2:13][C:12]3[N:14]=[N:15][CH:37]=[C:38]([CH3:39])[C:11]=3[C:10](=[O:26])[CH2:9]2)[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)NNC2=CC(=O)CC(c3cc(Cl)ccc3F)C2)cc1
Reactant: CC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Product: Cc1cnnc2c1C(=O)CC(c1cc(Cl)ccc1F)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.8 %

Procedure:
To a mixture of 5-(5-chloro-2-fluorophenyl)-1-[2-(4-methylphenylsulfonyl)hydrazino]cyclohexen-3-one (2.0 g), anhydrous potassium carbonate (1.68 g), methanol (20 ml) and 1,2-dimethoxyethane (10 ml) was added under ice-cooling 1-bromopropan-2-one (0.87 g), and the mixture was stirred for 2 hours at room temperature, and then for 6 hours at 80° C. Under reduced pressure, the solvent was evaporated, and to the residue was added ethyl acetate (70 ml) and water (30 ml). The mixture was shaken, and the separated upper layer was washed with water and concentrated under reduced pressure. The residue was purified with silica gel column chromatography to give 7-(5-chloro-2-fluorophenyl)-4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (0.338 g) as yellowish brown crystals.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[OH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1>>[CH2:1]([NH:3][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([OH:4])=[CH:6][CH:7]=1)[CH3:2]
Reactant: CCN
Reactant: O=Cc1ccc(O)cc1
Product: CCNCc1ccc(O)cc1

Procedure:
prepared by reaction of ethylamine with 4-hydroxy-benzaldehyde
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[CH2:26][O:25][C:24]4=[O:33])[CH2:19][CH2:18]3)=[O:16])=[C:10]([O:34][CH2:35][C:36]([F:39])([F:38])[F:37])[CH:9]=2)[CH2:3][CH2:2]1.CC([O-])=O.[Na+].[CH3:45][C:46]([CH3:48])=O.[BH3-]C#N.[Na+].Cl>CCO.CCOC(C)=O>[CH3:45][CH:46]([N:1]1[CH2:2][CH2:3][CH:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[CH2:26][O:25][C:24]4=[O:33])[CH2:19][CH2:18]3)=[O:16])=[C:10]([O:34][CH2:35][C:36]([F:39])([F:37])[F:38])[CH:9]=2)[CH2:5][CH2:6]1)[CH3:48]
Reactant: O=C(Cc1ccc(OC2CCNCC2)cc1OCC(F)(F)F)N1CCC(N2C(=O)OCc3ccccc32)CC1
Reactant: CC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)N1CCC(Oc2ccc(CC(=O)N3CCC(N4C(=O)OCc5ccccc54)CC3)c(OCC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the hydrochloride salt of 1-(1-(4-(4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one (0.20 g, 0.30 mmol) from Example 2 in EtOH (3 mL) was added NaOAc (0.05 g, 0.6 mmol), acetone (0.027 mL, 0.37 mmol), powdered 3 angstrom molecular seives (approx. 100 mg). The mixture was stirred at ambient temperature for 1 h and NaBH3CN (0.021 mg, 0.34 mmol) was added. The mixture was stirred for 14 h at ambient temperature. More acetone (0.027 mL, 0.37 mmol), molecular seives (approx. 100 mg), and NaBH3CN (0.021 mg, 0.34 mmol) were added and the mixture was stirred at ambient temperature for 48 h. The mixture was diluted with EtOAc, filtered, and the solvents were removed under reduced pressure. The residue was partitioned between CH2Cl2 (50 mL) and saturated aqueous NaHCO3 (2×25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was dissolved in EtOH (5 mL) and 1.5 equivalents of 6 N aqueous HCl was added. The solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2 (1 mL) and added to a rapidly stirred ether (20 mL). The precipitate was collected by filtration to give the hydrochloride salt of the title compound as an amorphous solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17](O)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O[N:30]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.N>CN(C)C=O.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][C:21](=[O:22])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:17](=[O:18])[NH2:30])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.6 %

Procedure:
To a solution of (S)-3-(4-benzyloxyphenyl)-2-tert-butoxycarbonylaminopropionic acid (5.00 g, 13.5 mmol) and 1-hydroxybenzotriazole monohydrate (2.50 g, 16.1 mmol) in N,N-dimethylformamide (50 ml) were added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (3.10 g, 16.1 mmol) and 28% aqueous ammonia solution (5 ml) under ice-cooling, and the mixture was stirred at room temperature for 24 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:ethyl acetate=2:1-1:1) to give tert-butyl (S)-[2-(4-benzyloxyphenyl)-1-carbamoylethyl]carbamate (1.53 g, yield 31%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])([CH3:12])[CH2:7][CH2:8][S:9]2)=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C1COCC1>[CH3:12][C:6]1([CH3:13])[C:5]2[C:10](=[CH:11][C:2]([C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:3][CH:4]=2)[S:9][CH2:8][CH2:7]1
Reactant: CCCCCC(=O)N(C)OC
Reactant: CC1(C)CCSc2cc(Br)ccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCC(=O)c1ccc2c(c1)SCCC2(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
A solution of 7-bromo-4,4-dimethyl-thiochroman (2.0 g, 7.78 mmole) in 45 mL of THF at −78° C. was, treated with 3.9 mL of 2.5M butyllithium. After 30 minutes at −78° C. a solution of hexanoic acid methoxy-methyl-amide (1.486 g, 9.33 mmole) in 5 mL of THF was added. The reaction mixture was stirred at −78° C. for 30 minutes, warmed to room temperature, quenched by the addition of 50 mL of saturated aqueous ammonium chloride solution and extracted with three 50 mL portions of ether. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The product was purified by flash chromatography (SiO2, 3% ethyl acetate in hexanes) to yield 1.183 g of 1-(4,4-dimethyl-thiochroman-7-yl)-hexan-1-one as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]=1[Cl:13].S(=O)(=O)(O)[OH:15]>>[OH:1][C:2]1[C:7]([C:8]([NH2:9])=[O:15])=[C:6]([Cl:10])[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]=1[Cl:13]
Reactant: N#Cc1c(O)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: O=S(=O)(O)O
Product: NC(=O)c1c(O)c(Cl)c(Cl)c(Cl)c1Cl
Yield: 97 %

Procedure:
a 10.0 g portion of this hydroxy-tetrachlorobenzonitrile was heated under an inert atmosphere at 130° C. for 15 minutes with 150 ml concentrated sulfuric acid. The product, hydroxytetrachlorobenzamide was readily isolated by filtering the H2O-diluted reaction mixture; yield 97.0%.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:11][C:12]1[CH:13]=[C:14]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:15]=[CH:16][C:17]=1[B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1.Br[CH2:33][CH2:34]Br>C1COCC1>[Cl:11][C:12]1[CH:13]=[C:14]([C:27]2([C:28]([O:30][CH3:31])=[O:29])[CH2:34][CH2:33]2)[CH:15]=[CH:16][C:17]=1[B:18]1[O:22][C:21]([CH3:23])([CH3:24])[C:20]([CH3:25])([CH3:26])[O:19]1
Reactant: COC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(Cl)c1
Reactant: BrCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)c(Cl)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 16.8 %

Procedure:
Lithium bis(trimethylsilyl)amide (7.08 mL, 7.08 mmol) was added dropwise to methyl 2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (1 g, 3.22 mmol) in THF (20 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 30 minutes and then 1,2-dibromoethane (0.305 mL, 3.54 mmol) was added to the reaction and was stirred at 0° C. for 5 minutes. The reaction mixture was quenched with saturated NH4Cl (50 mL) and was diluted with EtOAc (75 mL). The organic layer was separated and re-extracted with EtOAc (75 mL). The combined organics were washed with saturated brine (50 mL), dried (MgSO4), filtered and concentrated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 1-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxylate (0.182 g, 16.79%) as a colourless gum.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:21])=[C:4]([C:10]2[N:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[N:13]=[CH:12][CH:11]=2)[CH:5]=[C:6]([F:9])[C:7]=1I.[Cu][C:23]#[N:24]>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([F:21])=[C:4]([C:10]2[N:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[N:13]=[CH:12][CH:11]=2)[CH:5]=[C:6]([F:9])[C:7]=1[C:23]#[N:24]
Reactant: N#C[Cu]
Reactant: Fc1cc(-c2ccnn2C2CCCCO2)c(F)c(Cl)c1I
Solvent: CN1CCCC1=O
Product: N#Cc1c(F)cc(-c2ccnn2C2CCCCO2)c(F)c1Cl
Temperature: 170 °C
Reaction time: 7 h
Yield: 50.6 %

Procedure:
5-(3-Chloro-2,5-difluoro-4-iodophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (1.686 mmol, 0.716 g) and copper(I) cyanide (1.686 mmol, 0.151 g) were suspended in NMP. The resulting mixture was stirred at 170° C. for 7 h. The reaction was quenched by, pouring the mixture onto 12% ammonia solution and stirred for 20 min. The formed precipitate was filtered and washed with water. 0.276 g of the title product was obtained. Identification after the next step due to low solubility of the product.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[CH2:11]([P:18]([O:22][CH3:23])(=[O:21])[O:19][CH3:20])[P:12]([O:16][CH3:17])(=[O:15])[O:13][CH3:14]>>[CH3:10][O:9][C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH:11]([P:12]([O:13][CH3:14])(=[O:15])[O:16][CH3:17])[P:18]([O:22][CH3:23])(=[O:21])[O:19][CH3:20])=[O:8]
Reactant: COC(=O)CCCCCCl
Reactant: COP(=O)(CP(=O)(OC)OC)OC
Product: COC(=O)CCCCCC(P(=O)(OC)OC)P(=O)(OC)OC

Procedure:
Following the General Synthetic Procedure B, methyl 6-chlorohexanoate is reacted with tetramethyl methanebisphosphonate to produce tetramethyl 5-methoxycarbonylpentyl-methanebisphosphonate that is then hydrolyzed to yield 5-carboxypentyl-methanebisphosphonic acid, and then hydrogenated to reduce the carboxy group to a hydroxymethylene group. The resulting 6-hydroxyhexyl-methanebisphosphonic acid is then methacrylated with methacryloyl chloride to afford 6-methacryloxyhexyl-methanebisphosphonic acid.
Reaction SMILES: C1COCC1.[CH:6]1[CH:11]=[C:10]([CH:12]=[O:13])[C:9]([N+:14]([O-])=O)=[CH:8][CH:7]=1.O.C(=O)=O>CO>[CH:6]1[CH:11]=[C:10]([CH:12]=[O:13])[C:9]([NH2:14])=[CH:8][CH:7]=1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: O=C=O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccccc1C=O
Yield: 94.9 %

Procedure:
Under nitrogen, 12.3 g (13.6 mmol) lithium cobalt (I) phthalocyanine x 4.5 THF and 322 mg (2 mmol) O-nitrobenzaldehyde are agitated in 65 ml methanol for 90 hours at 20° C. The green reaction mixture is mixed with 10 ml water; CO2 and air are passed in for 5 min., and the blue precipitate is centrifuged which is washed with ethanol. The centrifugate collected is concentrated, and the residue separated into ether and water. Concentration of the ether phase, dried with sodium sulfate, produces 230 mg (96%) O-amino benzaldehyde.