Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[N:13]O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(=N[OH:22])CCCCC1.C1(=O)CCCCC1.C1(=O)CCCCCCCCCCC1.S(=O)(=O)(O)O.OS(O)(=O)=O.O=S(=O)=O>>[C:1]1(=[O:22])[NH:13][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: ON=C1CCCCCCCCCCC1
Reactant: ON=C1CCCCC1
Agent: O=C1CCCCCCCCCCC1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: O=C1CCCCC1
Product: O=C1CCCCCCCCCCCN1

Procedure:
Another industrial process is that commercially developed by Ube Industries-EMS. This process utilizes the fact that cyclohexanone oxime and caprolactam are good solvents for cyclododecanone oxime and laurolactam, respectively (for example, see Patent Reference 2). Specifically, a mixture of cyclododecanone and cyclohexanone is blended with an aqueous solution of hydroxylamine to produce oximes. Cyclohexanone oxime produced has a low melting point and is a good solvent for cyclododecanone oxime, so that the reaction can be conducted at 100° C. or lower and at an ambient pressure. Furthermore, cyclohexanone oxime is adequately hydrophilic for the oxime-forming reaction to quickly proceed, and the mixture is transferred to the rearrangement step without residual cyclohexanone or cyclododecanone. A rearrangement catalyst used is concentrated sulfuric acid or oleum. Whereas laurolactam produced has a high melting point, it is highly soluble in caprolactam having a low melting point. Therefore, the reaction can carried out even at a temperature of 100° C. or lower. The resulting rearrangement reaction solution is neutralized with ammonia water and then extracted with an organic solvent. Caprolactam can be dissolved in water to some extent, but is extracted into an organic solvent due to salting-out effect of ammonium sulfate. Next, a large amount of water is added to the solution containing extracted laurolactam and caprolactam, and caprolactam is extracted into the aqueous phase. From the separated organic phase, the organic solvent is recovered and laurolactam is purified by distillation. The aqueous phase is concentrated and after removing impurities, caprolactam is purified.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=4[F:51])[CH:34]=3)[O:32][C@@:10]1([CH2:52][OH:53])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O>C(OCC)(=O)C>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=4[F:51])[CH:34]=3)[O:32][C@@:10]1([CH:52]=[O:53])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)c(F)c1F
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CCOC(C)=O
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C=O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: 25 °C

Procedure:
To a solution of [(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenye methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 23n (1.36 g, 1.75 mmol) in ethyl acetate (30 mL) was added 2-iodoxybenzoic acid (735 mg, 2.62 mmol) at room temperature. The mixture was refluxed for 20 hours and cooled to room temperature. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound 23o as a yellow soild (1.32 g, 100%). This material was not further purified.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([OH:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.O.O.O.C([O-])(=O)C.[Na+].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Cl.Cl>O.C(#N)C>[F:20][C:21]([F:30])([F:31])[C:22]1[CH:23]=[C:24]([CH2:25][NH:1][C:2]2[CH:3]=[C:4]([S:8]([OH:11])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: Nc1cccc(S(=O)(=O)O)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=S(=O)(O)c1cccc(NCc2cccc(C(F)(F)F)c2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 23.2 %

Procedure:
To 52.0 g (0.30 mole) of 3-aminobenzenesulfonic acid in 225 ml of water was added 83.0 g (0.61 mole) of sodium acetate trihydrate and 75 ml of acetonitrile. The solution was stabilized at about 70° C. and a solution of 38.92 g (0.20mole) of 3-(trifluoromethyl)benzyl chloride in 75 ml of acetonitrile was added dropwise. The resulting orange solution was refluxed for 4 hrs, then acidified by the dropwise addition of 42 ml of conc. HCl while simultaneously removing 105 ml of acetonitrile by distillation. After standing overnight, a flocculent cream-colored solid crystalized which was removed by vacuum filtration. The collected solids were then slurried in 300 ml of warm (60° C.) water for 20 minutes and then filtered. The slurrying process was repeated using 300 ml of boiling methanol and the solids isolated by vacuum filtration. Air-drying in vacuo at about 60° C. gave 15.4 g (23.2% yield) of purified 3-(((3-(trifluoromethyl)phenyl)methyl)amino)benzenesulfonic acid as a white powder having a melting point greater than 275° C.
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:15]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[N:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:22]([O:24]C)=[O:23])[CH:12]=3)[N:7]=2)=[CH:4][C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2.[OH-].[Na+].O>CO>[S:1]1[C:5]([C:6]2[C:15]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[N:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:22]([OH:24])=[O:23])[CH:12]=3)[N:7]=2)=[CH:4][C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2
Reactant: COC(=O)c1ccc2nc(-c3cc4ccccc4s3)c(N3CCCCC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3cc4ccccc4s3)c(N3CCCCC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To a solution of methyl 2-(benzo[b]thiophen-2-yl)-3-(piperidin-1-yl)quinoxaline-6-carboxylate (70 mg, 0.17 mmol) in MeOH (20 mL) was added sodium hydroxide (28 mg, 0.69 mmol) and water (1 mL). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (10 mL) and adjusted to pH 4 with HCl (1N). The solids were collected by filtration to afford 2-(benzo[b]thiophen-2-yl)-3-(piperidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid (60 mg, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][NH2:12].C(N(CC)CC)C.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:33](=[O:34])[C:32]1[CH:36]=[CH:37][C:29]([C:28]([F:27])([F:38])[F:39])=[CH:30][CH:31]=1
Reactant: NCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)c1ccc(C(F)(F)F)cc1
Yield: 79.4 %

Procedure:
To a solution of 0.21 g of 3,5-dichloro-4-(3-aminopropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene and 0.07 g of triethylamine dissolved in 5 ml of dichloromethane was added dropwise a solution of 0.15 g of 4-trifluoromethylbenzoyl chloride dissolved in 5 ml of dichloromethane, while stirring under ice cooling. After stirring at room temperature for 6 hours, the reaction mixture was washed with water and then concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.25 g of 3,5-dichloro-4-(3-(4-trifluoromethylbenzamido)propyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (79% yield), m.p., 93.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]([OH:10])=O)[S:4][N:3]=1.C(Cl)(=O)C([Cl:14])=O>CN(C=O)C>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]([Cl:14])=[O:10])[S:4][N:3]=1
Reactant: O=C(O)c1snc(Cl)c1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1snc(Cl)c1Cl
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To 4.0 g (20.3 mmol) of 3,4-dichloroisothiazole-5-carboxylic acid were added 8 ml of oxalyl chloride and a catalytic amount of DMF, followed by stirring at 50° C. for 30 minutes to give rise to a reaction. The reaction mixture was concentrated under vacuum to obtain 3,4-dichloroisothiazole-5-carbonyl chloride.
Reaction SMILES: [CH3:1][S:2]([N:5]([CH3:29])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:20]2[C:15]([CH:16]=[N:17][C:18](OS(C(F)(F)F)(=O)=O)=[N:19]2)=[CH:14][CH:13]=1)(=[O:4])=[O:3].C(N(CC)C(C)C)(C)C.COC1C=C([CH2:47][N:48]2[CH2:53][CH2:52][N:51](C)[CH2:50][CH2:49]2)C=CC=1N.COCC(O)C>>[CH3:29][N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:20]2[C:15]([CH:16]=[N:17][C:18]([N:51]3[CH2:52][CH2:53][N:48]([CH3:47])[CH2:49][CH2:50]3)=[N:19]2)=[CH:14][CH:13]=1)[S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CN(c1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12)S(C)(=O)=O
Reactant: COc1cc(CN2CCN(C)CC2)ccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: CN1CCN(c2ncc3ccc(-c4ccccc4N(C)S(C)(=O)=O)n3n2)CC1
Temperature: 120 °C

Procedure:
Into a 8-dram vial, Trifluoro-methanesulfonic acid 7-[2-(methanesulfonyl-methyl-amino)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (89 mg, 0.20 mmol), N,N-Diisopropylethylamine (0.0757 mL, 0.435 mmol), 2-Methoxy-4-(4-methyl-piperazin-1-ylmethyl)-phenylamine (100 mg, 0.4 mmol) and 1-Methoxy-2-propanol (0.71 mL) were added. The reaction mixture was heated at 120° C. for 6 hours. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give N-Methyl-N-{2-[2-(4-methyl-piperazin-1-yl)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-methanesulfonamide as a yellow solid. LCMS (E/I+) 401.20 (M+H). NMR 1H (DMSO-d6)-9.90 (bs, 1H), 8.99 (s, 1H), 7.88 (d, 1H, J=7.02 Hz), 7.65 (d, 1H, J=7.48 Hz), 7.45-7.54 (m, 2H), 7.00 (d, 1H, J=4.70 Hz), 6.92 (d, 1H, J=4.70 Hz), 4.45 (d, 2H, J=12.95 Hz), 3.49 (d, 2H, J=11.09 Hz), 3.03-3.25 (m, 7H), 2.89 (s, 3H), 2.82 (s, 3H).
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].[C:10]1([CH2:16][CH2:17][C:18](=O)[CH3:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O>[C:2]([NH:6][N:7]=[C:18]([CH2:17][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:19])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(=O)CCc1ccccc1
Reactant: CC(C)(C)NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(CCc1ccccc1)=NNC(C)(C)C
Yield: 49 %

Procedure:
A solution of 50.46 g t-butyl hydrazine hydrochloride and 32 g of 50 percent aqueous sodium hydroxide in 70 ml of water is stirred in an ice water bath. About 55 g of 4-phenyl-2-butanone is added with stirring. The reaction and isolation are continued as in Example (a). The title compound is isolated as a fraction distilled under 0.9 mm pressure at 110° C.-119° C. The yield is about 49 percent based upon the initial amount of 4-phenyl-2-butanone added.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13](F)=[C:14]([CH:17]=2)[CH:15]=O)=[CH:6][CH:5]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[SH:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)(OCC)OCC.[O-]CC.[Na+].Cl>CN(C)C=O.C(O)(C)C.C(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[S:25][CH2:26][CH2:27][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:15][C:14]=3[CH:17]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOC(=O)CCCS
Reactant: CCOc1ccc(-c2ccc(F)c(C=O)c2)cc1
Agent: CC[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CCOC(=O)OCC
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(-c3ccc(OCC)cc3)ccc2SCC1
Temperature: 25 °C
Reaction time: 25 h
Yield: 57 %

Procedure:
Under an argon atmosphere, 5-(4-ethoxyphenyl)-2-fluorobenzaldehyde (1.0 g) was dissolved in 2 ml of dimethylformamide and 1.17 g of potassium carbonate was added. Thereafter, 1.18 ml of ethyl 4-mercaptobutyrate was added and was stirred at room temperature for 25 hours. After addition of 20 ml of diethyl carbonate and an ethanol solution (2.8 g) of 20% sodium ethoxide, stirring was conducted at room temperature for three hours. During cooling in ice, 21 ml of a 1N hydrochloric acid was added. The mixture was extracted with 50 ml and additional 20 ml of ethyl acetate. The organic layers were combined and washed with 20 ml of water twice. The resulting organic layer was concentrated to yield crystals, which crystals were loosen in 2 ml of isopropyl alcohol added. The crystals were filtered out and were washed with 4 ml of isopropyl ether twice. After vacuum drying, ethyl 7-(4-ethoxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylate (0.8 g, Yield 57%) was obtained.
Reaction SMILES: S(Cl)(Cl)=O.[N:5]1([CH:10](O)[CH:11]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[N:8]N=C1.[N:27]1C=CC=C[CH:28]=1>ClCCl>[N:5]1([CH:10]=[C:11]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[C:12]([CH3:13])([CH3:14])[CH3:15])[CH:9]=[N:8][CH:28]=[N:27]1
Reactant: CC(C)(C)C(COc1ccc(Cl)cc1Cl)C(O)n1cnnc1
Reactant: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)C(=Cn1cncn1)COc1ccc(Cl)cc1Cl
Yield: 75 %

Procedure:
With stirring, 100 ml of dichloromethane and 10 ml of thionyl chloride are cooled to -30° C. and then 17.5 g (0.05 mole) of 1-(1H-1,3,4-triazolyl)-2-(2,4-dichlorophenoxymethyl)-3,3-dimethylbutanol are added in portions. The reaction mixture is stirred for 2 hours and then a solution of 15 ml of pyridine in 30 ml of dichloromethane is added dropwise and the mixture is stirred for about 12 hours at room temperature. The clear solution is concentrated in vacuo and, after addition of ice, the residue is made alkaline with sodium carbonate and extracted with diethyl ether. The combined extracts are dried over sodium sulfate, filtered and concentrated. The yellowish oily residue is purified by column chromatography over silica gel with ethyl acetate as eluant. Yield: 75% of theory.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH:12]=[C:13]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)[C:14]([F:17])([F:16])[F:15])=[CH:7][C:6]=1[CH3:27])[CH3:2].Cl.[CH3:30][NH:31][OH:32].C(N(CC)CC)C>C(O)C>[CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:31]([CH3:30])[O:32][C:13]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[CH:12]=2)=[CH:7][C:6]=1[CH3:27])[CH3:2]
Reactant: CCOC(=O)c1ccc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1C
Reactant: CNO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1ccc(C2=CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)cc1C

Procedure:
0.62 g of 4-[3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoic acid ethyl ester (XVIIa) was mixed with 0.21 g of N-methylhydroxylamine hydrochloride and 0.42 ml of triethylamine in 10 ml of dry ethanol. The mixture was refluxed for 20 hours, evaporated to dryness and purified on silica gel giving 0.275 g (42%) of 4-[5-(3,5-Dichloro-phenyl)-2-methyl-5-trifluoromethyl-2,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid ethyl ester (VIIIa) as a colorless oil 1H-NMR (CDCl3, δ in ppm): 7.93 (d, 1H), 7.30-7.45 (m, 5H), 5.43 (s, 1H), 4.37 (q, 2H), 2.99 (s, 3H), 2.61 (s, 3H), 1.40 (t, 3H).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[CH:18][C:19](=[O:32])[C:20]3[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=3)[CH3:17])=[CH:12][CH:11]=2)[CH2:6]1)=[O:4].COC(C1CN(CC2C=CC(OCC3C4C=C(Cl)C=CC=4OC=3)=CC=2)C1)=O>>[O:32]=[C:19]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=1)[CH:18]=[C:16]([C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:7]2[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:8]2)=[CH:15][CH:14]=1)[CH3:17]
Reactant: COC(=O)C1CN(Cc2ccc(C(C)=CC(=O)c3cc(OC)c(OC)c(OC)c3)cc2)C1
Agent: COC(=O)C1CN(Cc2ccc(OCc3coc4ccc(Cl)cc34)cc2)C1
Product: COc1cc(C(=O)C=C(C)c2ccc(CN3CC(C(=O)O)C3)cc2)cc(OC)c1OC
Yield: 53 %

Procedure:
When the product of Step C was substituted for methyl-1-(4-((5-chlorobenzofuran-3-yl)methoxy)benzyl)azetidine-3-carboxylate in Example 25, Step E, the similar process afforded the title compound in 53% yield, as light yellow solid. 1H-NMR (CDCl3+CD3OD) 7.31 (d, 2H, J=8.18 Hz); 7.28 (d, 2H, J=8.28 Hz); 6.71 (s, 2H); 6.62 (s, 1H); 4.24 (s, 2H); 4.17-4.04 (m, 4H); 3.55-3.38 (s, 1H); 2.15 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@@H:14]1[NH2:19].C(N(CC)CC)C>C(O)CCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[NH2:19])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: N[C@@H]1CCCC[C@@H]1N
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: NC1CCCCC1Nc1nc(Cl)nc2[nH]ccc12
Yield: 63.2 %

Procedure:
A solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.53 mmol), cis-1,2-diaminocyclohexane (0.107 mL, 0.91 mmol) and triethylamine (0.150 mL, 1.08 mmol) in nBuOH (4 mL) was stirred at 70° C. for 4 h. It was then purified by HPLC to give N1-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)cyclohexane-1,2-diamine as a solid (89 mg).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:11][CH2:12][CH3:13])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].Br[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:19][CH:18]=1)[CH3:16].Cl>O1CCCC1>[C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:20]1[CH:19]=[CH:18][C:17]([CH:15]([CH:5]([C:4](=[O:3])[CH2:11][CH2:12][CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:16])=[CH:22][CH:21]=1)#[N:30]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: CC(Br)c1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(=O)C(C(=O)OCC)C(C)c1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
To a mixture of 60% sodium hydride in oil (0.82 g) and tetrahydrofuran (20 mL) was added dropwise a mixture of ethyl 3-oxohexanoate (4.35 g) in tetrahydrofuran (20 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. Then, 4′-(1-bromoethyl)biphenyl-2-carbonitrile (3.93 g) was added, and the mixture was stirred at 50° C. overnight. The reaction mixture was poured into 1 M hydrochloric acid (30 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless oil (4.70 g, 94%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([O:11]C)=[O:10])=[CH:4][CH:3]=1.Cl>O1CCCC1.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:13])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)c1ccc(Br)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C(=O)O)c1ccc(Br)cc1
Reaction time: 3 h

Procedure:
To a solution of methyl 2-(4-bromophenyl)propanoate (2 g, 8.2 mmol) in tetrahydrofuran (30 mL) and water (20 mL) was added (1.2 g, 41 mmol) at room temperature, the mixture solution was stirred for 3 hours, then diluting with ethyl acetate (100 mL), and acidified with hydrochoric acid (6 M) to ph=3. The organic layer was dried over sodium sulfate, and concentrated to dry. The result residue 2-(4-bromophenyl)propanoic acid (2 g) was used directly for the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@H:13]([N:17]2[CH2:20][C:19]4([CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]4)[CH2:18]2)[CH2:12][CH2:11]3)[CH:3]=1.[ClH:33]>CO.O1CCOCC1>[ClH:33].[ClH:33].[CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@H:13]([N:17]2[CH2:20][C:19]4([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[CH2:18]2)[CH2:12][CH2:11]3)[CH:3]=1
Reactant: Cc1cc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCN(C(=O)OC(C)(C)C)CC3)C2)ncn1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCNCC3)C2)ncn1
Reaction time: 2 h
Yield: 99.9 %

Procedure:
(R)-tert-butyl 2-(5-(6-methylpyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (72.6 g, 167 mmol) was suspended in methanol (363 mL) and 4M HCl in 1,4-dioxane (251 mL) was added. After stirring for 2 hours, the slurry was concentrated to dryness. The crude material was re-suspended in MeOH (500 mL) and concentrated (3×). The resulting solids were further dried under vacuum at 45° C. to afford the title compound (74.1 g, 99.9%). MS (ES+) 335.2 (M+H)+. 1H NMR (CD3OD) δ 2.16-2.23 (m, 5H), 2.59 (br s, 1H), 2.78-2.80 (m, 3H), 3.12 (br s, 1H), 3.19-3.24 (m, 4H), 3.37-3.49 (m, 1H), 4.14-4.23 (m, 3H), 4.49 (br s, 1H), 5.11 (br s, 1H), 7.84 (d, 1H), 8.30-8.34 (m, 2H), 8.46 (s, 1H), 9.36 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][CH:4]([C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:11][CH:12]=1)[C:5]([OH:7])=O.C1CN([P+](O[N:37]2N=[N:44][C:39]3C=CC=C[C:38]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.NCC#N.C(N(CC)CC)C>CN(C=O)C>[C:38]([CH2:39][NH:44][C:5](=[O:7])[CH:4]([C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:11][CH:12]=1)[CH2:3][CH:2]([CH3:1])[CH3:19])#[N:37]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CC(C)CC(C(=O)O)c1csc(-c2ccccc2)n1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CC(C(=O)NCC#N)c1csc(-c2ccccc2)n1
Reaction time: 3 h
Yield: 76.7 %

Procedure:
A solution comprised of 4-methyl-2-(2-phenylthiazol-4-yl)pentanoic acid (150 mg, 0.6 mmol), prepared as in Example 5, in DMF (5.0 mL) was treated with PyBOP (300 mg, 0.7 mmol), aminoacetonitrile hydrochloride (100 mg, 1 mmol) and triethylamine (250 μL, 1.5 mmol). The mixture was stirred for 3 hours and then partitioned between water (20 mL) and ethyl acetate (50 mL). The organic layer was separated and washed with 1 M saturated sodium bicarbonate solution, 1 M hydrochloric acid solution and water, dried (MgSO4) and concentrated. Product was purified from the residue by flash column on silica gel (60° A) with 40% ethyl acetate in hexane to provide N-cyanomethyl-4-methyl-2-(2-phenylthiazol-4-yl)pentanamide (120 mg, 0.46 mmol). Rf 0.30. 1H NMR (DMSO-d6): 1.01 (m, 6H), 1.31-1.59 (m, 3H), 3.91 (m, 1H), 4.14 (s, 2H), 7.44 (m, 4H), 7.81 (m, 2H), 8.61 (s, 1H). LCMS: 312.2.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.Cl.[NH2:11][OH:12].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)/[CH:5]=[N:11]\[OH:12]
Reactant: O=Cc1cccc(Cl)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O/N=C\c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To a suspension of 3-chlorobenzaldehyde (50 g, 355 mmol) and hydroxylamine hydrochloride (38 g, 543 mmol) in ethanol (200 mL) containing sodium acetate (46 g, 558 mmol) was heated under reflux for 3 h. After 30 min stirring at room temperature a white solid precipitated and the resulting mixture was then diluted with water and acidified with HCl (4 N). The white precipitate was then filtered off, washed with water and dried under high vacuum to afford the title compound (54 g, 98%) which was obtained as a white solid. Mp: 64-66° C.