Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH:15]=[N:14][C:13]([CH3:16])=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([NH:26][CH2:27][C@@H:28]3[C@H:33]([CH3:34])[CH2:32][CH2:31][CH2:30][NH:29]3)=[N:23][C:22]=2[CH:35]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([NH:26][CH2:27][C@@H:28]3[C@H:33]([CH3:34])[CH2:32][CH2:31][CH2:30][N:29]3[C:7]([C:6]3[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[N:11]3[CH:15]=[N:14][C:13]([CH3:16])=[N:12]3)=[O:9])=[N:23][C:22]=2[CH:35]=1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1nc2cc(Cl)ccc2o1
Reactant: Cc1ccc(-n2cnc(C)n2)c(C(=O)O)c1
Product: Cc1ccc(-n2cnc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-methyl-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzoic acid and 5-chloro-N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 479 [M+1]+.
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)CCCC)[CH3:2].[CH3:16][C:17]1[C:18](OS(C(F)(F)F)(=O)=O)=[C:19]([CH2:38]/[CH:39]=[C:40](\[CH3:48])/[CH:41]([CH3:47])[CH2:42][C:43]([O:45][CH3:46])=[O:44])[C:20]([O:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])=[C:21]2[C:25]=1[CH2:24][O:23][C:22]2=[O:26]>>[CH2:1]([C:18]1[C:17]([CH3:16])=[C:25]2[C:21]([C:22](=[O:26])[O:23][CH2:24]2)=[C:20]([O:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[C:19]=1[CH2:38]/[CH:39]=[C:40](\[CH3:48])/[CH:41]([CH3:47])[CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH3:2]
Reactant: CCCC[Sn](CC)(CCCC)CCCC
Reactant: COC(=O)CC(C)/C(C)=C/Cc1c(OS(=O)(=O)C(F)(F)F)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2
Product: CCc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1C/C=C(\C)C(C)CC(=O)OC)C(=O)OC2

Procedure:
By following the procedure of part A and substituting vinyltributyltin with ethyltributyltin, and substituting methyl (E) 6-(1,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6-trifluoromethanesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoate with methyl (E) 6-(1,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6-trifluoromethanesulfonyloxyisobenzofuran-5-yl)-3,4-dimethyl-4-hexenoate, there is obtained methyl (E) 6-(1,3-dihydro-6-ethyl-7-methyl-3-oxo-4-p-toluenesulfonyloxyisobenzofuran-5-yl)-3,4-dimethyl-4-hexenoate.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:11]([CH3:21])[C:12]([C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)=O>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[N:9]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[O:8][C:11]=2[CH3:21])=[CH:15][CH:16]=1
Reactant: CC(Br)C(=O)c1ccc(Br)cc1
Reactant: NC(=O)c1ccccc1
Product: Cc1oc(-c2ccccc2)nc1-c1ccc(Br)cc1
Temperature: 135 °C
Reaction time: 2 h

Procedure:
a mixture of benzamide (4.919 ml, 54.46 mmol) and 2,4′-dibromopropiophenone (10.60 g, 36.31 mmol) was heated in a 135° C. oil bath. The mixture became homogenous at >100° C. The reaction was stirred at 135° C. for 2 hours, after which time a precipitate had developed, and removed from the hot oil bath. Approximately 20 mL of acetonitrile was added to the mixture, which was left to equilibrate to room temperature. The precipitate was collected by filtration, rinsing with acetonitrile to afford a colorless solid. ESI+ m/z=314.0; 316.0 [MH]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N:19]3[CH2:30][CH2:29][C:22]4[N:23]=[C:24]([S:27][CH3:28])[N:25]=[CH:26][C:21]=4[CH2:20]3)[N:14]=2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH:31]OS([O-])=O.[K+]>C1COCC1.O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N:19]3[CH2:30][CH2:29][C:22]4[N:23]=[C:24]([S:27]([CH3:28])=[O:31])[N:25]=[CH:26][C:21]=4[CH2:20]3)[N:14]=2)=[O:12])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: O=S([O-])OO
Reactant: CSc1ncc2c(n1)CCN(c1cccc(C(=O)Nc3ccc(C(C)C)cc3)n1)C2
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1ccc(NC(=O)c2cccc(N3CCc4nc(S(C)=O)ncc4C3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred mixture of N-(4-isopropylphenyl)-6-[2-(methylthio)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]pyridine-2-carboxamide (400 mg, 0.953 mmol) in THF (40 ml) and water (16 ml) was added oxone (potassium peroxomonosulfate, 586 mg, 0.953 mmol). After stirring at room temperature for 3 hours, the reaction mixture was quenched by addition of 10% NaHSO3(aq.) (20 ml) and neutralized with sat'd NaHCO3(aq.) (16 ml). The solution was stirred for 20 minutes before extraction with ethyl acetate (2×60 ml). The combined organic extracts were dried (MgSO4), filtered, and concentrated to give the title compound as a light yellow, amorphous solid which was used without further purification (405 mg, 98%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].N1C=CC=CC=1.[C:15]([O:30][CH3:31])(=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O-])=[O:27]>C(Cl)Cl>[C:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])=[O:27])([O:30][CH3:31])=[O:29]
Reactant: Nc1ccccc1O
Reactant: COC(=O)CCCCCCCCCCC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CCCCCCCCCCC(=O)Nc1ccccc1O

Procedure:
To a stirred near solution of 2-aminophenol (0.24 g, 2.2 mM) in anhydrous methylene chloride (25 mL) was added dry pyridine (0.66 mL) and the mixture cooled in an ice-water bath. A solution of (7) (0.525 g, 2.0 mM) in methylene chloride (2 mL) was added over 1 minute (2×1.5 mL methylene chloride rinses), and the mixture allowed to stir cold. After 30 minutes the bath was removed. After stirring overnight at ambient temperatures, the mixture was filtered, the solvents removed in vacuo, and the residue pumped to remove all traces of pyridine. The product, (44) was used as is in subsequent steps.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]2=[N:10]1.C(N(CC)CC)C.[C:26](Cl)(=[O:30])[C:27]([CH3:29])=[CH2:28]>C(Cl)Cl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:26](=[O:30])[C:27]([CH3:29])=[CH2:28])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]2=[N:10]1
Reactant: C=C(C)C(=O)Cl
Reactant: Nc1ccc(O)c(-n2nc3ccc(Cl)cc3n2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Nc1ccc(O)c(-n2nc3ccc(Cl)cc3n2)c1
Reaction time: 1 h

Procedure:
To 10.4 g. (0.04 mole) of 2-(2-hydroxy-5-aminophenyl)-5-chlorobenzotriazole and 4.1 g. triethylamine in 400 ml. methylene chloride (no preservative) was added at 0°-5° C., under nitrogen, with stirring, 4.2 g. methacryloyl chloride in 30 ml. methylene chloride. The dropwise addition required about 30 minutes. The mixture was stirred at 0°-5° C. for an additional 30 minutes and then at room temperature for one hour. The mixture was then washed with equal volumes of water, 5% hydrochloric acid and water. The organic phase was dried over magnesium sulfate and poured onto a 2" column of silica gel (120 g.) which had been slurry packed with methylene chloride. The column was eluted with methylene chloride and 100 ml. fractions were taken. The fractions were examined by thin layer chromatography (TLC) on silica gel plates using 1:5, ethyl acetate:chloroform as the developing solvent. The fractions containing the product (r.f. 0.36) were combined and evaporated. The residual solid was crystallized from ethanol to give 2.2 g. of product, m.p. 204°-205° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8](Br)[C:9]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:5]=[O:6].O[C:21]1[CH:22]=C(C=[CH:27][CH:28]=1)C=O>>[CH2:11]([O:10][C:9]1[C:8]2[C:7](=[CH:22][CH:21]=[CH:28][CH:27]=2)[C:4]([CH:5]=[O:6])=[CH:3][CH:2]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=Cc1cccc(O)c1
Reactant: CCCCCCCCOc1c(Br)cc(C=O)cc1Br
Product: CCCCCCCCOc1ccc(C=O)c2ccccc12

Procedure:
The title compound was prepared using a procedure analogous to Aldehyde 3 substituting 4-hydroxy-1-naphthaldehyde for 3-hydroxybenzaldehyde.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[Cl:14])[CH2:2][CH2:3][CH3:4].ClC1C=C(C=CC=1OCC)C=[O:20]>>[CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]([OH:20])=[O:11])=[CH:8][C:7]=1[Cl:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCOc1ccc(C=O)cc1Cl
Reactant: CCCCOc1ccc(C=O)cc1Cl
Product: CCCCOc1ccc(C(=O)O)cc1Cl
Yield: 85 %

Procedure:
When the product of Step A was substituted for 3-chloro-4-ethoxybenzaldehyde in Example 49, Step A the identical process afforded the title compound in 85% yield. 1H-NMR (CDCl3) 0.96 (tr, 3H, J=7.38 Hz); 1.46-1.57 (m, 2H); 1.59-2.77 (m, 2H); 4.1 (tr, 2H, J=6.45 Hz); 6.93 (d, 1H, J=8.67 Hz); 7.96 (dd, 1H, J=8.64, 2.1 Hz); 8.1 (d, 1H, J=2.07 Hz).
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11](Cl)(=[O:15])[CH2:12][CH2:13][CH3:14].C([O:19]CC)C>N1C=CC=CC=1>[C:11]([O:15][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:3](=[O:4])[CH3:2])(=[O:19])[CH2:12][CH2:13][CH3:14]
Reactant: CCCC(=O)Cl
Reactant: O=C(CO)c1ccccc1
Reactant: CCOCC
Solvent: c1ccncc1
Product: CCCC(=O)Oc1ccccc1C(C)=O
Reaction time: 0.5 h

Procedure:
A mixture of 50 g (367 mmol) of 2-hydroxyacetophenone and 47 g (440 mmol) of butyryl chloride in 100 ml of pyridine is stirred for 30 minutes, then diluted with diethyl ether and washed successively with water and aqueous hydrochloric acid. The organic phase is then dried over sodium sulfate, concentrated under reduced pressure and coevaporated 3 times with toluene. By chromatography of the residue on a silica column using a 0-30% mixture of ethyl acetate in cyclohexane, 72 g of product are obtained in oil form.
Reaction SMILES: [NH2:1]C1C=NC2C(C=1NCC(C)(O)C)=CC=C(OCC1C=CC=CC=1)C=2.C(OCC(Cl)=O)C.C(OCC(Cl)=O)(=O)C.[CH2:41]([O:48][C:49]1[CH:50]=[CH:51][C:52]2[C:53]3[N:61]([CH2:62][C:63]([CH3:66])([OH:65])[CH3:64])[C:60]([CH2:67][O:68][CH2:69][CH3:70])=[N:59][C:54]=3[CH:55]=[N:56][C:57]=2[CH:58]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[NH2:1][C:55]1[C:54]2[N:59]=[C:60]([CH2:67][O:68][CH2:69][CH3:70])[N:61]([CH2:62][C:63]([CH3:64])([OH:65])[CH3:66])[C:53]=2[C:52]2[CH:51]=[CH:50][C:49]([O:48][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:58][C:57]=2[N:56]=1
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)O
Reactant: CC(C)(O)CNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Agent: CC(=O)OCC(=O)Cl
Agent: CCOCC(=O)Cl
Product: CCOCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)O

Procedure:
1-{[3-Amino-7-(benzyloxy)quinolin-4-yl]amino}-2-methylpropan-2-ol, prepared as described in Parts A and B of Example 54, was treated according to the general methods described in Parts C and D of Example 54 with ethoxyacetyl chloride used in lieu of acetoxyacetyl chloride in Part C. The product, (7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol, was treated according to the general methods of Parts F and G of Example 54 to provide (4-amino-7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as a white powder, mp 215.1-215.5° C.
Reaction SMILES: CN.C1COCC1.[CH2:8]([N:10](CC)CC)C.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21].O>ClCCl>[CH3:8][NH:10][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[C:17]([C:16]([F:27])([F:26])[F:15])[CH:18]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: CN
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A 2M methylamine-THF solution (20 ml) was added to a solution of triethylamine (7 ml) in dichloromethane (70 ml), a solution of 3-(trifluoromethyl)benzoyl chloride (5.0 g) in dichloromethane (30 ml) was added dropwise thereto under ice cooling, followed by stirring at room temperature for 72 hours. The reaction solution was poured into water, followed by extraction with chloroform. The organic layer was washed with saturated aqueous sodium bicarbonate solution and then saturated brine in this order and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The residue was dissolved again in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and then saturated brine in this order, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting solid was washed with diisopropylether, to obtain, as a colorless solid, N-methyl-3-(trifluoromethyl)benzamide (1.34 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]([CH3:14])[CH3:13])[C:10](=[O:15])[CH:9]([CH:16]([OH:20])[C:17]([OH:19])=[O:18])[O:8][CH:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:6]=2[CH:28]=1.O.[C:30]1(C)C=CC(S(O)(=O)=O)=C[CH:31]=1>C(O)C>[CH2:30]([O:18][C:17](=[O:19])[CH:16]([CH:9]1[O:8][CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[C:6]2[CH:28]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:11]([CH:12]([CH3:14])[CH3:13])[C:10]1=[O:15])[OH:20])[CH3:31]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)N1C(=O)C(C(O)C(=O)O)OC(c2ccccc2Cl)c2cc(Cl)ccc21
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(O)C1OC(c2ccccc2Cl)c2cc(Cl)ccc2N(C(C)C)C1=O
Yield: 665.8 %

Procedure:
A mixture of (3RS,5SR,αRS)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolic acid (0.15 g) obtained in Example 7, p-toluenesulfonic acid monohydrate (6 mg) and ethanol (20 ml) was heated for 10 hours under reflux. Ethanol was distilled off under reduced pressure. To the residue were added water (50 ml) and ethyl acetate (50 ml). The organic layer was washed with an aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure to leave (3RS,5SR,αRS)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolic acid ethyl ester (95 mg) as prisms, m.p. 126°-128° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[CH3:10].[C:11](Cl)(=[O:13])[CH3:12].[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([CH3:9])=[C:6]([CH3:8])[C:7]=1[C:11](=[O:13])[CH3:12]
Reactant: Cc1cc(C)c(Br)cc1C
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1c(C)c(C)cc(C)c1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.2 %

Procedure:
To a mixture of 1-bromo-2,4,5-trimethylbenzene (5.0 g, 25.0 mmol) and acetyl chloride (2.45 ml, 34.5 mmol) in dichloromethane (50 ml) was added aluminium chloride (4.42 g, 33.1 mmol) in dichloromethane (50 ml) and the reaction mixture was stirred at room temperature for 18 h. The mixture was poured into water and the two layers were separated. The organic phase was washed with saturated aqueous sodium hydrogen carbonate solution, dried (MgSO4) and filtered through silica. The filtrate was concentrated in vacuo to give the title compound (5.50 g).
Reaction SMILES: [CH3:1][N:2]([S:21]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)(=[O:23])=[O:22])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18](O)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.Cl.C[N:31](C)CCCN=C=NCC.CN(C)C=O>C(OCC)(=O)C.O>[CH3:1][N:2]([S:21]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)(=[O:23])=[O:22])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([NH2:31])=[O:19])[CH2:15][N:16]=1)=[CH:8]2
Reactant: CN(c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1nccs1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cccc2cc(C3=NCC(CC(N)=O)S3)[nH]c12)S(=O)(=O)c1nccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
A mixture of (2-{7-[methyl(1,3-thiazol-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (250 mg), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (114 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (144 mg) and N,N-dimethylformamide (10 mL) was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate (100 mL) and water (100 mL), and the organic layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained solid was washed with ethyl acetate to give the title compound (166 mg, yield 67%) as a white solid. melting point 216-218° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:36])[NH:10][CH2:11][C:12]([N:14]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]([C:25]([O:27]C)=[O:26])[CH2:16][CH:15]2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:13])=[CH:4][CH:3]=1.O.CO>[OH-].[K+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:36])[NH:10][CH2:11][C:12]([N:14]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]([C:25]([OH:27])=[O:26])[CH2:16][CH:15]2[C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])=[O:13])=[CH:6][CH:7]=1
Reactant: COC(=O)C1CC(C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc2ccc(Cl)cc2)C1c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)C1CC(C(=O)O)C(c2ccccc2)N1C(=O)CNC(=O)Nc1ccc(Cl)cc1
Yield: 68.5 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 3, but from 2.1 g of 2-tert-butyl 4-methyl (2RS,4RS,5SR)-1-{2-[3-(4-chlorophenyl)ureido]acetyl}-5-phenylpyrrolidine-2,4-dicarboxylate in a mixture of 4 cm3 of a normal aqueous potassium hydroxide solution, 20 cm3 of distilled water and 60 cm3 of methanol. After treatment, there are obtained 1.4 g of 2-tert-butyl hydrogen (2RS,4SR,5SR)-1-{2-[3-(4-chlorophenyl)ureido]acetyl}-5-phenylpyrrolidine-2,4-dicarboxylate, melting at 248° C.
Reaction SMILES: [K+].[C:2]([C@@H:4]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:5][C:6]([O-:8])=[O:7])#[N:3]>[Ni].O>[CH3:12][CH:10]([CH2:9][C@H:4]([CH2:2][NH2:3])[CH2:5][C:6]([OH:8])=[O:7])[CH3:11]
Reactant: CC(C)C[C@H](C#N)CC(=O)[O-]
Agent: [Ni]
Agent: [K+]
Solvent: O
Product: CC(C)C[C@H](CN)CC(=O)O
Temperature: 70 °C
Reaction time: 6 h

Procedure:
A hydrogenator (12000 L) is charged with water (942.1 L) and with the reaction mixture from Example 12, which contains (S)-3-cyano-5-methyl-hexanoic acid potassium salt (Formula 26, 4122.9 L). A Raney nickel suspension (219.6 kg, 50% w/w in H2O) is added. The hydrogenation is conducted under 50 psig at 35° C. After 6 h, the Raney nickel is filtered and the resulting filtrate is transferred to a reactor (16000 L) for crystallization. After adding H2O (1098 L), the pH of the solution is adjusted to 7.0-7.5 using HOAc (864.7 kg). The resulting precipitate is filtered and washed once with H2O (549 L) and twice with IPA (2,586 L each). The solid is recrystallized with IPA (12296 L) and H2O (6148 L). The mixture is heated to 70° C. and subsequently cooled to 4° C. After 5-10 h, the crystalline solid is filtered, washed with IPA (5724 L), and dried in a vacuum oven at 45° C. for 24 h to give pregabalin as a white crystalline solid (1431 kg, 30.0% overall yield, 99.5% purity and 99.75% ee).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=[S:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=[C:4]([Cl:16])[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O>[Cl:16][C:4]1[N:3]=[C:2]2[S:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:8][C:7]2=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(=S)Nc1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1nc2ccc(Cl)nc2s1
Temperature: 50 °C

Procedure:
A mixture of ethyl 2-(2,6-dichloropyridin-3-ylamino)-2-thioxoacetate (49.11 g, 175.9 mmol) and cesium carbonate (57.32 g, 175.9 mmol) in THF (350 mL) was heated at 50° C. for 6 h. The reaction suspension was then diluted with water (700 mL) and THF was removed in vacuo at 23° C. The resulting suspension was cooled to 0° C., and the precipitated solid was collected via vacuum filtration, washed with water, and dried in vacuo to provide ethyl 5-chlorothiazolo[5,4-b]pyridine-2-carboxylate as a yellow-orange solid. MS (ESI) m/z: Calculated: 242.0; Observed: 243.0 (M++1).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[C:26]1[CH3:37]>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:34]([C:27]3[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:25]([CH3:24])[C:26]=3[CH3:37])=[O:35])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1c(C(=O)O)c2ccccc2n1C
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3c(C)n(C)c4ccccc34)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 1,2-dimethyl-1H-indole-3-carboxylic acid. LC-MS (basic): tR=0.90 min; [M+H]+=503.2.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([NH2:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](=[S:35])[NH2:25])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(N)=O)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CCc1ccc(C2CC(C(N)=S)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
910 mg (2.63 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxamide (Example 139A) and 586 mg (1.45 mmol) of Lawesson reagent were reacted according to the General Method 10A. Yield: 849 mg (89% of theory).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[CH2:12]([O:15][C:16]1[C:23]([O:24][CH3:25])=[CH:22][C:19]([CH:20]=O)=[CH:18][C:17]=1[Br:26])[CH:13]=[CH2:14].[C:27](#[N:31])[CH2:28][C:29]#[N:30].N1CCCCC1>C(O)C.O>[CH2:12]([O:15][C:16]1[C:23]([O:24][CH3:25])=[CH:22][C:19]([CH:20]2[C:3]3[C:2](=[CH:1][C:10]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[CH:4]=3)[O:11][C:27]([NH2:31])=[C:28]2[C:29]#[N:30])=[CH:18][C:17]=1[Br:26])[CH:13]=[CH2:14]
Reactant: Oc1ccc2ccccc2c1
Reactant: C=CCOc1c(Br)cc(C=O)cc1OC
Reactant: N#CCC#N
Solvent: C1CCNCC1
Solvent: O
Solvent: CCO
Product: C=CCOc1c(Br)cc(C2C(C#N)=C(N)Oc3cc4ccccc4cc32)cc1OC
Temperature: 80 °C

Procedure:
2-Naphthol (170 mg, 1.2 mmol), 4-allyloxy-3-bromo-5-methoxy-benzaldehyde (271 mg, 1 mmol) and malononitrile (66 mg, 1 mmol) were taken in 7 ml ethanol at room temperature, charged with piperidine (50 μL) and then stirred at 80° C. under LC-MS control till the reaction was complete. The reaction mixture was cooled down to room temperature, diluted with 10 ml water, stirred for 2 h at room temperature, solids were collected by filtration, washed with 1:1 mixture of ethanol/water and dried (235 mg, 0.51 mmol, 51%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:10][CH:9]([N:11]([CH3:13])[CH3:12])[CH2:8][CH2:7][C:5]=2[N:6]=1.[C:14]([Cl:22])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[ClH:22].[ClH:22].[C:14]([NH:1][C:2]1[S:3][C:4]2[CH2:10][CH:9]([N:11]([CH3:13])[CH3:12])[CH2:8][CH2:7][C:5]=2[N:6]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(C)C1CCc2nc(N)sc2C1
Solvent: c1ccncc1
Product: CN(C)C1CCc2nc(NC(=O)c3ccccc3)sc2C1
Product: Cl
Reaction time: 8 h

Procedure:
3.0 g (15 mMol) of 2-amino-6-dimethylamino-4,5,6,7-tetrahydro-benzthiazole are dissolved in 15 ml of pyridine and 2.1 g (15 mMol) of benzoylchloride are added dropwise. After standing overnight the mixture is concentrated, mixed with soda solution and extracted with chloroform. The chloroform extract is concentrated and then chromatographed on silica gel (eluant: methylenechloride/methanol=9/1). The isolated base (melting point 174° C.) is dissolved in acetone and the dihydrochloride is precipitated with isopropanolic hydrochloric acid.