Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH2:39][CH:38]([NH2:42])[CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH2:39][CH:38]([NH:42][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:14][C:15]4[S:16][C:17]5[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=5[N:19]=4)=[N:4][C:5]=3[CH:10]=2)=[O:12])[CH2:37]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NC3CCCN(C(=O)OC(C)(C)C)C3)ccc21
Yield: 74.2 %

Procedure:
3-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (44 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (41 mg), 3-amino-piperidine-1-carboxylic acid tert-butyl ester (67 mg), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 592. 1H NMR (DMSO-d6, 400 MHz): δ 8.22 (m, 1H), 8.06 (s, 1H), 7.87 (s, 1H), 7.73 (br, 1H), 7.53 (br, 1H), 7.43 (d, 1H), 7.32 (d, 1H), 3.82 (br, 1H), 3.65 (s, 3H), 3.20 (m, 2H), 2.80 (m, 2H), 1.81 (m, 1H), and 1.39 (s, 9H) and 1.03 (d, 4H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][C:21]1[N:22]=[C:23](/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[O:24][CH:25]=1>>[F:37][C:34]([F:35])([F:36])[C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:16][C:13]3[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[N:2]4)=[CH:15][CH:14]=3)[N:22]=2)=[CH:29][CH:30]=1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: FC(F)(F)c1ccc(/C=C/c2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Product: FC(F)(F)c1ccc(/C=C/c2nc(COc3ccc(CCCCn4ccnn4)cc3)co2)cc1
Yield: 88.5 %

Procedure:
Using 4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenol (152 mg), 65% oily sodium hydride (28 mg) and 4-(chloromethyl)-2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl}-1,3-oxazole (212 mg), the same reaction as Example 2 was carried out to yield the titled compound (290 mg).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)[C:4]([SH:7])=[N:5][N:6]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](=[O:41])(=[O:40])[NH2:39])=[CH:34][C:33]=1[Cl:42])=[O:30]>CN(C=O)C>[NH2:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)[C:4]([S:7][CH2:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([S:38](=[O:41])(=[O:40])[NH2:39])=[CH:34][C:33]=2[Cl:42])=[O:30])=[N:5][N:6]=1
Reactant: Nc1nnc(S)n1-c1ccc(C2CC2)c2ccccc12
Reactant: NS(=O)(=O)c1ccc(NC(=O)CCl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nnc(SCC(=O)Nc2ccc(S(N)(=O)=O)cc2Cl)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
In a solution of 5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-[1,2,4]triazole-3-thiol (708 mg, 2.5 mmol), K2CO3 (380 mg, 2.5 mmol) in DMF (20 mL) was added 2-chloro-N-(2-chloro-4sulfamoylphenyl)acetamide (710 mg, 2.5 mmol). The reaction mixture was stirred at room temperature overnight. Upon completion of the reaction, the solvent was evaporated. The residue was purified by silica gel chromatography to yield 2-[5-Amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(2-chloro-4-sulfamoylphenyl)acetamide (1.26 g, 95%). 2-[5-Bromo-4-(4-cyclopropylnaphthalen-1-yl]-4H-[1,2,4]triazol-3-ylsulfannyl]-N-(2-chloro-4-sulfamoylphenyl)acetamide
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[C:6]([CH3:13])=[N:5]1)[CH3:3].C([Li])CCC.[I:19]I>O1CCCC1.CCCCC>[I:19][C:8]1[N:4]([CH:2]([CH3:1])[CH3:3])[N:5]=[C:6]([CH3:13])[C:7]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: II
Reactant: COC(=O)c1cn(C(C)C)nc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: COC(=O)c1c(C)nn(C(C)C)c1I
Temperature: -45 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of methyl 1-(1-methylethyl)-3-methyl-1H-pyrazole-4-carboxylate (2.00 g, 11.0 mmol) in dry tetrahydrofuran (22.0 mL) at −78° C., 2 M solution of butyllithium (6.04 mL, 12.1 mmol) in pentane was added dropwise. The reaction mixture was then warmed to −45° C. and stirred for 1 h. It was then cooled to −78° C. and a solution of iodine (3.06 g, 12.1 mmol) in THF (11.0 mL) was added. The reaction mixture was warmed to RT and stirred for 1 h. Then it was quenched with saturated NH4Cl solution and extracted with ethyl acetate (2×25 mL). The organic layers were combined, washed with brine and dried (MgSO4). Evaporation of solvent gave a tan solid as title compound (3.38 g, 11.0 mmol, 100% crude yield). MS m/z 309 (MH+); 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.41 (d, 6H) 2.47 (s, 3H) 3.82 (s, 3H) 4.77 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:54]([NH:57][C:58]1[S:59][C:60]([S:63](Cl)(=[O:65])=[O:64])=[CH:61][N:62]=1)(=[O:56])[CH3:55]>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:63]([C:60]1[S:59][C:58]([NH:57][C:54](=[O:56])[CH3:55])=[N:62][CH:61]=1)(=[O:64])=[O:65])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: CC(=O)Nc1ncc(S(=O)(=O)Cl)s1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1cnc(NC(C)=O)s1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (48 mg) was treated with 2-acetylamino-thiazole-5-sulfonyl chloride according to General Procedure E to give (S)-2-({(S)-7-(2-Acetylamino-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=O)[CH3:26])=[CH:21][C:20]=4[O:28][CH3:29])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl.[NH2:33][OH:34].C([O-])(=O)C.[NH4+].C(O)C.O>O>[F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[N:33][OH:34])[CH3:26])=[CH:21][C:20]=4[O:28][CH3:29])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NO
Reactant: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(C(C)=NO)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-piperidinyl]propoxy]-3-methoxyphenyl]ethanone (4.3 g, 10 mmol), prepared as in Example 3 above, hydroxylamine hydrochloride (1.3 g, 18 mmol), ammonium acetate (1.7 g, 22 mmol) and ethanol-H2O was stirred and refluxed for 16 hours. The reaction was poured into water, and the mixture was cooled in an ice bath for 2 hours. The resultant, white solid was collected washed with water, and dried to yield 4,6 g or hydrochloride salt of the oxime, m.p.=216°-218° C. The compound was dispersed in water, and ammonium hydroxide was added until the suspension was decidedly basic. The basic suspension was then extracted with dichloromethane, and after washing with water, drying (MgSO4) and concentrating the extract, 3.0 g of white solid melting at 168°-170° C. were harvested. The compound, was recrystallized from dimethylformamide to yield 2.3 g (52%) of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone oxime as a white solid, m.p.=168°-170° C. ANALYSIS: Calculated for C24H28FN3O4: 65.29%C 6.39%H 9.52%N Found: 65.27%C 6.44%H 9.46%N
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[CH:11]=[C:12]([C:16]2[O:17][C:18]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:19]=3[CH:20]=2)[CH:13]=[CH:14][CH:15]=1>O.Cl>[OH:9][C:10]1[CH:11]=[C:12]([C:16]2[O:17][C:18]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:19]=3[CH:20]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: COc1cccc(-c2cc3cc(C#N)ccc3o2)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1ccc2oc(-c3cccc(O)c3)cc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69 %

Procedure:
To a melted pyridine hydrochloride (15.0 g) at 160-180° C. was added 2-(3-methoxyphenyl)benzofuran-5-carbonitrile (120) in one portion and the stirring continued at 180° C. for 2.5 h. The mixture was cooled down, diluted with water (100 mL) and 1 M HCl (50 mL) and stirred at room temperature for 30 min. A precipitate formed was separated, washed with 1 M HCl (150 mL) and water (150 mL) and dried. The residue was purified by flash chromatography (silica gel, EtOAc/hexanes 1/3) followed by recrystallization to give 125 as white solid (1.50 g, 69%): mp 222-224° C. (EtOAc/hexanes). 1H NMR (DMSO-d6) δ9.78 (d, J=1.1 Hz, 1H), 8.21 (br s, 1H), 7.85 (d, J=8.2 Hz, 1H), 7.75 (ddd, J=8.2, 1.6, 1.1 Hz, 1H), 7.48 (s, 1H), 7.40 (dd, J=8.2, 1.1 Hz, 1H), 7.33 (dd, J=8.2, 7.7 Hz, 1H), 6.86 (ddd, J=8.2, 2.2, 1.1 Hz, 1H). HPLC (method B) tR 5.70 min (100.0 area %). Anal. (C15H9NO2) C, H, N.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([C:18](=O)[CH2:19]Br)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:22][CH3:23])[CH:7]=1)=[O:5])[CH3:2].[C:24]([N:27]([CH2:29][C:30]([NH2:32])=[S:31])[CH3:28])(=[O:26])[CH3:25]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([C:18]3[N:32]=[C:30]([CH2:29][N:27]([C:24](=[O:26])[CH3:25])[CH3:28])[S:31][CH:19]=3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:22][CH3:23])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(=O)N(C)CC(N)=S
Reactant: CCOC(=O)c1cn(CC)c2cc(C(=O)CBr)c(F)cc2c1=O
Solvent: CCO
Product: CCOC(=O)c1cn(CC)c2cc(-c3csc(CN(C)C(C)=O)n3)c(F)cc2c1=O

Procedure:
According to example 30, reacting 7-bromoacetyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid ethyl ester with 2-(N-acetyl-N-methylamino)thioacetamide in ethanol gave 1-ethyl-6-fluoro-7-[2-(N-acetyl-N-methylaminomethyl)-4-thiazolyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester, mp 173°-175° C. which was then hydrolyzed in refluxing 6N hydrochloric acid to give the title compound, mp 230°-234° C. (dec).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C1COCC1>[N:24]1([CH2:23][CH2:22][CH2:21][NH:20][C:17](=[O:19])[C@@H:9]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: NCCCN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)NCCCN1CCOCC1
Yield: 91.1 %

Procedure:
To a solution in 15 ml of anhydrous THF of tert-butyloxycarbonyl-D-phenylalanine N-hydroxysuccinimmidyl ester (500 mg, 1.38 mmol), N-(3-aminopropyl)-morpholine (1.328 mmol, 0.201 ml) is added. The stirring is maintained for 90 min. The solvent is then evaporated, and the residue dissolved with AcOEt (50 ml); the organic phase is washed with NaHCO3 1M (3×50 ml), HCl 1M (3×50 ml), saturated aqueous solution of sodium chloride (3×50 ml). The solution dried on anhydrous Na2SO4. Following the evaporation of the solvent, 474 mg of (ter-butyloxycarbonyl-D-phenylalanine-N-[3(morpholin-4-yl)propyl]amide) (1.21 mmol, yield=88%) are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:7](Br)=[CH:8][N:9]=1)[C:5]#[N:6].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.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>[NH2:1][C:2]1[CH:3]=[C:4]([C:7]([C:15]2[CH:14]=[CH:13][C:12]([Cl:11])=[CH:17][C:16]=2[Cl:18])=[CH:8][N:9]=1)[C:5]#[N:6]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: N#Cc1cc(N)ncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: N#Cc1cc(N)ncc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 64.7 %

Procedure:
A mixture of 2-amino-5-bromo-isonicotinonitrile (1.0 g, 5.1 mmol, prepared according to Example 3, Step 2.1), 2,4-dichloro-benzeneboronic acid (1.45 g, 7.6 mmol), Pd(PPh3)4 (292 mg, 0.25 mmol) and Na2CO3 (2.0 M solution in water, 8.8 mL) in DME (10 mL) was refluxed for 2 h under an inert atmosphere of argon. The reaction mixture was cooled to RT, diluted in AcOEt and washed with water. The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→3:7) to yield the title compound (880 mg, 3.3 mmol, 66%). MS: 264 [M+1]+; HPLC: AtRet=1.73; TLC: RF 0.31 (hexane/DCM/TBME 1:1:2).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:7][C:6](=[O:12])[CH:5]=[CH:4][C:3]1=2.[H-].[Li+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CN(C)C=O>[CH2:16]([N:7]1[C:8]2[CH2:9][CH2:10][CH2:11][C:2](=[O:1])[C:3]=2[CH:4]=[CH:5][C:6]1=[O:12])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCBr
Reactant: O=C1CCCc2[nH]c(=O)ccc21
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCCCCn1c2c(ccc1=O)C(=O)CCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 5,6,7,8-tetrahydro-5-oxo-2(1H)-quinolinone (10.0 g), lithium hydride (0.78 g), and dimethylformamide (400 ml) was stirred for 3 hrs at 25° C., under nitrogen. 1-Bromohexane (10.6 g) was added and the mxture was stirred for an additional eighteen hrs. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The layers were separted and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by high performance liquid chromatography (silica gel, two columns, eluted with 50% ethyl acetate/hexane). The appropriate fractions were collected and evaporated to give 4.6 (31%) of 1-hexyl-5,6,7,8-tetrahydro-5-oxo-2(1H)-quinolinone.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]3[O:19][CH2:20][C:21]4[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=4[CH:23](O)[C:17]=3[CH:16]=1)[CH:7]=[CH:6]2)[CH3:2].[SH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35]>>[C:34]([CH2:33][CH2:32][S:31][CH:23]1[C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[CH2:20][O:19][C:18]2[CH:29]=[CH:30][C:15]([O:14][CH2:13][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][CH:12]=[C:3]([CH2:1][CH3:2])[CH:4]=4)[N:9]=3)=[CH:16][C:17]1=2)([OH:36])=[O:35]
Reactant: CCc1ccc2nc(COc3ccc4c(c3)C(O)c3ccccc3CO4)ccc2c1
Reactant: O=C(O)CCS
Product: CCc1ccc2nc(COc3ccc4c(c3)C(SCCC(=O)O)c3ccccc3CO4)ccc2c1

Procedure:
2-(6-Ethylquinolin-2-yl)methoxy-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: CC[O-].[Na+].[CH3:5][C:6]1[S:10][CH:9]=[C:8]([CH:11]=O)[CH:7]=1.[C:13]([O:22]CC)(=[O:21])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:19]([O:18][C:16]([C:15](=[CH:11][C:8]1[CH:7]=[C:6]([CH3:5])[S:10][CH:9]=1)[CH2:14][C:13]([OH:22])=[O:21])=[O:17])[CH3:20]
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: Cc1cc(C=O)cs1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=Cc1csc(C)c1)CC(=O)O
Yield: 60 %

Procedure:
Sodium ethylate (17 g, 0.24 mol) was added under vigorous stirring to a solution of 5-methylthiophene-3-carbaldehyde (26 g 90% purity, 0.20 mol) and diethyl succinate (54 g, 0.31 mol) in ethanol (400 mL). The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 50° C. until the solvent distillation ceased. The obtained residue was diluted with 300 mL of 10% HCl and 500 mL of ethyl acetate. The mixture was shaken. The organic layer was separated, diluted with 700 mL of a saturated aqueous solution of NaHCO3, and shaken. The aqueous layer was separated, neutralized by 10% HCl to pH 2, and subjected to extraction by 1 L of ethyl acetate. The organic layer was evaporated in vacuum (˜20 mmHg) at 60° C. The residue was chromatographed on a layer of silica gel (200×150 mm) with hexane/ethyl acetate mixture (1:1). Fractions with the target product were collected and evaporated in vacuum to give the desired product 30 g (0.12 mol, 57%) as an oil.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:9][NH:8]C(=O)[C@H:6]1[C:11]([OH:13])=[O:12])[CH:2]([CH3:4])[CH3:3].Cl.O>CC(O)=O>[CH3:4][CH:2]([CH2:1][C@H:5]([CH2:9][NH2:8])[CH2:6][C:11]([OH:13])=[O:12])[CH3:3]
Reactant: CC(C)CC1CNC(=O)[C@H]1C(=O)O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)C[C@H](CN)CC(=O)O
Temperature: 110 °C
Yield: 80 %

Procedure:
A reactor vessel (60 L) was charged with (S)-4-isobutyl-2-oxo-pyrrolidine-3-carboxylic acid (Formula 10), HCl (36-38%, 30 L), and water (29 L). HOAc (1 L) was added to the solution and the resulting slurry was heated for 36-38 h at 80° C. and for an additional 6 h at 110° C. The extent of reaction was monitored by HPLC (C18 column, 4.6 mm×150 mm, detection at 200 nm). Water and excess HCl were evaporated to afford an oil, which was washed with MTBE (2×15 L). Water was added to the oil and the mixture was stirred until the solution cleared. The pH of the solution was adjusted to 5.2-5.5 using KOH (about 6 kg), which resulted in the precipitation of pregabalin. The mixture was heated to 80° C. and subsequently cooled to 4° C. After 10 h, crystalline pregabalin was filtered and washed with IPA (12 L). The filtrate was concentrated under vacuum to afford a residual oil. Water (7.5 L) and EtOH (5.0 L) were added to the residual oil and the resulting mixture was heated to 80° C. and then cooled to 4° C. After 10 h, a second crop of pregabalin crystals were filtered and washed with IPA (1 L). The combined pregabalin crystals were dried in a vacuum oven at 45° C. for 24 h. MS m/z [M+H]+160.1340. 1H NMR (300 MHz, D2O): δ 2.97 (dd, J=5.4, 12.9 Hz, 1H), 2.89 (dd, J=6.6, 12.9 Hz, 1H), 2.05-2.34 (m, 2H), 1.50-1.70 (sept, J=6.9 Hz, 1H), 1.17 (t, J=7.0 Hz, 2H), 0.85 (dd, J=2.2, 6.6 Hz, 6H). 13C NMR (75 ppm, D2O) δ 181.54, 44.32, 41.28, 32.20, 24.94, 22.55, 22.09. Yield 80-85%; ee>99.5%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.CS(C)=O.[BH4-].[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N+:10]([O-:12])=[O:11])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=[N+]([O-])CCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
To a solution of 1-bromo-4-((E)-2-nitro-vinyl)-benzene (1 g, 4.37 mmol) described in Manufacturing Example 207-1-1 in acetic acid (0.6 mL) and dimethyl sulfoxide (10 mL) was added sodium borohydride (265 mg, 6.99 mmol), which was stirred for 30 minutes at room temperature. The mixture was cooled with ice water and partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (948 mg). The title compound was used in the following reaction without any further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>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.C1(C)C=CC=CC=1>[C:12]1([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(-c2ccccc2)c1
Yield: 9853.7 %

Procedure:
Using Preparation Method 2, Methyl 3-bromobenzoate (3.86 g, 18.6 mmol) was reacted with phenyl boronic acid (2.4 g, 20.5 mmol) in the presence of 5 mol % Pd(PPh3)4, 18 mL of 2N Na2CO3, 9.4 mL of Ethanol and 37 mL of toluene. The resulting reaction mixture was purified using SiO2 with hexane/diethyl ether 98:2 to give a colourless thick oil (389 g, 96%). NMR 1H (ppm, CDCl3): 8.29 (s, 1H), 8.03 (d, J3=7.8 Hz, 1H), 7.79 (d, J3=7.8 Hz, 1H), 7.63 (d, J3=7.2 Hz, 2H), 7.54-7.26 (m, 4H), 3.96 (s, 3H). MS: M+1 463.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[C:10](Cl)(=[O:12])[CH3:11].O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[N:3]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CC(=O)Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1nc(Cl)cc(Cl)n1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
A solution of 4,6-dichloro-pyrimidin-2-ylamine (5 g, 30 mmol) and acetyl chloride (4.7 g, 60 mmol) in acetic acid (200 mL) was stirred at 80° C. under nitrogen overnight. The solution was cooled to RT and water (150 mL) was added. The mixture was extracted with ethyl acetate (3×150 mL), and the combined organics were washed with brine, dried over sodium sulfate and concentrated to give N-(4,6-dichloro-pyrimidin-2-yl)-acetamide (5.0 g, 79% yield).