Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][C@H:6]([OH:8])[CH2:5][N:4]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>N1C=CC=CC=1>[C:9]([N:4]1[CH2:5][C@H:6]([O:8][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[CH2:7][C@H:3]1[CH2:2][O:1][S:25]([C:22]1[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=1)(=[O:27])=[O:26])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: O=C(OCc1ccccc1)N1C[C@@H](O)C[C@@H]1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](OS(=O)(=O)c3ccc(C)cc3)CN2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82 %

Procedure:
To an ice-cold solution of 150 g (596.9 mmol) of (2R,4S)-2-hydroxymethyl-4-hydroxy-N-(carbobenzyloxy)pyrrolidine in 0.5 1 of pyridine was added 250 g (1.32 mol) of 4-toluenesulfonyl chloride in 3 portions to keep the temperature of the reaction below 15° C. for 1 hour and then warmed to room temperature. After 12 hours, an additional 125 g (656 mmol) of p-toluenesulfonyl chloride was added and the mixture was allowed to stir at room temperature for 16 additional hours. The mixture was then cooled with an ice bath and 3 1 of 10% aqueous HC1 solution was carefully added. The mixture was extracted with 2 x 250 ml of methylene chloride and dried over MgSO4. Evaporation of the solvent provided 274 g of the product as an oil (82% yield). NMR(CDC13): 7.70 & 7.40 (m,9H, aromatic), 5.0 (m,3H), 4.43 (dd,1H), 4.12 (m,1H), 4.02 (m,H), 3.70 (m,1H), 3.88 (m,1H), 2.42 (m,6H), 2.15 (m,2H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12](OCC(F)(F)F)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:42])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH3:41])[CH:36]=2)[CH:30]=1)=O)(C)(C)C.[C:44](O)([C:46]([F:49])([F:48])[F:47])=[O:45]>C(Cl)Cl>[CH3:41][C:37]1[CH:36]=[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:42])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:23])([F:22])[F:21])[C:12]([O:45][CH2:44][C:46]([F:49])([F:48])[F:47])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)[CH:40]=[CH:39][N:38]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)ccn1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from [2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M105) (0.41 g, 0.67 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (260 mg, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28](O)=[O:29])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][NH:35][CH3:36].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.O.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([N:35]([CH2:34][CH2:33][N:32]([CH3:37])[CH3:31])[CH3:36])=[O:29])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CNCCN(C)C
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)nc4CCC3C2C2CCCC2)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCN(C)C(=O)c1ccc2c(n1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCCC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 38.7 %

Procedure:
In a dried reaction flask, the crude 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid (Compound 1) (0.4 g, about 0.9 mmol), N,N,N′-trimethylethylenediamine (0.52 mL, 4.0 mmol), DIEA (0.34 mL, 1.965 mmol) and HATU (0.712 g, 1.873 mmol) were added to a mixed solvent of DMF (4.5 mL) and dichloromethane (4.5 mL). The mixture was stirred at room temperature for 4 days. Water and dichloromethane were added. The mixture was extracted with dichloromethane. The combined organic phase was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to obtain a crude yellow solid, which was then purified by silica gel column chromatography (dichloromethane:ethyl acetate:methanol=10:10:1) and concentrated. The resulting concentrate was washed with n-hexane to obtain a purified product (0.176 g) in 38.7% yield.
Reaction SMILES: [NH3:1].CO.[Cl:4][C:5]1[CH:6]=[C:7]2[C:13]3([CH2:17][CH2:16][N:15]([C:18](=[O:24])[C:19]([O:21]CC)=O)[CH2:14]3)[CH2:12][N:11]([C:25](=[O:33])[NH:26][C:27]3[S:28][C:29]([Cl:32])=[CH:30][N:31]=3)[C:8]2=[CH:9][CH:10]=1>O1CCCC1>[NH2:1][C:19](=[O:21])[C:18]([N:15]1[CH2:16][CH2:17][C:13]2([C:7]3[C:8](=[CH:9][CH:10]=[C:5]([Cl:4])[CH:6]=3)[N:11]([C:25]([NH:26][C:27]3[S:28][C:29]([Cl:32])=[CH:30][N:31]=3)=[O:33])[CH2:12]2)[CH2:14]1)=[O:24]
Reactant: N
Reactant: CCOC(=O)C(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)C(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 62 %

Procedure:
A saturated solution of ammonia-methanol (0.5 mL) and tetrahydrofuran (0.5 mL) were added to the ethyl 2-(5-chloro-1-((5-chlorothiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidin]-1′-yl)-2-oxoacetate (50 mg, 0.106 mmol) obtained in Example 43, and the obtained mixture was then stirred at room temperature for 14 hours. Thereafter, the reaction solution was concentrated in vacuo, and the obtained residue was then washed with chloroform to obtain the captioned compound (29.0 mg, 62%) in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][CH2:16][CH2:17]Cl)[C:8]([S:19]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[N:7]1.[CH3:35][NH2:36].Cl.CCOCC>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][CH2:16][CH2:17][NH:36][CH3:35])[C:8]([S:19]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)(=[O:20])=[O:21])=[N:7]1
Reactant: CN
Reactant: O=S(=O)(c1cccc2ccccc12)c1nn(Cc2cccc(Cl)c2)c2c(OCCCl)cccc12
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CNCCOc1cccc2c(S(=O)(=O)c3cccc4ccccc34)nn(Cc3cccc(Cl)c3)c12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(3-chloro-benzyl)-7-(2-chloro-ethoxy)-3-(naphthalene-1-sulfonyl)-1-H-indazole (0.065 g, 0.12 mmoles) and methylamine (0.48 mmoles) in DMF (1 mL) was stirred under nitrogen at 100° C. overnight. Mixture was cooled to room temperature, diluted with water, extracted with EtOAc, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum. Compound was purified by flash chromatography using as eluent 5% CH3OH/EtOAc. The purified compound was dissolved in methanol, 1M HCl in ether (0.1 mL, 0.1 mmoles) was added, and compound was dried to afford the title compound as the HCl salt, MS: (ES+) 507 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](F)[C:5]([F:9])=[C:6]([F:8])[CH:7]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:3]=1
Reactant: Fc1cc(Br)cc(F)c1F
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Fc1cc(Br)cc(N2CCOCC2)c1F
Temperature: 90 °C
Yield: 76 %

Procedure:
A mixture of 5-bromo-1,2,3-trifluorobenzene (2.5 g, 11.8 mmol), morpholine (1.0 mL, 11.8 mmol), K2CO3 (1.6 g, 11.8 mmol) and DMSO (2 mL) in a sealed tube was heated up to 90° C. for 2.5 h. The reaction mixture was cooled to room temperature and diluted with water. The resulting colorless precipitate was filtered, washed with water, and dried in vacuo to afford 4-(5-bromo-2,3-difluorophenyl)morpholine in 76% yield. 1H NMR (CDCl3, 400 MHz) δ 6.91-6.87 (m, 1H), 6.75-6.72 (m, 1H), 3.80-3.78 (m, 4H), 3.04-3.02 (m, 4H).
Reaction SMILES: [CH:1]1([CH2:4]O)[CH2:3][CH2:2]1.[NH:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH:1]1([CH2:4][N:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:3][CH2:2]1
Reactant: OCC1CC1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN(CC1CC1)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 354.4 %

Procedure:
To a mixture of cyclopropylmethanol (7.15 ml, 90 mmol), di-tert-butyl hydrazine-1,2-dicarboxylate (6.30 g, 27.1 mmol) and triphenylphosphine (28.5 g, 109 mmol) in THF (100 mL) was added di-tert-butyl azodicarboxylate (25 g, 109 mmol) portion wise at ambient temperature. The mixture was stirred for 2 hours then concentrated. Solid triphenylphosphineoxide was removed by filtration. The filtrate was concentrated and the residue was purified by flash chromatography (silica gel, eluted with a gradient of 5-25% EtOAc in hexane) to provide 27.5 g (96%) of title compound. 1H NMR (300 MHz, CDCl3) δ ppm 0.15-0.26 (m, 2H), 0.42-0.54 (m, 2H), 0.91-1.09 (m, 1H), 1.47 (s, 9H), 1.48 (s, 9H), 3.31 (d, J=6.10 Hz, 2H), 6.38 (s, 1H).
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH:10](Cl)[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20].[I-].[Na+]>CC(C)=O>[C:19]([NH:23][CH:10]1[CH2:11][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=[CH:9]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: ClC1C=CC(c2ccccc2)(c2ccccc2)C1
Reactant: CC(C)(C)N
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)NC1C=CC(c2ccccc2)(c2ccccc2)C1

Procedure:
A mixture of 4,4-diphenyl-2-cyclopentenyl chloride (0.20 g), t-butylamine (2 ml) and a catalytic amount of sodium iodide in acetone (4 ml) was refluxed for 15 hours and cooled. The mixture was evaporated in vacuo and water was added thereto extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of chloroform and methanol as an eluent to give N-t-butyl-4,4-diphenyl-2-cyclopentenylamine (0.15 g).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[C:29]4[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=4[CH:23]=[CH:22][CH:21]=3)=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][C:4]([CH2:36][CH2:37][C:38](=[O:44])[N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)([CH2:30][CH2:31][C:32]([O:34]C)=[O:33])[CH2:3]1.[OH-].[Na+].O>CO>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[C:29]4[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=4[CH:23]=[CH:22][CH:21]=3)=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][C:4]([CH2:36][CH2:37][C:38](=[O:44])[N:39]2[CH2:40][CH2:41][CH2:42][CH2:43]2)([CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH2:3]1
Reactant: CCCc1c(OCCCOc2cccc3c2CCCC3)ccc2c1OC(CCC(=O)OC)(CCC(=O)N1CCCC1)CC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCc1c(OCCCOc2cccc3c2CCCC3)ccc2c1OC(CCC(=O)O)(CCC(=O)N1CCCC1)CC2=O
Reaction time: 1 h
Yield: 25.8 %

Procedure:
To a solution of 240 mg (0.40 mmol) of the title product of Example 51 in 4 ml of methanol was added 0.15 ml of a 50% aqueous solution of sodium hydroxide and 1 ml of water. The mixture was stirred for 1 hour at reflux and then permitted to cool. The cooled reaction mixture was partitioned between ethyl acetate and 3N hydrochloric acid, and the aqueous layer was further extracted with two portions of ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and the solvent removed under reduced pressure. Chromatography of the residue over silica gel, using methanol/ethyl acetate/acetic acid as eluent, gave a glass which was triturated with diethyl ether to give the title compound (61 mg) as a solid, m.p. 160°-164° C.
Reaction SMILES: [CH3:1][C@@H:2]1[C@:25]2([O:31][CH2:30][C@H:28]([CH3:29])[CH2:27][CH2:26]2)[O:24][C@H:4]2[CH:5]=[C:6]3[C@@:20]([CH3:21])([C@@H:3]12)[C:19](=[O:22])[CH2:18][C@H:17]1[C@H:7]3[CH2:8][CH2:9][C@@H:10]2[C@:15]1([CH3:16])[CH2:14][CH2:13][C:12](=[O:23])[CH2:11]2.[Br-:32].[NH+]1C=CC=CC=1.O>O1CCCC1>[Br:32][CH:13]1[CH2:14][C@@:15]2([CH3:16])[C@@H:10]([CH2:9][CH2:8][C@@H:7]3[C@@H:17]2[CH2:18][C:19](=[O:22])[C@@:20]2([CH3:21])[C:6]3=[CH:5][C@@H:4]3[O:24][C@@:25]4([O:31][CH2:30][C@H:28]([CH3:29])[CH2:27][CH2:26]4)[C@@H:2]([CH3:1])[C@@H:3]32)[CH2:11][C:12]1=[O:23]
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C=C3[C@@H]4CC[C@H]5CC(=O)CC[C@]5(C)[C@H]4CC(=O)[C@]3(C)[C@H]1[C@@H]2C
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C=C3[C@@H]4CC[C@H]5CC(=O)C(Br)C[C@]5(C)[C@H]4CC(=O)[C@]3(C)[C@H]1[C@@H]2C
Temperature: 25 °C

Procedure:
500 mg of (25R)-5a-spirost-14-ene-3,12-dione is dissolved in 15 ml of tetrahydrofuran and mixed with 453 mg (1.1 eq) of pyridinium bromide-perbromide, dissolved in 25 ml of tetrahydrofuran. After two and one half hours of stirring at room temperature, the reaction is arrested by adding 20 ml of water and the mixture is extracted with dichloromethane. The organic phase is washed with sodium chloride solution, dried on magnesium sulfate, the solvent is removed and the residue is chromatographed with petroleum ether/ethyl acetate (4:1) on silica gel. The combined fractions are concentrated by evaporation and stirred overnight in 10 ml of methanol. After filtration and evaporation of the solvent, there is obtained:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[CH:14]=[CH2:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CC#N>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[C:12]=3[CH:14]=[CH2:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C=Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: C1CNCCN1
Solvent: CC#N
Product: C=Cc1c(N2CCNCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 54.4 %

Procedure:
A mixture of 1-cyclopropyl-8-ethenyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.40 g, 1.44 mmol), piperazine (0.80 g, 7.8 mmol), and CH3CN (3 mL) was refluxed for 16 hours. Workup was identical to that described in Example 1 to provide 0.28 g (54%) of the desired product; mp 213°-218° dec.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[CH:9][S:8][CH:7]=1)=[O:5])[CH3:2].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([N+:12]([O-:14])=[O:13])[S:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cscc1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1csc([N+](=O)[O-])c1Br
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
4-Bromo-thiophene-3-carboxylic acid ethyl ester (97.6 g, 0.415 mol) was added over 10 min via pipette to 18.0 M sulfuric acid (660 mL) at 0° C. After stirring 5 min at 0° C., fuming nitric acid (18 mL) dissolved in 18.0 M sulfuric acid (130 mL) was added via addition funnel over 30 min. After the addition was completed, the reaction mixture was stirred for 5 min at 0° C., and then was poured onto ice (3.5 kg). The resulting precipitate was collected by filtration and was washed sequentially with water (300 mL), 10% aqueous sodium bicarbonate solution (400 mL) and water (300 mL). The brown/yellow solid thus obtained was dried in a vacuum oven overnight at 40° C. to afford the crude product, 4-bromo-5-nitro-thiophene-3-carboxylic acid ethyl ester (97.9 g, 0.350 mol, 84%). This material was further purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 25% hexanes in dichloromethane) in 20 g portions prior to use in the next step (recovery=80-90%). 1H NMR (400 MHz, DMSO-d6) δ: 1.31 (3H, t, J=7.0 Hz), 4.30 (4H, q, J=7.0 Hz), 8.68 (1H, s).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][NH:6][NH2:7].C([O:13][C:14](=O)[CH:15]=[C:16]([NH2:20])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:20][C:16]1[NH:7][N:6]([CH2:5][C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=2)[C:14](=[O:13])[CH:15]=1
Reactant: NNCc1cccc(I)c1
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2cccc(I)c2)[nH]1
Reaction time: 8 h

Procedure:
A solution of 45 g of m-iodobenzylhydrazine in 70 ml of ethanol was added dropwise to a solution of 28.6 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1.5 g of p-toluenesulphonic acid in 350 ml of ethanol. After stirring overnight, the compound identified above had separated out as a precipitate and was filtered off and recrystallised from ethanol. Melting point: 186°, 16 g (28%).
Reaction SMILES: C(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:15][C:16]([O:18][C:19]([Cl:22])(Cl)Cl)=[O:17]>>[Cl:15][C:16]([O:18][CH:19]([Cl:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:17]
Reactant: O=Cc1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Cl)OC(Cl)c1ccccc1
Reaction time: 2 h

Procedure:
7.5 g (0.07 mole) benzaldehyde and 0.3 g (0.004 mole) pyridine are introduced in an apparatus similar to that of example 1. The mixture is brought to 45° C. and 8.5 g (0.043 mole) trichloromethyl chloroformate added drop by drop over 10 minutes. After 2 hours of stirring at 45° it is confirmed by NMR analysis that all the aldehyde has been converted to the α-chlorinated chloroformate with formula: ##STR7##
Reaction SMILES: C[O-].[Mg+2:3].C[O-].[CH3:6][C:7]1[CH:8]=[N:9][C:10]([CH2:16][S+:17]([O-:29])[C:18]2[NH:19][C:20]3[CH:21]=[CH:22][C:23]([O:27][CH3:28])=[CH:24][C:25]=3[N:26]=2)=[C:11]([CH3:15])[C:12]=1[O:13][CH3:14]>CO>[CH3:6][C:7]1[C:12]([O:13][CH3:14])=[C:11]([CH3:15])[C:10]([CH2:16][S@@:17]([C:18]2[N-:19][C:20]3[CH:21]=[CH:22][C:23]([O:27][CH3:28])=[CH:24][C:25]=3[N:26]=2)=[O:29])=[N:9][CH:8]=1.[Mg+2:3]
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: COc1ccc2[n-]c([S@@](=O)Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stoichiometric amount of 7.6 wt.-% methanolic solution of magnesium methanolate (18.1 mL) was added to the solution of 9.0 g of esomeprazole (99.28% e.e.) in 100 mL of methanol. The obtained reaction mixture was stirred at room temperature for 1 hour allowing to form esomeprazole magnesium salt in the meantime. After addition of 0.4 mL of water the reaction mixture was further stirred for 30 min. The formed inorganic solid salts were separated from the liquid by filtration through a layer of diatomite filter medium (Celite®). The volume of filtrate was then reduced by evaporation of methanol forming an esomeprazole magnesium solution with concentration 40-45 wt.-%. A mixture of 51 mL of acetone and 2.9 mL of water was added to the concentrate. The mixture was seeded with a 0.05 g of esomeprazole magnesium dihydrate form B. After a few minutes a precipitate was formed and the suspension was stirred for 4 hours. The product was filtered off, washed twice with 10 mL of a mixture of acetone and methanol (4/1(V/V)). The wet filter cake was dried for 20 hours at reduced pressure (200 mbar). 8.00 g of esomeprazole magnesium dihydrate form B was obtained (99.84% e.e. determined by chiral HPLC, 100% purity determined by HPLC, 6.1% of water content determined by Karl-Fisher, 1.98% of residual solvents content (methanol, acetone) as determined by GC).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([O:11]CC)=[O:10])=[CH:5][N:4]=1.[Li+].[OH-]>O1CCOCC1>[CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([OH:11])=[O:10])=[CH:5][N:4]=1
Reactant: CCOC(=O)c1cnc(SC)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CSc1ncc(C(=O)O)cn1
Reaction time: 8 h

Procedure:
1 Eq. of 2-methylthio-5-ethoxycarbonylpyrimidine were dissolved in dioxane and, after addition of 2 eq. of 2N LiOH, stirred overnight. The solvent was then removed under reduced pressure, and the residue was dissolved in EtOH. After addition of a stoichiometric amount of ethereal HCl, the solution was again evaporated to dryness. Water which was still present was removed by azeotropic drying with toluene once.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]([CH:19]=O)=[C:17]([CH:21]([CH3:23])[CH3:22])[CH:16]=[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:14]=2)=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCl.C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:19][C:18]1[C:13]([C:10]2[CH:9]=[CH:8][C:7]([F:6])=[CH:12][CH:11]=2)=[N:14][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:16][C:17]=1[CH:21]([CH3:23])[CH3:22]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)c1cc(-c2ccccc2)nc(-c2ccc(F)cc2)c1C=O
Agent: ClCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)c1cc(-c2ccccc2)nc(-c2ccc(F)cc2)c1C=C(Br)Br
Reaction time: 0.33 h
Yield: 98681 %

Procedure:
A solution of carbon tetrabromide (2.866 gm, 8.64 mmol) in CH2 Cl2 (8 ml) was added over a 10 minute period to a cold (-10° C.) solution of 2-(4-Fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinecarboxaldehyde (1.840 gm, 5.76 mmol) (the preparation of which is described in Example 3) and triphenylphosphine (4.590 gm, 17.5 mmol) in CH2Cl2 (30 ml). After the addition was complete, the cooling bath was removed and the mixture was stirred for 20 minutes. The solution was quenched with saturated NaHCO3 and extracted 2× with CH2Cl2. The combined organic layers were washed with saturated NaHCO3, dried (Na2SO4), filtered and concentrated. The concentrate was chromatographed (flash, Merck, SiO2, 1:1 CH2Cl2 : hexane) to give 3-(2,2-Dibromoethenyl)-2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenylpyridine as a white solid (2,701 gm, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13](OCC)=[O:14])=[C:11]([C:18]([F:21])([F:20])[F:19])[S:10][N:9]=2)=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[C:11]([C:18]([F:20])([F:19])[F:21])[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)nsc1C(F)(F)F
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: OCc1c(-c2ccc(Cl)cc2)nsc1C(F)(F)F
Temperature: -78 °C

Procedure:
Into a 50-mL round-bottom flask (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 3-(4-chlorophenyl)-5-(trifluoromethyl)-1,2-thiazole-4-carboxylate (1.0 g, 2.98 mmol, 1.00 equiv), toluene (5.0 mL). This was followed by the addition of DIBAL-H (20% in toluene) (4.23 g, 29.79 mmol, 2.00 equiv) dropwise with stirring at −78° C. The resulting solution was warmed to room temperature and stirred for 1 h at 30° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of 10 mL of water and 10 mL NH4Cl. The resulting solution was extracted with 3×20 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 0.72 g (82%) of [3-(4-chlorophenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methanol as a yellow solid. Mass spectrum (ESI, m/z): Calcd. for C11H7ClF3NOS, 294.0 (M+H). found 294.0.