Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11].CC(C)([O-])C.[K+].Br[CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].Cl>C1COCC1>[CH3:13][O:12][C:10](=[O:11])[CH:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:14])([F:15])[F:1])[CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]
Reactant: COC(=O)Cc1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CCBr
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(CCC(=O)OC(C)(C)C)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl 2-trifluoromethylphenylacetate (5 g) was dissolved in THF (75 mL). Potassium tert-butoxide (2.71 g) was added under ice-cooling, and the reaction solution was stirred for 30 minutes. tert-Butyl 3-bromopropionate (3.83 mL) was added to the reaction solution. The reaction solution was gradually heated until room temperature and stirred for four hours. A 1 N hydrochloric acid aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (carrier: Chromatorex Si; elution solvent: heptane:ethyl acetate=19:1→heptane:ethyl acetate=1:1) to obtain the title compound (6 g). The property values of the compound are as follows.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][CH2:11][C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:53][CH2:54][C:55]([CH3:58])([OH:57])[CH3:56]>CN(C=O)C>[OH:57][C:55]([CH3:58])([CH3:56])[CH2:54][NH:53][C:18]([C:14]1[S:13][C:12]([CH2:11][CH2:10][C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:21])=[N:16][C:15]=1[CH3:17])=[O:20]
Reactant: CC(C)(O)CN
Reactant: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)O)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)NCC(C)(C)O)s1
Reaction time: 15 h
Yield: 55.7 %

Procedure:
To a solution of 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-ethyl]-4-methyl-thiazole-5-carboxylic acid (80 mg, 0.26 mmol) in DMF (4 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (92 mg, 0.29 mmol), N,N-diisopropyl ethyl amine (168 mg, 1.3 mmol) and 1-amino-2-methyl-propan-2-ol (25 mg, 0.29 mmol). The resulting reaction mixture was stirred for 15 h and then evaporated. Purification by chromatography (silica, 0 to 10% methanol in dichloromethane) afforded the title compound (55 mg, 56%) as a colourless oil MS: m/e=380.4 [M+H]+.
Reaction SMILES: C(#N)C.N1C=CC=CC=1.F.[O:11]([C@H:19]1[C@H:33](/[CH:34]=[CH:35]/[C@@H:36]([O:44][Si](C(C)(C)C)(C)C)[CH2:37][C@H:38]([CH3:43])[CH2:39][CH2:40][CH2:41][CH3:42])[C:22]([S:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:21][CH2:20]1)[Si](C(C)(C)C)(C)C>N1C=CC=CC=1>[OH:11][C@H:19]1[C@H:33](/[CH:34]=[CH:35]/[C@@H:36]([OH:44])[CH2:37][C@H:38]([CH3:43])[CH2:39][CH2:40][CH2:41][CH3:42])[C:22]([S:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:21][CH2:20]1
Reactant: CCCC[C@@H](C)C[C@@H](/C=C/[C@@H]1C(SCCCCCC(=O)OC)=CC[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCC[C@@H](C)C[C@H](O)/C=C/[C@@H]1C(SCCCCCC(=O)OC)=CC[C@H]1O
Reaction time: 15 h
Yield: 86.4 %

Procedure:
To a solution of ice-cooled acetonitrile (1.5 mL) and pyridine (0.15 mL) was added hydrogen fluoride-pyridine (0.15 mL). To this solution was added methyl (11R,12S,13E,15S,17R)-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate (150 mg, 0.238 mmol) in pyridine (0.15 mL). The ice bath was removed and the solution was agitated for 15 hours, while returning it to room temperature. The reaction solution was poured into a mixture of ethyl acetate and saturated aqueous sodium hydrogencarbonate. The desired product was extracted from this mixed solution with ethyl acetate. The extract was washed with brine, then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, then was purified by silica gel column chromatography (40 to 50% ethyl acetate/hexane) to obtain methyl (11R,12S,13E,15S,17R)-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate (82 mg, 86%).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:14][CH2:13][CH:12](OS(C)(=O)=O)[CH2:11][CH2:10]2)[S:7][CH:8]=1)(=[O:3])[NH2:2].[C:20]([O-:23])(=[S:22])[CH3:21].[K+]>CN(C)C=O>[C:20]([S:22][CH:12]1[CH2:11][CH2:10][N:9]([C:6]2[S:7][CH:8]=[C:4]([C:1](=[O:3])[NH2:2])[N:5]=2)[CH2:14][CH2:13]1)(=[O:23])[CH3:21]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)OC1CCN(c2nc(C(N)=O)cs2)CC1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CCN(c2nc(C(N)=O)cs2)CC1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 67.9 %

Procedure:
To a solution of 1-(4-carbamoyl-1,3-thiazol-2-yl)-4-methanesulfonyloxypiperidine (1.59 g, 5.21 mmol) (obtained as described in Reference Example 15(3)) in dimethylformamide (80 ml) was added potassium thioacetate (1.19 g, 10.4 mmol) at room temperature, and the reaction mixture was stirred in an oil bath (90° C.) for 2.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:n-hexane (10:1) as the eluant to afford 4-acetylthio-1-(4-carbamoyl-1,3-thiazol-2-yl)piperidine (1.01 g, yield 68%) as a brown solid.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH:4]([CH3:6])[CH3:5].CC(C)([O-])C.[K+].[F:32][C:33]1[CH:34]=[C:35]([N:40]2[C:45](=[O:46])[C:44]([CH2:47][CH2:48][CH:49]=O)=[C:43]([C:51]3[CH:56]=[CH:55][C:54]([S:57]([CH3:60])(=[O:59])=[O:58])=[CH:53][CH:52]=3)[CH:42]=[N:41]2)[CH:36]=[CH:37][C:38]=1[F:39]>C1(C)C=CC=CC=1>[F:32][C:33]1[CH:34]=[C:35]([N:40]2[C:45](=[O:46])[C:44]([CH2:47][CH2:48][CH:49]=[CH:2][CH2:3][CH:4]([CH3:6])[CH3:5])=[C:43]([C:51]3[CH:56]=[CH:55][C:54]([S:57]([CH3:60])(=[O:58])=[O:59])=[CH:53][CH:52]=3)[CH:42]=[N:41]2)[CH:36]=[CH:37][C:38]=1[F:39]
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2CCC=O)cc1
Reactant: CC(C)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)CC=CCCc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Temperature: 25 °C

Procedure:
A mixture of isoamyltriphenylphosphonium bromide (414 mg, 1 mmol) and potassium t-butoxide (112 mg, 1 mmol) in toluene (25 mL) was refluxed for 30 minutes and then cooled to room temperature. The crude aldehyde was added and the mixture was refluxed for 14 hours. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and was washed with water, 10% citric acid, brine, dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (silica gel, 1:1 hexanes-ethyl acetate) provided the title compound as an oil (yield: 120 mg, 13%o) 1H NMR (300 MHz, DMSO-d6) δ 0.74 (d, J=7 Hz, 6H), 1.44 (m, 1H), 1.70 (t, J=7 Hz, 2H), 2.22 (m, 2H), 2.54 (m, 2H); 3.30 (s, 3H), 5.29 (m, 2H), 7.51 (m, 1H), 7.63 (m, 1H), 7.74 (d, J=9 Hz, 2H), 7.82 (m, 1H), 8.02 (s, 1H), 8.10 (d, J=9 Hz, 2H). MS (APCI+) nmz 473 (M+H)+ and (APCI−) m/z 471 (M−H)−, m/z 507 (M+Cl)−. Anal. calc. for C25H26F2N2O3S: C, 63.54; H, 5.54; N, 5.92. Found: C, 63.74; H, 5.67; N, 5.58.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1)([CH3:3])[CH3:2].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[CH:26]=[CH2:27].[OH-].[K+]>CN1C(=O)CCC1>[F:29][C:19]([F:18])([F:28])[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[CH2:26][CH2:27][N:9]1[C:10]2[CH:11]=[CH:12][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]=2[C:7]2[CH2:16][N:15]([CH3:17])[CH2:14][CH2:13][C:8]1=2
Reactant: C=Cc1cnccc1C(F)(F)F
Reactant: CC(C)c1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CC(C)c1ccc2c(c1)c1c(n2CCc2cnccc2C(F)(F)F)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-8-isopropyl-2-methyl-1H-pyrido[4,3-b]indole, 4-(trifluoromethyl)-3-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:26])[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[O:17])=[C:11]([F:27])[CH:10]=1)C1C=CC=CC=1>CO.[C].[Pd]>[F:27][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=1[N:15]([CH3:26])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[O:17]
Reactant: CN(C(=O)Nc1ccc(F)cc1)c1ccc(OCc2ccccc2)cc1F
Agent: [Pd]
Solvent: CO
Product: CN(C(=O)Nc1ccc(F)cc1)c1ccc(O)cc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 71.1 %

Procedure:
After dissolving N-(4-benzyloxy-2-fluorophenyl)-N′-(4-fluorophenyl)-N-methylurea (105 mg, 0.2881 mmol) in methanol (10 ml), 10% palladium carbon (20mg) was added and the mixture was stirred for 45 minutes at room temperature under a hydrogen atmosphere. The catalyst was filtered off, and then was washed with ethanol, and the solvent of the filtrate was distilled off under reduced pressure. The precipitated crystals were suspended in diethyl ether, and then filtered out, washed with diethyl ether and dried by aspiration to obtain the title compound (57 mg, 0.2048 mmol, 71.10%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:15]([NH2:18])(=[O:17])=[O:16])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][NH:12][CH2:11]1.[F:19][CH:20]([F:23])[CH2:21]I.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:15]([NH2:18])(=[O:16])=[O:17])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][N:12]([CH2:21][CH:20]([F:23])[F:19])[CH2:11]1
Reactant: FC(F)CI
Reactant: NS(=O)(=O)c1cnc(OC[C@@H]2CCNC2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1cnc(OC[C@@H]2CCN(CC(F)F)C2)c(Cl)c1
Temperature: 25 °C

Procedure:
A reaction mixture of EXAMPLE 400B (353 mg), 1,1-difluoro-2-iodoethane (268 mg) and Na2CO3 (283 mg) in N,N-dimethylformamide (10 mL) was heated at 80° C. overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Flash column purification with 2.5-3% methanol/dichloromethane provided the title compound.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:13][C:12]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:8][N:7]=1)=[O:5])[CH3:2].[I:34]N1C(=O)CCC1=O.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(#N)C>[CH2:1]([NH:3][C:4]([C:6]1[C:10]([I:34])=[C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:13][C:12]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCNC(=O)c1cc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Product: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1I
Temperature: 100 °C
Yield: 77 %

Procedure:
5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-isoxazole-3-carboxylic acid ethylamide (0.90 g, 1.94 mmol), N-Iodosuccinimide (0.44 g, 1 equiv.) and Ammonium cerium (IV) nitrate (0.53 g, 0.5 equiv) were suspended in Acetonitrile (55 ml) before heating to reflux (oil bath 100° C.) where upon the mixture became homogeneous. After 18 hrs the solution was cooled and the solvent removed in vacuo to give a thick orange oil. This was partitioned between DCM (25 ml) and water (10 ml), the organic layer was kept and washed with brine (2×25 ml) before drying over Na2SO4. The DCM was removed in vacuo to provide 0.88 g (77% yield) of the product as a orange/tan coloured powder.
Reaction SMILES: [C:1]1([C:7]2[C:8]([O:10][C:11](=[O:13])[CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:16])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:16][C:12]1[C:11](=[O:13])[O:10][C:8](=[O:9])[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C1OC(=O)C(c2ccccc2)=C1Cl
Temperature: 11 °C
Reaction time: 0.17 h

Procedure:
With ice-cooling, 10.0 g (57 mmol) of phenylmaleic anhydride were added to 57 ml of thionyl chloride, and the mixture was, over a period of 10 min, admixed dropwise with 9.08 g (115 mmol) of pyridine, the temperature being maintained at 10-12° C. The mixture was stirred at 10-12° C. for 30 min, heated at 75° C. for 10 min. using a preheated heating bath and allowed to cool, and excess thionylchloride was stripped off at 60° C. at reduced pressure. The residue was then boiled with 120 ml of toluene and filtered, and the residue was washed with 50 ml of hot toluene. The filtrate was concentrated under reduced pressure, titrated with petroleum ether and dried. Yield: 8.5 g, m.p. 82-83° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH:5]([CH3:14])[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][NH:9]1.C(N(CC)CC)C.[CH3:23][O:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([S:32](Cl)(=[O:34])=[O:33])=[C:27]([CH3:36])[CH:26]=1.Cl>ClCCl>[CH3:2][O:3][C:4](=[O:15])[CH:5]([CH3:14])[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[S:32]([C:28]1[C:29]([CH3:31])=[CH:30][C:25]([O:24][CH3:23])=[CH:26][C:27]=1[CH3:36])(=[O:34])=[O:33]
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: COC(=O)C(C)CCC1CCCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)CCC1CCCCN1S(=O)(=O)c1c(C)cc(OC)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 4-(piperidin-2-yl)butanoic acid methyl ester hydrochloride (1.26 g, 5.683 mmol) was dissolved in dichloromethane (25 ml) and triethylamine (4 ml, 28.417 mmol) and a solution of 4-methoxy-2,6-dimethylbenzenesulfonic acid chloride (2.67 g, 11.37 mmol) in dichloromethane (10 ml) was added. The mixture was stirred overnight at room temperature. 1 mol/l HCl solution (10 ml) was added to the reaction mixture, followed by phase separation and extraction of the aqueous phase with dichloromethane (2×20 ml). The combined organic phases were washed with saturated sodium chloride solution (20 ml), dried over sodium sulfate and concentrated to small volume under vacuum. The crude product was purified by column chromatography (silica gel) with hexane/dichloromethane/diethyl ether (400:100:50). Yield: 1.65 g (75%)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[N-:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[CH3:25][C:26]1[CH:27]=[N:28][C:29]([CH2:35][S+:36]([O-:48])[C:37]2[N-:38][C:39]3[CH:40]=[CH:41][C:42]([O:46][CH3:47])=[CH:43][C:44]=3[N:45]=2)=[C:30]([CH3:34])[C:31]=1[O:32][CH3:33].[Mg+2:49]>O>[CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH3:10])[C:5]([CH2:11][S@@:12]([C:13]2[N-:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[O:24])=[N:4][CH:3]=1.[CH3:25][C:26]1[C:31]([O:32][CH3:33])=[C:30]([CH3:34])[C:29]([CH2:35][S@@:36]([C:37]2[N-:38][C:39]3[CH:40]=[CH:41][C:42]([O:46][CH3:47])=[CH:43][C:44]=3[N:45]=2)=[O:48])=[N:28][CH:27]=1.[Mg+2:49]
Reactant: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Mg+2]
Solvent: O
Product: COc1ccc2[n-]c([S@@](=O)Cc3ncc(C)c(OC)c3C)nc2c1

Procedure:
Certain operational steps are well known in the art and, unless otherwise indicated, any known method for performing these functions may be used in the processes of this invention. For example, solvents may be removed by distillation in atmosphere or under vacuum. Drying may be accomplished by evaporation, spray drying, drying under vacuum, and freeze-drying. Stirring means any method for blending or mixing a reaction mixture. Reagents and/or reaction mixtures may be combined by adding one to the other, for example, water may be poured into a reaction mixture. In general the methods of this invention involve various such steps, e.g. combining esomeprazole base with a suitable counterion such as magnesium, to form esomeprazole magnesium, hydrating the esomeprazole magnesium by combining with water to form an esomeprazole magnesium hydrate, removing organic impurities and excess magnesium, and drying the esomeprazole magnesium hydrate (preferably trihydrate) to obtain a hydrate of esomeprazole magnesium in the form of an amorphous solid.
Reaction SMILES: B#B.[Br:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][C:5]=1[CH3:13].O.[OH-].[Na+]>C1COCC1>[Br:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][OH:9])=[CH:6][C:5]=1[CH3:13]
Reactant: Cc1cc(C(=O)O)ccc1Br
Agent: B#B
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CO)ccc1Br
Reaction time: 5 h
Yield: 63.1 %

Procedure:
Diborane in THF (1M; 220 ml) was added dropwise to a solution of 4-bromo-3-methylbenzoic acid (20.0 g) in THF (100 ml) at room temperature under nitrogen. The solution was stirred for 5 h, treated cautiously with water (20 ml) and aqueous sodium hydroxide (2N; 200 ml) and extracted with ether (3×100 ml). The dried extract was evaporated to give the title compound as a colourless oil (11.8 g).
Reaction SMILES: [NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1.CO.[O:14](C(OC(C)(C)C)=O)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=O>O1CCCC1>[C:18]([O:17][C:15](=[O:14])[NH:7][CH2:6][C:5]1[CH:8]=[C:9]([F:10])[C:2]([NH2:1])=[CH:3][C:4]=1[F:11])([CH3:21])([CH3:20])[CH3:19]
Reactant: N#Cc1cc(F)c(N)cc1F
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cc(F)c(N)cc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.4 %

Procedure:
A dried 50 ml two-neck round bottom flask was filled with argon gas. The solution of 4-amino-2,5-difluorobenzonitrile (0.5 g, 3.24 mmol) in tetrahydrofuran was put into the flask and cooled to 0° C. To the solution was added Borane-THF complex (2 eq, 6.49 mmol, 6.49 ml) slowly. The temperature of the mixture was raised and heated to reflux for 18 hours. After confirming the completion of the reaction with TLC, to the solution was added methanol slowly (generation of bubbles) and stirred for 2 hours. The methanol was removed under reduced pressure and the residue was extracted with ethylacetate. The ethylacetate layer was washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure to yield yellow syrup. The above obtained liquid was dissolved in tetrahydrofuran and added BOC2O (1.0 eq, 0.71 g) slowly and stirred for 12 hours at room temperature. After confirming the completion of the reaction with TLC, the reaction solution was extracted with ethylacetate, washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The obtained liquid was purified with column chromatography (n-hexane/ethyl acetate=4/1) to yield a white solid (0.43 g, 51.2%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:27][OH:28].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:27]\[OH:28])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cn1cc(C(=O)CC(c2ccc(Br)cc2)C2CCCCC2)ccc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(Br)cc2)C2CCCCC2)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-3-cyclohexyl-propionyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless foam, MS (ESI+): m/z=417.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[OH:35]>>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([NH:8][C@@H:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[CH3:10])[N:7]=2)[CH:23]=[CH:22][C:21]=1[OH:35]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: Cc1ccc([C@@H](C)Nc2cncc(Cl)n2)cc1
Product: COc1cc(-c2cncc(N[C@H](C)c3ccc(C)cc3)n2)ccc1O
Yield: 6.5 %

Procedure:
In a procedure analogous to Example 2, reaction of 6-chloro-N-[(1R)-1-(4-methylphenyl)ethyl]pyrazin-2-amine (56.8 mg, 0.229 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol 63 mg, 0.25 mmol) furnished the product (5 mg, 6%).
Reaction SMILES: [Br:1][C:2]1[C:10]([Br:11])=[C:9]2[C:5]([CH2:6][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]2=[O:12])=[CH:4][C:3]=1[OH:19].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[Br:1][C:2]1[C:10]([Br:11])=[C:9]2[C:5]([CH2:6][CH:7]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=C1c2c(cc(O)c(Br)c2Br)CC1c1ccccc1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1cc2c(c(Br)c1Br)C(=O)C(c1ccccc1)C2

Procedure:
Reaction of 6,7-dibromo-5-hydroxy-2-phenyl-1-indanone with ethyl bromoacetate according to the procedure of Example 1, STEP (a), affords the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:13]([CH3:14])[C:12](=[O:15])[C:9]3([CH2:11][CH2:10]3)[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1.C(O)C>Cl.O>[CH:16]1([N:7]2[CH2:8][C:9]3([CH2:11][CH2:10]3)[C:12](=[O:15])[N:13]([CH3:14])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Yield: 48.7 %

Procedure:
A mixture of 0.0449 g (0.000146 mole) of 2-chloro-9-cyclopentyl-8,9-dihydro-5-methylspiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-6(7H)-one (VII-53), 0.0222 g (0.00016 mole) of 4-amino-benzoic acid, 0.8 mL of ethanol, 3.2 mL of water and 3 drops of hydrochloric acid was heated at reflux for 17 hours. The mixture was cooled, and the precipitate which formed was collected by filtration to give 0.029 g of 4-[(9-cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxospiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-2-yl)amino]-benzoic acid (I-62a) as a white solid.