Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.[F:11][C:12]([F:34])([F:33])[C:13]1[CH:14]=[C:15]([C:23]2[N:27]=[CH:26][N:25](/[CH:28]=[CH:29]\[C:30]([OH:32])=O)[N:24]=2)[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>ClCCl.CO>[F:34][C:12]([F:11])([F:33])[C:13]1[CH:14]=[C:15]([C:23]2[N:27]=[CH:26][N:25](/[CH:28]=[CH:29]\[C:30]([N:2]([CH3:1])[CH2:3][C:4]3[CH:5]=[N:6][C:7]([CH3:10])=[N:8][CH:9]=3)=[O:32])[N:24]=2)[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: CNCc1cnc(C)nc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncc(CN(C)C(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)cn1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 4.2 %

Procedure:
In a 25 mL, 3N round-bottomed flask equipped with nitrogen inlet, N-methyl-1-(2-methylpyrimidin-5-yl)methanamine (1) (0.1 g, 1.0 eq.) and (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.178 g, 0.7 eq.) was charged along with dichloromethane (2 mL, 10 V). The reaction mixture was cooled to −20° C. and then added T3P (50% in EtOAc) (0.550 mL, 1.2 eq.) followed by DIPEA (0.250 mL, 2 eq.) was added to reaction mixture. The clear reaction mixture was stirred at −20° C. for 30 min. The progress of the reaction was followed by TLC analysis on silica gel with 5% Methanol in dichloromethane as mobile phase and visualization with UV, which shows that starting material was consumed after 30 min stirring at −30° C. Reaction mixture was diluted by dichloromethane wash with water (2×10 mL), organic layer dried over sodium sulfate and concentrated by rotary evaporation (25° C., 20 mm Hg) to afford crude compound (0.2 g). The crude reaction mixture was purified by column chromatography using 60/120 mesh silica and methanol: dichloromethane as mobile phase. The column was packed in dichloromethane and started eluting in MeOH in gradient manner starting with fraction collection (500 mL fractions). The compound started eluting from 2% methanol in dichloromethane. Fractions containing such TLC profile were collected together to obtain pure compound 0.01 g Yield (4.19%).
Reaction SMILES: [NH2:1][CH:2]1[C:12]2[C:13]3[C:5](=[C:6]([C:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=4)[NH:7][C:8]=3[C:9]([Cl:14])=[CH:10][CH:11]=2)[CH2:4][CH2:3]1.S(=O)(=O)(O)[OH:24].[OH-].[Na+]>C(O)(=O)C>[NH2:1][CH:2]1[C:12]2[C:13]3[C:5](=[C:6]([C:15]4[CH:20]=[CH:19][C:18]([C:21](=[O:24])[NH2:22])=[CH:17][CH:16]=4)[NH:7][C:8]=3[C:9]([Cl:14])=[CH:10][CH:11]=2)[CH2:4][CH2:3]1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(-c2[nH]c3c(Cl)ccc4c3c2CCC4N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: NC(=O)c1ccc(-c2[nH]c3c(Cl)ccc4c3c2CCC4N)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 17 %

Procedure:
A portion (1.0 g) of the compound obtained in Example 168 was dissolved in acetic acid (30 ml) and to the solution was added 50% sulfuric acid (60 ml). The mixture was stirred for 2 hours at 120° C. and allowed to cool. The reaction mixture was neutralized with 6N aqueous solution of sodium hydroxide and the insoluble matter was filtered off. The filtrate was extracted three times with ethyl acetate, washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was crystallized from ether to yield 170 mg (17%) of the titled compound.
Reaction SMILES: CO[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH:9]([NH2:15])[CH2:8][C:7]=2[CH:6]=1)=[O:4].[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22](Cl)(=[O:24])=[O:23])[CH:17]=1.[OH:26][NH2:27].[OH-].[K+]>ClCCl>[OH:26][NH:27][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH:9]([NH:15][S:22]([C:18]3[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=3)(=[O:24])=[O:23])[CH2:8][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)CC(N)CC2
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: NO
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NO)c1ccc2c(c1)CC(NS(=O)(=O)c1cccnc1)CC2

Procedure:
The title compound was prepared in two steps according to Scheme 6 by (1) treating amine VII with pyridine-3-sulfonyl chloride and TEA in dichloromethane, and (2) treating the ester intermediate with aqueous HONH2 and KOH. MS: calc'd (MH+) 348, exp (MH+) 348.4. 1H NMR (CD3OD, 400 MHz), 9.05 (s, 1H), 8.80 (d, 1H, J=4.4 Hz), 7.31 (d, 1H, J=8.0 Hz), 7.65 (m, 1H), 7.47 (d, 1H, J=8.0 Hz), 7.36 (s, 1H), 7.16 (d, 1H, J=8.0 Hz), 3.55 (m, 1H), 2.95 (m, 2H), 2.82 (m, 1H), 2.69 (m, 1H), 1.95 (m, 1H) 1.73 (m, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[CH:6][CH:5]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.O>C(O)C(C)C>[CH2:1]([O:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[CH:16][CH:17]=1)=[O:3])[CH:4]([CH3:17])[CH3:5]
Reactant: O=C(O)c1ccc(Cc2ccccc2O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)CO
Product: CC(C)COC(=O)c1ccc(Cc2ccccc2O)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
2-(4-Carboxybenzyl)phenol (603 mg) was dissolved in isobutanol (3 ml), added with sulfuric acid (0.6 ml) and stirred at 80° C. for 3 hours. The reaction mixture was added with water (5 ml) and extracted twice with ethyl acetate (5 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=5:1) to obtain 318 mg of the title compound. Yield: 42%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.Cl[C:16]1[N:17]=[CH:18][C:19]2[CH:24]=[C:23]([C:25]3[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH:30]=3)[NH:22][C:20]=2[N:21]=1.CN(C=O)C>C(O)CCC>[CH3:8][N:6]1[C:5](=[O:9])[C:4]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)=[CH:3][C:2]([NH:1][C:18]2[C:19]3[CH:24]=[C:23]([C:25]4[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH:30]=4)[NH:22][C:20]=3[N:21]=[CH:16][N:17]=2)=[CH:7]1
Reactant: Cn1cc(N)cc(-c2cncs2)c1=O
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3cnc(Cl)nc3[nH]2)CC1
Solvent: CN(C)C=O
Solvent: CCCCO
Product: Cn1cc(Nc2ncnc3[nH]c(C4=CCN(C(=O)OC(C)(C)C)CC4)cc23)cc(-c2cncs2)c1=O
Temperature: 120 °C
Reaction time: 15 h

Procedure:
5-Amino-1-methyl-3-thiazol-5-yl-1H-pyridin-2-one (99.0 mg, 0.478 mmol) was added to a solution of tert-butyl 4-(chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (133 mg, 0.398 mmol) in 1-butanol (2.0 L). The reaction was stirred at 120° C. for 15 h. DMF (1.5 mL) was added and the mixture was filtered. The filtrate was purified by HPLC to yield the title compound. 1H-NMR (CD3OD, 400 MHz): δ=1.50 (s, 9H), 2.57 (m, 2H), 3.67 (m, 2H), 3.73 (s, 3H), 4.13 (m, 2H), 6.30 (s, br, 1H), 6.62 (s, 1H), 8.21 (s, 1H), 8.33 (d, J=2.4 Hz, 1H), 8.34 (d, J=2.4 Hz, 1H), 8.47 (s, 1H), 8.99 (s, 1H). MS (ES+): m/z 506.08 [MH+]. HPLC: tR=2.62 min (ZQ2000, polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:23]=2[C@H:24]2[CH2:29][C@@H:28]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C@@H:27]([S:38][CH3:39])[C@@H:26]([CH3:40])[CH2:25]2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:41].C1C=C(Cl)C=C(C(OO)=[O:50])C=1.C1CCCCC=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:23]=2[C@H:24]2[CH2:29][C@@H:28]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:36])[CH3:34])[C@@H:27]([S@@:38]([CH3:39])=[O:50])[C@@H:26]([CH3:40])[CH2:25]2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:41]
Reactant: CS[C@H]1[C@@H](C)C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@H]1NC(=O)OC(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1[S@@](C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
To a solution of tert-butyl (1R,2S,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-(methylthio)cyclohexylcarbamate (1.0 equiv.) in CH2Cl2 (0.10 M) in a 0° C. bath was added mCPBA (1.2 equiv.). The capped solution was left stirring at rt for 1 hr. cyclohexene (10.0 equiv.) was added to quench any remaining mCBPA and after stirring for 5 minutes the solution was directly loaded onto ISCO SiO2 column and purified to yield tert-butyl (1R,2S,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-((R)-methylsulfinyl)cyclohexylcarbamate in 31% yield, LC/MS=603.2 (MH+), Rt=0.66 min; and tert-butyl (1R,2S,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-(methylsulfonyl)cyclohexylcarbamate in 37% yield. LC/MS (m/z)=619.2 (MH+), Rt=0.88 min.
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:12][C:13]1([C:20]([OH:22])=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]([C:25]1[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=1)[NH2:24].CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:1]([O:8][N:9]([CH2:12][C:13]1([C:20]([NH:24][NH:23][C:25]2[N:30]=[C:29]([C:31]([F:33])([F:32])[F:34])[CH:28]=[CH:27][N:26]=2)=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[CH:10]=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CN(CC1(C(=O)O)CCCCCC1)OCc1ccccc1
Reactant: NNc1nccc(C(F)(F)F)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=CN(CC1(C(=O)NNc2nccc(C(F)(F)F)n2)CCCCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.6 %

Procedure:
To a mixture of 1-[(Benzyloxy-formyl-amino)-methyl]-cycloheptanecarboxylic acid (0.10 g, 0.33 mmol), 2-hydrazino-4-(trifluoromethyl)pyrimidine (0.07 g, 0.39 mmol), NMM (0.10 g, 1.0 mmol) and HOAt (0.053 g, 0.39 mmol) in DMF (1 mL) at room temperature was added 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (0.075 g, 0.34 mmol). After stirring at room temperature 18 h, the reaction mixture was then purified by preparative, reverse-phase HPLC to afford the title compound as a white solid (0.11 g, 72%). MH+466.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([O:13][C:14]([CH:16]1[C:24]2[C:19](=[CH:20][C:21]([NH2:25])=[CH:22][CH:23]=2)[C:18](=[O:26])[CH2:17]1)=[O:15])[CH3:12].Cl>C(O)C.O1CCOCC1>[CH2:11]([O:13][C:14]([CH:16]1[C:24]2[C:19](=[CH:20][C:21]([NH:25][C:2]3[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=3)=[CH:22][CH:23]=2)[C:18](=[O:26])[CH2:17]1)=[O:15])[CH3:12]
Reactant: CCOC(=O)C1CC(=O)c2cc(N)ccc21
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)C1CC(=O)c2cc(Nc3ncccc3[N+](=O)[O-])ccc21
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-3-nitropyridine (1.48 g, 9.03 mmol), (R/S)-5-Amino-3-oxo-indan-1-carboxylic acid ethyl ester (1.98 g, 9.03 mmol) and 4M HCl in dioxane (2.3 mL, 9.0 mmol) in ethanol (15 mL) is refluxed for 9 h. The reaction mixture is left at rt overnight then a further equivalent of 4M HCl in dioxan is added. After 4 h refluxing, the solvent is evaporated and the crude mixture purified by MPLC eluting with EtOAc/Hexane to give (R/S)-5-(3-Nitro-pyridin-2-ylamino)-3-oxo-indan-1-carboxylic acid ethyl ester as a red solid. Title compound: ES-MS: 342.19 [M+H]+, tR=1.6 min (System 2)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][C:10](=[O:14])[N:11]([CH3:13])[CH3:12])=[C:4]([CH2:15]O)[C:3]=1[Cl:17].O=S(Cl)[Cl:20].ClC1C=NC=C(Cl)C=1CCl>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][C:10](=[O:14])[N:11]([CH3:13])[CH3:12])=[C:4]([CH2:15][Cl:20])[C:3]=1[Cl:17]
Reactant: CN(C)C(=O)OCc1cnc(N)c(Cl)c1CO
Reactant: O=S(Cl)Cl
Agent: ClCc1c(Cl)cncc1Cl
Product: CN(C)C(=O)OCc1cnc(N)c(Cl)c1CCl

Procedure:
Dimethyl-carbamic acid 6-amino-5-chloro-4-hydroxymethyl-pyridin-3-ylmethyl ester (18.5 mg, 0.071 mmol) was chlorinated with SOCl2 according to the synthesis of 3,5-dichloro-4-chloromethyl-pyridine. The resulting title compound was used for the next reaction without purification. MS (m/z): 278.0 [M+H+].
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1OB(O)O)=[O:2].Br[C:14]1[O:15][CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CO>[O:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH:1]=[O:2]
Reactant: O=Cc1ccccc1OB(O)O
Reactant: Brc1ccco1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=Cc1ccccc1-c1ccco1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
2-Formylphenylboric acid (300 mg, 2.0 mmol), 2-bromofuran obtained in Example 64a (588 mg, 4.0 mmol), and tetrakis triphenylphosphine palladium (15 mg) were dissolved in a mixed solvent of toluene (38 ml) and methanol (5 ml). The solution was added with 2M aqueous sodium carbonate solution (20 ml) and heated at 80° C. with stirring for 6 hours. The reaction mixture was stand for cooling, and then the solvent was evaporated. The mixture was extracted with dichloromethane, and the extract was washed with a mixture of 2M aqueous sodium carbonate solution (10 ml) and aqueous solution of ammonia (2 ml), and dried over sodium sulfate. Insoluble solids were removed by filtration, and the filtrate was evaporated under reduced pressure to obtain the title compound as crude yellow oil (126 mg). The resulting crude product was used in the next reaction without purification.
Reaction SMILES: [B:1](OC(C)C)([O:6]C(C)C)[O:2]C(C)C.Br[C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C([Li])CCC.O>O1CCCC1>[CH3:30][N:27]1[CH2:28][CH2:29][N:24]([S:21]([C:18]2[CH:19]=[CH:20][C:15]([B:1]([OH:6])[OH:2])=[CH:16][CH:17]=2)(=[O:23])=[O:22])[CH2:25][CH2:26]1
Reactant: CN1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(S(=O)(=O)c2ccc(B(O)O)cc2)CC1
Temperature: -78 °C
Reaction time: 16 h
Yield: 57.6 %

Procedure:
Triisopropyl borate (0.64 mL, 2.8 mmol) was added to a solution of 1-[(4-bromophenyl)sulfonyl]-4-methylpiperazine (0.602 g, 1.9 mmol; described: in Keasling, H. H. et el. J. Med. Chem. 1965, 8, 548-550) in anhydrous tetrahydrofuran (7 mL) at −78° C. under a nitrogen atmosphere followed by dropwise addition of n-butyllithium (1.4 mL, 2.2 mmol). The resulting mixture was stirred at −78° C. for 2 h and at room temperature for another 16 h. Water (2.0 mL) was added and the mixture stirred for 30 min and evaporated to dryness. The residue was pre-adsorbed onto silica and purified by column chromatography on silica using methylene chloride/methanol, (9:1 to 1:9), as the eluent. The product was re-crystallized from water to give 311 mg (58% yield) of the title compound as white crystals: mp 215-218° C.; 1H NMR (DMSO-d6, 400 MHz) δ 8.47 (br s, 2H), 8.05 (d, J=8 Hz, 2H), 7.73 (d, J=8 Hz, 2H), 3.77 (m, 2H), 3.40 (m, 2H), 3.13 (m, 2H), 2.71 (s, 3H), 2.65 (m, 2H); 13C NMR (DMSO-d6, 100 MHz) δ 133.7, 133.3, 124.7, 49.8, 41.6, 41.4; MS (TSP) m/z 285 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].C([O-])(O)=O.[Na+].Br[CH2:16][CH2:17][CH2:18][CH3:19].O>CS(C)=O>[CH2:16]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH2:5][OH:6])[CH:3]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCBr
Reactant: Nc1cccc(CO)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCNc1cccc(CO)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 3.69 g (30 mmol) of 3-amino benzyl alcohol in 20 ml DMSO was added 3.78 g (45 mmol) solid NaHCO3 and 2.91 ml (27 mmol) 1-bromobutane. The reaction was allowed to stir at 50° C. for 18 hours (overnight). Reaction was worked up by adding 250 ml water and product was extracted in ethyl acetate. Water was added, and the resultant mixture was extracted with EtOAc. The organic layer was washed with water and brine.
Reaction SMILES: [OH:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10]O)=[CH:7][CH:6]=1)[CH3:3].[ClH:12].[NH2:13][CH2:14][CH2:15][SH:16]>Cl>[ClH:12].[ClH:12].[NH2:13][CH2:14][CH2:15][S:16][CH2:10][C:8]1[O:9][C:5]([CH2:4][N:2]([OH:1])[CH3:3])=[CH:6][CH:7]=1
Reactant: NCCS
Reactant: CN(O)Cc1ccc(CO)o1
Agent: Cl
Product: CN(O)Cc1ccc(CSCCN)o1
Yield: 125.9 %

Procedure:
5-[[Hydroxy(methyl)amino]methyl]-2-furanmethanol (7.85 g) was added to a stirred solution of 2-aminoethanethiol hydrochloride (5.68 g) in concentrated hydrochloric acid (15 ml) at 0° during 45 mins. After 48 hr at 0° the crystalline solid which separated was mixed with isopropanol (40 ml), filtered and crystallised from ethanol to give the title compound (9.1 g) m.p. 164°-165° dec.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.O.C(N(CC)CC)C.[Cl:18][C:19]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:20]=1[C:21](Cl)=[O:22]>C1COCC1>[Cl:18][C:19]1[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][C:20]=1[C:21]([NH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([CH2:8][OH:9])[CH2:4][CH2:3]1)=[O:22]
Reactant: N[C@H]1CC[C@@H](CO)CC1
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CC[C@@H](CO)CC1)c1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cis-(4-Amino-cyclohexyl)-methanol (Tetrahedron Lett., 1970, 11, 4285-4288) (0.75 g, 5.80 mmol) in THF (10 ml) is added water (1.8 mL), triethylamine (2.023 mL, 14.51 mmol) and 2-chloro-5-(trifluoromethyl)benzoyl chloride (1.411 g, 5.80 mmol). The RM is stirred at RT for 1 hour. The reaction mixture is partitioned between EtOAc and water. The organic phase is washed successively with water, saturated sodium bicarbarbonate and saturated brine, dried over MgSO4, filtered and the solvent removed in vacuo. Purification by chromatography on a pre-packed silica gel column using 0-100% EtOAc in isohexane gradient elution gave the desired product as a colourless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][OH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:24]=[CH:23][C:14]([CH:15]=NC2C=CC=CC=2)=[CH:13][CH:12]=1>CCOCC>[Cl:10][C:11]1[CH:24]=[CH:23][C:14]([CH:15]=[N+:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[O-:9])=[CH:13][CH:12]=1
Reactant: ONc1ccc(F)cc1
Reactant: Clc1ccc(C=Nc2ccccc2)cc1
Solvent: CCOCC
Product: [O-][N+](=Cc1ccc(Cl)cc1)c1ccc(F)cc1

Procedure:
N-p-fluorophenylhydroxylamine (0.052 moles) was dissolved in ether (20 cc). This solution was treated with N-p-chlorobenzylideneaniline (0.05 moles) and dissolved in ether (50 cc). The product which separated was filtered and washed with ether to give α-p-chlorophenyl-N-p-fluorophenylnitrone.
Reaction SMILES: [CH:1]1([C@@H:6]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:33]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:33][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])=[CH:15][CH:16]=1
Reactant: Cc1ccc([C@@H](C(=O)OC(C)(C)C)C2CCCC2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)[C@H](c1ccc(CBr)cc1)C1CCCC1
Temperature: 25 °C

Procedure:
3.0 g (10.93 mmol) of tert-butyl(2S)-cyclopentyl-(4-methylphenyl)acetate were heated to reflux in 20 ml of chloroform, and 90 mg (0.55 mmol) of 2,2′-azobis(2-methylpropanenitrile) and 2.72 g (15.31 mmol) of N-bromosuccinimide were then added in 5 portions every 30 min. The mixture was stirred under reflux for 6 h and then cooled to RT and concentrated on a rotary evaporator. The residue was purified by chromatography on 120 ml of silica gel (mobile phase cyclohexane/ethyl acetate 4:1). This gave 2.8 g (72% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[NH:6][C:5]2[O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:4]=2[CH:3]=1.C[O-:18].[Na+]>CO>[OH:18][C:2]1[C:7](=[O:8])[NH:6][C:5]2[O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:4]=2[CH:3]=1
Reactant: C[O-]
Reactant: O=c1[nH]c2c(cc1Cl)-c1ccccc1CO2
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]c2c(cc1O)-c1ccccc1CO2

Procedure:
Add 23.1 gm of 2-chloro-4,6-dihydro-3H[2]benzopyrano[3,4-b]pyridin-3-one to 300 ml of methanol containing 30 gm of sodium methoxide. Heat the system in a steel bomb at about 200° C. for 12 hours. Stop the reaction and remove the solvent by stripping. Treat the residue with water and then isolate the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][N:6]=[C:7]([CH2:11][S+:12]([O-:26])[C:13]2[N-:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH:23]([F:25])[F:24])=[CH:19][C:20]=3[N:21]=2)[C:8]=1[O:9][CH3:10].[Na+:27]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][N:6]=[C:7]([CH2:11][S+:12]([O-:26])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH:23]([F:24])[F:25])=[CH:19][C:20]=3[N:21]=2)[C:8]=1[O:9][CH3:10].[OH-:2].[Na+:27]
Reactant: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[n-]2)c1OC
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Product: [OH-]

Procedure:
Pantoprazole sodium Form II can be prepared by forming a solution of pantoprazole and excess sodium hydroxide in acetone and crystallizing Form II from the solution. Preferably, pantoprazole is added as the free base, though the sodium salt may be used. Excess sodium hydroxide is conveniently added as a concentrated aqueous NaOH solution. Sodium hydroxide should be added in an amount of from about 1 to about 2 molar equivalents with respect to pantoprazole. In a particularly preferred procedure, pantoprazole is dissolved in about 3-6 volumes of acetone. The solution is cooled to about 0° C. Then, the concentrated NaOH solution is added. Crystallization of the novel form of pantoprazole sodium is substantially complete within about 1-5 hours. The crystals can then be separated from the acetone by conventional means, such as by filtering or decanting and they may be washed, preferably with acetone.
Reaction SMILES: [Mg].[CH:2](Br)=[CH2:3].[CH2:5]([O:12][CH2:13][CH:14]=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>O1CCCC1>[CH2:5]([O:12][CH2:13][CH:14]([O:15][C:16](=[O:18])[CH3:17])[CH:2]=[CH2:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=CCOCc1ccccc1
Reactant: C=CBr
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CC(COCc1ccccc1)OC(C)=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 49 %

Procedure:
Magnesium metal (5 g., 0.206 mole) is suspended in tetrahydrofuran (100 ml.) in a three-necked, round-bottomed flask protected by a dry ice condenser and equipped with a mechanical stirrer. The stirrer is started and vinyl bromide (22 g., 0.206 mole) in tetrahydrofuran is added at such a rate as to keep the solvent refluxing. The reaction mixture is refluxed for 0.5 hours after the addition is complete. The reaction mixture is then cooled to 0°-5° C. and benzyloxyacetaldehyde (24 g., 0.16 mole) in tetrahydrofuran (15 ml.) is added dropwise. After 1.5 hours at 0°-5° C., there is added acetic anhydride (26 g., 0.255 mole) and the reaction mixture is allowed to come to room temperature. After 20 hours at room temperature, ice water (500 ml.) is added and the product is extracted into ethyl acetate (3 × 100 ml.). The ethyl acetate extract is washed with brine, dried (Na2SO4), and distilled. There is obtained 17 g. (49%) of the title compound, b.p. 85°-95° C./0.05 mm.