Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]2[CH:15]=[C:14]([S:16](Cl)(=O)=O)[C:13]([Cl:20])=[CH:12][C:11]=2[Cl:21])=[N:4][N:5]([CH3:9])[C:6]=1[S:7][CH3:8]>[Zn].C(O)(=O)C>[Cl:1][C:2]1[C:3]([C:10]2[CH:15]=[C:14]([SH:16])[C:13]([Cl:20])=[CH:12][C:11]=2[Cl:21])=[N:4][N:5]([CH3:9])[C:6]=1[S:7][CH3:8]
Reactant: CSc1c(Cl)c(-c2cc(S(=O)(=O)Cl)c(Cl)cc2Cl)nn1C
Agent: [Zn]
Solvent: CC(=O)O
Product: CSc1c(Cl)c(-c2cc(S)c(Cl)cc2Cl)nn1C
Yield: 89.1 %

Procedure:
A mixture of 4-chloro-3-(5-chlorosulfonyl-2,4-dichlorophenyl)-1-methyl-5-methylthio-1H-pyrazole (7.71 g, 19 mmoles), 80 ml glacial acetic acid, and zinc dust (24.8 g, 380 mmoles) was subjected to reaction under reflux for 3.5 hours. The resulting solution was poured into ice-cold water, and the objective product was extracted with ethyl acetate. The extract solution was washed with water, dehydrated, and concentrated, giving the title compound (5.75 g) as oily matter, yield 89.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:40]=[C:39]([CH3:41])[C:5]([C:6]([NH:8][CH2:9][CH2:10][CH:11]([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C@H:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:21][N:22]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:15][CH2:14]2)[CH3:12])=[O:7])=[C:4]([CH3:42])[N:3]=1.O.NN>CCO>[NH2:22][CH2:21][C@H:20]([NH:19][CH:16]1[CH2:17][CH2:18][N:13]([CH:11]([CH3:12])[CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]2[C:39]([CH3:41])=[CH:40][C:2]([Cl:1])=[N:3][C:4]=2[CH3:42])[CH2:14][CH2:15]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Cc1cc(Cl)nc(C)c1C(=O)NCCC(C)N1CCC(N[C@@H](CN2C(=O)c3ccccc3C2=O)c2ccccc2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cc(Cl)nc(C)c1C(=O)NCCC(C)N1CCC(N[C@@H](CN)c2ccccc2)CC1
Yield: 67.5 %

Procedure:
Following general procedure D: a solution of 6-chloro-N-(3-{4-[(R)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-1-phenyl-ethylamino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide (194 mg, 0.33 mmol), hydrazine hydrate (0.05 ml ml, 0.1 mmol) in EtOH (2 ml) was stirred at rt overnight. Purification of the crude product by chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 100:10:2) afforded N-{3-[4-((R)-2-Amino-1-phenyl-ethylamino)-piperidin-1-yl]-butyl}-6-chloro-2,4-dimethyl-nicotinamide (102 mg, 67%).
Reaction SMILES: [C:1]1([C@H:7]([C@H:9]2[O:14][CH2:13][CH2:12][N:11]([C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[CH2:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[CH3:32][S:33]([O:8][C@H:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C@H:9]1[O:14][CH2:13][CH2:12][N:11]([C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[CH2:10]1)(=[O:35])=[O:34]
Reactant: C[C@H](c1ccccc1)N1CCO[C@H]([C@H](O)c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](c1ccccc1)N1CCO[C@H]([C@H](OS(C)(=O)=O)c2ccccc2)C1
Reaction time: 6 h
Yield: 54.8 %

Procedure:
To a solution of 50 (0.05 g, 0.17 mmol) in dichloromethane (1 ml) at room temperature was added polymer supported Hünig's base ((Argonaut, 3.56 mmol/g, 0.089 g, 0.32 mmol, 1.9 eq) and methanesulphonyl chloride (0.02 g, 0.19 mmol). The mixture was stirred under nitrogen for 6 hours then filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (eluent: ethyl acetate/heptane 33/67 (v/v)) to give 51 as a colourless oil (0.035 g, 55%%); MW 375.49; C20H25NO4S 1H NMR (CDCl3) 7.20-7.35 (10H, m), 5.46 (1H, d), 3.79-3.88 (2H, m), 3.59 (1H,td), 3.4 (1H, q), 2.68-2.78 (2H, m), 2.68 (3H, s), 2.03-2.24 (2H, m), 1.34 (3H, d). m/z [M+H]+ 376.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]([C:14]([O:16]CC)=[O:15])[C:7]2=[O:19].O.Cl>CCO>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]([C:14]([OH:16])=[O:15])[C:7]2=[O:19]
Reactant: CCOC(=O)c1c[nH]c2ccc(Br)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1c[nH]c2ccc(Br)cc2c1=O
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 95.7 %

Procedure:
2N Sodium hydroxide (506 mL, 1011.43 mmol) was added to a stirred suspension of ethyl 6-bromo-4-oxo-1H-quinoline-3-carboxylate (59.9 g, 202.29 mmol) in EtOH (590 mL) and the resulting solution stirred at 75° C. for 1.5 h. Water was added and the mixture cooled to 0° C. The pH of the solution was adjusted to 3 using hydrochloric acid and the precipitate collected by filtration. The solid was washed with water, EtOH/water (1:1) then Et2O before being dried to afford the desired material (51.9 g, 96%) as a beige solid. NMR Spectrum: 1H NMR (500 MHz, DMSO-d6) δ 7.80 (1H, d), 8.05 (1H, d), 8.37 (1H, s), 8.93 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=270.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C:4]([NH:7][C:8](=[O:34])[C@@H:9]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:13]([OH:25])[CH:12]=1)([CH3:6])[CH3:5].[CH2:36]([N:38]=[C:39]=[O:40])[CH3:37]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:35])[C:4]([NH:7][C:8](=[O:34])[C@@H:9]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:13]([O:25][C:39](=[O:40])[NH:38][CH2:36][CH3:37])[CH:12]=1)([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(O)c1)NC(=O)OC(C)(C)C
Reactant: CCN=C=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCNC(=O)Oc1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)NC(C)(C)C(=O)OC)ccc1OCc1ccccc1
Temperature: 50 °C

Procedure:
2-[(S)-3-(4-benzyloxy-3-hydroxy-phenyl)-2-tert-butoxycarbonylamino-propionylamino]-2-methyl-propionic acid methyl ester (1.2 mmol), was dissolved in dichloromethane (5 ml) and ethyl isocyanate (0.31 ml) added. A catalytic amount of DMAP was added and the solution was heated at 50° C. for 7 hours. The reaction mixture was evaporated to dryness and the crude product purified by chromatography on silica gel eluting with a mixture of ethyl acetate-hexane. 2-[(S)-3-(4-Benzyloxy-3-ethylcarbamoyloxy-phenyl)-2-tert-butoxycarbonylaminopropionyl-amino]-2-methyl-propionic acid methyl ester was obtained as a white crystalline solid, 410 mg; Rf 0.29 (ethyl acetate-hexane 1:1); NMR (500 MHz, CDCl3) 1.39 (ca 3H, s), 1.41 (ca 3H, s), 1.43 (ca 9H, s), 2.86 (1H, dd J 14, 8), 3.08 (1H, dd J 14, 5), 3.25-3.32 (2H, m), 3.70 (3H, s), 4.23 (1H, br), 5.00 (1H, br t J 5), 5.07 (2H, s), 6.15 (1H, s), 6.91 (1H, d J 8), 6.99-7.02 (2H, m), 7.28-7.42 (ca 5H, m); HPLC/MS retention time 5.98 min, m/z 558 (MH+).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13](COCC[Si](C)(C)C)[C:12]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:24][CH2:23]3)=[N:11][C:10]=2[C:38](OC)=[O:39])=[CH:5][CH:4]=1.[Li+].[OH-].[CH2:46]1[CH2:50]OC[CH2:47]1.O>>[CH:46]([N:22]1[CH2:27][CH2:26][N:25]([C:38]([C:10]2[N:11]=[C:12]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[C:33]([C:34]([F:35])([F:36])[F:37])=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:24][CH2:23]3)[NH:13][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:42])([F:43])[F:1])=[CH:4][CH:5]=2)=[O:39])[CH2:24][CH2:23]1)([CH3:50])[CH3:47]
Reactant: COC(=O)c1nc(N2CCN(c3ncccc3C(F)(F)F)CC2)n(COCC[Si](C)(C)C)c1-c1ccc(C(F)(F)F)cc1
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(C)N1CCN(C(=O)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2-c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of methyl 5-(4-(trifluoromethyl)phenyl)-2-(4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate from step (d) above (500. mg, 0.794 mmol) in THF:H2O (5:1) was added LiOH (29 mg, 1.19 mmol, Aldrich) at 0° C. The mixture was stirred at RT for 16 h and the solvents were removed. The residue was dissolved in H2O (20 mL) and the aqueous solution was adjusted to pH ˜7. Then, the solvents were removed and the residue was purified on silica gel using ISCO Combiflash® system with EtOAc/Hexanes (1:4) as the eluant to give the title compound as a white solid. MS (ESI, positive ion) m/z: 616 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([S:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH2:16][NH2:17])[CH:13]=[CH:14][CH:15]=2)=[N:2]1.[C:18]([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([C:30](OCC)=[O:31])[NH:24][C:23]2=[O:35])#[N:19].C(N(C(C)C)CC)(C)C>C(O)C>[C:18]([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([C:30]([NH:17][CH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][S:6][C:3]3[N:4]=[CH:5][NH:1][N:2]=3)[CH:11]=1)=[O:31])[NH:24][C:23]2=[O:35])#[N:19]
Reactant: CCOC(=O)c1nc2ccc(C#N)cc2c(=O)[nH]1
Reactant: NCc1cccc(OCCSc2nc[nH]n2)c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc2nc(C(=O)NCc3cccc(OCCSc4nc[nH]n4)c3)[nH]c(=O)c2c1
Temperature: 90 °C
Reaction time: 48 h
Yield: 26 %

Procedure:
A suspension of 1-(3-{[2-(1H-1,2,4-triazol-3-ylthio)ethyl]oxy}phenyl)methanamine obtained in Reference Example 3 (300 mg, 0.999 mmol), ethyl 6-cyano-4-oxo-3,4-dihydroquinazoline-2-carboxylate obtained in Reference Example 51 (200 mg, 0.822 mmol) and diisopropylethylamine (0.180 mL, 1.05 mmol) in ethanol (2 mL) was stirred at 90° C. for 2 days. The reaction solvent was evaporated under reduced pressure, and the residue was purified by preparative HPLC (GILSON 215LIQUD HANDLER, 322PUMP, UV/VIS-156, SHISEIDO CAPCELL PACK C-18 UG120 S-5 (20 mmφ×50 mm), mobile phase: distilled water (containing 0.1% trifluoroacetic acid)/acetonitrile (containing 0.1% trifluoroacetic acid), gradient: distilled water/acetonitrile=90/100/100, time: 10 min, flow rate: 25 mL/min, detection wavelength: 220 nm), and the obtained crude crystals were recrystallized from ethanol to give the title compound as a white powder (97.4 mg, 26%).
Reaction SMILES: CN(C)C1N=CC([C:9]2[N:10]=[C:11]([CH2:36][CH3:37])[C:12]([NH:17][C@H:18]3[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH2:19]3)=[N:13][C:14]=2[CH2:15][CH3:16])=C(C)C=1.[CH3:40][C:41]1[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][C:42]=1B(O)O>>[CH2:36]([C:11]1[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:27])[CH2:19]2)=[N:13][C:14]([CH2:15][CH3:16])=[C:9]([C:42]2[CH:43]=[CH:44][C:45]([O:47][CH3:48])=[CH:46][C:41]=2[CH3:40])[N:10]=1)[CH3:37]
Reactant: COc1ccc(B(O)O)c(C)c1
Reactant: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(-c2cnc(N(C)C)cc2C)nc1CC
Product: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2C)nc1CC

Procedure:
Following the procedure for the preparation of benzyl (3R,4S)-3-({5-[6-(dimethylamino)-4-methylpyridin-3-yl]-3,6-diethylpyrazin-2-yl}amino)-4-ethoxypyrrolidine-1-carboxylate and but substituting 2-methyl-4-methoxy-phenyl boronic acid provided the title compound as an amorphous solid. 1H NMR (CDCl3) δ 1.04, 1.21, 2.04, 2.40, 2.65, 3.22˜3.26, 3.41, 3.52˜3.68, 3.75, 3.94, 4.03, 4.68, 5.08, 6.70, 6.74, 7.02, 7.28˜7.32; IR (liq.) 2971 (s), 2339 (w), 2166 (w), 2082 (w), 1957 (w), 1708 (s), 1564 (s), 1482 (s), 1420 (s), 1395 (s), 1349 (s), 1242 (s), 1169 (s), 1125 (s), 1096 (s) cm−1 HRMS (ESI) calcd for C30H38N4O4+H1 519.2971. found 519.2974.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([CH3:31])=[C:21]([NH:23][C:24]([N:26]4[CH:30]=[CH:29][N:28]=[CH:27]4)=[S:25])[CH:22]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[N:32]1C=CC(N)=[C:34](N)[CH:33]=1>CN(C=O)C>[NH2:32][C:33]1[CH:34]=[CH:27][N:28]=[CH:29][C:30]=1[NH:26][C:24]([NH:23][C:21]1[CH:22]=[C:17]([C:15]([N:12]2[CH2:13][CH2:14][CH:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH2:10][CH2:11]2)=[O:16])[CH:18]=[CH:19][C:20]=1[CH3:31])=[S:25]
Reactant: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1NC(=S)n1ccnc1
Reactant: Nc1ccncc1N
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1NC(=S)Nc1cnccc1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)-1H-imidazole-1-carbothioamide (281.1) in DMF continued from the prior step was added pyridine-3,4-diamine (0.034, 0.32 mmol). The mixture was stirred at room temperature for 3 hours. LCMS showed the reaction was complete. The reaction was carried to the next step without workup or purification. m/z (ES+) 471 (M+H)+.
Reaction SMILES: [CH:1](O)=O.[CH2:4]([O:11][C:12]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH:15]1[C:20]([C:22]1[O:23][C:24]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:25]=2[CH:26]=1)=[O:21])=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C=O.[OH-].[Na+]>O>[CH2:4]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([CH3:1])[CH2:16][CH:15]1[C:20]([C:22]1[O:23][C:24]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:25]=2[CH:26]=1)=[O:21])=[O:13])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(c1cc2cc(F)ccc2o1)C1CNCCN1C(=O)OCc1ccccc1
Reactant: O=CO
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCN(C(=O)OCc2ccccc2)C(C(=O)c2cc3cc(F)ccc3o2)C1
Yield: 96 %

Procedure:
97% Formic acid (0.19 g, 4 mmol) was added to a stirred mixture of (RS)-2-[1-(5-fluoro-benzofuran-2-yl)methanoyl]-piperazine-1-carboxylic acid benzyl ester, D49 (0.57 g, 1.5 mmol) in water (5 ml). Stirring was continued as a 37% formaldehyde solution in water (0.155 g) was added. The resultant mixture was heated at 100° C. for 3.5 h, cooled, diluted with water (30 ml) and basified with 2N sodium hydroxide. The mixture was extracted with ethyl acetate (2×) and the combined extracts dried (Na2SO4) and the solvent removed in vacuo to afford the title compound (0.57 g, 96%).
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[N:8]=[C:9]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:10]([CH2:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[C:11]=1Br.O>C1COCC1>[Br:6][C:7]1[N:8]=[C:9]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:10]([CH2:13][C:14]([N:16]2[CH2:17][CH2:18][N:19]([C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:20][CH2:21]2)=[O:15])[CH:11]=1
Reactant: O=C(Cn1c(-c2ccccc2)nc(Br)c1Br)N1CCN(c2ncccn2)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cn1cc(Br)nc1-c1ccccc1)N1CCN(c2ncccn2)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 17.1 %

Procedure:
9.4 mL 2.5 mol/L butyllithium solution in THF was added dropwise to 11.8 g 2-(4,5-dibromo-2-phenyl-imidazol-1-yl)-1-(4-pyrimidin-2-yl-piperazin-1-yl)-ethanone in 150 mL THF at −78° C. under argon. The reaction mixture was stirred 2 h at −78° C. followed by careful and dropwise addition of water to the mixture. The resulting mixture was stirred 30 min at −78° C. and then again water was added at 0° C. The mixture was extracted with ethyl acetate. The organic layer was dried and evaporated. The residue was purified chromatoraphie on silica (petrolether 1/ethylacetate 1). Diisopropylether was added to the residue and the precipitate was filtered and dried to give 1.7 g desired product. Rt: 0.94 (method B), ESI+: 427
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[OH-].[Na+].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>O.CCOCC>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:1]2[CH2:8][CH2:7][CH2:6][C@H:2]2[C:3]([OH:5])=[O:4])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Yield: 74.6 %

Procedure:
In this example, L-proline (11.5 g; 0.10 mole) and caustic soda (8.0 g; 0.2 moles) are dissolved in 100 ml water, and a solution of p-methylphenylsulfonyl chloride (20.9 g) dissolved in ether (80 ml) is added thereto with vigorous stirring under cooling in an ice bath (5°-10° C.). After reaction for about 5 hours, the reaction mixture is left standing, and the upper ether layer is removed. The remaining aqueous layer is admixed with 2N hydrochloric acid to adjust the pH to 3-4. After being left standing in a cool place (0°-5° C.), the deposited crystals are filtered off. The crystals are recrystallized from an aqueous 60% ethanol solution (about 200 ml), whereby p-methylphenylsulfonyl-L-proline (compound number 15; 20.1 g; m.p. 57°-59° C.) was obtained. Yield: 70%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:33]=[CH:32][C:20]2[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][CH2:23][O:24][C:19]=2[CH:18]=1>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C:17]2[CH:33]=[CH:32][C:20]3[N:21]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:22][CH2:23][O:24][C:19]=3[CH:18]=2)=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCOc2cc(N)ccc21
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCc1[nH]c(C(=O)Nc2ccc3c(c2)OCCN3C(=O)OC(C)(C)C)nc1Cl
Yield: 54.2 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (100 mg, 0.59 mmol), thionyl chloride (5 mL), pyridine (10 mL) and tert-butyl 7-amino-2,3-dihydro-4H-1,4-benzoxazine-4-carboxylate obtained in Example (95b) (0.3 g, 1.20 mmol), to obtain 0.13 g of the title compound as a pale yellow solid (56%).
Reaction SMILES: [CH:1]([C:4]1([CH2:9][CH2:10][OH:11])[O:8][CH2:7][CH2:6][O:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:11][CH2:10][CH2:9][C:4]1([CH:1]([CH3:3])[CH3:2])[O:8][CH2:7][CH2:6][O:5]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)C1(CCO)OCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C1(CCOS(C)(=O)=O)OCCO1
Temperature: 25 °C
Yield: 100.7 %

Procedure:
To a solution of 2-(2-isopropyl-1,3-dioxolan-2-yl)-ethanol (8.0 g, 50 mmol) and triethylamine (23.5 mL, 170 mmol) in anhydrous CH2Cl2 (120 mL) was added methanesulfonyl chloride (11.6 mL, 150 mmol) at 0° C., and the reaction mixture was stirred at rt till the reaction was finished. The reaction mixture was washed with water and brine, dried over Na2SO4, filtered, and concentrated to give the crude 2-(2-isopropyl-1,3-dioxolan-2-yl)ethyl methanesulfonate (12 g, crude), which was used for the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:27])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])=[CH:15][CH:14]=2)=[CH:5][C:4]=1[N:28]=[CH:29]N(C)C)#[N:2].[NH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1.ClCCl.CO>CO>[CH2:25]([O:24][C:22]([N:21]=[S:19]([CH3:27])([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][O:11][C:6]2[CH:5]=[C:4]3[C:3]([C:1]([NH:33][C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)=[N:2][CH:29]=[N:28]3)=[CH:8][C:7]=2[O:9][CH3:10])=[CH:14][CH:15]=1)=[O:20])=[O:23])[CH3:26]
Reactant: Nc1cccnc1
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(COc2cc(N=CN(C)C)c(C#N)cc2OC)cc1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)N=S(C)(=O)c1ccc(COc2cc3ncnc(Nc4cccnc4)c3cc2OC)cc1
Yield: 42 %

Procedure:
According to GWP 5, the reaction of N′-(2-cyano-5-{4-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzyloxy}-4-methoxyphenyl)-N,N-dimethylformimidamide (85 mg, 0.19 mmol) with 3-aminopyridine (21 mg, 0.22 mmol) and chromatographic purification (silica gel, dichloromethane/methanol: 0→30% methanol) gives the desired product in 42% yield (39 mg).
Reaction SMILES: [C:1]([O-:5])(=O)[CH2:2][CH3:3].[Na+].[CH2:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17][CH3:18])[C:11]=1[OH:19])[CH2:8][CH3:9]>OS(C(F)(F)F)(=O)=O>[CH2:16]([C:12]1[CH:13]=[C:14]([C:1](=[O:5])[CH2:2][CH3:3])[CH:15]=[C:10]([CH2:7][CH2:8][CH3:9])[C:11]=1[OH:19])[CH2:17][CH3:18]
Reactant: CCCc1cccc(CCC)c1O
Reactant: CCC(=O)[O-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Product: CCCc1cc(C(=O)CC)cc(CCC)c1O

Procedure:
Sodium propanoate (0.88 g, 1.5 eq) and 2,6-dipropylphenol (1.09 g, 1.0 eq) were combined in Triflic Acid (5.0 g) as in Example 13, step 1. The resulting waxy solid was purified by chromatography on silica gel using ethyl acetate:hexanes:acetic acid (10:90:1) to give the titled phenol.
Reaction SMILES: C(O)(=O)C.C(O)(=O)C(O)=O.[CH2:11]([NH:14][NH2:15])[CH2:12][CH3:13].[CH:16](=O)[C:17]([CH3:19])=[O:18]>O>[CH2:11]([NH:14][N:15]=[CH:16][C:17](=[O:18])[CH3:19])[CH2:12][CH3:13]
Reactant: CCCNN
Reactant: CC(=O)C=O
Agent: O=C(O)C(=O)O
Solvent: CC(=O)O
Solvent: O
Product: CCCNN=CC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 119.6 %

Procedure:
Acetic acid (2.9 mL, 50 mmol) was added to a solution of n-propylhydrazine oxalate (5.0 g, 30 mmol) in water (100 mL). This mixture was added to a solution of pyruvaldehyde (4.39 g, 3.96 mL, 24.4 mmol) in water (500 mL). The solution was stirred at room temperature overnight. The aqueous phase was extracted with CH2Cl2 (4×) and the combined organic extracts were washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated to afford 2-oxopropanal propylhydrazone (3.74 g, 96%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[I:9](O)(=O)(=O)=O.S(=O)(=O)(O)O.II>C(O)(=O)C.O>[I:9][C:3]1[CH:4]=[CH:5][C:6]([NH2:8])=[N:7][C:2]=1[CH3:1]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: Cc1cccc(N)n1
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(N)ccc1I
Temperature: 80 °C
Yield: 384.2 %

Procedure:
To a stirred solution of 6-methyl-pyridin-2-ylamine (30 g, 278 mmol, 1 eq) in acetic acid (167 mL) was added periodic acid (12.7 g, 55.6 mmol, 0.2 eq) followed by addition of sulphuric acid (4.8 mL, 90.8 mmol, 0.34 eq), water (33 mL) and iodine (28.7 g, 111 mmol, 0.4 eq) at room temperature. Resulting reaction mixture was heated at 80° C. for 6 hours. After complete consumption of starting material, reaction mixture was cooled and poured into sodium thiosulfate solution (200 mL), reddish oil was settled down at the bottom. Reaction mixture was decanted from reddish oil, and filtrate was basified with 50% sodium hydroxide solution (100 mL), yellow colored solid was formed. Resulting solid was extracted with diethyl ether (2×200 mL) and dried over sodium sulfate. Organic layer was concentrated under reduced pressure to afford brown semi solid (60 g, crude). Crude was purified by column chromatography using silica gel (100-200 mesh). Desired compound was eluted at 15% EtOAc in hexane to get title compound as faint brown solid (50 g, 77%). 1H NMR (400 MHz, CDCl3) δ: 2.52 (s, 3H), 4.43 (bs, 2H), 6.09 (d, J=8.4 Hz, 1H), 7.65 (d, J=8.44 Hz, 1H). LC-MS (m/z): 235.3 (M+H).
Reaction SMILES: C(OC([N:8]([C:25]1[CH:26]=[C:27]([C:30](N2C=CN=C2)=[O:31])[S:28][CH:29]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=O)(C)(C)C.[OH-].[Na+].[NH2:39][CH2:40][CH:41]([OH:44])[CH2:42][OH:43]>C(Cl)(Cl)Cl>[OH:44][CH:41]([CH2:42][OH:43])[CH2:40][NH:39][C:30]([C:27]1[S:28][CH:29]=[C:25]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:26]=1)=[O:31]
Reactant: CCCCCCCCCCCCCCCCN(C(=O)OC(C)(C)C)c1csc(C(=O)n2ccnc2)c1
Reactant: NCC(O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCNc1csc(C(=O)NCC(O)CO)c1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a mixture containing 4.1 g. of 1-{4-[N-(tert-butyloxycarbonyl)-N-(hexadecyl)amino]-2-thiophenecarbonyl}imidazole, 50 ml. of chloroform, and 50 ml. of 5 N sodium hydroxide is added 1.1 g. of 3-amino-1,2-propanediol. The solution is vigorously stirred for 24 hours, the layers are separated, and the chloroform solution is washed once with 50 ml. of 1 N sodium hydroxide. The solvent is evaporated and the residue is heated for 30 minutes at 40° C. in 50 ml. of anhydrous trifluoroacetic acid. The solvent is again evaporated and the oil is crystallized from acetone to yield light yellow crystals of N-(2,3-dihydroxypropyl)-4-hexadecylamino-2-thiophenecarboxamide.