Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C@H:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7])=[CH:4][C:3]=1[O:24][CH3:25].[C:26]([NH:29][C:30]1[NH:31][C:32](=[O:47])[C:33]([CH2:43][CH2:44][CH:45]=O)=[C:34]([N:36]([C:40](=[O:42])[CH3:41])[C:37](=[O:39])[CH3:38])[N:35]=1)(=[O:28])[CH3:27].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C.CO>[C:26]([NH:29][C:30]1[NH:31][C:32](=[O:47])[C:33]([CH2:43][CH2:44][CH2:45][NH:1][C:2]2[CH:23]=[CH:22][C:5]([C:6]([NH:8][C@H:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7])=[CH:4][C:3]=2[O:24][CH3:25])=[C:34]([N:36]([C:37](=[O:39])[CH3:38])[C:40](=[O:42])[CH3:41])[N:35]=1)(=[O:28])[CH3:27]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(N)c(OC)c1)C(=O)OCC
Reactant: CC(=O)Nc1nc(N(C(C)=O)C(C)=O)c(CCC=O)c(=O)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCO
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(NCCCc2c(N(C(C)=O)C(C)=O)nc(NC(C)=O)[nH]c2=O)c(OC)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Both diethyl N-(4-amino-3-methoxybenzoyl)-(L)-glutamate (3.52 g, 9.99 mmoles) and 3-(2-acetylamino-4-diacetylamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propionaldehyde (3.08 g, 9.99 mmoles) were stirred in absolute ethanol (100 mL) under nitrogen while glacial acetic acid (6 mL) was added dropwise during 1 minute. After solution was achieved (0.5 hour), activated 3 Å molecular sieves (20 mL) were added and stirring was continued 2 hours. The reaction mixture was chilled (ice bath) and sodium cyanoborohydride (628 mg, 9.99 mmoles) added in one portion. After stirring cold 0.5 hour, the bath was removed and the reaction mixture allowed to warm to ambient temperature. The reaction mixture was filtered after 16 hours and the solids were rinsed with ethanol (100 mL). The filtrate was spin evaporated and dried to a cream foam that was dissolved in ethyl acetate (100 mL). The organic phase was washed (2×100 mL 1:1 brine/water) and poured onto a silica gel column (175 g, pre-wet with ethyl acetate). The column was rinsed with ethyl acetate (400 mL) and then the product eluted with 5% added methanol. Like fractions were combined by spin evaporation and dried to give a white solid; yield, 2.07 g (32%); mp 73°-84° C. (eff.); 1H-NMR (DMSO-d6) δ 1.15 and 1.17 (2t overlapped, 6H), 1.65 (br m, 2H) 1.9-2.3 (br m, 4H), 2.12 (s, 3H), 2.20 (s, 6H), 2.40 (t, 2H), 3.10 (br m, 2H), 3.80 (s, 3H), 4.0-4.2 (2 q overlapped, 4H), 4.39 (m, 1H), 5.46 (br t, 1H), 6.47 (d, Jo=8 Hz, 1H), 7.29 (d, Jm=2 Hz, 1H), 7.42 (dxd, Jo=8 Hz, Jm=2 hz, 1H), 8.28 (d, 1H), 11.9 (v br s, 2H); uv (MeOH) 306 nm max (25800), 258 min (3940), 227 sh (17800), 205 max (32400), mass spec (FAB) m/e 645.6 (62%), 442.5 (81), 400.1 (100).
Reaction SMILES: [C:1]([O:7][C@@H:8]1[C@@H:13]([O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:12]([O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C@@H:11]([CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[O:10][C@H:9]1[O:36][C:37]1[C:45]2[C:40](=[N:41][CH:42]=[CH:43][C:44]=2[CH2:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])=[CH:50][CH:49]=2)[NH:39][N:38]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:61][N:62]([CH3:66])[CH2:63][CH2:64]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:61][N:62]([CH3:66])[CH2:63][CH2:64][N:39]1[C:40]2=[N:41][CH:42]=[CH:43][C:44]([CH2:46][CH2:47][C:48]3[CH:49]=[CH:50][C:51]([O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])=[CH:52][CH:53]=3)=[C:45]2[C:37]([O:36][C@@H:9]2[O:10][C@H:11]([CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:33])([CH3:34])[CH3:32])[C@@H:12]([O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C@H:13]([O:14][C:15](=[O:20])[C:16]([CH3:17])([CH3:19])[CH3:18])[C@H:8]2[O:7][C:1](=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5])=[N:38]1
Reactant: CN(C)CCO
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccc(OC(=O)C(C)(C)C)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCn1nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c2c(CCc3ccc(OC(=O)C(C)(C)C)cc3)ccnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-4-[2-(4-pivaloyloxyphenyl)ethyl]-1H-pyrazolo-[3,4-b]pyridine (75 mg) in tetrahydrofuran (0.5 mL) were added 2-dimethylaminoethanol (9 mg), triphenylphosphine (26 mg) and diethyl azodicarboxylate (40% toluene solution, 0.059 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=15/1) to give 1-(2-dimethylaminoethyl)-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-4-[2-(4-pivaloyloxyphenyl)ethyl]-1H-pyrazolo[3,4-b]pyridine (79 mg). This material was dissolved in methanol (2 mL). To the solution was added sodium methoxide (28% methanol solution, 0.04 mL), and the mixture was stirred at 50° C. for 3 hours. The reaction mixture was purified by column chromatography on silica gel (eluent: dichloromethane/methanol =5/1−1/1) to give the title compound (16 mg).
Reaction SMILES: [CH3:1][S:2]([O:5][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH3:7])(=[O:4])=[O:3].[CH3:16]C(O)CCCCCCCCC.CS(Cl)(=O)=O.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][S:2]([O:5][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:7])(=[O:4])=[O:3]
Reactant: CCCCCCCCCC(C)O
Reactant: CCCCCCCCC(C)OS(C)(=O)=O
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCC(C)OS(C)(=O)=O
Reaction time: 3.5 h
Yield: 95 %

Procedure:
2-Methanesulfonyloxyundecane was prepared as described for 2-methanesulfonyloxydecane from 2-undecanol (30.0 ml, 144 mmol), methanesulfonylchloride (15.5 ml, 200 mmol) and diisopropylethylamine (30.8 ml, 177 mmol) in dry CH2Cl2 (240 ml). After stirring for 3.5 hrs, the reaction was processed as previously stated but at 4 times the volumes to provide 2-methanesulfonyloxyundecane (31.35 g, 95%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1C(OCC1C=CC=CC=1)=O)([CH3:4])([CH3:3])[CH3:2].C(=O)=O.[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:22])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C=O
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1

Procedure:
Benzyloxycarbonyl-L-proline tert.butyl ester (205 g.) is dissolved in absolute ethanol (1.2 l) and hydrogenated at normal pressure with 10% Pd on carbon (10 g.) until only a trace of carbon dioxide is observed in the hydrogen exit gas (24 hours). The catalyst is filtered off and the filtrate is concentrated in vacuo at 30 mm Hg. The residue is distilled in vacuo, to obtain L-proline tert.butyl ester, b.p.1mm 50°-51°.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:11]([F:12])=[CH:10][C:9]([N:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[C:8]([F:26])[CH:7]=1)=[O:5])[CH3:2].[ClH:27]>O1CCOCC1.C(OCC)C>[ClH:27].[CH2:1]([NH:3][C:4](=[O:5])[C:6]1[CH:7]=[C:8]([F:26])[C:9]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:10][C:11]=1[F:12])[CH3:2]
Reactant: CCNC(=O)c1cc(F)c(N2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCNC(=O)c1cc(F)c(N2CCNCC2)cc1F
Reaction time: 0.5 h
Yield: 98 %

Procedure:
tert-butyl 4-(4-(ethylcarbamoyl)-2,5-difluorophenyl)piperazine-1-carboxylate (0.020 g, 0.054 mmol) was diluted with 4.0M HCl in dioxane (3 mL) and stirred for 30 min. The thick white precipitate that formed was diluted with ethyl ether (10 mL) and stirred until a fine suspension resulted. The precipitate was filtered under nitrogen and dried in vacuum to afford N-ethyl-2,5-difluoro-4-(piperazin-1-yl)benzamide hydrochloride (16.2 mg, 0.053 mmol, 98% yield) as a white solid. ESI-MS: m/z 270 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:10](=[O:23])[N:11]([CH3:22])[C:12]2([CH2:19][CH2:18][N:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[C:13]=1[OH:14].C(=O)([O-])O.[Na+].S(Cl)([Cl:32])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:32][C:9]1([C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[CH3:1])[C:13](=[O:14])[C:12]2([CH2:19][CH2:18][N:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[N:11]([CH3:22])[C:10]1=[O:23]
Reactant: O=S(=O)(Cl)Cl
Reactant: CON1CCC2(CC1)C(O)=C(c1cc(C)ccc1C)C(=O)N2C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CON1CCC2(CC1)C(=O)C(Cl)(c1cc(C)ccc1C)C(=O)N2C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(2,5-dimethyl-phenyl)-4-hydroxy-8-methoxy-1-methyl-1,8-diaza-spiro[4.5]dec-3-en-2-one (compound P2.1) (35 mg, 0.111 mmol) and sodium hydrogen carbonate (23 mg, 0.274 mmol) in chloroform (5 ml) at −5° C. was added sulfuryl chloride (0.009 ml, 15.0 mg, 0.111 mmol) in chloroform (0.25 ml) dropwise. The reaction mixture was stirred at 0° C. for 30 minutes and at room temperature overnight, poured on saturated aqueous sodium carbonate, the layers separated, the water phase extracted with ethyl acetate (3×20 ml), the combined organic phases washed with saturated aqueous sodium carbonate and brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/cyclohexane 2:1). Yield: 26 mg of 3-chloro-3-(2,5-dimethyl-phenyl)-8-methoxy-1-methyl-1,8-diaza-spiro[4.5]decane-2,4-dione (title compound P1.5) as a pale yellow gum.
Reaction SMILES: O1C2C=CC(C3(C(NC4C=CC=C(Br)N=4)=O)CC3)=CC=2OC1.[Cl-].C([Zn+])C(C)C.[O:29]1[C:33]2[CH:34]=[CH:35][C:36]([C:38]3([C:41]([NH:43][C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50][CH:51]5[CH2:56]CCC[CH2:52]5)[N:45]=4)=[O:42])[CH2:40][CH2:39]3)=[CH:37][C:32]=2[O:31][CH2:30]1>>[O:29]1[C:33]2[CH:34]=[CH:35][C:36]([C:38]3([C:41]([NH:43][C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50][CH:51]([CH3:56])[CH3:52])[N:45]=4)=[O:42])[CH2:40][CH2:39]3)=[CH:37][C:32]=2[O:31][CH2:30]1
Reactant: O=C(Nc1cccc(CC2CCCCC2)n1)C1(c2ccc3c(c2)OCO3)CC1
Agent: CC(C)C[Zn+]
Agent: O=C(Nc1cccc(Br)n1)C1(c2ccc3c(c2)OCO3)CC1
Agent: [Cl-]
Product: CC(C)Cc1cccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)n1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-isobutylpyridin-2-yl)cyclopropanecarboxamide was prepared from 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-bromopyridin-2-yl)cyclopropanecarboxamide and isobutylzinc(II) chloride in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-(cyclohexylmethyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:19]([C@@H:22]1[C@@H:29]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C@@H:28]([OH:40])[C@@H:27]([CH2:41][OH:42])[O:26][C@H:23]1[S:24][CH3:25])=[N+:20]=[N-:21]>CN(C)C1C=CN=CC=1.ClCCCl.C(Cl)(Cl)Cl>[N:19]([C@@H:22]1[C@@H:29]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C@@H:28]([OH:40])[C@@H:27]([CH2:41][O:42][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:26][C@H:23]1[S:24][CH3:25])=[N+:20]=[N-:21]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(CO[C@H]2[C@@H](O)[C@@H](CO)O[C@@H](SC)[C@@H]2N=[N+]=[N-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: COc1ccc(CO[C@H]2[C@@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O[C@@H](SC)[C@@H]2N=[N+]=[N-])cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
A mixture of t-butyldiphenylsilyl chloride (151 mg, 0.54 mmol), 4-dimethylaminopyridine (90 mg, 0.73 mmol) and methyl 2-azido-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-galactopyranoside (15) (130 mg, 0.36 mmol) in dry 1,2-dichloroethane (8 mL) was stirred at 80° C. for 2 hours. The resulting clear solution was cooled to room temperature, diluted with CHCl3 (20 mL), washed with H2O (3×20 mL), brine solution (20 mL), dried over MgSO4 and evaporated. The residue was purified by chromatography using hexane—ether 2:1 as the mobile phase to give methyl 2-azido-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-galactopyranoside (16) (142 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7](I)[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[CH:19].C(OCC)(=O)C>CCCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([NH2:6])=[C:7]([C:19]#[C:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Cl:11])[CH:8]=1
Reactant: C#Cc1ccccc1Cl
Reactant: Nc1c(F)cc(Cl)cc1I
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Nc1c(F)cc(Cl)cc1C#Cc1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 10 step A from 4-chloro-2-fluoro-6-iodoaniline (500 mg, 1.84 mmol) and 1-chloro-2-ethynyl-benzene (302 mg, 2.21 mmol). Brown solid (1.05 g, 68%). Rf 0.3 (1:9 Ethyl acetate:heptane) as a bright blue spot under UV light.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[NH:24][C:25]([NH:27][CH3:28])=[O:26])[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([C:16]([OH:18])=O)[CH:14]=2)[N:9]=[CH:8][CH:7]=1.CN.CO.[CH2:33]([N:35](CC)CC)C.F[P-](F)(F)(F)(F)F.CN([PH+](N(C)C)N(C)C)C>CN(C)C=O.O.C(OCC)(=O)C>[CH3:33][NH:35][C:16]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[O:19][CH3:20])[N:9]=[CH:8][CH:7]=[C:6]2[O:5][C:4]1[CH:21]=[CH:22][C:23]([NH:24][C:25]([NH:27][CH3:28])=[O:26])=[C:2]([Cl:1])[CH:3]=1)=[O:18]
Reactant: CCN(CC)CC
Reactant: CNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(=O)O)cc23)cc1Cl
Agent: CN
Agent: CN(C)[PH+](N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(=O)NC)cc23)cc1Cl
Reaction time: 15 h
Yield: 82 %

Procedure:
After dissolving 4-(3-chloro-4-(((methylamino) carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylic acid (100 mg, 0.250 mmol) in dimethylformamide (3 ml), there were added a 40% methylamine-methanol solution (0.100 ml), triethylamine (0.250 ml) and 1H-1,2,3-benzotriazol-1-yloxy) (tri(dimethylamino))phosphonium hexafluorophosphate (221mg, 0.500 mmol) in that order at room temperature, and the mixture was stirred for 15 hours. The reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, the residue was suspended in ethyl acetate and diluted with hexane, and the crystals were filtered out and blow-dried to obtain the title compound (85.0 mg, 0.204 mmol, 82%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:23])[CH2:12][C:13]2[CH:18]=[C:17]([Br:19])[C:16]([O:20][CH3:21])=[C:15]([Br:22])[CH:14]=2)=[CH:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:25]([O:24][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:23])[CH2:12][C:13]2[CH:18]=[C:17]([Br:19])[C:16]([O:20][CH3:21])=[C:15]([Br:22])[CH:14]=2)[CH:6]=[CH:7][C:2]=1[NH:1][S:38]([C:35]1[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=1)(=[O:40])=[O:39])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1c(Br)cc(CC(=O)NCCc2ccc(N)c(OCc3ccccc3)c2)cc1Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1c(Br)cc(CC(=O)NCCc2ccc(NS(=O)(=O)c3ccc(C)cc3)c(OCc3ccccc3)c2)cc1Br
Temperature: 25 °C
Reaction time: 54 h

Procedure:
To a solution of N-[2-(4-amino-3-benzyloxy-phenyl)-ethyl]-2-(3,5-dibromo-4-methoxy-phenyl)-acetamide (0.836 g, 0.00152 mol) and p-toluenesulfonyl chloride (0.440 g, 0.00231 mol) in 40 mL of methylene chloride qas added 4 mL of pyridine. The reaction mixture was stirred for 54 h at room temperature, washed with 1N HCl, 1N NaOH solutions, dried over Na2SO4 and evaporated. A residue was crystallized from ethyl acetate-hexanes mixture. Yield 0.933 g (87%).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].O[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[C:27]#[N:28])=[CH:19][CH:18]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>ClCCl.C1(C)C=CC=CC=1>[C:12]([C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH:23]([O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=3)[C:27]#[N:28])=[CH:21][CH:22]=2)=[C:7]([CH2:8][CH2:9][CH3:10])[C:2]=1[OH:1])(=[O:14])[CH3:13]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: N#Cc1cccc(C(OC2CCCCO2)c2ccc(CO)cc2)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCc1c(OCc2ccc(C(OC3CCCCO3)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
Stir a solution of 1-(2,4-dihydroxy-3-propyl-phenyl)-ethanone (1.75 g, 9 mmol), 3-[(4-hydroxymethyl-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile (2.9 g, 9 mmol), toluene (10 mL), and dichloromethane (10 mL) at −20° C. Add 1,1′-(azodicarbonyl)dipiperidine (4.5 g, 18 mmol) followed by tributylphosphine (4.5 mL, 18 mmol) and allow the resulting yellow solution to stir at room temperature overnight. Concentrate the resulting thick reaction mixture and dilute with ether (50 mL). Cool the slurry to 0° C. with stirring, for 30 minutes. Filter the reaction mixture, concentrate, and purify via silica chromatography eluting with 1:1 hexanes:(5:4:1 hexanes:dichloromethane:ethyl acetate) to give the title compound (3 g, 67%), as an orange thick oil. LCMS (m/z) 498 M−1.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([C@:6]2([C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][N:28]=4)[CH2:23][CH2:22]3)=[O:20])[CH2:10][CH2:9][C@@H:8]([NH:11]C(=O)OC(C)(C)C)[CH2:7]2)[CH2:2]1.[ClH:37]>CCOCC>[ClH:37].[ClH:37].[O:1]1[CH2:5][CH2:4][C@H:3]([C@:6]2([C:19]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:32]=[C:31]([C:33]([F:35])([F:34])[F:36])[CH:30]=[CH:29][N:28]=4)[CH2:25][CH2:26]3)=[O:20])[CH2:10][CH2:9][C@@H:8]([NH2:11])[CH2:7]2)[CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@](C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)([C@H]2CCOC2)C1
Agent: Cl
Solvent: CCOCC
Product: N[C@@H]1CC[C@@](C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)([C@H]2CCOC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl [(1R,3S)-3-[(3R)-tetrahydrofuran-3-yl]-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]carbamate (260 mg, 0.51 mmol) was dissolved in a 2 M solution of of hydrogen chloride in ether (8 mL). After being stirred at room temperature overnight, the reaction mixture was concentrated under vacuum to provide the desired product (290 mg) as a light yellow solid. MS calculated for C20H27F3N4O2: (M+H) 413.2; found 413.0.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][NH2:10])[CH:2]=[CH2:3].[CH3:11][NH:12][S:13]([C:16]1[CH:17]=[C:18]([C:26](Cl)=[O:27])[C:19]2[O:24][CH2:23][CH2:22][O:21][C:20]=2[CH:25]=1)(=[O:15])=[O:14]>>[CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][NH:10][C:26]([C:18]1[C:19]2[O:24][CH2:23][CH2:22][O:21][C:20]=2[CH:25]=[C:16]([S:13](=[O:15])(=[O:14])[NH:12][CH3:11])[CH:17]=1)=[O:27])[CH:2]=[CH2:3]
Reactant: C=CCN1CCCC1CN
Reactant: CNS(=O)(=O)c1cc2c(c(C(=O)Cl)c1)OCCO2
Product: C=CCN1CCCC1CNC(=O)c1cc(S(=O)(=O)NC)cc2c1OCCO2
Yield: 52.6 %

Procedure:
In a similar manner to the above example, 84 g of dextrorotatory 1-allyl-2-aminomethyl-pyrrolidine was reacted with 175 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride to give, after purification, 125 g of dextrorotatory-N-(1-allyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide (M.P.: 104°-105° C.; yield: 52.6%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([CH:23]=[C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:21][CH:22]=1>>[C:31]1([C:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:23][C:20]2[O:21][CH:22]=[C:18]([CH2:17][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[CH:4][CH:3]=3)[N:19]=2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: ClCc1coc(C=C(c2ccccc2)c2ccccc2)n1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: C(=C(c1ccccc1)c1ccccc1)c1nc(COc2ccc(CCCn3ccnc3)cc2)co1
Yield: 88 %

Procedure:
In substantially the same manner as in Working Example 47, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(2,2-diphenyl ethenyl)oxazole to give 2-(2,2-diphenylethenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole as an oily product. The yield was 88%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-])=O)[C:3]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)C>[Ni].O>[NH2:9][C:4]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: O=[N+]([O-])c1c(O)ccc(Br)c1Oc1ccccc1
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: Nc1c(O)ccc(Br)c1Oc1ccccc1
Yield: 81.8 %

Procedure:
A solution of 4-bromo-2-nitro-3-phenoxyphenol (0.468 g, 1.51 mmol) in ethanol (11.2 mL, 192 mmol) was degassed with nitrogen and treated with a slurry of Raney Nickel 2800 in water (0.468 ml). The reaction mixture was degassed again with nitrogen and hydrogenated with a balloon of hydrogen for 30 min. The reaction suspension was diluted with dichloromethane and methanol and filtered through a pad of Celite. The pad of Celite was washed with ethyl acetate and dichloromethane and the filtrate was concentrated in vacuo to give brown oil. Purification by flash column chromatography (100% CH2Cl2 to 30% CH3CN/CH2Cl2 [CH3CN contained 5% MeOH]) gave the desired product (346 mg, 82%) as a tan solid. LCMS calculated for C12H11BrNO2 (M+H)+: m/z=280.0, 282.0. found: 280.0, 282.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH3:19])[C:12]([CH3:18])=[C:13]([CH:17]=2)[C:14]([OH:16])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.C(Cl)(C(Cl)=O)=O.[NH2:26][C:27]1[C:28]([F:35])=[C:29]([OH:34])[CH:30]=[CH:31][C:32]=1[F:33].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C.C1COCC1.O>[F:35][C:28]1[C:29]([OH:34])=[CH:30][CH:31]=[C:32]([F:33])[C:27]=1[NH:26][C:14](=[O:16])[C:13]1[CH:17]=[C:9]([C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=2)[CH:10]=[C:11]([CH3:19])[C:12]=1[CH3:18]
Reactant: Nc1c(F)ccc(O)c1F
Reactant: Cc1cc(-c2cc(F)cc(F)c2)cc(C(=O)O)c1C
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2cc(F)cc(F)c2)cc(C(=O)Nc2c(F)ccc(O)c2F)c1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 15.5 %

Procedure:
To a solution of 5-(3,5-difluorophenyl)-2,3-dimethyl-benzoic acid (240 mg, 0.92 mmol, 1.1 eq) in CH2Cl2 (12 mL) was added (COCl)2 (348 mg, 2.75 mmol, 3.3 eq) and DMF (5 drops). The reaction mixture was stirred at room temperature for 1.5 h, then concentrated under reduced pressure to remove the organic solvent and excess reagent. The residue obtained was dissolved in THF (10 mL) and added dropwise to a solution of 3-amino-2,4-difluorophenol (intermediate X(a)) (121 mg, 0.83 mmol, 1.0 eq) and NaHCO3 (386 mg, 4.6 mmol, 5.0 eq) in THF (10 mL) at 0° C. After the addition, the reaction mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (CH2Cl2:MeOH, 500:1 to 200:1) to give the title compound as a yellow solid (50 mg, 15%).