Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][NH:22][CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:24]2)[O:12]1.[BH3-]C#N.[Na+].[CH3:43][C:44](O)=O.CC=O>CO.O>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:19])([CH3:20])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH2:43][CH3:44])[CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:30])[CH2:24]2)[O:12]1
Reactant: CC(=O)O
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CNC1CC(CCC(=O)OCc3ccccc3)C1)O[C@H]2n1cnc2c(N)ncnc21
Agent: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)OCc2ccccc2)C1
Temperature: 30 °C
Reaction time: 1.5 h
Yield: 66 %

Procedure:
To a mixture of benzyl 3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)cyclobutyl)propanoate (3.76 g, 7.2 mmol) and NaBH3CN (5.9 g, 93.6 mmol) in MeOH (40 mL) was added AcOH to adjust to pH=6. Then, 40% MeCHO (8.7 mL, 122.5 mmol) was added and the mixture was stirred at 30° C. for 1.5 h. Water (15 mL) was added and the mixture was concentrated in vacuo. Then, the mixture was extracted with DCM (30 mL×3). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude was purified by SGC (DCM: MeOH=100:1-20:1) to obtain the target (2.6 g, yield: 66%) as a white solid. 1H NMR (500 MHz, MeOD): δH 8.26 (s, 1H), 8.23 (m, 1H), 7.37-7.28 (m, 5H), 6.24 (s, 1H), 5.52-5.49 (m, 1H), 5.10-5.06 (m, 3H), 4.41-4.40 (m, 1H), 3.20-2.90 (m, 2H), 2.80-2.60 (m, 2H), 2.12-1.77 (m, 4H), 1.74-1.60 (m, 3H), 1.39 (s, 3H), 1.26-1.22 (m, 3H), 0.94-0.89 (m, 3H) ppm; ESI-MS (m/z): 551.3 [M+1]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:11]1[N:16]=[C:15]2[O:17][C:18]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)=[C:19]([C:20]([NH:22][CH3:23])=[O:21])[C:14]2=[CH:13][C:12]=1[I:31])[S:7]([CH3:10])(=[O:9])=[O:8].C(N(CC)CC)C.S(=O)(=O)=O.N1C=CC=CC=1.O>CS(C)=O>[I:31][C:12]1[CH:13]=[C:14]2[C:19]([C:20]([NH:22][CH3:23])=[O:21])=[C:18]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[O:17][C:15]2=[N:16][C:11]=1[N:6]([CH2:5][CH2:4][CH2:3][CH:2]=[O:1])[S:7]([CH3:10])(=[O:9])=[O:8]
Reactant: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCCCO)S(C)(=O)=O)c(I)cc12
Agent: O=S(=O)=O
Solvent: CS(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCCC=O)S(C)(=O)=O)c(I)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(N-(4-hydroxybutyl)methylsulfonamido)-5-iodo-N-methyl-2-p-tolylfuro[2,3-b]pyridine-3-carboxamide (1 eq., 190 mg) in DMSO (1.7 ml) was added triethyl amine (8 eq., 0.38 ml) and pyridine sulfur trioxide (3 eq., 163 mg). The mixture was stirred at room temperature for 1 h. Water was added. The mixture was extracted with EtOAc. The organic layer was washed with water three times, dried over MgSO4 and concentrated to yield the crude title compound which was used in next step without purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([OH:15])[C@H:10]([NH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:17]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][CH:18]=1.CN(C1C=CC=CN=1)C.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([OH:15])[C@H:10]([NH:16][C:23]([C:20]2[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=2)=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)[C@H](N)C1
Reactant: O=C(O)c1ccncc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H](O)[C@H](NC(=O)c2ccncc2)C1
Temperature: 5 °C
Reaction time: 48 h

Procedure:
36.85 g of (3R,4S)-3-Amino-4-hydroxy-azepane-1-carboxylic acid tert-butyl ester, 19.70 g 4-pyridinecarboxylic acid, and 9.76 g dimethylaminopyridine were dissolved in 500 mL CH2Cl2 and cooled to 5° C. 33.01 g DCC was dissolved in 250 mL CH2Cl2 and added to the above mixture within 2 h. The reaction mixture was stirred for 48 h at rt. 200 mL water was added and the mixture is stirred for 2 h at rt. The precipitate was filtered off and the organic phase was extracted two times with 500 mL water. The organic solvent was evaporated in vacuo. The crude product was then submitted to column chromatography (SiO2, ethyl acetate/methanol 99:1) to give 46.2 g (86%) of 1 g as a white solid. MS (ESI): m/z (%): 334 (MH+), 336 ([M−H]+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:20]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[CH:4][C:5]([NH:8]CC2C=CC(OC)=C(OC)C=2)=[N:6][CH:7]=1.C(=O)(O)[O-].[Na+].CCCCCC>FC(F)(F)C(O)=O>[Cl:1][C:2]1[C:3]([CH:20]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: COc1ccc(CNc2cc(C(c3c(F)cccc3F)S(=O)(=O)c3ccc(Cl)cc3)c(Cl)cn2)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(C(c2c(F)cccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Temperature: 65 °C
Yield: 67.8 %

Procedure:
The 5-chloro-4-[(4-chlorophenylsulfonyl)(2,6-difluorophenyl)methyl]-2-(3,4-dimethoxybenzylamino)pyridine (293 mg, 0.506 mmol) obtained in Example 295 was dissolved in trifluoroacetic acid (4 ml). The resulting solution was heated at 65° C. for 2 hours. The reaction mixture was concentrated. The residue thus obtained was basified with a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate, and concentrated. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=2:1 eluate was concentrated. The solid thus obtained was recrystallized from ethyl acetate-hexane to give the title compound (147 mg, 0.343 mmol, 68%) as a white solid.
Reaction SMILES: [F:1][C@H:2]1[C@H:7]2[NH:8]C(=O)[O:10][C@H:6]2[CH2:5][C@H:4]([CH2:12][OH:13])[C@H:3]1[OH:14].[Li+].[OH-]>O.CO>[NH2:8][C@@H:7]1[C@H:2]([F:1])[C@H:3]([OH:14])[C@@H:4]([CH2:12][OH:13])[CH2:5][C@@H:6]1[OH:10]
Reactant: O=C1N[C@@H]2[C@H](F)[C@H](O)[C@@H](CO)C[C@@H]2O1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N[C@@H]1[C@H](F)[C@H](O)[C@@H](CO)C[C@@H]1O
Yield: 78.9 %

Procedure:
A mixture of (3aS,4S,5R,6R,7aS)-4-fluoro-5-hydroxy-6-(hydroxymethyl)hexahydrobenzo[d]oxazol-2(3H)-one (704 mg, 3.43 mmol) and LiOH (2.71 g, 113 mmol) in water (35 mL) and MeOH (26 mL) was stirred at reflux for 2 h. The solvents were evaporated to give the crude product. This was purified by SiO2 column, eluted with 20%-30% 2 M NH3 MeOH solution in DCM give (1S,2S,3S,4R,5R)-2-amino-3-fluoro-5-(hydroxymethyl)cyclohexane-1,4-diol (485 mg, 80%) as a white solid. 1H NMR (400 MHz, MeOD) δ 4.74 (d, J=52.0 Hz, 1H), 3.96-3.99 (m, 1H), 3.65-3.73 (m, 2H), 3.49 (ddd, J=28.0 Hz, 10.5 Hz, 1.6 Hz, 1H), 3.05 (d, J=31.0 Hz, 1H), 2.09-2.19 (m, 1H), 1.96 (dt, J=14.5 Hz, 3.7 Hz, 1H), 1.46-1.53 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].N1C=CN=C1.[C:14]([O:18][C:19]([N:21]1[CH2:28][CH:27]2[N:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:23]([CH2:24][C:25]([C:40]3[S:44][C:43]([CH2:45][O:46][CH2:47][CH2:48][OH:49])=[N:42][CH:41]=3)=[C:26]2[C:37]([OH:39])=[O:38])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.CO>[C:14]([O:18][C:19]([N:21]1[CH2:28][CH:27]2[N:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:23]([CH2:24][C:25]([C:40]3[S:44][C:43]([CH2:45][O:46][CH2:47][CH2:48][O:49][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6])=[N:42][CH:41]=3)=[C:26]2[C:37]([OH:39])=[O:38])[CH2:22]1)=[O:20])([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1CC2CC(c3cnc(COCCO)s3)=C(C(=O)O)C(C1)N2C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CC(c3cnc(COCCO[Si](C)(C)C(C)(C)C)s3)=C(C(=O)O)C(C1)N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 108.9 %

Procedure:
TBDMS-Cl (184 mg, 1.22 mmol), and imidazole (131 mg, 1.95 mmol) were added to a stirred solution of the compound D7 (256 mg, 0.488 mmol) in THF (2.5 mL). The reaction mixture was stirred at rt for 15 h. The crude mixture was partitioned between Et2O and aq. sat. NH4Cl. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The crude oil was dissolved in THF (4.5 mL), MeOH (0.7 mL), and water (0.7 mL), and K2CO3 (34 mg, 0.024 mmol) was added. The mixture was stirred at rt for 3 h. The mixture was partitioned between Et2O and aq. sat. NH4Cl, and the aq. layer was extracted once more with Et2O. The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed in vacuo to yield the title compound (0.34 g, quantitative yield) as a yellow oil that was not further purified. LC-MS: tR=1.10 min, ES+: 640.50.
Reaction SMILES: [F:1][C:2]([F:21])([C:7]([F:20])([F:19])[CH2:8][O:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][CH2:4][CH2:5][OH:6].C1(CCCCOCCC=O)C=CC=CC=1>>[F:1][C:2]([F:21])([C:7]([F:19])([F:20])[CH2:8][O:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:3][CH2:4][CH:5]=[O:6]
Reactant: OCCCC(F)(F)C(F)(F)COCCCc1ccccc1
Agent: O=CCCOCCCCc1ccccc1
Product: O=CCCC(F)(F)C(F)(F)COCCCc1ccccc1

Procedure:
Obtained from Intermediate 41 (0.68 g, 2.20 mmol) by the procedure described in Intermediate 13. 4,4,5,5-Tetrafluoro-6-(3-phenylpropoxy)hexanal was obtained (0.32 g, 47%) as oil.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[CH:5][C:4]=1[C:14]1[N:15]=[CH:16][N:17]([C:19]2[CH:20]=[C:21]([NH2:26])[CH:22]=[CH:23][C:24]=2[CH3:25])[CH:18]=1)[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C[O:38][C:39](=O)[C:40]1[CH:45]=[C:44]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:43]=[C:42]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[C:41]=1[O:55][CH3:56].C([O-])(O)=O.[Na+]>C1COCC1>[C:46]([C:44]1[CH:43]=[C:42]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[C:41]([O:55][CH3:56])=[C:40]([CH:45]=1)[C:39]([NH:26][C:21]1[CH:22]=[CH:23][C:24]([CH3:25])=[C:19]([N:17]2[CH:18]=[C:14]([C:4]3[CH:5]=[N:6][N:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:3]=3[CH2:1][CH3:2])[N:15]=[CH:16]2)[CH:20]=1)=[O:38])([CH3:49])([CH3:47])[CH3:48]
Reactant: COC(=O)c1cc(C(C)(C)C)cc(NS(C)(=O)=O)c1OC
Reactant: CCc1c(-c2cn(-c3cc(N)ccc3C)cn2)cnn1-c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1c(-c2cn(-c3cc(NC(=O)c4cc(C(C)(C)C)cc(NS(C)(=O)=O)c4OC)ccc3C)cn2)cnn1-c1ccccc1
Reaction time: 0.08 h
Yield: 40.2 %

Procedure:
3-[4-(5-Ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-phenylamine (Example 3) (80 mg, 0.23 mmol) was dissolved in THF (5 mL) under N2 and 0.9 mL of 1 M LiHMDS (0.9 mmol) was slowly added. After stirring for 5 min, a solution of 73.5 mg (0.23 mmol) of 5-tert-butyl-3-methanesulfonylamino-2-methoxy-benzoic acid methyl ester (Example 1) in 5 mL of THF was added. The mixture was stirred at room temperature for 45 min, then saturated NaHCO3 (10 mL) was slowly added. The resulting mixture was then extracted with CH2Cl2 (100 mL). Chromatography (30 to 100% EtOAc in hexanes) provided the title compound as a tan foam (58 mg, 40%). ESI MS m/z 627 [C34H38N6O4S+H]+.
Reaction SMILES: S(O)(O)(=O)=O.[NH:6]1[CH:10]=[CH:9][N:8]=[C:7]1[NH2:11].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]([C:25](OCC)=[O:26])[C:20](OCC)=[O:21].N12CCCN=C1CCCCC2>CN(C=O)C>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[C:25]([OH:26])=[N:11][C:7]2[N:6]([CH:10]=[CH:9][N:8]=2)[C:20]=1[OH:21]
Reactant: Nc1ncc[nH]1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1F
Agent: O=S(=O)(O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Oc1nc2nccn2c(O)c1-c1ccccc1F
Temperature: 100 °C

Procedure:
5 g (27.5 mmol) 1H-Imidazol-2-ylamine sulfate are dissolved in 31.7 mL DMF. 7 g (27.5 mmol) diethyl (2-fluorophenyl)malonate are added. After dropwise addition of 12.3 mL (82.6 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene the reaction mixture is stirred at 100° C. over night. The DMF is evaporated and the darkbrown oily residue treated with 150 mL water (complete dissolution). 2M HCl (60 mL) is added at room temperature until a pH of 1. After stirring for 1 h at ice bath cooling the formed crystals are collected by filtration to yield the product (3.43 g=48.3%), which is used without further purification. Another crop of 0.41 g (6.1%) is obtained by evaporating the solvent, treating the oily residue with water and 2M HCl. After stirring for five hours the crystals are collected and washed with water.
Reaction SMILES: Br[C:2]1[C:3]2[CH:4]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18][CH:5]3[N:6](C(OC(C)(C)C)=O)[C:7]=2[CH:8]=[CH:9][CH:10]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:38]1[C:46]2[C:45]3[CH:47]=[CH:48][CH:49]=[CH:50][C:44]=3[O:43][C:42]=2[C:41](B(O)O)=[CH:40][CH:39]=1.N#N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[CH:38]1[C:46]2[C:45]3[CH:47]=[CH:48][CH:49]=[CH:50][C:44]=3[O:43][C:42]=2[C:41]([C:2]2[C:3]3[C@@H:4]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18][C@@H:5]4[NH:6][C:7]=3[CH:8]=[CH:9][CH:10]=2)=[CH:40][CH:39]=1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC2c3c(Br)cccc3N(C(=O)OC(C)(C)C)C2CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: c1cc2c(c(-c3cccc4c3oc3ccccc34)c1)[C@@H]1CCNCC[C@@H]1N2
Temperature: 80 °C
Yield: 46.1 %

Procedure:
A 30-mL shaker vial was charged with di(tert-butyl) 10-bromo-1,2,4,5,5a,10b-hexahydroazepino[4,5-b]indole-3,6-dicarboxylate (0.10 g, 0.214 mmol), potassium phosphate (0.068 g, 0.32 mmol), 4-dibenzofuranboronic acid (0.136 g, 0.642 mmol), and DMF (2 mL). The vial was purged with N2, and tetrakis(triphenylphosphine)palladium (0.025 g, 0.02 mmol) was added and the mixture was agitated at 250 RPM with heating at 80° C. overnight. The mixture was filtered through Celite, washing with MeOH (3-5 mL), and sulfonic acid resin (DOWEX®50W-X2, washed and dried, 4.8 meq/g dry weight) was added (1 g). The vial was then purged with N2, capped and agitated at 250 RPM with heating at 65° C. for 72 h. The mixture was filtered through a scintered funnel and the resin was washed 1:1 methylene chloride/methanol and then consecutively washed with MeOH and THF to ensure that all excess reagent was removed from the resin (the methanol and THF washes are alternated to swell and then shrink the resin to help expel reagents from inside the resin). The resin was then washed with 4M ammonium hydroxide in methanol (4×2 ml) and THF (2×2 ml) into an accurately weight round-bottomed flask. The filtrate was concentrated to give 0.035 g (47%) of a white solid: MS (EI) m/z 355 (MH+); HPLC rt=3.86 min (95%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[CH:7]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:6][CH:5]1[CH3:22])(=[O:3])[CH3:2].[CH3:23][N:24](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:23]#[N:24])=[CH:11][CH:12]=2)[CH:7]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:6][CH:5]1[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(Br)cc2C(Nc2ccccc2)CC1C
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CC(=O)N1c2ccc(C#N)cc2C(Nc2ccccc2)CC1C
Temperature: 120 °C
Reaction time: 2 h

Procedure:
100 mg (0.278 mmol) of 1-acetyl-6-bromo-2-methyl-4-phenylamino-1,2,3,4-tetrahydroquinoline), 36 mg (0.31 mmol) of zinc cyanide, and 18 mg (0.015 mmol) of tetrakis(triphenylphosphine)palladium(0) were added to 1.5 mL of DMF, and the mixture was stirred for 2 hours at 120° C. under an argon atmosphere. After completion of the reaction, water was added to the reaction liquid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dehydrated over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue (104 mg) was purified by using silica gel preparatory thin layer chromatography (ether:hexane=5:1), and thus 63 mg (cis:trans=3:1, 74.1%) of the title compound was obtained as a colorless amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.Cl[C:11]1[C:12](=[O:27])[N:13]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH:14]=[C:15]([Cl:17])[N:16]=1>>[Br:8][C:7]1[C:2]([NH:1][C:11]2[C:12](=[O:27])[N:13]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[CH:14]=[C:15]([Cl:17])[N:16]=2)=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: COc1ccc(Cn2cc(Cl)nc(Cl)c2=O)cc1
Reactant: Nc1ncc(Cl)cc1Br
Product: COc1ccc(Cn2cc(Cl)nc(Nc3ncc(Cl)cc3Br)c2=O)cc1
Yield: 58 %

Procedure:
The title compound was prepared in 58% yield from 2-amino-3-bromo-5-chloropyridine and 3,5-dichloro-1-(4-methoxy-benzyl)-1H-pyrazin-2-one in a manner analogous to that for the preparation of Compound 26. 1H NMR (400 MHz, DMSO-d6): δ 9.58 (s, 1H), 8.51 (d, 1H, J=2.4 Hz), 8.40 (d, 1H, J=2.4 Hz), 7.51 (s, 1H), 7.36 (d, 2H, J=8.8 Hz), 6.92 (d, 2H, J=8.8 Hz), 5.00 (s, 2H), 3.73 (s, 3H). MS (ES) [m+H] calc'd for C17H13BrCl2N4O2, 455, 457, 459; found 455, 457, 459.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][S:9]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:11])=[O:10])=[CH:6][CH:5]=1)([O-])=O>CCOC(C)=O.C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][S:9]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:11])=[O:10])=[CH:19][CH:20]=1
Reactant: CCOC(=O)CCS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCS(=O)(=O)Cc1ccc(N)cc1
Reaction time: 5 h
Yield: 100 %

Procedure:
A solution of ethyl 3-(4-nitrobenzylsulfonyl)propanoate (Intermediate 41, 3.9 g; 12.9 mmol) in EtOAc (100 ml) and ethanol (200 ml) was treated with palladium (400 mg, 5% on C). The mixture was stirred under hydrogen for 5 hours, filtered and the solvent removed in vacuo to give the title compound as an off-white solid (3.5 g, quant).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8](N)=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:6]=1)=[O:4].C(ON=O)CC(C)C.[Br:27]CBr.C[Si](C)(C)Br>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([Br:27])=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:6]=1)=[O:4]
Reactant: BrCBr
Reactant: COC(=O)c1cnc(N)c(-c2ccc(Cl)cc2)n1
Agent: CC(C)CCON=O
Agent: C[Si](C)(C)Br
Product: COC(=O)c1cnc(Br)c(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 36b, using 5-amino-6-(4-chloro-phenyl)-pyrazine-2-carboxylic acid methyl ester as starting material and isoamylnitrite, dibromomethane and trimethylbromosilane as reagents to give the title compound which was used in the next step without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]([C:12]2[CH:13]=[C:14]([CH:40]=[CH:41][CH:42]=2)[CH2:15][N:16]2[C:20](=[O:21])[C:19]3([CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[N:18]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:17]2)=[O:11])[CH2:3][CH2:2]1.Cl.[O:44]1CCOCC1>>[O:21]=[C:20]1[C:19]2([CH2:22][CH2:23][NH:24][CH2:25][CH2:26]2)[N:18]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:17][N:16]1[CH2:15][C:14]1[CH:13]=[C:12]([CH:42]=[CH:41][CH:40]=1)[C:10]([O:9][CH2:8][C:7]([N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)=[O:44])=[O:11]
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1cccc(C(=O)OCCN3CCOCC3)c1)CN2c1ccccc1
Agent: Cl
Product: O=C(OCC(=O)N1CCOCC1)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl 3-(3-((2-morpholinoethoxy)carbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.22 g, 0.38 mmol) was added 4M solution of HCl in dioxane (4 mL). After stirring at room temperature for 2 hours, the reaction mixture was concentrated in vacuo to obtain 2-morpholino-2-oxoethyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as a hydrochloride salt.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[C:5]([N:7]=[C:8]=[O:9])=O.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:20][C:19]=1[NH:32][NH:33]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:20][C:19]=1[N:32]1[C:8](=[O:9])[NH:7][C:5]([C:4]2[CH:10]=[CH:11][C:12]([C:13]([F:16])([F:15])[F:14])=[C:2]([F:1])[CH:3]=2)=[N:33]1
Reactant: O=C=NC(=O)c1ccc(C(F)(F)F)c(F)c1
Reactant: CC(C)(C)OC(=O)NNc1cc(CNC(=O)C(C)(C)C)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(C(F)(F)F)c(F)c3)[nH]c2=O)c1
Yield: 68 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 3-fluoro-4-(trifluoromethyl)benzoyl isocyanate (Intermediate-99, 2.0 g), tert-butyl 2-(2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate (Intermediate-94, 1.0 g), DCM (15 mL), and trifluoro acetic acid (3.0 mL) to afford 0.900 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.12 (s, 9H), 4.29 (d, J=5.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 1H), 7.44 (s, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.86-8.10 (m, 3H), 8.19 (m, 1H), 12.86 (s, 1H); MS (m/z): 471.35 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17]>>[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([NH:4][C:3]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:2]=1[Cl:1])=[O:17]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Product: O=C(Nc1cc([N+](=O)[O-])ccc1Cl)c1cccc(Cl)c1

Procedure:
2-chloro-5-nitroaniline (Aldrich, 25.7 mmol) was used in general procedure 1 with 3-chlorobenzoyl chloride (26.5 mmol). The product was purified by silica gel chromatography (40% EtOAc/Hex) to give 3-chloro-N-(2-chloro-5-nitrophenyl)benzamide as a brown solid. MS (Q1) 294.0 (M)+