Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[N:7]([CH3:8])[CH2:6][CH2:5][N:4]2[N:9]=[C:10]([NH2:12])[CH:11]=[C:3]12.[C:13]([O:16][CH2:17][C:18]1[C:19]([N:33]2[CH2:44][CH2:43][N:42]3[C:35](=[CH:36][C:37]4[CH2:38][C:39]([CH3:46])([CH3:45])[CH2:40][C:41]=43)[C:34]2=[O:47])=[N:20][CH:21]=[CH:22][C:23]=1[C:24]1[CH:29]=[C:28](Br)[C:27](=[O:31])[N:26]([CH3:32])[CH:25]=1)(=[O:15])[CH3:14].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:13]([O:16][CH2:17][C:18]1[C:19]([N:33]2[CH2:44][CH2:43][N:42]3[C:35](=[CH:36][C:37]4[CH2:38][C:39]([CH3:46])([CH3:45])[CH2:40][C:41]=43)[C:34]2=[O:47])=[N:20][CH:21]=[CH:22][C:23]=1[C:24]1[CH:29]=[C:28]([NH:12][C:10]2[CH:11]=[C:3]3[CH:2]([CH3:1])[N:7]([CH3:8])[CH2:6][CH2:5][N:4]3[N:9]=2)[C:27](=[O:31])[N:26]([CH3:32])[CH:25]=1)(=[O:15])[CH3:14]
Reactant: CC1c2cc(N)nn2CCN1C
Reactant: CC(=O)OCc1c(-c2cc(Br)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C)C4C)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 47.8 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 4,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine 287i (123 mg, 1.0 eq., 0.74 mmol), [4-(5-bromo-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-3-yl]methyl acetate 273a (400 mg, 1.0 eq., 0.74 mmol), Pd2(dba)3 (68 mg, 0.1 eq., 0.074 mmol), Xantphos (86 mg, 0.2 eq., 0.148 mmol), Cs2CO3 (487 mg, 2.0 eq., 1.48 mmol), and dioxane (15 mL). After three cycles of vacuum/N2 flush, the mixture was stirred at 100° C. for 2 hr. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica-gel column chromatography eluting with 20:1 ethyl acetate/methanol to afford 318a as a brown solid (221 mg, 48%). MS-ESI: [M+H]+ 624.9
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([NH:19][S:20]([C:23]3[CH:24]=[N:25][C:26](Cl)=[C:27]([Br:29])[CH:28]=3)(=[O:22])=[O:21])[CH2:15][CH2:14]2)=[O:12])[CH3:9])=[CH:4][CH:3]=1.C[CH2:32][N:33](C(C)C)[CH:34](C)C.CNC.C1COCC1>CN1C(=O)CCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([NH:19][S:20]([C:23]3[CH:24]=[N:25][C:26]([N:33]([CH3:34])[CH3:32])=[C:27]([Br:29])[CH:28]=3)(=[O:22])=[O:21])[CH2:15][CH2:14]2)=[O:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](NC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2cnc(Cl)c(Br)c2)CC1)c1ccc(F)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](NC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2cnc(N(C)C)c(Br)c2)CC1)c1ccc(F)cc1

Procedure:
Trans-4-(5-Bromo-6-chloro-pyridine-3-sulfonylamino)-cyclohexanecarboxylic acid [(R)-1-(4-fluoro-phenyl)-ethyl]-amide (Example 241, 300 mg, 0.580 mmol) was dissolved in NMP (3 ml). DIPEA (202 ul, 1.16 mmol) was added followed by dimethylamine in THF (2M, 0.87 ml, 1.74 mmol). The reaction mixture was microwaved at 160° C. for 15 min., after which LCMS indicated that the reaction was complete. The mixture was diluted with EtOAc and washed H2O. The organic layer was concentrated in vacuo and purified via column chromatography using a biotage SP1, 12+M column, with 50% EtOAc in heptane as calculated gradient to yield the title compound as a white solid (258 mg, 84%). MS MH+ 529.9
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]([C:18](=[O:34])[NH:19][C:20](=O)[C:21]1[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[C:23]([O:31][CH3:32])[CH:22]=1)[NH:10]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18](=[O:34])[NH:19][C:20]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[C:23]([O:31][CH3:32])[CH:22]=2)=[N:10]1
Reactant: COC(=O)c1ccc(C(=O)NC(=O)N(NC(=O)OC(C)(C)C)c2c(Cl)cccc2Cl)cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nn(-c3c(Cl)cccc3Cl)c(=O)[nH]2)cc1OC
Yield: 52.5 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-9 by using tert-butyl 2-(2,6-dichlorophenyl)-2-((3-methoxy-4-(methoxycarbonyl)benzoyl)carbamoyl)hydrazinecarboxylate (1.5 g, 2.9 mmol), DCM (20 mL) and trifluoro acetic acid (2.0 mL) to afford 0.600 g of desired product. 1H NMR (300 MHz, DMSO do): δ 3.80 (s, 3H), 3.80 (s, 3H), 7.49-7.71 (m, 3H), 7.74-7.79 (m, 3H), 12.85 (s, 1H); MS (m/z): 393.95 (M)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([CH:9]=[CH:10][CH2:11]O)=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16].[Cl-].[Li+].N1C(C)=CC(C)=CC=1C.CS([Cl:33])(=O)=O>CN(C)C=O.O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([CH:9]=[CH:10][CH2:11][Cl:33])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: COCOc1ccc(C=CCO)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: COCOc1ccc(C=CCCl)cc1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
Under a current of argon, a solution of 1.50 g of 4-methoxymethoxy-3-nitrocinnamyl alcohol in 15 ml of dimethyl formamide and 292 mg of anhydrous lithium chloride and 0.9 ml of 2,4,6-collidine added thereto as kept cooled with ice were stirred for 10 minutes and the produced mixture and 0.5 ml of methanesulfonyl chloride added as kept cooled with ice were stirred for four hours. The resultant reaction mixture was combined with water and extracted from ethyl acetate. The consequently separated organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. By concentrating the residue from drying under a vacuum, 1.62 g of 4-methoxymethoxy-3-nitrocinnamyl chloride was obtained in the form of a colorless oily substance. This product was put to use in its unpurified form in the following reaction.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[CH:4][CH:3]=1.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH:18]1([CH2:17][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:24]3[S:23][CH:27]=[CH:26][CH:25]=3)=[CH:3][CH:4]=2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: OB(O)c1cccs1
Reactant: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(-c2cccs2)cc1
Temperature: 25 °C
Yield: 4.4 %

Procedure:
A mixture of 2-(4-bromo-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (102.5 mg, 0.27 mmol), tetrakis(triphenylphosphine)palladium(0) (15.6 mg, 0.014 mmol), 2-thiopheneboronic acid (69.2 mg, 0.54 mmol), and a 2M aqueous sodium carbonate solution (405 μL, 0.81 mmol) in 1,2-dimethoxyethane (9 mL) was heated under reflux for 24 h. The reaction mixture was allowed to cool to 25° C. and then filtered to remove the catalyst. The filtrate was concentrated in, vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-N-thiazol-2-yl-2-(4-thiophen-2-yl-phenyl)-propionamide (4.5 mg, 4%) as a yellow solid: mp 194° C. (dec); EI-HRMS m/e calcd for C21H22N2OS2 (M+) 382.1174, found 382.1175.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10]C1C=CC=CC=1>CN(C)C=O>[C:1]1([NH:7][C:8](=[O:9])[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccccc1
Solvent: CN(C)C=O
Product: NC(=O)Nc1ccccc1
Temperature: 80 °C
Reaction time: 9.5 h

Procedure:
To a solution of phenyl isocyanate(1.0 equiv.) in dimethyl formamide (1 ml) the corresponding aniline (1.0 equiv.) was added. The reaction mixture was stirred at 80° C. until complete (3-16 hrs.), then removed solvent under vacuum. The purification, yields and spectral characteristics for each individual compound are listed below. Additional synthetic methods are provided for in PCT US96/02260 filed Feb. 16, 1996 whose disclosure is incorporated herein by reference.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](Cl)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]([Sn](C)(C)C)=[N:38]1>O1CCOCC1.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.[Cu]I>[C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:39]4[C:40]5[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=5)[N:37]([CH3:36])[N:38]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Reactant: Cn1nc([Sn](C)(C)C)c2ccccc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4nn(C)c5ccccc45)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (35.0 mg, 0.066 mmol) and 1-methyl-3-(trimethylstannyl)-1H-indazole (24.0 mg, 0.079 mmol) in dioxane (0.9 mL) was added Pd(PPh3)4 (4.0 mg, 3.03×10−3 mmol) and CuI (4.0 mg, 0.018 mmol). The reaction was degassed for 5 minutes with N2 and then heated at 100° C. overnight. After cooling, the reaction mixture was diluted with EtOAc, extracted with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 70% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C35H34ClN4O3S: 625.2; found: 625.3.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][CH:7]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([NH:19][C@@H:20]([CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:21][NH:22]C(=O)OC(C)(C)C)=[CH:15][N+:16]([O-:18])=[O:17])[CH2:9]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][CH:7]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([NH:19][C@@H:20]([CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:21][NH2:22])=[CH:15][N+:16]([O-:18])=[O:17])[CH2:9]1
Reactant: COCCCOC(c1ccccc1)C1CCCN(C(=C[N+](=O)[O-])N[C@H](CNC(=O)OC(C)(C)C)CC2CCCCC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCCOC(c1ccccc1)C1CCCN(C(=C[N+](=O)[O-])N[C@H](CN)CC2CCCCC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 126.9 %

Procedure:
Tert-butyl (S)-2-(1-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)-2-nitrovinylamino)-3-cyclohexylpropylcarbamate (12 mg, 0.02 mmol) was dissolved in 1:1 TFA/CH2Cl2 (3 mL) and stirred for 30 min at rt. LC-MS showed the reaction was complete. After concentration, the mixture was purified by prep HPLC to afford (2S)—N2-(1-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)-2-nitrovinyl)-3-cyclohexylpropane-1,2-diamine (12.4 mg, 68%). LC-MS (3 min) tR=1.38 min. m/z 489 (M+1).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOC(C)=O>CN(C=O)C>[CH2:20]([NH:27][C:8]1[C:9](=[O:10])[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6](=[O:19])(=[O:18])[C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C(NCc2ccccc2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 51.3 %

Procedure:
A mixture of 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.150 g, 0.500 mmol) and benzylamine (0.110 ml, 1.001 mmol) in DMF (2 ml) was heated in the microwave reactor at 120° C. for 15 mins. EtOAc was added, the mixture was washed with brine and evaporated to dryness. The residue was purified by silica gel column chromatography (Horizons Biotage) using 15-20% EtOAc in petroleum ether 40-60° C. as eluent to give the title compound (0.095 g, 51%) as a solid. 1H NMR (500 MHz CDCl3): δ 7.50-7.38 (m, 5H), 7.34-7.25 (m, 3H), 7.06-6.98 (m, 2H), 5.55 (bs, 1H), 4.02 (d, 2H), 1.77 (9H, s); 13C NMR (125 MHz, CDCl3): δ 159.8, 136.8, 133.0, 131.9, 129.8, 129.0, 128.7, 128.2, 127.6, 124.8, 108.2, 61.6, 48.4, 27.9; Mass Spectrum M+H+ 371.
Reaction SMILES: [CH:1]1([C@H:7]([NH:41][C:42]([C:44]2[CH:49]=[N:48][CH:47]=[CH:46][N:45]=2)=[O:43])[C:8]([NH:10][C@@H:11]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:12]([N:14]2[CH2:18][C@@H:17]3[CH2:19][CH2:20][CH2:21][C@@H:16]3[C@H:15]2[C:22]([NH:24][C@@H:25]([CH2:34][CH2:35][CH3:36])[CH:26]([OH:33])[C:27]([NH:29][CH:30]2[CH2:32][CH2:31]2)=[O:28])=[O:23])=[O:13])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CC1(C)N([O])C(C)(C)CCC1.Cl[O-].[Na+].S(=O)(O)[O-].[Na+]>ClCCl>[CH:1]1([C@H:7]([NH:41][C:42]([C:44]2[CH:49]=[N:48][CH:47]=[CH:46][N:45]=2)=[O:43])[C:8]([NH:10][C@@H:11]([C:37]([CH3:38])([CH3:39])[CH3:40])[C:12]([N:14]2[CH2:18][C@@H:17]3[CH2:19][CH2:20][CH2:21][C@@H:16]3[C@H:15]2[C:22]([NH:24][C@@H:25]([CH2:34][CH2:35][CH3:36])[C:26](=[O:33])[C:27]([NH:29][CH:30]2[CH2:31][CH2:32]2)=[O:28])=[O:23])=[O:13])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC[C@H](NC(=O)[C@@H]1[C@H]2CCC[C@H]2CN1C(=O)[C@@H](NC(=O)[C@@H](NC(=O)c1cnccn1)C1CCCCC1)C(C)(C)C)C(O)C(=O)NC1CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=S([O-])O
Solvent: ClCCl
Product: CCC[C@H](NC(=O)[C@@H]1[C@H]2CCC[C@H]2CN1C(=O)[C@@H](NC(=O)[C@@H](NC(=O)c1cnccn1)C1CCCCC1)C(C)(C)C)C(=O)C(=O)NC1CC1
Reaction time: 2 h

Procedure:
The title compound is prepared by oxidation of the product of Step h with a suitable oxidizing reagent such as Dess-Martin periodinane or TEMPO and sodium hypochlorite. Specifically, in a flask containing 1.31 g of (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)-N-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide in 40 mL of dichloromethane is added at room temperature 1.06 g of Dess-Martin periodinane. After 2 hours of stirring, 50 mL of sodium bisulfite (1N) is added, and the mixture is stirred for 30 minutes. The 2 phases are separated, the organic is washed with water twice, brine and dried over Na2SO4. The crude product was purified by chromatography on silica (ethyl acetate 20-100% in Hexanes) to give the title compound. The diastereoisome ratio is determined by chiral HPLC normal phase.
Reaction SMILES: Cl[CH2:2][C:3]#[C:4][CH2:5][NH:6][C:7](=[O:22])[C:8]([OH:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:23]([NH2:25])[CH3:24]>CO>[CH2:23]([NH:25][CH2:2][C:3]#[C:4][CH2:5][NH:6][C:7](=[O:22])[C:8]([OH:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:24]
Reactant: O=C(NCC#CCCl)C(O)(c1ccccc1)c1ccccc1
Reactant: CCN
Solvent: CO
Product: CCNCC#CCNC(=O)C(O)(c1ccccc1)c1ccccc1
Yield: 77.9 %

Procedure:
A solution of N-(4-chloro-2-butynyl)-2-hydroxy-2,2-diphenylacetamide (1.0 g) and 70% aqueous ethylamine (4.32 g) in methanol (3 ml) was stirred at room temperature for 30 minutes and then evaporated in vacuo. The residue was dissolved in chloroform (30 ml) and the solution was washed with sodium chloride aqueous solution, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of chloroform and methanol (5:1}as an eluent to give N-(4-ethylamino-2-butynyl)-2-hydroxy-2,2-diphenylacetamide (0.8 g), which was treated with 4N methanolic hydrogen chloride to give N-(4-ethylamino-2-butynyl)-2-hydroxy-2,2-diphenylacetamide hydrochloride (0.65 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.Cl[C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12]>[OH-].[Na+].O1CCOCC1>[CH2:14]([O:13][C:11]([N:5]1[CH2:6][CH:2]([OH:1])[CH2:3][CH:4]1[C:7]([OH:9])=[O:8])=[O:12])[CH:15]=[CH2:16]
Reactant: C=CCOC(=O)Cl
Reactant: O=C(O)[C@@H]1CC(O)CN1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=CCOC(=O)N1CC(O)CC1C(=O)O

Procedure:
To a solution of 4-hydroxyproline (0.25M) in 4N sodium hydroxide (78ml), at 0°-5° C., was added allyl chloroformate (0.31M) in dioxan (156 ml) and 4N sodium hydroxide (78 ml). The dioxan solution and sodium hydroxide were added simultaneously, in batches, allowing the temperature to return to below 5° C. after each addition. The mixture was stirred for a further hour, washed with ethyl acetate, acidified (conc. HCl) and extracted into ethyl acetate. The organic phase was washed with brine, dried and evaporated to give 1-allyloxycarbonyl-4-hydroxypyrrolidine-2-carboxylic acid as a viscous syrup. This (0.1M) was treated with 4-methoxybenzyl chloride (0.19M) and triethylamine (0.2M) in DMF (200 ml), under argon, at 70° C. for 10 hours. Ethyl acetate was added and the mixture was washed with water and brine and evaporated to give a gum. This was subjected to medium pressure chromatography (gradient elution with ether to ether/1% methanol) to give 4-methoxybenzyl 1-allyloxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylate.
Reaction SMILES: [Cl:1][Cl:2].C(=O)=O.II.[SH:8][C:9]1[N:14]=[CH:13][CH:12]=[CH:11][N:10]=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][Cl:2].[Cl:1][S:8][C:9]1[N:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Sc1ncccn1
Agent: ClCl
Agent: II
Agent: O=C=O
Solvent: ClC(Cl)(Cl)Cl
Product: ClSc1ncccn1

Procedure:
A solution of chlorine in CCl4 is prepared by condensing 4.38 ml liquified Cl2 at dry-ice temperature, and then adding 75 ml CCl4 at -10° to it. To this solution at 0° is added two small crystals of iodine, and then 10.0 g 2-mercaptopyrimidine in 35 ml CCl4 dropwise over 1.5 hours. After stirring another hour, the solvent, excess Cl2 and HCl are evaporated in vacuo, leaving 5.I as residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:4]=1[C:5]1([C:26]3[C:17](=[CH:18][C:19]4[O:24][CH2:23][CH2:22][O:21][C:20]=4[CH:25]=3)[O:16][CH2:15]1)[C:6](=[O:14])[NH:7]2.[NH:27]1[C:35]2[C:30](=CC=C[CH:34]=2)[C@@:29]2([C:47]3[C:38](=CC4OCCOC=4C=3)OC2)C1=O.Br.BrCC1C=CC=CN=1.BrCCOCCOC>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:4]=1[C:5]1([C:26]3[C:17](=[CH:18][C:19]4[O:24][CH2:23][CH2:22][O:21][C:20]=4[CH:25]=3)[O:16][CH2:15]1)[C:6](=[O:14])[N:7]2[CH2:34][C:35]1[CH:30]=[CH:29][CH:47]=[CH:38][N:27]=1
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: COc1cc2c(c(OC)c1)C1(COc3cc4c(cc31)OCCO4)C(=O)N2
Agent: Br
Agent: BrCc1ccccn1
Agent: COCCOCCBr
Product: COc1cc(OC)c2c(c1)N(Cc1ccccn1)C(=O)C21COc2cc3c(cc21)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 9.70 and making non-critical variations using 4′,6′-dimethoxy-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 1-bromo-2-(2-methoxyethoxy)ethane, 4′,6′-dimethoxy-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (78%) as a colorless solid: mp 187-188° C.; 1H NMR (300 MHz, DMSO-d6) δ8.59-8.34 (m, 1H), 7.86-7.66 (m, 1H), 7.44-7.19 (m, 2H), 6.51-6.32 (m, 1H), 6.32-6.14 (m, 3H), 5.17-4.80 (m, 2H), 4.79-4.50 (m, 2H), 4.25-3.95 (m, 4H), 3.66 (s, 3H), 3.61 (s, 3H); 13C NMR (75 MHz, CDCl3) δ178.7, 162.0, 156.7, 155.8, 155.6, 149.4, 144.3, 144.2, 137.7, 137.1, 122.7, 121.5, 120.3, 111.1, 108.9, 98.9, 93.1, 89.5, 64.5, 63.9, 57.1, 55.6, 46.2; MS (ES+) m/z 447.1 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:27]=[CH:28][C:29]([C:31](=[O:38])[CH:32]([CH2:34][C:35]([OH:37])=[O:36])[CH3:33])=[CH:30][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].C(O)C>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:27]=[CH:28][C:29]([C:31](=[O:38])[CH:32]([CH2:34][C:35]([OH:37])=[O:36])[CH3:33])=[CH:30][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(C(=O)C(C)CC(=O)O)ccc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc2cc(C(=O)C(C)CC(=O)O)ccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 72 from methyl 4'-[(2-n-butyl-5-(2-carboxymethyl-propionyl)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and aquous sodium hydroxide/ethanol.
Reaction SMILES: [C:1]([O:5][C:6]([O:8]N=C(C1C=CC=CC=1)C#N)=O)([CH3:4])([CH3:3])[CH3:2].[CH:19]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:21][CH2:20]1.Cl>C(OCC)(=O)C>[CH:19]1([N:22]2[CH2:27][CH2:26][N:25]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:8])[CH2:24][CH2:23]2)[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: C1CN(C2CC2)CCN1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C2CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Solid 2-(t-butoxycarbonyloxyimino)-2-phenylacetonitrile (3.2 g, 0.013 mole) was added in one portion to a solution of 1.5 g (0.012 mole) 1-cyclopropylpiperazine in 30 ml ethyl acetate. The solution was stirred at room temperature for 3 hours and then treated with 100 ml dilute aqueous HCl. The aqueous phase was separated, extracted with additional ethyl acetate (discarded), treated with excess 10% NaOH, and extracted with ether. The ether extracts were dried (MgSO4), filtered, and evaporated in vacuo to yield a semi-solid residue. Recrystallization from hexane at -70° C. gave 1.9 g white, crystalline solid, m.p. 65°-67° C. Calculated for C12H22N2O2 (226.32): C, 63.98; H, 9.80; N, 12.38; O, 14.14. Found: C, 63.82; H, 9.82; N, 12.60; O, 13.90.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[C:17]=1[C:23]#[N:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[S:31](Cl)(=[O:34])(=[O:33])[NH2:32].C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][S:31](=[O:34])(=[O:33])[NH2:32])[C:17]=1[C:23]#[N:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1COc1cccc(N)c1C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1COc1cccc(NS(N)(=O)=O)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-tert-butyl-2-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate (Example 15d, 8.65 g, 26.1 mmol) in dimethyl acetamide (48 mL) were added pyridine (8.44 mL, 104 mmol) and sulfamoyl chloride (6.03 g, 52.2 mmol). The reaction mixture was stirred at room temperature for 1 hour, neutralized with saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The extract was dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound as a clear oil, which was used immediately in the next step. MS 311 (MH+-boc).