Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH2:21]Br)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][CH2:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(C(C)C)CC)(C)C>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH2:21][N:37]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][CH2:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CCCCOCCCCCCNCc2ccccc2)cc1
Reactant: O=c1ccc2c([C@H](CBr)OC3CCCCO3)ccc(OCc3ccccc3)c2[nH]1
Solvent: CCN(C(C)C)C(C)C
Product: O=c1ccc2c([C@H](CN(CCCCCCOCCCCc3ccccc3)Cc3ccccc3)OC3CCCCO3)ccc(OCc3ccccc3)c2[nH]1
Temperature: 25 °C
Yield: 54.3 %

Procedure:
8-(Benzyloxy)-5-[(1R)-2-bromo-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]quinolin-2(1H)-one (100 mg), N-benzyl-6-(4-phenylbutoxy)hexan-1-amine (Tetrahedron Letters. 1994, 35, 9375) (112 mg) and diisopropylethylamine (77 μl) were heated in a reacti-vial at 120° C. for 4 h prior to cooling to room temperature. The mixture was purified by chromatography (Hexane-EtOAc 2:1, biotage) afforded the title compound (85 mg). LCMS RT=3.46 min
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]=3[Cl:29])=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:10]=2)[O:5][C:4]([CH3:31])([CH3:30])[CH2:3]1.[C:32](Cl)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34].CCN(CC)CC>C(Cl)Cl>[Cl:29][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:19]=1[C:8]1[N:7]=[C:6]2[O:5][C:4]([CH3:31])([CH3:30])[CH2:3][CH:2]([NH:1][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[C:11]2=[CH:10][C:9]=1[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)c1ccc(-c2nc3c(cc2-c2ccc(Cl)cc2)C(N)CC(C)(C)O3)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nc3c(cc2-c2ccc(Cl)cc2)C(NC(=O)C(C)(C)C)CC(C)(C)O3)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product of Step A (100 mg, 0.22 mmol) in 5.0 mL of CH2Cl2 was added pivaloyl chloride (32 μL, 0.26 mmol) and NEt3 (46 μL, 0.33 mmol). After stirring at rt for 16 h, the reaction mixture was concentrated. Chromatography on a Biotage 25+M cartridge using 1:1 v/v EtOAc/hexanes as the eluant afforded the product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=S)=[N:8][CH:9]=[C:10]([Cl:12])[CH:11]=1.[NH3:29]>>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[NH:29])=[N:8][CH:9]=[C:10]([Cl:12])[CH:11]=1
Reactant: Fc1cccc(Cl)c1COc1cc(Cl)cnc1NC(=S)Nc1ccc(Cl)cc1
Reactant: N
Product: N=C(Nc1ccc(Cl)cc1)Nc1ncc(Cl)cc1OCc1c(F)cccc1Cl

Procedure:
A mixture of yellow men:uric oxide (0.36 g, 0.0017 mol), N-[3-(2-chloro-6-fluorobenzyloxy)-5-chloropyrid-2-yl]-N'-4-chlorophenylthiourea (0.64 g, 0.0014 mol)and methanolic ammonia solution (20 ml) was stirred for 1 day at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent followed by recrystallisation from ethanol gave the desired product. Yield 0.09 g (15%), m.p. 162°-163 ° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8](Br)[CH:9]([Br:13])[N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.N1C=CC=CC=1>C1CCCCC1>[N+:10]([C:9]([Br:13])=[CH:8][C:5]1[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])C(Br)C(Br)c1ccc(Cl)cc1
Solvent: C1CCCCC1
Solvent: c1ccncc1
Product: O=[N+]([O-])C(Br)=Cc1ccccc1

Procedure:
To a refluxing solution of 1-(4-chlorophenyl)-1,2-dibromo-2-nitroethane (from example 1) in cyclohexane (200 mL) is added a solution of pyridine (6 mL, 74 mmoles) in cyclohexane (200 mL) over a 1 hour period. The mixture is refluxed for an additional hour. The refluxing mixture is then extracted with approximately 200 mL of dilute HCL and 2×200 mL H2O. The organic layer is dried over magnesium sulfate (anhydrous) filtered, and the solvent removed from the filtrate by evaporation to yield a yellow solid. The solid is recrystallized from cyclohexane to give beta-nitrobromostyrene.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][O:64][C:65]1[CH:71]=[C:70]([N+:72]([O-:74])=[O:73])[CH:69]=[CH:68][C:66]=1[NH2:67]>>[CH3:63][O:64][C:65]1[CH:71]=[C:70]([N+:72]([O-:74])=[O:73])[CH:69]=[CH:68][C:66]=1[NH:67][C:30]([CH:20]1[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:17]2([C:12]3[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=3)[NH:15][C:16]2=[O:38])[CH:21]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[F:29])=[O:31]
Reactant: COc1cc([N+](=O)[O-])ccc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc([N+](=O)[O-])ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Yield: 14.1 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.4 g, 0.69 mmol), was reacted with diisopropylethylamine (0.46 g, 3.6 mmol), diphenylphosphinic chloride (0.34 g, 1.4 mmol), then reacted with 2-methoxy-4-nitroaniline (Aldrich) (0.18 g, 1.1 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (2-methoxy-4-nitro-phenyl)-amide as a white solid (Yield 0.06 g, 14%).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[CH:5]=[CH:4][C:3]1=2.[OH-:21].[K+]>C(O)(C)(C)C>[O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][C:13]3[CH:14]=[CH:15][C:16]([C:17]([NH2:18])=[O:21])=[CH:19][CH:20]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: N#Cc1ccc(Oc2ccc3c(c2)CCCC3=O)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCCC3=O)cc1
Reaction time: 72 h
Yield: 91.1 %

Procedure:
Combine 4-(5-Oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-benzonitrile (5.34, 20.3 mmol), t-butyl alcohol (100 ml), and KOH (5.7 g, 101.5 mmol). After the reaction stirs for 72 hours at room temperature, concentrate under reduced pressure and then add ethyl acetate. Wash the organic phase with water, a brine solution, and then dry the organic layer over Na2SO4. Flash chromatograph using 2/1 CH2Cl2/ethyl acetate eluent to afford 5.20 g, 18.5 mmol (91% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 2.1-2.2 (2H, m), 2.6-2.7 (2H, m), 2.9-3.0 (2H, m), 5.6-6.2 (2H, br m); 6.85 (1H, s), 6.9-7.0 (1H, m), 7.05-7.15 (2H, m), 7.8-7.9 (2H, m) 8.05-8.10 (1H, m); MS m/z 284 (M+3).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][O:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClN1C(=O)CCC1=O.[CH:37]1([CH2:40][N:41]2[C:49]3[N:48]=[C:47]([CH2:50][C:51]4[CH:56]=[CH:55][C:54]([NH:57][CH3:58])=[CH:53][CH:52]=4)[NH:46][C:45]=3[C:44](=[O:59])[N:43]([CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=3[F:67])[C:42]2=[O:68])[CH2:39][CH2:38]1>ClCCl>[CH:37]1([CH2:40][N:41]2[C:49]3[N:48]=[C:47]([CH2:50][C:51]4[CH:52]=[CH:53][C:54]([N:57]([CH3:58])[C:7]([C:6]5[C:2]([CH3:1])=[N:3][O:4][CH:5]=5)=[O:9])=[CH:55][CH:56]=4)[NH:46][C:45]=3[C:44](=[O:59])[N:43]([CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=3[F:67])[C:42]2=[O:68])[CH2:39][CH2:38]1
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: Cc1nocc1C(=O)O
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nocc1C(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 22 %

Procedure:
A mixture of 3-methyl-isoxazole-4-carboxylic acid (7.3 mg, 0.057 mmol) in dichloromethane (1.0 mL) cooled to 0° C. was treated with triphenylphosphine (17 mg, 0.063 mmol), and N-chlorosuccinimide (10 mg, 0.074 mmol). This mixture was stirred at 0° C. for 15 min and at 25° C. for 20 min. At this time, the reaction was treated with 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione (50 mg, 0.11 mmol). The reaction was then stirred at 25° C. for 18 h. At this time, the reaction was diluted with dichloromethane (50 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×10 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by HPLC (15–60% acetonitrile/water (0.075% trifluoroacetic acid in both solvents) over 40 min). Fractions with the desired product were combined and concentrated in vacuo. The resulting residue was diluted with dichloromethane (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (25 mL). The aqueous layer was re-extracted with dichloromethane (1×50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was dried in vacuo for 24 h to afford 3-methyl-isoxazole-4-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (6.8 mg, 21.8%) as an off-white solid: EI-HRMS m/e calcd for C29H27N6O4 (M+) 542.2078, found 542.2077.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]([NH2:16])=[CH:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17]C1C=CC(S(O)(=O)=O)=CC=1.O>C(OC)(OC)OC>[CH2:1]([N:8]1[C:9]2[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=2[N:16]=[CH:17]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1ccc(Br)cc1NCc1ccccc1
Solvent: COC(OC)OC
Solvent: O
Product: Brc1ccc2ncn(Cc3ccccc3)c2c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of N1-benzyl-5-bromobenzene-1,2-diamine (450 mg, 1.63 mmol) in HC(OMe)3 (15 mL) was added TsOH.H2O (30 mg, 0.16 mmol). The mixture was stirred at 100° C. for 4 h. The reaction solution was concentrated, and the residue was washed with water and extracted with EtOAc. The organic layer was concentrated to give the crude 1-benzyl-6-bromo-1H-benzo[d]imidazole. The crude product was used in next step without further purification. LCMS (m/z): 287.1/288.1 [M+H]+/[M+2H]+
Reaction SMILES: [C:1]1([N:7]=[C:8]([S:11][CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]#[CH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH:10]=[CH:9][C:8](=[N:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[S:11][CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:22][CH:21]=1
Reactant: Fc1ccc(S)cc1
Reactant: C#CC(=Nc1ccccc1)SCC1CCCCC1
Solvent: ClC(Cl)Cl
Product: Fc1ccc(SC=CC(=Nc2ccccc2)SCC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.4 %

Procedure:
Cyclohexylmethyl N-phenylpropynthioimidate (0.34 g) was dissolved to chloroform (8 mL), chloroform (2 mL) solution of 4-fluorothiophenol (0.14 g) was added dropwise under ice-cooling, and then it was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by medium pressure HPLC (hexane/ethyl acetate=98/2) to obtain cyclohexylmethyl 3-(4-fluorophenylthio)-N-(phenyl)thioacrylimidate (0.25 g) as pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[NH:7][C:6]=2[CH:15]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:22]([Cl:37])=[CH:21][N:20]=1.[NH4+].[OH-]>C(Cl)Cl.CO>[Cl:37][C:22]1[C:23]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[N:24][C:19]([NH:1][C:2]2[C:3]([O:16][CH3:17])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[NH:7][C:6]=3[CH:15]=2)=[N:20][CH:21]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CC(=O)Nc2cc(N)c(OC)cc2C1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCN1CC(=O)Nc2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)c(OC)cc2C1
Yield: 24.8 %

Procedure:
In an analogous manner to procedure 1656g, 8-amino-4-ethyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (70 mg, 0.30 mmol) and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (101 mg, 0.30 mmol) were coupled to provide N-{(1R,2R)-2-[5-chloro-2-(4-ethyl-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methane-sulfonamide (40 mg, 20%) as a mustard yellow solid following preparative tlc (DCM/MeOH/c.NH4OH=90/9/1); 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 8.00 (s, 1H), 7.49 (s, 1H), 7.46 (s, 1H), 6.82 (s, 1H), 5.53 (d, J=7 Hz, 1H), 5.31 (d, J=7 Hz, 1H), 3.94 (s, 3H), 3.74 (s, 2H), 3.40 (s, 2H), 3.29 (m, 1H), 2.87 (s, 3H), 2.77 (q, J=7 Hz, 2H), 2.23 (m, 2H), 1.84 (m, 2H), 1.38 (m, 2H), 1.27 (m, 2H), 1.20 (t, J=7 Hz, 3H); MS (m/e) 538 (M+1); mp 216° C. (dec.).
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][C@@H:7]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH2:6][N:5]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:15])(=O)[NH2:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:36]2)=CC=1>O1CCCC1>[CH3:13][S:10]([O:9][C@H:7]1[CH2:6][N:5]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:4]([C:1](=[S:36])[NH2:2])[CH2:8]1)(=[O:12])=[O:11]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C(N)=S)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 2 h
Yield: 152.4 %

Procedure:
To a solution of (2S, 4R) -2-carbamoyl-4-methane-sulfonyloxy-1- (4-nitrobenzyloxycarbonyl)pyrrolidine (7 g) in tetrahydrofuran (210 ml) was added 2,4-bis(4-methoxyphenyl) -1, 3-dithia-2,4-diphosphetane-2,4-disulfide (3.65 g) and the solution was stirred for 2 hours under refluxing. After the solvent was removed, the resulting oily residue was subjected to a column chromatography on silica gel (150 g) eluting with a mixture of n-hexane and ethyl acetate (2:3 V/V) to give (2S, 4R) -4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl) -2-thiocarbamoylpyrrolidine (5.55 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([O:11][CH3:12])[CH:8]=2)[C:3]1=[O:15].CC(C)([O-])C.[K+].[CH:22]1(Br)[CH2:26][CH2:25][CH2:24][CH2:23]1.O>C(O)(C)(C)C>[CH:22]1([C:2]2([CH3:1])[CH2:10][C:9]3[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([O:11][CH3:12])[CH:8]=3)[C:3]2=[O:15])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)C2
Reactant: BrC1CCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2
Reaction time: 1 h

Procedure:
A solution of 2-methyl-5-methoxy-6,7-dichloro-1-indanone (7.35 g., 0.03 mole) in tert.-butyl alcohol (100 ml.) is refluxed in an inert atmosphere and treated with potassium tert.-butoxide (4.48 G., 0.04 mole). After onehalf hour at reflux cyclopentyl bromide (9.9 g., 0.06 mole) is added and refluxing is continued for 1 hour. The reaction is poured into water (1 l.) affording 2-cyclopentyl-2-methyl-5-methoxy-6,7-dichloro-1-indanone which melts at 109°-111°C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[N:7][NH:8]2)=[CH:4][C:3]=1[C:20]#[N:21].S(=O)(=O)(O)[OH:23]>C(O)(=O)C.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[N:7][NH:8]2)=[CH:4][C:3]=1[C:20]([NH2:21])=[O:23]
Reactant: N#Cc1cc2c(/C=C/c3cccc(F)c3)n[nH]c2cc1F
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)c1cc2c(/C=C/c3cccc(F)c3)n[nH]c2cc1F
Temperature: 110 °C
Reaction time: 0.83 h

Procedure:
To a suspension of 89 mg of 6-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carbonitrile obtained by Example 100 in 0.4 mL of acetic acid and 0.4 mL of water was added 1.2 mL of concentrated sulfuric acid, and stirred at 110° C. for 50 minutes. After allowing to cool, ice was added, and extracted with a mixed solvent of 20 mL of ethyl acetate and 10 mL of tetrahydrofuran. The organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. After making the organic layer pass through an alumina pad (2.5 diameter ×2 cm), the solvent was evaporated, to afford 76 mg of the title compound as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=2)O1>>[Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:30]3[CH:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=3)=[CH:14][C:6]1=2
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1Cl
Product: Nc1ccc(-c2cnc3c(c2)N(Cc2c(F)ccc(F)c2Cl)CCN3)cn1
Yield: 52 %

Procedure:
1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (87 mg) was coupled to 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-ylamine as in General Procedure 4B to give the title compound as a light brown solid (52% yield). M.p.>200° C., LCMS: m/z=388.10 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.28 (2H, m), 3.51 (2H, m), 4.52 (2H, d, J=1.3 Hz), 6.58 (1H, dd, J=8.6, 0.8 Hz), 7.00 (1H, d, J=2.0 Hz), 7.05 (1H, m), 7.14 (1H, m), 7.30 (2H, s), 7.54 (1H, d, J=2.0 Hz), 7.58 (1H, dd, J=8.6, 2.5 Hz), 8.13 (1H, dd, J=2.4, 0.6 Hz).
Reaction SMILES: C(OC([NH:8][NH:9][C:10]([C:12]1[N:13]=[C:14]([S:17][CH2:18][C:19]([NH:21][CH2:22][C@@H:23]2[O:28][CH2:27][CH2:26][N:25]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=3)[CH2:24]2)=[O:20])[S:15][CH:16]=1)=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:37][C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][C:33]=1[Cl:36])[CH2:29][N:25]1[CH2:26][CH2:27][O:28][C@@H:23]([CH2:22][NH:21][C:19](=[O:20])[CH2:18][S:17][C:14]2[S:15][CH:16]=[C:12]([C:10]([NH:9][NH2:8])=[O:11])[N:13]=2)[CH2:24]1
Reactant: CC(C)(C)OC(=O)NNC(=O)c1csc(SCC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NNC(=O)c1csc(SCC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)n1
Reaction time: 8 h

Procedure:
The resultant product (4.01 g) of (42-1) was dissolved in methylene chloride (30 mL), trifluoroacetic acid (10 mL) was added, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, a 1 mol/L aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from a mixed solvent of ethyl acetate and methanol to give the title compound (453 mg) as white crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[F:12][CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1>>[F:12][CH:13]1[CH2:17][CH2:16][N:15]([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=2)[CH2:14]1
Reactant: FC1CCNC1
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Product: Cc1nc(N2CCC(F)C2)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 6-chloro-2-methyl-3-nitropyridine and 3-fluoropyrrolidine following the method used to prepare Intermediate 51. LCMS (ES+) 226 (M+H)+, RT 2.847 minutes (method 1).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[Cl:27][C:28]1[CH:42]=[CH:41][C:31]2[N:32]=[C:33]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[S:34][C:30]=2[CH:29]=1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:38]2[CH2:39][CH2:40][N:35]([C:33]3[S:34][C:30]4[CH:29]=[C:28]([Cl:27])[CH:42]=[CH:41][C:31]=4[N:32]=3)[CH2:36][CH2:37]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: Clc1ccc2nc(N3CCNCC3)sc2c1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3nc4ccc(Cl)cc4s3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 6-chloro-2-piperazin-1-yl-benzothiazole.
Reaction SMILES: [BrH:1].[CH2:2]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([OH:17])[C:14]([OH:16])=[CH:15][C:8]=2[CH2:7][CH2:6]1)[CH:3]=[CH2:4].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[C:32]1([SH:38])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[BrH:1].[CH2:2]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([OH:17])[C:14]([OH:16])=[C:15]([S:38][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:8]=2[CH2:7][CH2:6]1)[CH:3]=[CH2:4]
Reactant: C=CCN1CCc2cc(O)c(O)cc2CC1
Reactant: Sc1ccccc1
Agent: Br
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Product: C=CCN1CCc2cc(O)c(O)c(Sc3ccccc3)c2CC1

Procedure:
Following the procedures outlined in Example 2 the 3-allyl-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide was treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone to give the 7,8-dione which was then reacted with, for example, thiophenol to obtain the corresponding 3-allyl-7,8-dihydroxy-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, m.p. 103°-123° C.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:15][C:16]3[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=3[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:11]([CH3:14])[CH:12]=2)[C:7]([CH3:28])([CH3:27])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH:29](=O)[CH:30]([CH3:32])[CH3:31].C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.C(#N)C>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N:15]([C:16]3[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=3[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:29][CH:30]([CH3:32])[CH3:31])=[C:11]([CH3:14])[CH:12]=2)[C:7]([CH3:28])([CH3:27])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccccc1Nc1cc2c(cc1C)N(C(C)C)CCC2(C)C
Reactant: CC(C)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(=O)c1ccccc1N(CC(C)C)c1cc2c(cc1C)N(C(C)C)CCC2(C)C
Yield: 34.4 %

Procedure:
Ethyl [(1-isopropyl-4,4,7-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl)amino)benzoate (Compound 20, 0.12 g, 0.32 mmol) was dissolved in a 10% acetic acid in acetonitrile solution (2.0 mL). The solution was treated with isobutyraldehyde (0.10 mL, 1.1 mmol) and then sodium cyanoborohydride (22 mg, 0.35 mmol) and the reaction stirred at room temperature for 7 hours. 1 M aqueous NaOH was added until pH=6 was reached and the solution was extracted with ether (2×), washed with brine, and dried (Na2SO4). The filtered solution was concentrated under reduced pressure and the residue purified using flash column chromatography (10% ethyl acetate in hexanes) to give the title compound (48 mg) as an oil.