Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH:2]1[C:3]([OH:5])=[O:4].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>CN(C=O)C>[N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH:2]1[C:3]([O:5][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)OCc1ccccc1

Procedure:
Boc-DL-Pip-OH (2.29 g, 10 mmol) and benzyl bromide (1.79 ml, 15 mmol) were reacted in DMF (20 ml) in the presence of triethylamine (2.1 ml, 15 mmol) to obtain Boc-DL-Pip-OBzl as an oily product. This product was reacted with 2 N HCl/dioxane (5 eq.) for 3 hours to obtain H-DL-Pip-OBzl-HCl.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].CS(O[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)(=O)=O>O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
4-Nitrobenzenethiol (5.93 mmol, 1.15 g), and sodium hydride (8.12 mmol, 0.325 g) were combined in tetrahydrofuran and stirred at 0° C. for 30 minutes. tert-Butyl 4-(methyl-sulfonyloxy)piperidine-1-carboxylate (8.89 mmol, 2.484 g) was added and the reaction mixture heated at 60° C. overnight. The reaction mixture was concentrated under vacuum and residue dissolved in dichloromethane and washed with water. The organic layer was separated, dried and concentrated under vacuum. The residue was purified by silica column chromatography (eluent: dichloromethane) to afford the title compound (1.45 g). MS (ESI) m/z 339.5 [M+H]+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Ni](Cl)Cl.[Zn].N1C=CC=CC=1>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]2[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:3][CH:4]=1
Reactant: Cc1ccc(Br)cc1
Reactant: COC(=O)c1ccccc1Cl
Agent: Cl[Ni]Cl
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1-c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 100 ml flask, 50 ml of dry pyridine, 4.28 g (0.025 mol) of 4-bromotoluene, 4.26 g (0.025 mol) of methyl 2-chlorobenzoate, 0.32 g (0.0025 mol) of anhydrous nickel chloride, 1.31 g (0.005 mol) of triphenylphosphine and 4.90 g (0.075 mol) of zinc powder were charged under a nitrogen atmosphere and stirred at room temperature for 30 minutes. The mixture was heated by an oil bath and reacted at 85° C. for 3 hours. The reaction solution was analyzed by gas chromatography. The results are shown in Table 1. The data confirming the structure are shown below.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=O.C(Cl)(=O)C(Cl)=O.Cl.[C:20]1([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl.O>[C:20]1([CH:26]2[CH2:27][CH2:28][N:29]([C:10]([CH:2]3[CH2:1][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3]3)=[O:12])[CH2:30][CH2:31]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=C(O)C1Cc2ccccc2C1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(C1Cc2ccccc2C1)N1CCC(c2ccccc2)CC1
Temperature: 25 °C
Yield: 44.8 %

Procedure:
750 mg (4.6 mmol) of 2,3-dihydro-1H-inden-2-carboxylic acid (prepared as described in Hacksell, J. Med. Chem., 24, 429, 1981) were dissolved in 15 mL of CH2Cl2 and 0.65 mL (7.4 mmol) of oxalyl chloride were added dropwise at 0° C. under a nitrogen atmosphere. The solution was allowed to warm to room temperature in 2 h, then the solvent was removed in vacuo. The resulting acyl chloride was dissolved in 10 mL of CH2Cl2 and added to a solution of 909 mg (4.6 mmol) of 4-phenylpiperidine hydrochloride and 1.9 mL (13.8 mmol) of triethylamine in 15 mL of CH2Cl2 at 0° C. The reaction mixture was allowed to warm to room temperature overnight, then water was added and the organic phase was washed with 5% HCl and dried. The solvent was removed in vacuo and the resulting crude product was purified by flash chromatography, eluting with a mixture Et2O/Petroleum ether 7:3, yielding 630 mg of the title compound. IR (cm−1)=2944, 1636, 1494. NMR (300 MHz, CDCl3, δ ppm): 7.35 (m, 2H); 7.25-7.1 (m, 7H); 4.85 (m, 1H); 4.15 (m, 1H); 3.55 (m, 1H); 3.4-3.3 (m, 2H); 3.3-3.1 (m, 3H); 2.85-2.6 (m, 2H); 2.0-1.9 (m, 2H); 1.75.1.6 (m, 2H). MS (m/z): 306.0 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:20][CH:21]=[CH2:22])[C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35])[CH2:28]CN.Cl.[CH3:39][N:40](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl.C(OCC)(=O)C>[CH3:37][O:36][C:32]1[CH:31]=[C:27]([CH:26]=[C:25]([O:24][CH3:23])[C:33]=1[O:34][CH3:35])[CH2:28][N:40]([CH3:39])[C:10](=[O:12])[C@@H:9]([N:8]([CH2:20][CH:21]=[CH2:22])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=CCN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Reactant: COc1cc(CCN)cc(OC)c1OC
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C=CCN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)N(C)Cc1cc(OC)c(OC)c(OC)c1

Procedure:
Combine (S)-2-[N-(t-butoxycarbonyl)-allylamino]-3-phenyl-propioic acid (0.91 g, 2.97 mmol), (3,4,5-trimethoxy)-benzylmethylamine (0.63 g, 2.97 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.63 g, 3.27 mmol), 1-hydroxybenzotriazole (0.349 g, 3.27 mmol), and diisopropylethylamine (0.77 mL, 6.27 mmol) in dichloromethane (30 mL) and stir for 18 hours. Dilute with ethyl acetate and extract with 1M hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride. Dry the separated organic layer over MgSO4, filter and evaporate in vacuo. Chromatograph on silica gel eluting with 30% ethyl acetate/hexane to give the title compound: TLC Rf =0.30 (silica gel, 30% ethyl acetate/hexane).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16](Cl)=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)C(C)C)(C)C.[Cl:30][C:31]1[N:32]([CH2:39][C:40]([OH:44])([CH3:43])[CH2:41][OH:42])[CH:33]=[C:34]([N+:36]([O-:38])=[O:37])[N:35]=1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:42][CH2:41][C:40]([OH:44])([CH3:43])[CH2:39][N:32]3[CH:33]=[C:34]([N+:36]([O-:38])=[O:37])[N:35]=[C:31]3[Cl:30])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Reactant: O=C(Cl)N1CCN(c2ccc(OC(F)(F)F)cc2)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(O)(COC(=O)N1CCN(c2ccc(OC(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 55.6 %

Procedure:
4-(4-Trifluoromethoxyphenyl)piperazine-1-carbonylchloride (0.26 g, 0.85 mmol), N,N-diisopropylethylamine (0.30 ml, 1.7 mmol) and 4-dimethylaminopyridine (21 mg, 0.17 mmol) were added to a suspension of 2-chloro-1-(2,3-dihydroxy-2-methylpropyl)-4-nitroimidazol prepared in Example 3 (0.30 g, 1.3 mmol) in toluene (5 ml) followed by stirring at 100° C. for 2.5 hours. The mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=9/1) to afford 3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 4-(4-trifluoromethoxyphenyl)piperazine-1-carboxylate (0.24 g, yield 55%) as a light yellow oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2.[CH:21]([Si:24](Cl)([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])([CH3:23])[CH3:22]>C1COCC1>[Br:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([Si:24]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:21]([CH3:23])[CH3:22])[CH:16]=[CH:15]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)ccc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 99.5 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.0 M in THF, 28 mL, 28 mmol) was slowly added to a solution of 5-bromoindole (5.00 g, 25.5 mmol) in THF (60 mL) at −78° C., under nitrogen atmosphere. The reaction mixture was stirred at −78° C. for 20 minutes, then triisopropylsilylchloride (5.7 mL, 26.8 mmol) was added. The resulting mixture was stirred at −78° C. for 20 minutes, then warmed to room temperature over a period of 1 hour. The reaction was quenched by addition of a saturated aqueous solution of NH4Cl, diluted with water, and the resulting mixture was extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered and evaporated under reduced pressure to give a crude oil that was purified by flash chromatography (hexane 100%) providing 8.94 g (99% yield) of 5-bromo-1-triisopropylsilanyl-1H-indole as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH2:7][C:8]([OH:10])=[O:9])[C:4](=[O:11])[O:3]1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[O:6][CH:5]([CH2:7][C:8]([O:10][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)[C@H](CC(=O)O)O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)C(CC(=O)O[Si](C)(C)C(C)(C)C)O1
Temperature: 22 °C
Reaction time: 18 h
Yield: 95.6 %

Procedure:
A solution of (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid (13.20 g, 75.8 mmol) in N,N-dimethylformamide (25 ml) was treated at 22° C. with imidazole (10.56 g, 0.155 mmol) followed by tert-butyldimethylsilyl chloride (12.0 g, 79.6 mmol) and the resulting mixture was stirred at 22° C. for 18 hours. The reaction mixture was then diluted with toluene (500 ml), washed with water (3 times), saturated sodium bicarbonate and brine. After drying (magnesium sulfate), the solvent was evaporated under reduced pressure to give an oil. Distillation under vacuum gave 20.9 g (96% yield) of the title material as a clear oil: Bp 80-90° C./0.1 torr (bulb to bulb distillation, air bath temperature). 1H NMR (400 MHz, CDCl3) δ: 0.33 (s, 3), 0.36 (s, 3), 1.00 (s, 9), 1.11 (s, 3), 1.37 (s, 3), 2.72 (m, 2), 4.35 (dd, 1, J=4, 6).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:39])=[C:7]([CH:38]=1)[CH2:8][N:9]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C@H:16]([CH3:30])[CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:23]([CH3:29])=[N:24][CH:25]=[N:26][C:27]=2[CH3:28])=[O:21])[CH2:12][CH2:11]1)#[N:2].Br[CH2:41][C:42]([O:44][CH3:45])=[O:43].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:45][O:44][C:42](=[O:43])[CH2:41][O:37][C:34]1[CH:33]=[CH:32][C:31]([N:9]([CH2:8][C:7]2[CH:38]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[F:39])[CH:10]2[CH2:11][CH2:12][N:13]([C@H:16]([CH3:30])[CH2:17][CH2:18][NH:19][C:20]([C:22]3[C:27]([CH3:28])=[N:26][CH:25]=[N:24][C:23]=3[CH3:29])=[O:21])[CH2:14][CH2:15]2)=[CH:36][CH:35]=1
Reactant: Cc1ncnc(C)c1C(=O)NCC[C@@H](C)N1CCC(N(Cc2cc(C#N)ccc2F)c2ccc(O)cc2)CC1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(N(Cc2cc(C#N)ccc2F)C2CCN([C@H](C)CCNC(=O)c3c(C)ncnc3C)CC2)cc1
Temperature: 80 °C
Yield: 87.8 %

Procedure:
A mixture of COMPOUND 233 (91 mg, 0.17 mmol), methyl bromoacetate (29 mg, 0.19 mmol) and K2CO3 (47 mg, 0.34 mmol) in DMF (1.7 mL) were heated at 80° C. for 25 h to give COMPOUND 237 as a yellow foam (90 mg, 87%) after work-up and purification. 1H NMR (CDCl3) δ 0.93-1.25 (m, 2H), 1.01 (d, 3H, J=6.9 Hz), 1.58 (m, 1H), 1.76 (m, 3H), 2.16 (m, 1H), 2.50 (s, 6H), 2.55 (m, 1H), 2.68-2.88 (m, 3H), 3.31-3.53 (m, 2H), 3.78 (s, 3H), 3.82 (m, 1H), 3.93 (s, 2H), 4.54 (s, 2H), 6.57 (m, 2H), 6.76 (m, 2H), 7.17 (m, 1H), 7.52 (m, 2H), 8.28 (m, 1H), 8.83 (s, 1H). ES-MS m/z 603 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][C@H:4]([N:8]1[CH2:12][C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:10][C:9]1=[O:21])[C:5]([OH:7])=O.[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([NH2:29])=[N:25]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([NH:29][C:5](=[O:7])[C@@H:4]([N:8]2[CH2:12][C:11]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])=[CH:10][C:9]2=[O:21])[CH2:3][CH:2]([CH3:1])[CH3:22])=[N:25]1
Reactant: Cn1ccc(N)n1
Reactant: Cc1ccccc1OC1=CC(=O)N([C@@H](CC(C)C)C(=O)O)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccccc1OC1=CC(=O)N([C@@H](CC(C)C)C(=O)Nc2ccn(C)n2)C1
Temperature: 0 °C
Yield: 18.9 %

Procedure:
To a solution of (S)-4-methyl-2-(2-oxo-4-o-tolyloxy-2,5-dihydro-pyrrol-1-yl)-pentanoic acid (0.208 g, 0.69 mmol) in N,N-dimethylformamide (4 mL) was added 1-methyl-1H-pyrazol-3-ylamine (0.080 g, 0.82 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.620 g, 1.40 mmol). The mixture was stirred at 0° C. and triethylamine (0.150 g, 1.48 mmol) was added. The mixture was stirred at room temperature for 3 h and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 25 g, 20% to 100% ethyl acetate/hexanes) which afforded (S)-4-methyl-2-(2-oxo-4-o-tolyloxy-2,5-dihydro-pyrrol-1-yl)-pentanoic acid (1-methyl-1H-pyrazol-3-yl)-amide (0.050 g, 19%) as a tan solid: HR-ES-MS m/z calculated for C21H26N4O3 [M+H]+ 383.2078, observed 383.2077, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00-0.90 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H), 1.20-1.92 (m, 3H), 2.19 (s, 3H), 3.73 (s, 3H), 4.20 (d, J=18.1 Hz, 1H), 4.57 (d, J=18.1 Hz, 1H), 4.63 (s, 1H), 4.87 (dd, J=10.3, 4.8 Hz, 1H), 6.40 (d, J=1.8 Hz, 1H), 7.17-7.33 (m, 3H), 7.36 (d, J=7.2 Hz, 1H), 7.55 (d, J=1.8 Hz, 1H), 10.72 (s, 1H).
Reaction SMILES: C(OC([N:8]([CH:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([Cl:29])=[CH:21][N:22]=[C:23]([Cl:28])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:11]1)[CH3:9])=O)(C)(C)C.ClC1C2C=CC=C(S(Cl)(=O)=[O:42])C=2C(Cl)=CN=1.C(OC(N(C1CCNC1)C)=O)(C)(C)C.ClC1C2C=CC=C(S(Cl)(=O)=O)C=2C(Br)=CN=1.C(OC(N([C@H]1CCNC1)C)=O)(C)(C)C>>[OH:42][C:23]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:18]([S:15]([N:12]3[CH2:13][CH2:14][CH:10]([NH:8][CH3:9])[CH2:11]3)(=[O:16])=[O:17])[C:19]=2[C:20]([Cl:29])=[CH:21][N:22]=1.[ClH:28]
Reactant: O=S(=O)(Cl)c1cccc2c(Cl)ncc(Cl)c12
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Cl)c23)C1
Agent: CN(C(=O)OC(C)(C)C)C1CCNC1
Agent: CN(C(=O)OC(C)(C)C)[C@H]1CCNC1
Agent: O=S(=O)(Cl)c1cccc2c(Cl)ncc(Br)c12
Product: CNC1CCN(S(=O)(=O)c2cccc3c(O)ncc(Cl)c23)C1
Product: Cl

Procedure:
3-[N-(tert-Butoxycarbonyl)-N-methylamino]-1-(1,4-dichloro-5-isoquinolinesulfonyl)pyrrolidine (Intermediate 25) can be prepared by using 1,4-dichloro-5-isoquinolinesulfonyl chloride and 3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine in the method of Example 35-1, Step A instead of 1-chloro-4-bromo-5-isoquinolinesulfonyl chloride and (S)-3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine, respectively, and then used in the method of Example 35-1, Step B in a similar manner to obtain the title compound as hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:20]=1[C:19]1[C:10](=[C:11]3[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:22])([CH3:21])[C:13](=[O:23])[NH:12]3)[C:9](=[O:24])[O:8]2.[C:25](=O)([O-])[O-].[Cs+].[Cs+].CI.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:20]=1[C:19]1[C:10](=[C:11]3[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:22])([CH3:21])[C:13](=[O:23])[N:12]3[CH3:25])[C:9](=[O:24])[O:8]2
Reactant: COc1cccc2oc(=O)c3c4c(ccc3c12)NC(C)(C)C(=O)N4
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccc2oc(=O)c3c4c(ccc3c12)NC(C)(C)C(=O)N4C
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of tetracyclic lactone ix (100 mg, 0.32 mmol) in DMF (5 mL) was added cesium carbonate (263 mg, 0.81 mmol) and methyl iodide (100 μL, 1.60 mmol). The mixture was stirred at 40° C. overnight, poured into water (30 mL) and extracted with EtOAc(3×30 mL). The combined extracts were washed with brine and dried (MgSO4), the solvent was removed under reduced pressure to yield a product that was used in the next step with no further purification. A small portion of the residue was purified by reverse phase preparative HPLC for characterization. 1H NMR (acetone-d6) δ 8.69 (d, J=8.4 Hz, 1H), 7.39 (t, J=8.4 Hz, 1H), 7.31 (d, J=8.4, 1H), 7.02 (d, J=8.4, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.04 (br, 1H), 4.06 (s, 3H), 3.27 (s, 3H) 1.32 (s, 6H). Anal. Calcd for C19H18N2O4⅓CF3COOH⅓H2O: C, 61.78; H, 5.01; N, 7.33. Found: C, 61.64; H, 4.84; N, 7.51.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.[Li]CCCC.[Br:15][C:16]1[C:17](=[O:21])[CH2:18][CH2:19][CH:20]=1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>C1COCC1.O>[Br:15][C:16]1[C:17](=[O:21])[CH2:18][CH2:19][C:20]=1[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1
Reactant: CSc1ccc(Br)cc1
Reactant: O=C1CCC=C1Br
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Li]CCCC
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc(C2=C(Br)C(=O)CC2)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a -78° C. solution of 4-bromothioanisole (35.1 g, 173 mmol) in THF (500 mL) was added nBuLi (1.6M in hexanes, 107.5 mL, 172 mmol). The solution was stirred for 45 min, then a solution of 2-bromo-2-cyclopenten-1-one (25.4 g, 158 mmol) in THF (150 mL) was added and the mixture was allowed to warm to 0° C. and was quenched with saturated aqueous NH4Cl. The majority of the solvent was removed in vacuo and the residue was suspended in water and extracted with two portions of EtOAc. The organic layers were washed with brine, dried over MgSO4, faltered and concentrated. This material was dissolved in DMF (300 mL), cooled to 0° C. and treated with PDC (72.4 g, 192 mmol). The resulting mixture was warmed to r.t. and stirred for 2 h, then poured into H2O (1.2 L) and extracted with two 500 mL portions of EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give the title compound as a light brown solid which was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]3[C:11]([CH2:26][CH2:27][CH2:28][OH:29])([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12]([C:14](N(OC)C)=[O:15])=[N:13][N:7]3[C:6]=2[CH:30]=1.[CH3:31][Li]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]3[C:11]([CH2:26][CH2:27][CH2:28][OH:29])([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12]([C:14](=[O:15])[CH3:31])=[N:13][N:7]3[C:6]=2[CH:30]=1
Reactant: CON(C)C(=O)C1=NN2c3cc(F)ccc3OCC2C1(CCCO)c1ccccc1
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(=O)C1=NN2c3cc(F)ccc3OCC2C1(CCCO)c1ccccc1
Temperature: -78 °C

Procedure:
8-Fluoro-3-(3-hydroxypropyl)-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamide (5-7; a racemic mixture, 2.6 g, 6.29 mmol) was dissolved in anhydrous THF (50 mL) and cooled to −78° C. Methyllithium (11.8 mL, 3M in diethylether, 18.9 mmol) was added and the reaction stirred to 25° C. Upon completion the reaction was quenched by the addition of NH4Cl (50 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. Flash column chromatography (ISCO Redisep 0-100% EtOAc/hexanes gradient) provided 1-[8-fluoro-3-(3-hydroxypropyl)-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazin-2-yl]ethanone (5-8; a racemic mixture). 1H NMR (300 MHz, CDCl3) δ 7.28 (m, 4H), 7.07 (m, 2H), 6.78 (dd, J=8.9, 5.1 Hz, 1H), 6.58 (ddd, J=8.9, 8.2, 3.1 Hz, 1H), 4.15 (dd, J=10.5, 3.5 Hz, 1H), 3.75 (m, 2H), 3.71 (dd, J=10.8, 3.5 Hz, 1H), 2.95 (t, J=10.8 Hz, 1H), 2.55 (dt, J=13.0, 4.0 Hz, 1H), 2.55 (s, 3H), 2.37 (dt, J=13.0, 4.0 Hz, 1H), 1.74 (m, 1H), 1.42 (m, 1H); MS (M+H+, C21H21FN2O3) 369.3 found 369.4 required. This compound was resolved on the Chiracel OD column using MeOH as eluant into its separate enantiomers.
Reaction SMILES: [Mg].[Cl:2][C:3]1[S:4][C:5](Cl)=[CH:6][CH:7]=1.[C:9]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.Cl>C1COCC1.C1C=CC=CC=1.O>[Cl:2][C:3]1[S:4][C:5]([C:9]2([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)s1
Reactant: O=C1CCCCC1
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: OC1(c2ccc(Cl)s2)CCCCC1
Yield: 81.2 %

Procedure:
To a Grignard reagent prepared from magnesium (26.7 g), 2,5-dichlorothiophene (16.83 g) and anhydrous THF (70 ml) was added dropwise in small portions a solution of cyclohexanone (XIa) (9.815 g) in anhydrous THF (30 ml) with stirring under ice-cooling in nitrogen atmosphere. The mixture was made to react at room temperature for 3 hours and after addition of water and acidification with 5% hydrochloric acid, extracted with chloroform. The extract was washed with water, dried and evaporated. The residue was applied to column chromatography on silica gel (70 g). From the benzene fraction, 1-(5-chloro-2-thienyl)cyclohexanol (Xa) (17.6 g) was obtained as an oil (yield 81.2%).
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[C:13]([CH2:15][N:16]=[C:17]=[S:18])[N:12]=[N:11]2)[CH:7]=[C:6]([F:19])[C:5]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.Cl>O>[F:3][C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[C:13]([CH2:15][NH:16][C:17]([NH:2][CH3:1])=[S:18])[N:12]=[N:11]2)[CH:7]=[C:6]([F:19])[C:5]=1[N:20]1[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: CN
Reactant: Fc1cc(-n2cc(CN=C=S)nn2)cc(F)c1N1CCOCC1
Agent: Cl
Solvent: O
Product: CNC(=S)NCc1cn(-c2cc(F)c(N3CCOCC3)c(F)c2)nn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 40% methylamine (10 mL) was added 4-[2,6-difluoro-4-(4-isothiocyanatomethyl-[1,2,3]triazol-1-yl)-phenyl]-morpholine (0.2 g), obtained in Example 33, and stirred at room temperature for 30 min. The reaction mixture was neutralized with 1N HCl and diluted with water. Water layer was extracted with ethyl acetate (20 mL×2) and the combined organic layer was washed with brine and dried over sodium sulfate. Upon concentration and purification of the resulting residue by silica gel column chromatography (eluent; chloroform/ethylacetate, 8:2), the title compound was obtained as pale yellow crystals (0.12 g, 50%). Mp. 181° C.