Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@:3]1([CH:35]([CH3:37])[CH3:36])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:27]=[CH:26][C:18]([C:19]([O:21]C(C)(C)C)=[O:20])=[C:17]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH:16]=3)[N:9]=2)[C:4]1=[O:34])#[N:2].[ClH:38]>C(OCC)(=O)C>[ClH:38].[C:1]([C@@:3]1([CH:35]([CH3:37])[CH3:36])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:27]=[CH:26][C:18]([C:19]([OH:21])=[O:20])=[C:17]([O:28][CH2:29][C:30]([F:31])([F:33])[F:32])[CH:16]=3)[N:9]=2)[C:4]1=[O:34])#[N:2]
Reactant: CC(C)[C@]1(C#N)CCN(c2ccnc(Nc3ccc(C(=O)OC(C)(C)C)c(OCC(F)(F)F)c3)n2)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)[C@]1(C#N)CCN(c2ccnc(Nc3ccc(C(=O)O)c(OCC(F)(F)F)c3)n2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl 4-((4-((3S)-3-cyano-3-isopropyl-2-oxopyrrolidin-1-yl)pyrimidin-2-yl)amino)-2-(2,2,2-trifluoroethoxyl)benzoate (120 mg) obtained in Step A of Example 292 was added dropwise a solution of 4 M hydrogen chloride in ethyl acetate (6.0 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate to give the title compound (71 mg).
Reaction SMILES: [C:1]1([CH:7]2[O:17][C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][N:9]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:23]([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][C:28]=1[CH3:36])([CH3:25])[CH3:24].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH:23]([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([N:14]2[CH2:15][CH2:16][C:11]3([O:17][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:8][N:9]([CH2:18][C:19]([F:21])([F:22])[F:20])[CH2:10]3)[CH2:12][CH2:13]2)=[O:32])=[CH:29][C:28]=1[CH3:36])([CH3:25])[CH3:24]
Reactant: Cc1cc(C(=O)O)ccc1OC(C)C
Reactant: FC(F)(F)CN1CC(c2ccccc2)OC2(CCNCC2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)N2CCC3(CC2)CN(CC(F)(F)F)CC(c2ccccc2)O3)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To 10-phenyl-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecane (hydrochloride salt) (150 mg, 0.39 mmol) and 4-isopropoxy-3-methyl-benzoic acid (75 mg, 0.39 mmol) in DMF (1 mL) was added at room temperature O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (162 mg, 0.43 mmol) and diisopropylethylamine (337 μL, 1.94 mmol) and reaction mixture was stirred at room temperature for 30 minutes. The reaction was diluted with ethyl acetate and washed with 1M NaOH and then brine solution. The organic layer was separated, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography using 10-60% EtOAc/hexane to give the desired compound as a white foam (147 mg, 73%) ESI-MS m/z calc. 490.2. found 491.4 (M+1)+; Retention time: 2.42 minutes (3 min run).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH2:25])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:33][CH:34]([F:37])[CH2:35]N.C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH:25][CH2:35][CH:34]([F:37])[F:33])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(N)=O)C1
Reactant: NCC(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(=O)NCC(F)F)C1
Yield: 57 %

Procedure:
Following general method 7, employing (S)-3-{[1-(3-fluorophenyl)-4-ureido-1H-pyrrole-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester and 2,2-difluoroethylamine, afforded the crude desired product. Column chromatography (silica, 12 g column, ISCO, 0-50% ethyl acetate in DCM) afforded the title compound as a glass (100 mg, 57%). LCMS (method B): RT=3.81 min, M+H+=510.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH:8]([CH:12]=C)[CH2:7][C:6]=2[N:5]=[CH:4][N:3]=1.[BH4-].[Na+].C[OH:17]>ClCCl>[Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH:8]([CH2:12][OH:17])[CH2:7][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: C=CC1CCc2c(Cl)ncnc2C1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: OCC1CCc2c(Cl)ncnc2C1
Yield: 90 %

Procedure:
Ozone was bubbled through a cooled (−78° C.) solution of 4-chloro-7-vinyl-5,6,7,8-tetrahydroquinazoline (reagent preparation 3, 0.35 g, 1.8 mmol) in methanol (5 mL) and dichloromethane (30 mL) until a blue color persisted. The solution was then sparged with N2 for 10 minutes and sodium borohydride (0.14 g, 3.6 mmol) was added portionwise. After 30 minutes the reaction mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and then concentrated in vacuo to provide (4-chloro-5,6,7,8-tetrahydroquinazolin-7-yl)methanol (0.32 g, 90% yield) as a waxy solid. MS (ES) for C9H11ClN2O: 199 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([CH3:13])[CH:5]=1)[CH3:2].CO>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([CH3:13])[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc([N+](=O)[O-])c(C)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOc1ccc(N)c(C)c1
Reaction time: 4 h
Yield: 92 %

Procedure:
Compound 404a (250 mg, 1.38 mmol) was dissolved in EtOAc (10 mL) and MeOH (10 mL) and transferred to a 250 mL hydrogenation flask. 10% Pd/C (25 mg, 10% w/w) was added and the sample was hydrogenated for 4 h at 35 psi H2. Upon completion, the mixture was filtered over a bed of Celite and then concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with NaHCO3 (50 mL×3). The organic layer was dried over Na2SO4 to yield a dark-red oil (192 mg, 92%): TLC Rf 0.30 (20% EtOAc/hexanes). 1NMR (600 MHz, CDCl3) δ 6.67 (s, 1H), 6.62 (m, 2H), 3.97-3.93 (q, 2H, J=6.96 Hz), 3.42 (s, 2H), 2.16 (s, 3H), 1.38-1.35 (t, 3H, J=7.02 Hz). NMR (150 MHz, CDCl3) δ 152.3, 138.1, 124.4, 117.45, 116.34, 113.1, 64.2, 17.9, 15.2. Elemental analysis calculated for C9H13NO: C, 71.49; H, 8.67; N, 9.26. Found: C, 71.42; H, 8.76; N, 9.04.
Reaction SMILES: [S:1]1(=[O:14])(=[O:13])[C:5]2=[CH:6][CH:7]=[CH:8][C:9]3=[CH:10][CH:11]=[CH:12][C:3](=[C:4]23)[NH:2]1.[H-].[Na+].Br[CH2:18][CH2:19][CH:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)[CH3:21]>CN(C)C=O>[F:34][C:31]1[CH:30]=[CH:29][C:28]([N:25]2[CH2:24][CH2:23][N:22]([CH:20]([CH3:21])[CH2:19][CH2:18][N:2]3[C:3]4[CH:12]=[CH:11][CH:10]=[C:9]5[CH:8]=[CH:7][CH:6]=[C:5]([C:4]=45)[S:1]3(=[O:13])=[O:14])[CH2:27][CH2:26]2)=[CH:33][CH:32]=1
Reactant: O=S1(=O)Nc2cccc3cccc1c23
Reactant: CC(CCBr)N1CCN(c2ccc(F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(CCN1c2cccc3cccc(c23)S1(=O)=O)N1CCN(c2ccc(F)cc2)CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 25.9 %

Procedure:
A solution of naphtho[1,8-cd]isothiazole 1,1-dioxide (3.25 g) in dimethylformamide (50 cc) is poured over 30 minutes into a mixture of sodium hydride (0.76 g) in a 50% dispersion in vaseline oil and dimethylformamide (10 cc), under a current of argon. The reaction medium is stirred for 2 hours at a temperature of about 20° C. 1-(4-bromo-2-butyl)-4-(4-fluorophenyl)piperazine (5 g) in dimethylformamide (100 cc) is added over 10 minutes. The reaction mixture is stirred for 15 hours at a temperature close to 20° C., then concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residual oil is purified by flash-chromatography on silica column, under a current of argon at medium pressure (0.5-1.5 bar) with a mixture of dichloromethane and ethyl acetate (80-20 vol) as eluant. After recrystallization from boiling acetonitrile (13 cc), 2-{3-[4-(4-fluorophenyl)-1-piperazinyl]butyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (1.8 g) is obtained, m.p. 122° C.
Reaction SMILES: [CH2:1]([Li])CCC.C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:26][O:27][C:28]1[CH:35]=[C:34]([O:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH3:42])[CH:33]=[CH:32][C:29]=1[CH:30]=O.O>O1CCCC1>[CH3:26][O:27][C:28]1[CH:35]=[C:34]([O:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH3:42])[CH:33]=[CH:32][C:29]=1[CH:30]=[CH2:1]
Reactant: [Li]CCCC
Reactant: COCCOCOc1ccc(C=O)c(OC)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1ccc(OCOCCOC)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
12.5 ml (31.2 mmol) of n-butyllithium is added dropwise to a solution at −40° C. of 11.1 g (31.2 mmol) of methyl-triphenyl-phosphonium diluted in 100 ml of tetrahydrofuran. The reaction mixture is stirred at 0° C. for 30 minutes and then cooled to −25° C. and a solution of 5 g (20.8 mmol) of 2-methoxy-4-(2-methoxy-ethoxymethoxy)-benzaldehyde diluted in 50 ml of tetrahydrofuran is added dropwise. The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is treated by adding water and then extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered, and evaporated. The raw product is purified by silica column chromatography, eluted with a heptane/ethyl acetate mixture 75/25 to give 4.4 g (90%) of 2-methoxy-4-(2-methoxy-ethoxymethoxy)-1-vinyl-benzene in the form of a colorless oil.
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH:35]=O)=[CH:15][N:16]3[CH2:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:22][C:21]=3[O:33][CH3:34])=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:37]([CH2:42][CH:43]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:39][CH2:40][CH3:41])=[O:38]>O1CCOCC1>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH:35]=[C:42]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:43])=[CH:15][N:16]3[CH2:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])=[CH:22][C:21]=3[O:33][CH3:34])=[CH:12][CH:11]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)OC(C)(C)C)ccc1Cn1cc(C=O)c2ccc(C(=O)NCC3CCCC3)cc21
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)C(C)=Cc1cn(Cc2ccc(C(=O)OC(C)(C)C)cc2OC)c2cc(C(=O)NCC3CCCC3)ccc12
Yield: 100.6 %

Procedure:
A solution of t-butyl 4-[6-(N-cyclopentylmethylcarbamoyl)-3-formylindol-1-ylmethyl]3-methoxybenzoate (Example 1, part(f)) (2.8 g) and (carbethoxyethylidene)triphenylphosphorane (4.6 g) in dioxane (29 ml) was heated at reflux for 18 hours. The solvent was evaporated. The resultant residue was purified by flash chromatography on silica gel (192 ml), eluting with 1:4 ethyl acetate:hexane to give t-butyl 4-[6-(N-cyclopentylmethylcarbamoyl)-3-(2-ethoxycarbonyl-1-propenyl)indol-1-ylmethyl]-3-methoxybenzoate (3.3 g, 100%) as a light yellow solid; mp 118°-120°; NMR (80 MHz, CDCl3) 2.15(d, 3H, CCH3), 3.40(dd, 2H, NHCH2), 5.42(s, 2H, NCH2), 6.22(br t, 1H, NH), 6.78(d, 1H, Ar).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7](Br)[S:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[H][H]>CO.[Pd]>[C:1]([NH:4][C:5]1[N:6]=[CH:7][S:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)Nc1nc(Br)sc1C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)Nc1ncsc1C
Yield: 13.1 %

Procedure:
A solution of 4-acetamido-2-bromo-5-methylthiazole (2.3 g) and sodium acetate (0.8 g) in methanol (60 ml) was hydrogenated at atmospheric pressure over 10% Pd/C catalyst until the theoretical uptake of hydrogen had occurred. The catalyst was removed by filtration and washed with methanol and the filtrate was evaporated to dryness. The residue was extracted with hot CCl4 and the extracts were evaporated. The residue was recrystallised once from petroleum ether (b.p. 60°-80° C.) and once from hexane to give 4-acetamido-5-methylthiazole (0.2 g) m.p. 62°-4° C. (Found: C, 46.6; H, 5.3; N, 18.1. C6H8N2OS requires C, 46.1; H, 5.2; N, 17.9%).
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]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.I[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36]>C(OCC)(=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]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[N:7]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)CI
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nn(CC(C)(C)C)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
A mixture of 4′-[(3-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.24 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 1-iodo-2,2-dimethylpropane (2 mL) was added, and the mixture was stirred at 40° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.6 g, 50%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH2:13]S(F)(=O)=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:18](Br)[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>C(#N)C.C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>[C:21]1([C:19](=[O:20])[CH:18]=[CH:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=S(=O)(F)Cc1ccccc1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: CC#N
Product: O=C(C=Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 152.9 %

Procedure:
A catalytic amount (about 500 mg) of dibenzo-18-crown-6-ether and 68 g of anhydrous powdered potassium carbonate were added to a solution of 18.4 g phenylmethane-sulphonyl fluoride and 10.0 g of phenacyl bromide in 100 ml of acetonitrile at room temperature, while stirring. The mixture was then stirred under reflux for 10 hours. The reaction mixture was allowed to cool down to room temperature and was then concentrated by stripping off the solvent under reduced pressure. The residue was chromatographed over a silica gel column using toluene as the eluent. The eluate was evaporated. In this manner, 16.0 g of 1,3-di-phenyl-prop-2-en-1-one were obtained in the form of a solid substance of melting point 56° C.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([Si:13]([CH3:16])([CH3:15])[CH3:14])=[C:6]2[CH2:12][CH2:11][O:10][C:7]2=[N:8][CH:9]=1)[CH:2]=[CH2:3].[O:17]1CCCC1.C12BC(CCC1)CCC2.CN(C)CCN(C)C.OO.[OH-].[Na+]>O1CCCC1>[CH3:14][Si:13]([CH3:16])([CH3:15])[C:5]1[C:4]([CH2:1][CH2:2][CH2:3][OH:17])=[CH:9][N:8]=[C:7]2[O:10][CH2:11][CH2:12][C:6]=12
Reactant: C=CCc1cnc2c(c1[Si](C)(C)C)CCO2
Reactant: C1CCOC1
Agent: B1C2CCCC1CCC2
Agent: CN(C)CCN(C)C
Agent: OO
Product: C[Si](C)(C)c1c(CCCO)cnc2c1CCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To a solution of 5-allyl-4-(trimethylsilyl)-2,3-dihydrofuro[2,3-b]pyridine (9.00 g, 38.6 mmol) in tetrahydrofuran (300 mL) was added boron trifluoride diethyl ether complex (5.38 mL, 42.5 mmol) under ice-cooling, and the mixture was warmed to room temperature. A 9-borabicyclo[3.3.1]nonane tetrahydrofuran solution (0.4M, 241 mL, 96.4 mmol) was added. After stirring for 1 hr, N,N,N′,N′-tetramethylethylenediamine (3.20 mL, 21.2 mmol) was added, and a mixed solution of 30% aqueous hydrogen peroxide (100 mL) and 2.5M aqueous sodium hydroxide solution (100 mL) was further added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→60/40) to give the title compound (6.64 g, yield 68%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH:15]([CH3:19])[C:16]([NH2:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][CH:15]([C:16](=[O:17])[NH2:18])[CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(Br)C(N)=O
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(N[C@H]1CCN(C(=O)OC(C)(C)C)C1)C(N)=O
Temperature: 80 °C

Procedure:
To a solution of MeCN (3 mL) was added 3-Amino-pyrrolidine-1-carboxylic acid tert-butyl ester (0.186 g, 1 mmol), 2-Bromo-propionamide (0.15 g, 1 mmol) and potassium carbonate (0.153 g, 1.1 mmol). The resulting mixture was heated at 80° C. overnight and partitioned between dichloromethane and water. The combined organic extracts were washed with brine, dried, and evaporated. The residue was purified by flash column chromatography on silica gel, eluting with MeOH/CH2Cl2 (20/80) to afford the title product.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:5][C:4](=[O:14])[CH2:3]1.F[B-](F)(F)F.[CH3:20][O+](C)C>C(Cl)Cl>[CH3:20][O:14][C:4]1[CH2:3][C@@H:2]([CH3:1])[C@H:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=1
Reactant: C[O+](C)C
Reactant: C[C@@H]1CC(=O)N[C@H]1Cc1ccccc1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC1=N[C@@H](Cc2ccccc2)[C@H](C)C1
Yield: 73.8 %

Procedure:
A solution of the product of Example 62 (400 mg, 2.0 mmol) in methylene chloride (25 mL) was treated with trimethyloxonium tetrafluoroborate (361 mg, 2.4 mmol) by the method of Example 3 to produce the title material (300 mg, 40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]2[C:22](=[O:23])[NH:21][C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[S:18]2)[CH2:11][CH2:10]1.[H-].[Na+].[CH2:30](I)[CH3:31]>CN(C)C=O>[CH2:30]([N:21]1[C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=2[S:18][CH:17]([CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:14][CH2:13]2)[C:22]1=[O:23])[CH3:31]
Reactant: CCI
Reactant: COc1ccccc1N1CCN(CCC2Sc3ccccc3NC2=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)C(CCN2CCN(c3ccccc3OC)CC2)Sc2ccccc21
Temperature: 0 °C

Procedure:
In a solution of 1.0 g of 2-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2H-1,4-benzothiazin-3(4H)-one, in 10 ml of dimethylformamide, was added 120 mg of 60% sodium hydride in oil at room temperature with stirring. The mixture was stirred for 10 minutes and 480 mg of ethyl iodide was added thereto. The whole mixture was stirred for further two hours, poured into ice-water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), and concentrated. The residue was subjected to a column chromatography on silica-gel (50 g). From the eluate with hexane-ethyl acetate (2:1, v/v) was obtained 4-ethyl-2-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2H-1,4-benzothiazin-3(4H)-one as an oily substance (0.60 g). This product was crystallized as the hydrochloride. The yield was 0.50 g (39%). Recrystallization from methanol-ether gave colorless prisms, m.p. 142°-144° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C@H:7]1[N:12]([C:13](=O)[CH2:14][C@@H:15]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][C:26]=2[S:35]([C:38]([F:41])([F:40])[F:39])(=[O:37])=[O:36])[CH2:16][S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:11][CH2:10][O:9][CH2:8]1)[CH2:4][CH3:5])[CH3:2].CO.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[CH2:1]([N:3]([CH2:6][C@H:7]1[N:12]([CH2:13][CH2:14][C@@H:15]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:32])=[O:33])=[CH:27][C:26]=2[S:35]([C:38]([F:40])([F:39])[F:41])(=[O:37])=[O:36])[CH2:16][S:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:11][CH2:10][O:9][CH2:8]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)C[C@@H]1COCCN1C(=O)C[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCN(CC)C[C@@H]1COCCN1CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
A mixture of 4-((R)-4-((R)-3-((diethylamino)methyl)morpholino)-4-oxo-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 91, 200 mg, 0.31 mmol) and 1 M borane-tetrahydrofuran complex (662 μl, 0.66 mmol) was stirred at room temperature for 16 hours. The reaction mixture was treated carefully with MeOH (5 ml) and concentrated HCl (1 ml). The mixture was heated at 80° C. for 3 hours, cooled to r.t, and the pH was adjusted to pH 10 with 4 N aqueous sodium carbonate. The mixture was diluted with ethyl acetate (300 ml), washed successively with water (150 ml) and brine (150 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO, eluting with 0→20% MeOH/DCM over 15 minutes) to give the title product (109 mg, yield: 56%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:22])[CH:18]=3)[N:13]=1)[CH2:8][CH2:7]2.[N:23]1([CH2:28][C:29](O)=[O:30])[CH:27]=[N:26][CH:25]=[N:24]1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:29](=[O:30])[CH2:28][N:23]4[CH:27]=[N:26][CH:25]=[N:24]4)[CH:18]=3)[N:13]=1)[CH2:8][CH2:7]2
Reactant: O=C(O)Cn1cncn1
Reactant: Nc1ccc2nc(NC3CCc4cccc(F)c43)ccc2c1
Product: O=C(Cn1cncn1)Nc1ccc2nc(NC3CCc4cccc(F)c43)ccc2c1

Procedure:
The title compound was prepared in accordance with the general method described in example 6 from rac-N2-(7-fluoro-indan-1-yl)-quinoline-2,6-diamine and 1,2,4-triazol-1-acetic acid; MS: m/e=401.5 (M−H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[C:7]([S:10][C:11]1[C:20]([Cl:21])=[CH:19][C:18]2[CH2:17][CH:16]([NH:22][CH2:23][CH3:24])[CH2:15][CH2:14][C:13]=2[CH:12]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)=[O:28]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[C:7]([S:10][C:11]1[C:20]([Cl:21])=[CH:19][C:18]2[CH2:17][CH:16]([N:22]([CH2:23][CH3:24])[C:27]([O:29][C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)=[O:28])[CH2:15][CH2:14][C:13]=2[CH:12]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(OC(=O)Cl)cc1
Reactant: CCNC1CCc2cc(SC(C)(C)C(=O)OC(C)(C)C)c(Cl)cc2C1
Solvent: ClCCl
Product: CCN(C(=O)Oc1ccc(C)cc1)C1CCc2cc(SC(C)(C)C(=O)OC(C)(C)C)c(Cl)cc2C1
Temperature: 25 °C
Reaction time: 144 h
Yield: 29 %

Procedure:
To a mixture of 2-(3-chloro-6-ethylamino-5,6,7,8-tetrahydro-naphthalen-2-ylsulfanyl)-2-methyl-propionic acid tert-butyl ester and borane complex (80 mg; 201 μmol), dissolved in CH2Cl2 (2 mL), at 0° C. is added p-tolyl chloroformate (35 μL; 241 μmol). The reaction was slowly warmed to RT and allowed to stir at RT for 6 days. The solvent was removed under reduced pressure and the crude residue was purified by flash chromatography (SiO2) eluting with a hexanes-EtOAc gradient to afford 30 mg (29%) of 2-[3-chloro-6-(ethyl-p-tolyloxycarbonyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-ylsulfanyl]-2-methyl-propionic acid tert-butyl ester as a clear oil.