Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11].Cl.[NH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH:28]([C:31]([N:33]2[CH2:42][C:41]3[CH:40]=[N:39][N:38]([CH3:43])[C:37]=3[NH:36][C:35]3[CH:44]=[C:45]([CH3:48])[CH:46]=[CH:47][C:34]2=3)=[O:32])[CH2:27][CH2:26]1.Cl.Cl.[CH3:51][C:52]([CH3:62])([CH3:61])[CH2:53][CH2:54][N:55]1[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1>CN(C=O)C.CCOC(C)=O>[CH3:43][N:38]1[C:37]2[NH:36][C:35]3[CH:44]=[C:45]([CH3:48])[CH:46]=[CH:47][C:34]=3[N:33]([C:31]([CH:28]3[CH2:29][CH2:30][CH:25]([CH2:24][NH:23][C:10]([N:58]4[CH2:57][CH2:56][N:55]([CH2:54][CH2:53][C:52]([CH3:62])([CH3:61])[CH3:51])[CH2:60][CH2:59]4)=[O:11])[CH2:26][CH2:27]3)=[O:32])[CH2:42][C:41]=2[CH:40]=[N:39]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)C1CCC(CN)CC1
Reactant: CC(C)(C)CCN1CCNCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)C1CCC(CNC(=O)N2CCN(CCC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.1 %

Procedure:
DIEA (0.30 ml, 1.7 mmol) and 1,1′-carbonyldiimidazole (39 mg, 0.24 mmol) were added to a solution of (4-aminomethyl-cyclohexyl)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydro-chloride (Compound number 149) (78 mg, 0.20 mmol) in DMF (4.0 ml) and the mixture was stirred at room temperature for 2 h. 1-(3,3-Dimethyl-butyl)-piperazine dihydrochloride from Example E4 (56 mg, 0.23 mmol) was added and the mixture was stirred at room temperature for 18 h. The mixture was diluted with EtOAc, washed with brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 10% methanol:90% di-chloromethane) to give a white solid identified as the title compound (32 mg, 29%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[CH:13]=[CH:14][C:15]([C:26]4[C:27]([F:32])=[N:28][CH:29]=[CH:30][CH:31]=4)=[CH:16][C:17]=3[C@:18]32[CH2:24][O:23][C:22]([NH2:25])=[N:21]3)=[C:9]([F:33])[CH:8]=1)(=O)=O.[CH3:36][C:37]([OH:41])([C:39]#[CH:40])[CH3:38].C(NC(C)C)(C)C>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.CN(C=O)C>[NH2:25][C:22]1[O:23][CH2:24][C@:18]2([N:21]=1)[C:17]1[CH:16]=[C:15]([C:26]3[C:27]([F:32])=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:14]=[CH:13][C:12]=1[O:11][C:10]1[C:19]2=[CH:20][C:7]([C:40]#[C:39][C:37]([CH3:38])([OH:41])[CH3:36])=[CH:8][C:9]=1[F:33]
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(OS(=O)(=O)C(F)(F)F)cc12
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC(C)(O)C#Cc1cc(F)c2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3F)ccc1O2
Temperature: 85 °C

Procedure:
A 15 ml resealable tube was charged with (S)-2-amino-5′-fluoro-2′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl trifluoromethanesulfonate (300 mg, 0.584 mmol), tetrakis(triphenylphosphine)palladium(0) (67.5 mg, 0.058 mmol), copper(i) iodide (11.13 mg, 0.058 mmol), DMF (2922 μL), 2-methylbut-3-yn-2-ol (114 μL, 1.169 mmol) and diisopropylamine (416 μL, 2.92 mmol). The mixture was capped with argon, sealed and heated at 85° C. for 1 hr. Concentration and purification of the crude residue by silica gel chromatography (10-60% CH2Cl2/MeOH/NH4OH 90:10:1 in CH2Cl2) afforded (S)-4-(2-amino-5′-fluoro-2′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl)-2-methylbut-3-yn-2-ol. MS m/z=448.0 [M+H].
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=O)(C)(C)C.[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.[NH2:35][C@@H:36]1[CH2:41][CH2:40][CH2:39][CH2:38][C@@H:37]1[CH2:42][OH:43]>>[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:35][C@@H:36]2[CH2:41][CH2:40][CH2:39][CH2:38][C@@H:37]2[CH2:42][OH:43])=[O:18])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: N[C@@H]1CCCC[C@@H]1CO
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Product: CON=C1C[C@@H](C(=O)N[C@@H]2CCCC[C@@H]2CO)N(S(=O)(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-sulfonyl chloride, and [(1S,2R)-2-aminocyclohexyl]methanol, the title compound was obtained in 41% purity by HPLC. MS(ESI+): m/z=486.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]#[C:16][CH3:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[O:20]1[CH2:24]CC[CH2:21]1>>[CH3:21][O:20][CH2:24][N:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]#[C:16][CH3:17])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CC#Cc1cc(C)nc(Nc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Product: CC#Cc1cc(C)nc(N(COC)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
2-Anilino-4-methyl-6-(1-propynyl)pyrimidine (2.2 g) was added to a suspension in 50 ml of tetrahydrofuran of 0.5 g of sodium hydride (60%) of which oily component was removed with n-hexane, and the mixture was stirred for 30 minutes at 50°-55° C. After cooling to room temperature, 1.0 g of chloromethyl methyl ether was added to the mixture and stirred for 3 hours. The reaction mixture was poured into water and extracted with 150 ml of toluene. the toluene layer was washed with water, dried over Glauber's salt and concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.7 g (yield: 63%) of 2-(N-methoxymethylanilino)-4-methyl-6-(1-propynyl)pyrimidine.
Reaction SMILES: C1([NH2+]C2CCCCC2)CCCCC1.[C:14]([O:18][C:19]([NH:21][CH:22]([CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[C:23]([O-:25])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15]>Cl>[C:14]([O:18][C:19]([NH:21][CH:22]([CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30]1)[C:23]([OH:25])=[O:24])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)NC(C(=O)[O-])C1CCCC1
Agent: C1CCC([NH2+]C2CCCCC2)CC1
Agent: Cl
Product: CC(C)(C)OC(=O)NC(C(=O)O)C1CCCC1

Procedure:
tert-Butoxycarbonylamino-cyclopentyl-acetate dicyclohexylammonium salt (2.85 g, 6.6 mmol; commercially available from Bachem) was dissolved in 1M HCl. Immediate EtOAc extractions were washed with brine and dried over anhydrous Na2SO4. Following concentration in vacuo, tert-Butoxycarbonylamino-cyclopentyl-acetic acid was isolated as a white foamy solid (1.6 g, quant) and was used without further purification. LCMS found 241.9 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:13])[C:5]([N+:14]([O-:16])=[O:15])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.Br[CH2:26][C:27]1[CH:31]=[CH:30][S:29][CH:28]=1>>[CH3:1][C:2]1[N:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:13])[C:5]([N+:14]([O-:16])=[O:15])=[C:4]([CH2:26][C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)[CH:3]=1
Reactant: COC(=O)Cn1c(C)cc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1=O
Reactant: BrCc1ccsc1
Product: COC(=O)Cn1c(C)cc(Cc2ccsc2)c([N+](=O)[O-])c1=O
Yield: 81 %

Procedure:
This compound is prepared from 5 g (13.4 mmol) of methyl 6-methyl-3-nitro-2-oxo-4-[[(trifluoromethyl)sulphonyl]oxy]-1,2-dihydropyridine-1-acetate and 2.9 g (16.4 mmol) of 3-bromomethyl-thiophene according to the method described in 1.5. 3.5 g of product are obtained in the form of yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:9]=[N:10][O:11][C:12]=2[CH:13]2[CH2:15][CH2:14]2)=[O:7])=[C:4]([N:18]([CH3:23])S(C)(=O)=O)[C:3]=1[O:24][CH2:25][CH3:26].S(=O)(=O)(O)O.O.[OH-].[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:9]=[N:10][O:11][C:12]=2[CH:13]2[CH2:15][CH2:14]2)=[O:7])=[C:4]([NH:18][CH3:23])[C:3]=1[O:24][CH2:25][CH3:26]
Reactant: CCOc1c(Br)ccc(C(=O)c2cnoc2C2CC2)c1N(C)S(C)(=O)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCOc1c(Br)ccc(C(=O)c2cnoc2C2CC2)c1NC
Temperature: 70 °C
Reaction time: 4 h
Yield: 23.3 %

Procedure:
A mixture of 4-[4-bromo-3-ethoxy-2-(N-methyl-N-methylsulphonylamino)benzoyl]-5-cyclopropylisoxazole (0.5 g) and concentrated sulphuric acid (6 ml) in acetic acid (9 ml) was heated at 70° C. for 4 hours, then at 90° C. for 4 hours. The mixture was poured into excess water and carefully brought to pH 5.5 by the addition of 2M sodium hydroxide solution, extracted with ethyl acetate, dried (anhydrous magnesium sulphate), evaporated and purified by column chromatography to yield 4-[4-bromo-3-ethoxy-2-(methylamino)benzoyl]-5-cyclopropylisoxazole (0.096 g), NMR 1.15(m,2H), 1.25(m,2H), 1.4(t,3H), 2.5(m,1H), 2.9(s,3H), 3.9(q,2H), 6.8(d,1H), 7.05(d,1H), 7.1(s,1H), 8.25(s,1H).
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][CH:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.IC.[C:40]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH2:22][CH:23]([N:26]([CH3:40])[S:27]([CH3:30])(=[O:29])=[O:28])[CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC(NS(C)(=O)=O)CC2)n1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC(N(C)S(C)(=O)=O)CC2)n1
Yield: 84.4 %

Procedure:
Reaction of N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}methanesulfonamide (Example 17) (114 mg, 0.21 mmol) with iodomethane (0.5 mL, 8.1 mmol) and K2CO3 (2 g, 14.5 mmol) in DMF (5 mL) gave N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-methylmethanesulfonamide (98 mg) in 84% yield: mp (CH2Cl2/MeOH) 231-233° C.; 1H NMR (DMSO-d6) δ 7.89 (d, J=8.2 Hz, 1H), 7.69 (t, JHF=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 6.95 (d, J=7.9 Hz, 1H), 4.82-4.72 (m, 2H), 3.98 (s, 3H), 3.98-3.90 (m, 2H), 3.82-3.79 (m, 4H), 3.70-3.69 (m, 4H), 3.11-2.98 (m, 2H), 2.94 (s, 3H), 2.68 (s, 3H), 1.77-1.70 (m, 4H); Anal. Calcd. for C23H30F2N8O4S: C, 50.0; H, 5.5; N, 20.3. Found: C, 49.9; H, 5.6; N, 20.3%.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][C:5]2[C:7]([N:12]=[CH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[OH:20])=[CH:8][CH:9]=[C:10]([OH:11])[C:4]=2[O:3]1.[CH3:22][N:23]=[C:24]=[O:25].C(Cl)Cl>C(N(CC)CC)C>[CH3:22][NH:23][C:24](=[O:25])[O:11][C:10]1[C:4]2[O:3][C:2]([CH3:21])([CH3:1])[CH2:6][C:5]=2[C:7]([N:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])=[CH:8][CH:9]=1
Reactant: CN=C=O
Reactant: CC1(C)Cc2c(N=Cc3ccccc3O)ccc(O)c2O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)Oc1ccc(N=Cc2ccccc2O)c2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 66 h
Yield: 92.9 %

Procedure:
To a 350 milliliter glass pressure bottle equipped with a magnetic stirrer was added 6.00 grams (0.021 moles) of 2,3-dihydro-2,2-dimethyl-4-(2-hydroxybenzylideneamino)benzofuran-7-ol prepared in part A, 1.4 grams (0.024 moles) of methyl isocyanate, 100 milliliters of methylene chloride and 0.1 milliliters of triethylamine. The resulting reaction mixture was stirred for 66 hours at room temperature and then concentrated under reduced pressure to give a yellow solid material. The yellow solid material was washed with hexane and dried to yield 6.64 grams (0.0195 moles) of 2,3-dihydro-2,2-dimethyl-4-(2-hydroxybenzylideneamino)benzofuran-7-yl methylcarbamate in the form of a yellow solid having a melting point of 201°-203° C. and the following structural formula: ##STR18##
Reaction SMILES: [C:1]1([S:7]([NH:10][CH2:11][C:12]2[N:13]=[C:14]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)[S:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)CC)C>C(Cl)Cl>[C:1]1([S:7]([NH:10][CH2:11][C:12]2[N:13]=[C:14]([N:17]3[CH2:20][CH:19]([O:21][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:18]3)[S:15][CH:16]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=S(=O)(NCc1csc(N2CC(O)C2)n1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(c2nc(CNS(=O)(=O)c3ccccc3)cs2)C1
Reaction time: 1 h
Yield: 0.1 %

Procedure:
To a solution of 1-[4-(benzenesulfonylamino)methyl-1,3-thiazol-2-yl]-3-hydroxyazetidine (1.06 g, 3.26 mmol) (obtained as described in Reference Example 65(2)) in methylene chloride (50 ml) were added methanesulfonyl chloride (0.38 ml, 4.89 mmol) and triethylamine (0.68 ml, 4.89 mmol) in an ice bath and the mixture was stirred for 1 hour. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 1-[4-(benzenesulfonylamino)methyl-1,3-thiazol-2-yl]-3-methanesulfonyloxyazetidine (1.16 mg, yield 91%) as a pale yellow solid.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17])([O:3][CH2:4][CH3:5])=[O:2].[CH3:18][C:19](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[C:19]([O:17][C:13]1[CH2:14][CH2:15][CH2:16][C:12]=1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:20])[CH3:18]
Reactant: CCOC(=O)CCCCCCC1CCCC1=O
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CCCCCCC1=C(OC(C)=O)CCC1
Reaction time: 16 h

Procedure:
A stirred solution of 100 g. of 2-(6-carbethoxyhexyl)cyclopentan-1-one (Example 9) in 250 ml. of acetic anyhydride containing 0.940 g. of p-toluenesulfonic acid monohydrate is heated to boiling under partial reflux allowing distillate at 118° C. or less (i.e., acetic acid) to escape through a Vigreaux column equipped with a condenser to collect the distillate. After 16 hours, during which period acetic anhydride is added in portions in order to keep the solvent level at at least 100 ml., the solution is cooled and poured cautiously into a stirred cold mixture of saturated sodium bicarbonate solution (400 ml.) and hexane (250 ml.). The resulting mixture is stirred for an additional 30 minutes during which period solid sodium bicarbonate is added periodically to insure a basic solution. The hexane layer is separated and washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness. Distillation of the residual oil gives 102 g. (87%) of pale yellow oil, b.p. 118° C. (0.07 mm).
Reaction SMILES: [H-].[Na+].CCCCCC.[C:9]([O:28][CH2:29][C@@H:30]([OH:34])[CH2:31][CH2:32][OH:33])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:35](Cl)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CS(C)=O.O>[CH2:35]([O:33][CH2:32][CH2:31][C@H:30]([OH:34])[CH2:29][O:28][C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: OCC[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCCCCC
Product: O[C@@H](CCOCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 43.4 %

Procedure:
Sodium hydride (74 mg, 1.85 mmol, 60% in oil) was loaded under argon circumstance in three necked flask and hexane (2 ml) was added thereto. After stirring for a while, it was allowed to stand and the supernatant was removed by syringe. By repeating this procedure three times, the oil of sodium hydride was removed. After drying in vacuo anhydrous dimethyl sulfoxide (DMSO) (2 ml) was added and the solution was cooled to 0° C. (S)-1-Trityloxy-2,4-butandiol (0.62 g, 1.68 mmol) prepared by Example 2-(2) in DMSO (3 ml) was dropped by taking care of the temperature over a one hour period at room temperature to the solution. Then the solution was stirred for 1 hour. To the solution was dropped benzyl chloride (0.213 ml, 1.85 mol) in DMSO (3 ml) over a one hour period at the range of 0° C. to 5° C. and then the solution was stirred for 4 hours. To the reaction mixture was added water (5 ml) and the solution was extracted with ethyl acetate. The extract was washed with water (8 ml) twice and with saturated brine once, dried on sodium sulfate, filtered and condensed in vacuo. The residue was subjected to silica gel chromatography to (S)-4-benzyloxy-1-trityloxy-2-butanol (0.32 g, yield 45%).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12](Br)[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]C[CH2:25][CH2:26][CH3:27].[CH:28]([Si:31](OS(C(F)(F)F)(=O)=O)([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])([CH3:30])[CH3:29]>C1COCC1>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][C:17]([Si:31]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[CH:28]([CH3:30])[CH3:29])=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([Si:31]([CH:32]([CH3:34])[CH3:33])([CH:26]([CH3:27])[CH3:25])[CH:28]([CH3:30])[CH3:29])[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1n2Cc1ccccc1
Reactant: [Li]CCCC
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)[Si](c1ccc2c(c1)c1cc([Si](C(C)C)(C(C)C)C(C)C)ccc1n2Cc1ccccc1)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
A 2 L dry round bottom flask was charged with N-benzyl-3,6-dibromocarbazole 3 (49 g, 0.118 mol) and 1 L of dry THF was added. The mixture was stirred until N-benzyl-3,6-dibromocarbazole 3 was dissolved. The mixture was then cooled to −78° C. and 2.5 M n-BuLi in hexanes (104 ml, 0.26 mol) was added dropwise. The mixture was stirred at −78° C. for 15 min and triisopropylsilyl-trifluoromethyl sulfonate (66 ml, 0.26 mol) was added. The mixture was left to warm up to room temperature overnight. The mixture was then quenched with sat. NH4Cl, extracted with methyl-t-butyl ether, dried over Na2SO4, filtered, concentrated, and purified over a 330 g SiO2 column to yield 9-benzyl-3,6-bis-triisopropylsilanyl-9H-carbazole 4 23.0 g (35%) as a transparent oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Br:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:18][N:19]=2)=[CH:11][CH:10]=1>C1COCC1>[Br-:7].[CH3:1][N+:2]1[CH:6]=[CH:5][N:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[O:16][C:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:18][N:19]=3)=[CH:13][CH:14]=2)[CH:3]=1
Reactant: BrCc1ccc(-c2ncc(-c3ccccc3)o2)cc1
Reactant: Cn1ccnc1
Solvent: C1CCOC1
Product: C[n+]1ccn(Cc2ccc(-c3ncc(-c4ccccc4)o3)cc2)c1
Product: [Br-]

Procedure:
To a round-bottomed flask previously purged with anhydrous argon are added 1-methylimidazole (Aldrich) (0.257 mL, 0.265 g, 3.2 mmol), 2-(4-bromomethyl-phenyl)-5-phenyl-oxazole [1] (1.013 g, 3.224 mmol) and anhydrous THF (15 mL).
Reaction SMILES: CO.C(Cl)(Cl)Cl.[C:7]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[N:14]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]3[C:37]4[C:32](=[CH:33][C:34]([O:40][CH3:41])=[C:35]([O:38][CH3:39])[CH:36]=4)[N:31]=[CH:30][N:29]=3)[CH2:24][CH2:23]1)[C:13]2=[O:42])(=[O:9])[CH3:8].[BH4-].[Na+]>O>[CH3:39][O:38][C:35]1[CH:36]=[C:37]2[C:32](=[CH:33][C:34]=1[O:40][CH3:41])[N:31]=[CH:30][N:29]=[C:28]2[N:25]1[CH2:26][CH2:27][CH:22]([N:14]2[C:13](=[O:42])[C:12]3[C:17](=[CH:18][CH:19]=[C:10]([CH:7]([OH:9])[CH3:8])[CH:11]=3)[N:16]([CH3:20])[C:15]2=[O:21])[CH2:23][CH2:24]1
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)c5cc(C(C)=O)ccc5n(C)c4=O)CC3)c2cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: COc1cc2ncnc(N3CCC(n4c(=O)c5cc(C(C)O)ccc5n(C)c4=O)CC3)c2cc1OC
Temperature: 60 °C
Yield: 72.6 %

Procedure:
In a solvent mixture of 3ml of methanol and 3 ml of chloroform was dissolved 200.0 mg (0.41 mmol) of Compound 63 obtained in Example 50, and sodium borohydride was added thereto in excess, followed by heating at 60° C. for 30 minutes. After cooling, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed and dried, and the solvent was distilled off under reduced pressure. To the residue was added ether, and the precipitated crystals were collected by filtration and dried to give 146.4 mg (yield: 73%) of Compound 60 as white crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:13]([S:14][CH3:15])=[CH:12][C:11]([N:16]3[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]3)=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH2:9])=[O:8].[C:23](=[O:26])([O-])[O-:24].[K+].[K+]>CN(C=O)C.CO.O>[C:3]([O:24][C:23](=[O:26])[NH:22][CH:19]1[CH2:18][CH2:17][N:16]([C:11]2[CH:12]=[C:13]([S:14][CH3:15])[C:3]3[C:2]([NH2:1])=[C:6]([C:7](=[O:8])[NH2:9])[S:5][C:4]=3[CH:10]=2)[CH2:21][CH2:20]1)([CH3:13])([CH3:4])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CSc1cc(N2CCC(N)CC2)cc2sc(C(N)=O)c(N)c12
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cc(N2CCC(NC(=O)OC(C)(C)C)CC2)cc2sc(C(N)=O)c(N)c12
Temperature: 70 °C
Yield: 206.4 %

Procedure:
To a solution of 0.211 g (0.577 mmol) of the above amide in DMF (5 mL) was added 1.6 mL (1.8 mmol) of a 10% solution of 2-thioacetamide in MeOH along with 0.80 g (5.8 mmol) of potassium carbonate. The mixture was heated to 70° C. for 15 h then cooled to room temperature and diluted with H2O which caused a solid to precipitate from solution. The solid was collected by filtration, washed with H2O and dried under vacuum to provide 0.260 g (100%) of [1-(3-amino-2-carbamoyl-4-methylthio-benzo[b]thiophen-6-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester as a yellow solid.
Reaction SMILES: O=[C:2]([CH2:16][CH2:17][C:18]([O-:20])=[O:19])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.C(Cl)(=O)OCC.[CH2:34]([O:41][C:42]([NH:44][C@H:45]1[CH2:49][O:48][NH:47][C:46]1=[O:50])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[CH2:34]([O:41][C:42]([NH:44][C@H:45]1[CH2:49][O:48][N:47]([C:2]2([C:3]([O:5][CH2:6][C:7]3[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=3)=[O:4])[CH2:16][CH2:17][C:18](=[O:19])[O:20]2)[C:46]1=[O:50])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C([O-])CCC(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(N[C@H]1CONC1=O)OCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(C(=O)OCc2ccc([N+](=O)[O-])cc2)(N2OC[C@H](NC(=O)OCc3ccccc3)C2=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
In 10 ml of dichloromethane was dissolved 282 mg of Compound (1), and the solution was cooled on a sodium chloride-ice bath, to which were added 140 μ1 of triethylamine and 96 μ1 of ethyl chlorocarbonate. To the mixture was added 119 mg of (4S)-4-benzyloxycarbonylamino-3-isoxazolidinone. The mixture was stirred for one hour under ice-cooling and for one hour at room temperature. The solvent was evaporated off under reduced pressure. The residue was subjected to extraction with ethyl acetate, and the organic layer was washed with an aqueous solution of sodium hydrogen carbonate, then with a saturated saline solution, followed by drying (MgSO4). Then, the solvent was evaporated off, and the residue was subjected to a silica gel chromatography, followed by elution with 1,2-dichloroethane-ethyl acetate (9:1), then with hexane-ethyl acetate (1:1) to give 73 mg of the subject Compound (9).