Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:14]([CH3:19])=[N:15][O:16][C:17]=1[CH3:18]>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[C:14]([CH3:19])=[N:15][O:16][C:17]=2[CH3:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1noc(C)c1N
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: c1ccncc1
Product: Cc1noc(C)c1NS(=O)(=O)c1ccc(Br)cc1
Yield: 86.6 %

Procedure:
Prepared from 4-bromobenzenesulfonyl chloride (4.56 g, 17.9 mmol) and 4-amino-3,5-dimethylisoxazole (2.02 g, 18.0 mmol) in pyridine (36 ml) according to the method of intermediate 1, to give the title compound as a white solid (5.15 g, 15.5 mmol, 87%). 5H (CDCl3, 300K) 7.69 (2H, dd, J=6.9 Hz 1.7 Hz), 7.65 (2H, dd, J=6.9 Hz 1.7 Hz), 6.11 (1H, s), 2.12 (3H, s), 1.91 (3H, s). m/z (ES+, 70V) 333.0 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[C:13]([C:14](=[O:17])[CH2:15][CH3:16])=[CH:12][CH:11]=[C:10](Cl)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:20]([NH:27][CH2:28][CH2:29][NH2:30])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(N(CC)C(C)C)(C)C>CS(C)=O.C(OCC)(=O)C.O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[C:13]([C:14](=[O:17])[CH2:15][CH3:16])=[CH:12][CH:11]=[C:10]([NH:30][CH2:29][CH2:28][NH:27][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CCC(=O)c1ccc(Cl)nc1NC(=O)OC(C)(C)C
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCC(=O)c1ccc(NCCNC(=O)OC(C)(C)C)nc1NC(=O)OC(C)(C)C

Procedure:
730 mg (2.4 mmol) of tert-butyl(6-chloro-3-propanoylpyridin-2-yl)carbamate (Example 23A) were initially charged in 7 ml of DMSO, and 512 mg (3.2 mmol) of N-Boc-ethylenediamine and 640 μl (3.7 mmol) of N,N-diisopropylethylamine were added. The reaction mixture was irradiated in the microwave reactor at 90° C. for 45 min. The reaction mixture was taken up in a mixture of ethyl acetate and water. The organic phase was washed with saturated aqueous ammonium chloride solution and then with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated on a rotary evaporator. The reaction mixture was chromatographed on silica gel (mobile phase cyclohexane/ethyl acetate 5:1→1:1). This gave 530 mg (53% of theory) of the product as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:23]
Reactant: CCOC(=O)CCCCCBr
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCOc1cc(C=O)ccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 12 h
Yield: 67.6 %

Procedure:
To a solution of 3-hydroxy-4-nitrobenzaldehyde (0.80 g, 4.78 mmol), in DMF (15 mls) was added ethyl 6-bromohexanoate (1.30 g, 5.82 mmol) and potassium carbonate (1.23 g, 8.91 mmol). The mixture was stirred at 70° C. for 12 hours, cooled, poured into water and extracted twice with ethyl acetate. The combined organic fractions were washed once with water and dried over anhydrous magnesium sulfate. After the solvents were removed under reduced pressure, a red oil remained which was purified by column chromatography (70% hexane/30% ethyl acetate) to give 6-(5-formyl-2-nitro-phenoxy)-hexanoic acid ethyl ester as a yellow oil (1.00 g, 67%). 1H NMR (400 MHz, CDCl3) δ: 10.06 (s, 1H), 7.92 (d, 1H, J=8.8 Hz), 7.58 (d, 1H, J=1.2 Hz), 7.54 (dd, 1H, J=8 Hz, J=1.6 Hz), 4.20 (q, 2H, J=6.8 Hz), 4.14 (t, 2H, J=7.2 Hz), 2.36 (t, 2H, J=8.0 Hz), 1.90 (m, 2H), 1.73 (m, 2H), 1.57 (m, 2H), 1.29 (t, 3H, J=6.8 Hz). 13C NMR (400 MHz, CDCl3) δ: 173.79, 169.46, 151.87, 143.23, 133.66, 125.32, 121.93, 115.88, 69.65, 60.42, 34.12, 28.54, 25.40, 24.52, 14.25. IR (neat): 3396, 3110, 3080, 3047, 2944, 2869, 2735, 1730, 1705, 1607, 1531, 1489, 1465, 1434, 1381, 1351, 1311, 1272, 1161, 1093, 1063, 1030, 961, 863 cm−1.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.Cl[CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16]>>[CH3:16][C:15]([CH3:17])=[CH:14][CH2:13][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: CC(C)=CCCl
Reactant: O=Cc1cccc2[nH]ccc12
Product: CC(C)=CCn1ccc2c(C=O)cccc21

Procedure:
The same procedures used in Example 1 were repeated except for using 725 mg of indole-4-carbaldehyde and 1-chloro-3-methyl-2-butene instead of the benzyl bromide used in Example 1 to give 554 mg of 1-(3-methyl-2-butenyl)indole-4-carbaldehyde as an orange-colored oily substance. The yield thereof was found to be 52%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:15]C)=[C:12](Br)[CH:13]=2)=[CH:4][CH:3]=1.C([Li])CCC.C[O:23][B:24](OC)[O:25]C.Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH3:15])=[C:12]([B:24]([OH:25])[OH:23])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1Br
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1B(O)O
Temperature: -78 °C
Yield: 73 %

Procedure:
5-(4-chlorophenyl)-2-ethyl-1-bromobenzene (10 g, 0.03 mol) is dissolved in THF (250 ml), and the temperature is brought to −78° C. n-Butyllithium (1.33 molar solution in hexanes, 34.6 ml,) is added dropwise over 30 minutes, maintaining the temperature at around −78° C. The reaction mixture is stirred for one and half hours, then trimethylborate (4.9 g, 0.05 mol) is added dropwise and the reaction mixture stirred for two hours. A solution of 2N aqueous hydrochloric acid (100 ml) is added dropwise, and once the addition is complete the mixture is stirred for two hours. The mixture is concentrated to remove most of the tetrahydrofuran, then diluted with water and extracted with diethyl ether. The organic extracts are washed with water and brine, combined, dried over anhydrous sodium sulfate, filtered and the filtrate evaporated in vacuo. The residue is further purified by flash column chromatography on silica gel, eluting with 7% ethyl acetate in hexane to give 5-(4-chloro-phenyl)-2-methylphenylboronic acid (5.4 g).
Reaction SMILES: [CH2:1]1[O:3][C@H:2]1[CH2:4][OH:5].[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1>C(O)C>[N:6]1([CH2:1][C@@H:2]([OH:3])[CH2:4][OH:5])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: OC[C@H]1CO1
Reactant: C1COCCN1
Solvent: CCO
Product: OC[C@H](O)CN1CCOCC1
Temperature: 25 °C
Yield: 102.2 %

Procedure:
A solution of (S)-glycidol (1.00 mL, 15.0 mmol) and morpholine (1.96 mL, 22.5 mmol, 2.5 equiv.) in abs. ethanol was heated in a microwave for 4 min. at 140 0° C., cooled to room temperature and concentrated at 70° C. under a 12 mbar vacuum to afford (2R)-3-(4-morpholinyl)-1,2-propanediol (2.47 g, 102%): 1H NMR (CDCl3) δ 2.37 (dd J=4.0, 12.4 Hz, 1H), 2.40-2.48 (m, 2H), 2.57 (dd, J=9.6, 12.4 Hz, 1H), 2.62-2.71 (m, 2H), 3.50 (dd, J=4.2, 11.4 Hz, 1H), 3.65-3.79 (m, 5H), 3.79-3.88 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:15]([CH2:16][CH2:17][N:18]4C(=O)C5C(=CC=CC=5)C4=O)[CH:14]=[N:13][C:12]=3[C:29]3[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=3)=[CH:10][C:5]=2[N:4]([CH3:36])[C:3]1=[O:37].NN>C(O)C>[NH2:18][CH2:17][CH2:16][N:15]1[C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3](=[O:37])[N:4]([CH3:36])[C:5]=3[CH:10]=2)=[C:12]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)[N:13]=[CH:14]1
Reactant: Cc1cccc(-c2ncn(CCN3C(=O)c4ccccc4C3=O)c2-c2ccc3c(c2)n(C)c(=O)n3C)c1
Agent: NN
Solvent: CCO
Product: Cc1cccc(-c2ncn(CCN)c2-c2ccc3c(c2)n(C)c(=O)n3C)c1
Temperature: 23 °C
Yield: 73.8 %

Procedure:
To a stirred, hot solution of 2-{2-[5-(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-4-m-tolyl-imidazol-1-yl]-ethyl}-isoindole-1,3-dione (90 mg, 0.18 mmoles) in 5 mL ethanol was added aqueous 35 wt % hydrazine (50 pL). The resulting mixture was heated at reflux for 4 hours. The mixture (white precipitate visible) was cooled to 23° C. and concentrated in vacuo. The residue was taken up in 3 N HCl and methanol and extracted with ethyl acetate. The ethyl acetate extract was washed with 3 N HCl. The combined acidic aqueous layers were extracted with ethyl acetate (2 times). The acidic aqueous layer was made basic (pH 10–11) with Na2CO3 and extracted with ethyl acetate (3 times). These ethyl acetate extracts were combined and dried (Na2SO4), filtered, and the filtrate was concentrated to give 48 mg of 5-[3-(2-Amino-ethyl)-5-m-tolyl-3H-imidazol-4-yl]-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one as an off white film/solid. MS (APCI) m/z 362 (M+1).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:26]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=2)=[O:27])[C:11](=[O:25])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:13]=1[CH3:14])=[CH2:7])CCC.C(=O)([O-])O.[Na+]>Cl>[C:6]([C:8]1[CH:9]=[C:10]([C:26]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=2)=[O:27])[C:11](=[O:25])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:13]=1[CH3:14])(=[O:5])[CH3:7]
Reactant: C=C(OCCCC)c1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)c1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C
Yield: 51.5 %

Procedure:
Aqueous hydrochloric acid (2.0M, 50 μl) was added to a solution of 5-(1-butoxyvinyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (38 mg, 67.5 μmol) in DNT (0.5 ml). After 20 min. the solution was neutralized with aqueous sodium hydrogen carbonate. The reaction mixture was purified by preparative HPLC to give the title compound as a white solid (17.6 mg, 51%).
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[C:7](=[NH:14])[S:6]1)([CH3:4])([CH3:3])[CH3:2].[O:15]=[C:16]1[CH2:20][CH2:19][CH:18]([C:21](O)=[O:22])[CH2:17]1>>[CH2:10]([C:8]1=[CH:9][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6]/[C:7]/1=[N:14]\[C:21]([CH:18]1[CH2:19][CH2:20][C:16](=[O:15])[CH2:17]1)=[O:22])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1cn(C(C)(C)C)sc1=N
Reactant: O=C1CCC(C(=O)O)C1
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1CCC(=O)C1

Procedure:
The product from Example 92B and 3-oxocyclopentanecarboxylic acid (Aldrich) were processed using the method described in Example 92C to afford the title compound. 1H NMR (DMSO-d6) δ 0.91 (t, J=7.5 Hz, 3H), 1.25-1.36 (m, 2H), 1.57 (s, 9H), 1.55-1.84 (m, 2H), 1.98-2.06 (m, 1H), 2.13-2.28 (m, 3H), 2.39-2.42 (m, 2H), 2.61-2.66 (m, 2H), 3.27-3.34 (m, 1H), 8.55 (s, 1H). MS (ESI+) m/z 323 (M+H)+. Anal. calcd. for C17H26N2O2S: C, 63.32; H, 8.13; N, 8.69. Found: C, 63.19; H, 8.07; N, 8.66.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:16][CH2:17][C:18](=O)[CH2:19][CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:17]([CH:18]([NH:2][CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:19][CH3:20])[CH3:16]
Reactant: NCCNC(=O)OCc1ccccc1
Reactant: CCC(=O)CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCC(CC)NCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
Benzyl 2-aminoethylcarbamate hydrochloride (2 g, 8.65 mmol) was dissolved in dichloromethane (50 ml) and 3-pentanone (3.7 ml, 35 mmol) was added. The reaction mixture was stirred for 1 hour at room temperature. Sodium triacetoxy borohydride (5.5 g, 26 mmol) was added and the reaction mixture was then stirred for 16 hours at room temperature. The solution was washed with saturated aqueous sodium hydrogen carbonate solution (40 ml). The dichloromethane phase was dried over anhydrous magnesium sulphate and the solvent was removed. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 concentrated aqueous ammonia (95:5:0.5 by volume). This gave the title compound as an oil (1.8 g).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([CH2:21][CH3:22])[C:19]([C:23](=[O:26])[CH2:24][CH3:25])=[CH:18][C:17]=2[CH3:27])=[CH:12][CH:11]=1.C(OCC)(=O)C>C1COCC1>[Br:1][C:18]1[C:17]([CH3:27])=[C:16]([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)[N:20]([CH2:21][CH3:22])[C:19]=1[C:23](=[O:26])[CH2:24][CH3:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(=O)c1cc(C)c(-c2ccc(Cl)cc2)n1CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(=O)c1c(Br)c(C)c(-c2ccc(Cl)cc2)n1CC
Temperature: -78 °C
Reaction time: 5 h
Yield: 77.9 %

Procedure:
A solution of N-bromosuccinimide (0.35 g, 1.99 mmol) in THF (10 ml) was added dropwise to a stirred solution of 1-(5-(4-chlorophenyl)-1-ethyl-4-methyl-1H-pyrrol-2-yl)propan-1-one (compound 51b, 0.5 g, 1.81 mmol) in THF (25 ml) at about −78° C. The resulting reaction mixture was stirred at about −78° C. for 5 hr. The reaction mixture was then allowed to warm to 25° C. slowly during further 3 to 4 hr. The progress of the reaction was monitored by TLC. The solvent was evaporated from the reaction mixture under reduced pressure and to the residue so obtained was added ethyl acetate (50 ml). The mixture so obtained was washed with saturated sodium bicarbonate solution (1×30 ml) followed by washing with water (1×30 ml). The combined organic layer was then dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was then purified by flash column chromatography 10% ethyl acetate in hexanes as an eluent to obtain the title compound (0.5 g, 78.0%).
Reaction SMILES: CC1(C)[O:7][C:6]2[CH:8]=[CH:9][C:10]([CH:12]([OH:35])[CH2:13][NH:14][C@H:15]3[CH2:24][CH2:23][C:22]4[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:20][CH:21]=4)[CH2:16]3)=[CH:11][C:5]=2[CH2:4][O:3]1.Cl>O1CCCC1>[OH:35][CH:12]([C:10]1[CH:9]=[CH:8][C:6]([OH:7])=[C:5]([CH2:4][OH:3])[CH:11]=1)[CH2:13][NH:14][C@H:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:20][CH:21]=2)[CH2:16]1
Reactant: CCOC(=O)CCCCOc1ccc2c(c1)C[C@@H](NCC(O)c1ccc3c(c1)COC(C)(C)O3)CC2
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CCCCOc1ccc2c(c1)C[C@@H](NCC(O)c1ccc(O)c(CO)c1)CC2
Yield: 65.7 %

Procedure:
Ethyl 5-[(2S)-2-[[(2RS)-2-(2,2-dimethylbenzo[1,2-d]-1,3-dioxan-6-yl)-2-hydroxyethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy]valerate (207 mg) was dissolved in tetrahydrofuran (2 ml), and 1 N hydrochloric acid (2.0 ml) was added to the solution at room temperature. After reaction for an hour, the reaction mixture was concentrated in vacuo. A saturated aqueous sodium bicarbonate solution was added to the residue, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. Purification of the residue by medium pressure liquid column chromatography on aminopropyl silica gel (eluent: chloroform/methanol=10/1) gave ethyl 5-[(2S)-2-[[(2RS)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy]valerate (Compound 1) (125 mg) as an amorphous.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[C:10]([S:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:9]=[C:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[OH:23])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH2:31]([O:33][C:34]([C:36]1[NH:37][C:38]([S:41](Cl)(=[O:43])=[O:42])=[N:39][CH:40]=1)=[O:35])[CH3:32]>ClCCl>[CH2:31]([O:33][C:34]([C:36]1[NH:37][C:38]([S:41]([N:16]2[CH2:17][CH2:18][CH:13]([S:12][C:10]3[CH:9]=[C:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]([OH:23])=[C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[CH:11]=3)[CH2:14][CH2:15]2)(=[O:42])=[O:43])=[N:39][CH:40]=1)=[O:35])[CH3:32]
Reactant: CC(C)(C)c1cc(SC2CCNCC2)cc(C(C)(C)C)c1O
Reactant: CCOC(=O)c1cnc(S(=O)(=O)Cl)[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cnc(S(=O)(=O)N2CCC(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)[nH]1
Reaction time: 0.05 h
Yield: 65.9 %

Procedure:
To 2,6-di-tert-butyl-4-(piperidin-4-ylsulfanyl)-phenol hydrochloride (Ex. 3c, 405 mg, 1.13 mmol) in 6 mL of dichloromethane was added triethylamine (303 mg, 3 mmol). After stirring for 3 min, 2-chlorosulfonyl-3H-imidazole-4-carboxylic acid ethyl ester (Ex. 8a, 270 mg, 1.13 mmol) in 2 mL of dichloromethane was added. The reaction was stirred for 2 h and then quenched with saturated NaH2PO4 (30 mL). The mixture was extracted with Ethyl acetate (50+30 mL) and the combined organic phase was washed with water (50 mL), dried over Na2SO4, and concentrated under reduced pressure. Chromatography (5-70% Ethyl acetate/hexanes) gave 2-[4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-piperidine-1-sulfonyl]-3H-imidazole-4-carboxylic acid ethyl ester as a yellow foamy solid (390 mg, 66%). 1H NMR (400 MHz, CDCl3): δ 10.92 (bs, 0.5H), 10.71 (bs, 0.5H), 7.77 (bs, 1H), 7.25 (s, 2H), 5.30 (s, 1H), 4.39 (q, J=7.2 Hz, 2H), 3.80 (dt, J=12.4, 4.4 Hz, 2H), 3.00-2.88 (m, 3H), 2.02-1.98 (m, 2H), 1.68 (m, 2H), 1.42 (s, 18H), 1.38 (t, J=7.2 Hz, 3H). 13C NMR: δ 154.6, 136.9, 132.0, 122.0, 60.9, 46.1, 44.5, 34.5, 31.7, 30.4, 14.5. ESI/CI-MS m/z 525 ([M+H]+), 523 ([M−H]−).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]2[CH2:17][CH2:18][CH:12]1[CH2:13][CH:14]([N:19]1[CH2:24][CH2:23][C:22]3([C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][N:26]([C:34](OC(C)(C)C)=[O:35])[CH2:25]3)[CH2:21][CH2:20]1)[CH2:15]2)=[O:10])[C:2]1C=CC=CC=1>CO.[Pd]>[CH3:9][N:11]([CH3:12])[C:34]([N:26]1[CH2:25][C:22]2([CH2:23][CH2:24][N:19]([CH:14]3[CH2:15][CH:16]4[N:11]([C:9]([O:8][C@@H:1]5[CH2:2][CH2:1][O:8][CH2:2]5)=[O:10])[CH:12]([CH2:18][CH2:17]4)[CH2:13]3)[CH2:20][CH2:21]2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1)=[O:35]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C2(CCN(C3CC4CCC(C3)N4C(=O)OCc3ccccc3)CC2)C1
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)N1Cc2ccccc2C2(CCN(C3CC4CCC(C3)N4C(=O)O[C@@H]3CCOC3)CC2)C1
Reaction time: 8 h

Procedure:
tert-Butyl 1′-(8-(benzyloxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H -spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate 4b (2.700 g, 4.638 mmol) was dissolved in methanol (30 mL) and treated with 10% wet Pd/C (2.7 g) and NH4COOH (5.844 g, 92.756 mmol). The mixture was allowed to stir vigorously overnight under an empty balloon (for venting). LC/MS analysis shows complete conversion to the desired product. The reaction mixture was filtered through a pad of Celite under a nitrogen atmosphere, and the filter cake was rinsed with methanol (4×30 mL). The filtrate was concentrated to provide the crude product, which was taken up in a mixture of EtOAc (100 mL) and NaHCO3 sat (100 mL). Some product stays undissolved in both layers. The biphasic mixture was filtered, and the precipitate was washed with H2O (20 mL) and vacuum dried overnight to provide 1.01 g pure tert-butyl 1′-(8-azabicyclo[3.2.1]octan-3-yl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate 4c. The filtrate layers were separated, and the aqueous layer was extracted with Et2O (100 mL) and CH2Cl2 (2×100 mL). The combined organic layers were dried on Na2SO4 and concentrated to provide additional product 4c (600 mg). LC/MS m/z [M+H]+ 412.4, retention time 2.16 min (10-99% CH3CN—H2O gradient, with 0.05% TFA, 5 min).
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:6]=2[N:7]=1.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19].N1C=CN=C1.O>CN(C=O)C>[Si:22]([O:1][CH2:2][C:3]1[NH:4][C:5]2[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:6]=2[N:7]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc2nc(CO)[nH]c2c(OC)c1OC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nc(CO[Si](C)(C)C(C)(C)C)[nH]c2c(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Hydroxymethyl-4,5,6-trimethoxybenzimidazole (354 mg) was dissolved in dry DMF (2 mL), tert-butyldimethylchlorosilane (270 mg) and imidazole (45 mg) were added to the solution under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture to conduct extraction with ethyl acetate. The resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by preparative TLC on silica gel (chloroform:methanol=12:1) to obtain the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][CH2:38][O:39][CH3:40])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH3:40][O:39][CH2:38][CH2:37][NH:36][S:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:28]=1)(=[O:34])=[O:35]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: COCCNS(=O)(=O)c1cccc(Br)c1
Product: COCCNS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 3-bromo-N-(2-methoxy-ethyl)-benzenesulfonamide (example B.33) (265 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (320 mg, 56%). MS (ISP) 569.1 [(M+H)+]; mp 186-188° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH2:7][CH2:6][CH2:5]2.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[SH:20]>CN(C)C=O>[N+:11]([C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[S:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=1)[CH2:5][CH2:6][CH2:7]2)([O-:13])=[O:12]
Reactant: Sc1ccccn1
Reactant: O=[N+]([O-])c1cc2c(cc1Br)CCC2
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc2c(cc1Sc1ccccn1)CCC2

Procedure:
4.8 g. of 5-bromo-6-nitroindan, 4.5 g. of potassium tert.-butylate, 4.4 g. of 2-pyridinethiol are heated in 50 ml. of absolute dimethylformamide for 3 hours under nitrogen to 80°. The mixture is concentrated under vacuum; the residue is combined with ethyl acetate and extracted four times with water. The ethyl acetate phase is concentrated, and the residue is purified on a silica gel column (system: cyclohexane/ethyl acetate 4:1). After crystallization from ethanol, 3.3 g. of 5-nitro-6-(2-pyridylthio)indan is obtained, m.p. 74°.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:17][CH3:18])=[C:7]([CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].Cl.[C:20]([O:23][CH2:24][CH3:25])(=[O:22])[CH3:21]>O1CCCC1>[C:1]([C:5]1[C:6]([O:17][CH3:18])=[C:7]([CH:8]([OH:9])[CH2:21][C:20]([O:23][CH2:24][CH3:25])=[O:22])[CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(C)=O
Reactant: COc1c(C=O)cc(C(C)(C)C)cc1C(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)c1cc(C(C)(C)C)cc(C(C)(C)C)c1OC
Reaction time: 4 h
Yield: 86 %

Procedure:
Under argon atmosphere, 7.5 mL (4.01 mmol, 2 equivalents) of the solution of ethyl bromozincacetate in terahydrofuran obtained in Example 43 was added dropwise to a solution of 0.5 g (2.01 mmol) of 3,5-di-tert-butyl-2-methoxybenzaldehyde in 5 mL of THF at 5˜7° C. The mixture was stirred at 5˜7° C. for 4 hours. 5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 15 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, crystals were loosened with 4 mL of n-hexane to obtain 0.58 g of the desired product (yield 86%).