Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[CH3:10].C(N(CC)CC)C.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(CO)ccc1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(CO[Si](C)(C)C(C)(C)C)ccc1Br

Procedure:
To a solution of 2-bromo-5-hydroxymethyltoluene (87.4 g) in methylene chloride (350 ml) were added, under ice-cooling with stirring, trietylamine (72.7 ml) and 4-dimethylaminopyridine (DMAP)(500 mg), and then thereto was added t-butyldimethylsilyl chloride (65.5 g). The mixture was stirred at 0° C. for 15 minutes, and stirred at room temperature for 3 hours. The reaction mixture is filtrated, and the filtrate was concentrated under reduced pressure. To the residure was added water (100 ml), and the mixture was extracted with ethyl acetate.
Reaction SMILES: Br.[CH3:2][S:3]([CH2:5][CH2:6][CH2:7][NH2:8])=[O:4].C(N(CC)CC)C.[CH2:16]([N:34]=[C:35]=[O:36])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>CC(C)=O>[CH3:2][S:3]([CH2:5][CH2:6][CH2:7][NH:8][C:35]([NH:34][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:36])=[O:4]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: CS(=O)CCCN
Agent: Br
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)NCCCS(C)=O
Temperature: 25 °C

Procedure:
10.6 Grams of 3-(methylsulfinyl)propylamine hydrobromide, 5.6 g of triethylamine and 100 ml of acetone were charged in a flask equipped with a stirrer, a condenser and a calcium chloride drying tube and stirred at room temperature. To the resulting solution was slowly added dropwise 14.8 g of octadecyl isocyanate. After completion of the addition, the temperature of the solution was returned to room temperature, followed by refluxing with heating for 2 hours. The reaction mixture was cooled to room temperature, and the precipitated crystal was filtered off under reduced pressure and washed with distilled water. The crystal was recrystallized from 2-propanol to obtain 14.9 g of the desired product. m.p. 105° C.
Reaction SMILES: [CH:1]12[NH:16][CH:5]([CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8]1)[CH2:4][O:3][CH2:2]2.[CH3:17][C:18]1[C:26]2[CH2:25][O:24][C:23](=[O:27])[C:22]=2[CH:21]=[CH:20][C:19]=1[C@@H:28]1[CH2:30][O:29]1>C(O)C>[OH:29][C@H:28]([C:19]1[CH:20]=[CH:21][C:22]2[C:23](=[O:27])[O:24][CH2:25][C:26]=2[C:18]=1[CH3:17])[CH2:30][N:16]1[CH:1]2[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:6][CH:5]1[CH2:4][O:3][CH2:2]2
Reactant: CC(C)(C)OC(=O)N1CC2COCC(C1)N2
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Solvent: CCO
Product: Cc1c([C@@H](O)CN2C3COCC2CN(C(=O)OC(C)(C)C)C3)ccc2c1COC2=O
Temperature: 140 °C

Procedure:
Commercially available tert-Butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate (300 mg, 1.3 mmol) and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (INTERMEDIATE 2) (380 mg, 2.0 mmol) were dissolved in ethanol (10 ml) and heated in a microwave reactor at 140° C. for 1 hour. The reaction was concentrated and purified by MPLC on ISCO RediSep® purification column and eluted with 50%-100% ethyl acetate/hexane to provide tert-butyl 9-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:31]=1.[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1>CN(C)C(=O)C.C(OCC)(=O)C>[C:28]([C:25]([C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]3[N:5]([CH:31]=[C:2]([NH:1][C:35]([CH:32]4[CH2:34][CH2:33]4)=[O:36])[N:3]=3)[CH:6]=2)[CH:12]=1)=[O:30])([CH3:27])[CH3:26])#[N:29]
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)cn4c3)c2)c1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.486 mmol) in N,N-dimethylacetamide (2.0 mL) was added cyclopropanecarbonyl chloride (46 μL, 0.510 mmol), and the mixture was stirred at room temperature for 8 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (NH silica gel, hexane/ethyl acetate=50/50→0/100), and fractions containing the desired product were concentrated under reduced pressure. The residue was triturated with ethyl acetate and diisopropyl ether to give the title compound (100 mg, 43%) as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][CH:8](OS(C)(=O)=O)[CH2:9][CH:3]1[CH2:4][CH2:5]2.C([O:17][C:18]([S-:20])=[S:19])C.[Na+].C1(C)C=CC=CC=1>O>[CH3:1][N:2]1[C@@H:3]2[CH2:9][CH:8]([S:19][C:18]([SH:20])=[O:17])[CH2:7][C@H:6]1[CH2:5][CH2:4]2
Reactant: CCOC(=S)[S-]
Reactant: CN1C2CCC1CC(OS(C)(=O)=O)C2
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CN1[C@@H]2CC[C@H]1CC(SC(=O)S)C2
Temperature: 30 °C

Procedure:
Tropine-3-mesylate (25 g, 0.114 mol) and sodium ethylxanthate (19.7 g, 0.137 mol) were added to stirred toluene (0.075 L) under nitrogen. The stirred mixture was maintained at 30° C. for 6 h. Water (0.05 L) was added and after 15 min stirring the phases were separated. The toluene phase, containing the title compound, was used directly in the preparation of tropine-3-thiol as in Step 4b.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[CH3:19][O:20][NH:21][CH3:22]>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:21]([O:20][CH3:19])[CH3:22])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CNOC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.6 %

Procedure:
To a stirred solution of 4-bromobenzoyl chloride (20.0 g, 91.1 mmol) in dichloromethane (300 mL) at −78° C. was added triethylamine (28.0 mL, 200.0 mmol), and O,N-dimethylhydroxylamine hydrochloride (9.33 g, 95.6 mmol). The resulting solution was allowed to warm to room temperature, stirred for 1.5 hours, and then concentrated. The residue was triturated in acetone and the resulting solid was dissolved in ethyl acetate washed with water and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 4-bromo-N-methoxy-N-methylbenzamide (18.6 g, 84%). To a solution of 4-bromo-N-methoxy-N-methylbenzamide (3.0 g, 12.29 mmol) in THF (30 mL) at 0° C. under nitrogen was added 2-thienyllithium (1.0 M in THF, 15 mL, 15 mmol) slowly over 10 minutes. The solution was stirred at 0° C. for 1 hour, poured into a saturated aqueous ammonium chloride solution (150 mL), and extracted several times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue was triturated with ether to give (4-bromophenyl)(thien-2-yl)methanone as a brown solid (1.1 g, 34%). MS (ES) m/z 266.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:31]1[CH2:32][CH2:33][N:28]([C:22]3[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:20])[CH2:29][CH2:30]1)=[O:19])=[N:5]2
Reactant: Cc1cccc(C)c1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Product: COc1nc2ccc(F)cc2nc1NC(=O)N1CCN(c2c(C)cccc2C)CC1
Yield: 65 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(2,6-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 65%). 1H NMR (300 MHz, CDCl3): δ 2.26 (s, 3H), 3.20 (s, 4H), 3.71 (s, 3H), 4.12-4.18 (m, 4H), 6.99-7.01 (m, 3H), 7.26-7.32 (m, 2H), 7.53-7.81 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[CH3:8][NH:9][C:10](=[O:47])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:32]1[NH:33][C:34]([C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=2)=[CH:35][NH+:36]=1)[NH:17][C:18](C1CCCN(C2C=CC=CN=2)C1)=[O:19].CCN(C(C)C)C(C)C.[CH2:57]([N:64]=C=O)[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[CH2:57]([NH:64][C:18]([NH:17][C@H:16]([C:32]1[NH:33][C:34]([C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=2)=[CH:35][NH+:36]=1)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]([NH:9][CH3:8])=[O:47])=[O:19])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1
Reactant: CNC(=O)CCCCC[C@H](NC(=O)C1CCCN(c2ccccn2)C1)c1[nH]c(-c2ccc3ccccc3c2)c[nH+]1
Reactant: O=C=NCc1ccccc1
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)CCCCC[C@H](NC(=O)NCc1ccccc1)c1[nH]c(-c2ccc3ccccc3c2)c[nH+]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The amine from Example 327, BB2 (1 eq.) was dissolved in DCM, then DIPEA (1 eq.) and benzyl isocyanate were added. After stirring for 1 hr at RT the solvent were removed under reduced pressure and the crude was purified by preparative RP-HPLC, using H2O (0.1% TFA) and MeCN (+0.1% TFA) as eluents (column: C18). The desired fractions were lyophilized to afford the titled compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 8.36 (1H, s), 8.16 (1H, s), 8.07 (1H, d, J=8.6 Hz), 8.02-7.93 (2H, m), 7.91 (1H, dd, J=8.6 Hz, J2=1.5 Hz), 7.71-7.55 (3H, m), 7.35-7.19 (5H, m), 6.75-6.67 (2H, m), 4.97-4.87 (1H, m), 4.30-4.15 (2H, m), 2.53 (3H, d, J=4.6 Hz), 2.04 (2H, t, J=7.4 Hz), 1.97-1.83 (2H, m), 1.55-1.44 (2H, m), 1.42-1.22 (4H, m). MS (ES) C29H33N5O2 requires: 483, found: 484 (M+H)+.
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][C:3]1[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:5]([OH:7])=O.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>>[Cl:14][C:15]1[CH:16]=[C:17]([N:18]2[C:1](=[O:13])[CH2:2][C:3]3[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:5]2=[O:7])[CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)Cc1ccccc1C(=O)O
Reactant: Nc1cccc(Cl)c1
Product: O=C1Cc2ccccc2C(=O)N1c1cccc(Cl)c1
Yield: 58 %

Procedure:
A mixture of homophthalic acid (45.0 g., 0.25 mole) and m-chloroaniline (31.8 g., 0.25 mole) was heated by an oil bath to 175°-180° C. for two hours. When removed from the oil bath, the reaction mixture solidified and was recrystallized twice from ethanol/ethyl acetate, giving 2-(m-chlorophenyl)-isoquinoline-1,3 (2H, 4H)-dione, 36.0 g. (58% yield), m.p. 160°-161° C.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([OH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][CH:15]([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1)[CH2:16][O:17][CH:18]([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([O:21][CH:15]([CH3:14])[CH2:16][O:17][CH:18]([CH3:20])[CH3:19])=[CH:29][CH:28]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(O)c(Cl)c1=O
Reactant: CC(C)OCC(C)Oc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)OCC(C)Oc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Reaction time: 2 h
Yield: 59.5 %

Procedure:
In 15 ml of N,N-dimethylformamide were dissolved 1.0 g of 2-t-butyl-4-chloro-5-hydroxy-3(2H)-pyridazinone and 1.6 g of 4-(1-methyl-2-isopropoxyethoxy)-benzyl bromide, and thereto was added 1.0 g of anhydrous potassium carbonate. The mixture was heated under stirring on an oil bath at 100° to 120° C. for 2 hours. Then, procedures similar to those in Preparation Example 2 were conducted to give 1.2 g of the aimed compound, m.p. 60.0°~62.0° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[CH2:18]([N:25]1[C@@H:30]2[C@H:31]([C:33]#[N:34])[CH2:32][C@@:26]1([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:27]([OH:35])[CH2:28][CH2:29]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>ClCCl>[CH2:18]([N:25]1[C@@H:30]2[C@H:31]([C:33]#[N:34])[CH2:32][C@@:26]1([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:27]([O:35][C:6](=[O:7])[C:5]1[CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:4]=1)[CH2:28][CH2:29]2)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: N#C[C@@H]1C[C@@]2(c3ccccc3)[C@H](O)CC[C@@H]1N2Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#C[C@@H]1C[C@@]2(c3ccccc3)[C@H](OC(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.8 %

Procedure:
3,5-Bis(trifluoromethyl)benzoyl chloride (2.76 g, 10 mmol) was added dropwise to an ice-cold solution of (1R*,2R*,5S*,6R*)-8-benzyl-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 31; 3 g, 9.4 mmol), triethylamine (2 g, 20 mmol) and 4-N,N-dimethylaminopyridine (200 mg, 1.6 mmol) in dichloromethane (30 ml). The mixture was stirred at room temperature for 20 hours. The mixture was concentrated in vacuo then partitioned between ethyl acetate and brine. The organics were separated, dried (MgSO4), filtered and concentrated. The residue was chromatographed on silica gel eluting with 10 and 20% ethyl acetate/iso-hexanes to afford the title compound (4.87 g, 93%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH:11]=[C:10]([CH3:14])[N:9]2[CH3:15])=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>C(Cl)Cl.[Al]>[Br:16][C:11]1[C:12](=[O:13])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]([CH3:15])[C:10]=1[CH3:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(=O)n(-c2ccc(F)cc2)n1C
Agent: [Al]
Solvent: ClCCl
Product: Cc1c(Br)c(=O)n(-c2ccc(F)cc2)n1C
Reaction time: 24 h
Yield: 62.4 %

Procedure:
To a solution of 2-(4-fluoro-phenyl)-1,5-dimethyl-1,2-dihydro-pyrazol-3-one (0.5 g) in methylene chloride (10 mL) was added N-bromosuccinimide (0.43 g). The reaction vessel was wrapped in aluminium foil and stirred for 24 hours. The solvent was evaporated in vacuo and the residue was dissolved in EtOAc and water. The phases were separated and the aqueous phase was extracted with more EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and reduced in vacuo to give a crude residue. Flash column chromatography over silica gel using ISCO combiflash chromatography and eluting with EtOAc/heptane afforded the desired 4-bromo-2-(4-fluoro-phenyl)-1,5-dimethyl-1,2-dihydro-pyrazol-3-one (0.43 g) as an off-white solid. MS (ESI+): 287.0 ([M+H]+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][S:9]([CH2:12][CH2:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)(=[O:11])=[O:10])[C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1.C(O)(=O)C[C:28](CC(O)=O)([C:30](O)=[O:31])[OH:29]>C(O)CO.O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:3]2[C:4]([NH:8][S:9]([CH2:12][CH2:13][C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)(=[O:11])=[O:10])=[N:5][CH:6]=[N:7][C:2]=2[O:29][CH2:28][CH2:30][OH:31])=[CH:20][CH:21]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: O=S(=O)(CCc1cccs1)Nc1ncnc(Cl)c1-c1ccc(Cl)cc1
Solvent: OCCO
Solvent: O
Product: O=S(=O)(CCc1cccs1)Nc1ncnc(OCCO)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
2-Thiophen-2-yl-ethanesulfonic acid [6-chloro-5-(4-chloro-phenyl)-pyrimidin-4-yl]-amide (930 mg) was added to a solution of K-tert. butylate (1.16 g) in ethylene glycol (10 ml). The mixture was stirred at 110° C. for 12 h before it was diluted with water (150 ml), acidified with 10% aq. citric acid (13 ml). The resulting precipitate was collected, washed with water and diethyl ether and dried to give (820 mg) 2-thiophen-2-yl-ethanesulfonic acid [5-(4-chloro-phenyl)-6-(2-hydroxy-ethoxy) -pyrimidin-4-yl]-amide as a beige powder. LC-MS: tR=4.43 min, [M+1]+=440.01, [M−1]−=437.99.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[N:28]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[C:37]([O:36][C:34]([N:28]1[CH2:33][CH2:32][N:31]([CH2:12][C:9]2[C:10](=[O:11])[N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[N:6]=[C:7]([C:18]3[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=3)[CH:8]=2)[CH2:30][CH2:29]1)=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)Cn1nc(-c2ccc(S(C)(=O)=O)cc2)cc(COS(C)(=O)=O)c1=O
Product: CC(C)Cn1nc(-c2ccc(S(C)(=O)=O)cc2)cc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1=O
Yield: 75.9 %

Procedure:
Following the procedure of Example 1(10), 2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 75.9%).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]#[N:12].N1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][CH2:2][C:3]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]#[N:12])=[O:4]
Reactant: O=C(Br)CBr
Reactant: N#C[C@@H]1CCCN1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#C[C@@H]1CCCN1C(=O)CBr
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.2 %

Procedure:
To a cold solution (−10° C.) of bromoacetyl bromide (2.0 g, 10.0 mmol) in CH2Cl2 (30 mL), a solution of (S)-pyrrolidine-2-carbonitrile (480 mg, 5.0 mmol) and pyridine (1.4 g, 210 mmol) together with a catalytic amount of DMAP (50 mg) in CH2Cl2 (10 mL) was added over a 30 minute period. After stirring for about 10 minutes, the reaction temperature was gradually increased to room temperature. Stirring at room temperature was continued overnight. The residue was diluted with CH2Cl2 (60 mL), washed with ice water and cold 10% sodium bicarbonate aqueous solution to give crude product (1.01 g; yield of 93%). Column chromatography purification of the crude product resulted in pure 1-(2-bromo-acetyl)-(S)-pyrrolidine-2-carbonitrile (892 mg; 82.6% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]2[C:5]([S:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([C:17]([OH:19])=O)[C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>C1(C)C=CC=CC=1.CN(C=O)C>[CH3:1][C:2]1[CH:15]=[C:14]2[C:5]([S:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([C:17]([Cl:22])=[O:19])[C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc2sc3cccc(C(=O)O)c3c(=O)c2c1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1ccc2sc3cccc(C(=O)Cl)c3c(=O)c2c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
0.21 g (0.78 mmoles) of 7-methyl-9-oxo-9H-thioxanthene-1-carboxylic acid are suspended in 30 ml of toluene containing 2 drops of DMF and 0.35 g of thionyl chloride. After stirring for 1 hour at 80° C. the mass is cooled to room temperature obtaining a yellow solution of 7-methyl-9-oxo-9H-thioxanthene-1-carbonyl chloride.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH:29]2[C:24]([CH2:25][N:26]([CH2:30][C:31]#[CH:32])[CH2:27][CH2:28]2)=[C:5]2[C:6]([OH:23])([OH:22])[CH:7]=[C:8]([CH:10]([CH3:21])[CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:9]=[C:4]2[O:3]1.[H][H]>C(O)C>[CH3:33][C:2]1([CH3:1])[CH:29]2[C:24]([CH2:25][N:26]([CH2:30][CH2:31][CH3:32])[CH2:27][CH2:28]2)=[C:5]2[C:6]([OH:23])([OH:22])[CH:7]=[C:8]([CH:10]([CH3:21])[CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:9]=[C:4]2[O:3]1
Reactant: C#CCN1CCC2C(=C3C(=CC(C(C)CCCc4ccc(F)cc4)=CC3(O)O)OC2(C)C)C1
Reactant: [H][H]
Solvent: CCO
Product: CCCN1CCC2C(=C3C(=CC(C(C)CCCc4ccc(F)cc4)=CC3(O)O)OC2(C)C)C1

Procedure:
5,5-Dimethyl-8-(4-p-fluorophenyl-1-methylbutyl)-2-(2-propynyl)-10-hydroxy-1,2,3,4-tetrahydro-5H[1]benzopyrano [4,3-c]pyridin-10-ol was hydrogenated in ethanol using 5% palladium on carbon as a catalyst. When two equivalents of hydrogen were taken up, the catalyst was filtered and solution concentrated to give the desired product.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH2:21][CH2:22][C:23](Cl)=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:1]([C:5]1[C:6]([NH:14][C:23](=[O:24])[CH2:22][CH2:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Reactant: O=C(Cl)CCc1ccccc1
Product: CC(C)(C)c1c(NC(=O)CCc2ccccc2)nn2cccnc12

Procedure:
The product from Example 105B and 3-phenylpropionyl chloride were processed using the method analogous to that described in Example 105C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.40 (s, 9H), 2.56-2.67 (m, 2H), 2.90 (t, J=7.6 Hz, 2H), 6.99 (dd, J=7.0, 3.9 Hz, 1H), 7.17-7.31 (m, 5H), 8.48 (dd, J=4.1, 1.7 Hz, 1H), 8.92 (dd, J=7.1, 1.7 Hz, 1H), 9.74 (s, 1H); MS (DCI) m/z 323 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH:17]1[C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([S:27](Cl)(=[O:29])=[O:28])[C:21]=2[CH:20]=[CH:19][N:18]=1.CO.C(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH:17]1[C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([S:27]([N:8]3[CH2:9][CH2:10][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][CH2:7]3)(=[O:29])=[O:28])[C:21]=2[CH:20]=[CH:19][N:18]=1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: CC(C)CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)CN1CCN(S(=O)(=O)c2cccc3cnccc23)CC1
Reaction time: 2 h
Yield: 78.1 %

Procedure:
In 30 ml of chloroform were added 1.42 g of 1-isobutylpiperazine and 2.76 g of potassium carbonate, and to the mixture was added dropwise 50 ml of a chloroform solution containing 2.28 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the chloroform solution, the mixed solution thus obtained was stirred at a temperature of 15° C. to 25° C. for two hours, and then the reaction solution was washed with 20 ml of a 1N aqueous sodium hydroxide solution and extracted twice with a 5N aqueous hydrochloric acid solution. The aqueous hydrochloric acid layer was rendered alkaline, extracted three time with 30 ml of chloroform, and the chloroform layer extracted was washed with water and dried with anhydrous magnesium sulfate. After the chloroform was distilled therefrom under reduced pressure, the residue obtained was subjected to a silica gel column chromatography (silica gel: 100 g; solvent: 2% methanol-chloroform) to give 2.60 g of 1-(5-isoquinolinesulfonyl)-4-isobutylpiperazine, i.e., Compound (47) in a yield of 78%.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[C:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](F)=[CH:13][CH:12]=1)#[N:10]>N1C=CC=CC=1>[CH:5]12[N:8]([C:14]3[C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:11]([C:9]#[N:10])=[CH:12][CH:13]=3)[CH:1]([CH2:7][CH2:6]1)[CH2:2][CH2:3][CH2:4]2
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: C1CC2CCC(C1)N2
Solvent: c1ccncc1
Product: N#Cc1ccc(N2C3CCCC2CC3)c2ccccc12
Yield: 3.8 %

Procedure:
Alternatively, the title compound was also obtained using the following procedure: 8-Azabicyclo[3,2,1]octane (20 mg, 0.18 mmol), 1-cyano-4-fluoronaphthalene (46 mg, 0.27 mmol) and pyridine (0.5 mL) were heated overnight at 100° C., concentrated in vacuo and the residue purified by preparative TLC (dichloromethane, 3× eluted) to afford the title compound (1.8 mg, 4.0%) as a yellow oil.