Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([SH:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].CO.Cl[CH2:27][CH2:28][N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[CH:30]1>C(O)C>[C:1]([S:20][CH2:27][CH2:28][N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[CH:30]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCn1cnc2ccccc21
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: c1ccc(C(SCCn2cnc3ccccc32)(c2ccccc2)c2ccccc2)cc1
Yield: 38 %

Procedure:
To a solution of trityl mercaptan (9.7 g, 35 mmol) in ethanol (90 ml) was added, at 0° C., a sodium methoxide-methanol solution (28%) (7.1 ml). To the reaction mixture was added 1-(2-chloroethyl)benzimidazole (6.32 g, 35 mmol), which was heated for 2 hours under reflux. Insoluble substances were filtered off, and the filtrate was concentrated under reduced pressure. The concentrate was subjected to a silica gel column chromatography (3.0×40 cm: ethyl acetate:hexane=1:1→2:1) to give 1-(2-tritylthioethyl)benzimidazole (5.6 g, 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:19](O)=[O:20])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.FC1C=CC([N:30]2C3C(=CC=C(C4C=CN=CC=4)C=3)C(=O)C(C(N)=O)=C2)=CC=1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:19]([NH2:30])=[O:20])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2cc(Cl)ccc2c1=O
Reactant: NC(=O)c1cn(-c2ccc(F)cc2)c2cc(-c3ccncc3)ccc2c1=O
Product: NC(=O)c1cn(-c2ccc(F)cc2)c2cc(Cl)ccc2c1=O

Procedure:
1,4-Dihydro-7-chloro-1-(4-fluorophenyl)-4-oxo-3-quinolinecarboxamide [IV; R=H, R1 =4-FC6H4, R2 =H, R6 =H, X=Cl]was prepared from 2.65 g 1,4-dihydro-7-chloro1-(4-fluorophenyl)-4-oxo-3-quinolinecarboxylic acid by the procedure of Example 1, part (h), and was obtained (1.26 g) in the form of a colorless solid, m.p. 253-255° C when recrystallized from acetonitrile.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12]([NH:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])(=[O:14])=[O:13])[CH:8]=2)[O:3]1.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[Br:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50]Br)[CH:45]=1>CC#N>[Br:43][C:44]1[CH:45]=[C:46]([CH:47]=[CH:48][CH:49]=1)[CH2:50][N:15]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[S:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:24])([CH3:1])[CH2:11][CH2:10]2)(=[O:14])=[O:13]
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc2c(c1)CCC(C)(C)O2
Reactant: BrCc1cccc(Br)c1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN(Cc1cccc(Br)c1)S(=O)(=O)c1ccc2c(c1)CCC(C)(C)O2
Temperature: 90 °C
Yield: 84 %

Procedure:
To the solution of tert-butyl 2-(2,2-dimethylchroman-6-sulfonamido)acetate (500 mg, 1.407 mmol) in MeCN (15 mL) was added resin-supported BEMP (786 mg, 1.547 mmol) and 1-bromo-3-(bromomethyl)benzene (598 mg, 2.391 mmol). The mixture was heated in a microwave synthesizer at 90° C. for 3 hours. The reaction mixture was filtered, rinsed alternatively with dichloromethane and methanol. The filtrate was concentrated to give a reddish orange residue, which was purified by silica chromatography to obtain a white powder (620 mg, 84% yield). 1H NMR (500 MHz, CDCl3) δ 7.60-7.54 (m, 2H), 7.40 (d, J=7.4 Hz, 1H), 7.35 (s, 1H), 7.19 (dt, J=15.1, 7.6 Hz, 2H), 6.88-6.81 (m, 1H), 4.47 (s, 2H), 3.80 (s, 2H), 2.80 (t, J=6.7 Hz, 2H), 1.83 (t, J=6.7 Hz, 2H), 1.35 (s, 6H), 1.35 (s, 9H). LRMS [ESI, MH+] m/z calcd for C24H31BrNO5S 524.11, found 524.1.
Reaction SMILES: [F:1][CH2:2][CH:3]([NH:14][O:15][CH3:16])[CH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:6]=1[Cl:13].C(N(CC)CC)C.[CH3:24][N:25]1[CH:29]=[C:28]([C:30](Cl)=[O:31])[C:27]([C:33]([F:36])([F:35])[F:34])=[N:26]1>ClCCl>[F:1][CH2:2][CH:3]([N:14]([O:15][CH3:16])[C:30]([C:28]1[C:27]([C:33]([F:36])([F:35])[F:34])=[N:26][N:25]([CH3:24])[CH:29]=1)=[O:31])[CH2:4][C:5]1[C:6]([Cl:13])=[CH:7][C:8]([Cl:12])=[CH:9][C:10]=1[Cl:11]
Reactant: CONC(CF)Cc1c(Cl)cc(Cl)cc1Cl
Reactant: Cn1cc(C(=O)Cl)c(C(F)(F)F)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C(=O)c1cn(C)nc1C(F)(F)F)C(CF)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 24 °C
Reaction time: 3 h
Yield: 52.5 %

Procedure:
To a stirred solution of N-[1-fluoromethyl-2-(2,4,6-trichlorophenyl)-ethyl]-O-methyl-hydroxylamine (0.20 g; 0.70 mmol), prepared as described in example P6f2 and triethylamine (0.12 ml; 0.84 mmol) in dichloromethane (1.6 ml) under nitrogen at 4° C. was added dropwise 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (0.15 g; 0.70 mmol). The reaction mixture was stirred at 24° C. for 3 h under nitrogen. Triethylamine (0.19 ml; 1.4 mmol) was added again to the mixture followed by 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (74 mg; 0.35 mmol). The mixture was stirred at 24° C. for 18 h. The mixture was washed with 1M sodium hydroxide (20 ml), 1M hydrochloric acid (20 ml) and brine (20 ml). Organics were dried over sodium sulfate. The solvent was removed in vacuo. The crude was subject to flash chromatography (eluant: c-hexane/ethyl acetate 90:10 to 50:50) to afford 0.17 g (51% of theory) of 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [1-fluoromethyl-2-(2,4,6-trichlorophenyl)-ethyl]-methoxy-amide as a yellow solid (melting point: 131-133° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([N+:11]([O-])=O)[CH:4]=1.CCO.CC(O)=O.Cl>O.C([O-])([O-])=O.[Na+].[Na+].[Fe].CCOC(C)=O>[CH:7]([C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[NH2:11])=[O:8]
Reactant: COc1ccc(C=O)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(C=O)c(N)c1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
A flask was charged with 4-methoxy-2-nitrobenzaldehyde (14.7 g, 81.2 mmol, 1.0 eq), EtOH (270 mL), glacial AcOH (270 mL), H2O (135 mL), degassed and filled with argon. Then Fe powder (325 mesh) (27.2 g, 0.49 mol, 6.0 eq) was added followed by addition of concentrated HCl (12.24 mL, 0.148 mol, 1.8 eq). After stirring the reaction mixture for 1 hour at 60-65° C. (oil bath) TLC (EtOAc/Hex=4:6) showed that no starting material was left. The reaction mixture was cooled down to RT, diluted with 200 mL of H2O and neutralized with Na2CO3 to pH=7-8. The product was extracted into CH2Cl2. The emulsion that formed was filtered through celite, organic layer was washed with brine, dried over Na2SO4, concentrated giving 12.0 g (98% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]1[N:26]=[C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[S:24][N:23]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9]([N:30]2[CH2:29][CH2:28][N:27]([C:25]3[S:24][N:23]=[C:22]([C:18]4[S:17][CH:21]=[CH:20][CH:19]=4)[N:26]=3)[CH2:32][CH2:31]2)=[O:16])[O:4][N:3]=1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Reactant: c1csc(-c2nsc(N3CCNCC3)n2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4cccs4)ns3)CC2)c1C
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 34.2 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (251 mg, 0.872 mmol), 1-[3-(2-thienyl)-1,2,4-thiadiazol-5-yl]piperazine (200 mg, 0.793 mmol) and diisopropylethylamine (0.152 ml, 0.872 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 3.5 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 106 mg (31.1%) of the desired product as a solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:15]3[CH:16]=[N:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:19]=3)[N:10]([S:11]([CH3:14])(=[O:13])=[O:12])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1.O>CC(O)(C)C.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:33][C:34]1[CH:40]=[CH:39][C:37]([NH:38][C:2]2[N:7]=[CH:6][C:5]3[CH:8]=[C:9]([C:15]4[CH:16]=[N:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:19]=4)[N:10]([S:11]([CH3:14])(=[O:13])=[O:12])[C:4]=3[CH:3]=2)=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Cl)cc3n2S(C)(=O)=O)cn1
Reactant: Nc1ccc(F)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Nc4ccc(F)cc4)cc3n2S(C)(=O)=O)cn1
Temperature: 80 °C
Yield: 42 %

Procedure:
Pd2(dba)3 (9.2 mg, 0.01 mmol) was added to a mixture of tert-butyl 4-(6-chloro-1-(methylsulfonyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)-1H-pyrazole-1-carboxylate (15) (40 mg, 0.101 mmol), cesium carbonate (131 mg, 0.403 mmol), 4-fluoroaniline (19 μL, 0.202 mmol) and di-tBuX-Phos (17.1 mg, 0.040 mmol) in t-BuOH containing water (3%) (1.1 mL). The reaction mixture was heated at 80° C. for 1.5 hr under microwave irradiation. It was then diluted with EtOAc and washed with water. The organic extracts were dried over MgSO4, filtered and concentrated under vacuum. The residue was then purified by prep TLC (DCM/MeOH, 95/5) to afford 20 mg of title compound mixed with some starting material. This mixture was used in the next step without further purification. 1H NMR (500 MHz, CDCl3) 1.69 (s, 9H), 2.90 (s, 3H), 6.69 (d, J=0.9 Hz, 1H), 7.05-7.09 (m, 2H), 7.33-7.37 (m, 2H), 7.46 (br m, 1H), 7.93 (d, J=0.9 Hz, 1H), 8.35 (d, J=0.9 Hz, 1H), 8.48 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](O)=O)[CH:5]=[CH:4][CH:3]=1.[C:11]1([NH2:18])[C:12]([NH2:17])=[CH:13][CH:14]=[CH:15][CH:16]=1>>[Br:1][C:2]1[N:7]=[C:6]([C:8]2[NH:18][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1cccc(Br)n1
Product: Brc1cccc(-c2nc3ccccc3[nH]2)n1
Temperature: 220 °C
Yield: 65 %

Procedure:
The mixture of 6-Bromopyridine-2-carboxylic acid (2.01 g, 10 mmol) and benzene-1,2-diamine (1.08, 10 mmol) in polyphosphoric acid was heated at 220° C. for 4 h. The solution was poured into ice-water, and the formed precipitate was collected by filtration and further washed with NaHCO3 and water. After recrystallization in ethanol, the desired product was obtained in yield of 65% (1.76 g). 1H NMR (400 MHz, CDCl3, ppm): 8.31 (d, 2H, J=7.2 Hz), 8.03 (t, 1H, J=7.6 Hz), 7.63 (m, 2H), 7.24 (s, 2H). 13C NMR (100 MHz, CDCl3): 150.20, 148.63, 142.46, 139.46, 135.32, 129.87, 128.04, 124.30, 123.29, 122.92, 120.21, 110.09.
Reaction SMILES: C(O[C:4](=[O:9])[C:5](Br)([CH3:7])[CH3:6])C.[CH:10]1([NH:18][C:19]([NH2:21])=[S:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([NH:18][C:19]2[S:20][C:5]([CH3:6])([CH3:7])[C:4](=[O:9])[N:21]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: NC(=S)NC1CCCCCCC1
Product: CC1(C)SC(NC2CCCCCCC2)=NC1=O

Procedure:
Synthesis was performed from ethyl-2-bromo-2-methylpropanoate and N-cyclooctylthiourea according to Method C1.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13]Cl)[CH:10]=2)[NH:5][CH:4]=1)#[N:2].[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][N:15]=[N+:16]=[N-:17])[CH:10]=2)[NH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1c[nH]c2ccc(CCCl)cc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c[nH]c2ccc(CCN=[N+]=[N-])cc12
Temperature: 80 °C
Yield: 95.4 %

Procedure:
A mixture of 1.92 g (9.38 mmol) 3-cyano-5-(2-chloroethyl)indole (reference example 4) and 1.53 g (23.5 mmol) sodium azide in 10 mL DMF is heated to 80° C. for three hours, followed by azeotroping with toluene. The resulting residue is chromatographed (2:1 hexane:ethyl acetate) to provide 1.89 g of the product as a brown solid in 95% yield. 1H NMR (CDCl3): δ 3.03 (2H, t, J=7.1 Hz), 3.57 (2H, t, J=7 Hz), 7.20 (1H, dd, J=8, 1 Hz), 7.43 (1H, d, J=8 Hz), 7.62 (1H, s), 7.73 (1H, d, J=3 Hz), 8.81 (1H, br). MS (ion spray) m/z 212 (M+H)+, 169 (M−N3)+.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH:3]=[C:4]([CH3:6])[CH3:5].BrC(C)(C)CC(F)(F)F.[N-:18]=[N+:19]=[N-:20]>CCOCC>[N:18]([C:4]([CH3:6])([CH3:5])[CH2:3][C:2]([F:8])([F:7])[F:1])=[N+:19]=[N-:20]
Reactant: CC(C)=CC(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: CC(C)(Br)CC(F)(F)F
Solvent: CCOCC
Product: CC(C)(CC(F)(F)F)N=[N+]=[N-]

Procedure:
The reaction mixture was distilled at ca. 65 mmHg pressure until 70 g of condensate had been collected; further distillate when examined by g.l.c. (2 m silicone, 50°) contained none of the required azide. The distillate was added to ice water (500 ml), shaken, and the lower organic layer (17.1 g) separated, shaken with an excess of aqueous sodium bicarbonate solution, then with water, and dried (Na2SO4). The washings were added to the ice-water layer, which was then extracted three times with ether. The combined ether extracts were washed with an excess of aqueous sodium bicarbonate solution, then with water and dried. The ether was removed to leave a residue of the azide concentrate (13.0 g). The azide was not isolated in the pure state, but as a precaution was handled diluted with ether, olefin and unchanged bromo-compound. The separated organic layer (17.1 g, above) by g.l.c. (2 m silicone, 50°) contained 1,1,1-trifluoro-3-methyl-2-butene (27%), 3-bromo-1,1,1-trifluoro-3-methylbutane (17%) and the azide. The product yields estimated by g.l.c. were 3-azide-1,1,1-trifluoro-3-methylbutane (10.0 g, 15%), 1,1,1-trifluoro-3-methyl-2-butene (27.5 g, 55%), and 3-bromo-1,1,1-trifuloro-3-methylbutane unreacted (4.4 g, 5%). The remaining material was partly accounted for as 1,1,1-trifluoro-3-methyl-2-butene in the ether distillate.
Reaction SMILES: C(NC(N1C2C(=C(CC3C4C(=NC=C(C5C=NC=CC=5)C=4)NC=3)C=CC=2)C=C1)=O)CCC.[CH2:33]([NH:37][C:38]([N:40]1[C:48]2[C:43](=[C:44]([CH:49]([OH:65])[C:50]3[C:58]4[C:53](=[N:54][CH:55]=[C:56]([C:59]5[CH:60]=[N:61][CH:62]=[CH:63][CH:64]=5)[CH:57]=4)[NH:52][CH:51]=3)[CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41]1)=[O:39])[CH2:34][CH2:35][CH3:36]>>[CH2:33]([NH:37][C:38]([N:40]1[C:48]2[C:43](=[C:44]([C:49]([C:50]3[C:58]4[C:53](=[N:54][CH:55]=[C:56]([C:59]5[CH:60]=[N:61][CH:62]=[CH:63][CH:64]=5)[CH:57]=4)[NH:52][CH:51]=3)=[O:65])[CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41]1)=[O:39])[CH2:34][CH2:35][CH3:36]
Reactant: CCCCNC(=O)n1ccc2c(C(O)c3c[nH]c4ncc(-c5cccnc5)cc34)cccc21
Agent: CCCCNC(=O)n1ccc2c(Cc3c[nH]c4ncc(-c5cccnc5)cc34)cccc21
Product: CCCCNC(=O)n1ccc2c(C(=O)c3c[nH]c4ncc(-c5cccnc5)cc34)cccc21

Procedure:
The product of Step 2 of Scheme 41 can alternatively be reacted to form the corresponding compounds with methylene linker at the 3 position of the azaindole. For example, 4-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-indole-1-carboxylic acid butylamide P-1656 was prepared from 4-[Hydroxy-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-indole-1-carboxylic acid butylamide 520 as shown in Scheme 41a.
Reaction SMILES: [CH:1]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]2[CH2:6][CH2:7][CH2:8][CH:4]2[CH2:3][N:2]1C(OC(C)(C)C)=O.[ClH:21].O1CCOCC1>>[ClH:21].[CH:1]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]2[CH2:6][CH2:7][CH2:8][CH:4]2[CH2:3][NH:2]1
Reactant: CCOC(=O)C1C2CCCC2CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C1NCC2CCCC21

Procedure:
The product of Step 4, 2-tert-butyl 1-ethyl hexahydrocyclopenta[c]pyrrole-1,2(1H)-dicarboxylate, was dissolved in anhydrous 4N hydrochloric acid/dioxane for 1 hour at room temperature, and the solvent removed under reduced pressure, to provide racemic (1S,3aR,6aS)-ethyl octahydrocyclopenta[c]pyrrole-1-carboxylate hydrochloride as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[C:6](=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16]C)[N:5]=[C:4]1[CH3:18])[CH3:2].B(Br)(Br)Br>ClCCl>[CH2:1]([N:3]1[C:7](=[O:8])[C:6](=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[N:5]=[C:4]1[CH3:18])[CH3:2]
Reactant: CCN1C(=O)C(=Cc2ccccc2OC)N=C1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCN1C(=O)C(=Cc2ccccc2O)N=C1C
Temperature: -40 °C
Yield: 88.4 %

Procedure:
3-Ethyl-3,5-dihydro-5-(2′-methoxybenzylidene)-2-methylimidazol-4-one (1.2 g) was dissolved in dichloromethane (20 ml) and boron tribromide (1.5 ml) was added dropwise while stirring the mixture at −40° C. Thereafter, the mixture was stirred under ice-cooling for 1 hr, poured into ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3-ethyl-3,5-dihydro-5-(2′-hydroxybenzylidene) -2-methylimidazol-4-one (1 g) as red crystals. The crystals and (S)-glycidyl nosylate (1.3 g) were dissolved in dimethylformamide (20 ml) and potassium carbonate (1.38 g) was added. The mixture was heated at 50° C. for 2 hr, poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oily product (1.02 g). This oily product and 4-(naphthalen-2-yl)piperidine were dissolved in methanol (10 ml) and the mixture was refluxed under heating for 2 hr. After cooling, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (0.52 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[S:11][CH2:12][CH3:13].C([BH3-])#N.[Na+]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[S:11][CH2:12][CH3:13]
Reactant: CCSc1cc2cc[nH]c2cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCSc1cc2c(cc1Cl)NCC2
Yield: 50.4 %

Procedure:
6-Chloro-5-ethylthioindole (D63) (0.35 g, 1.67 mmol) was treated with sodium cyanoborohydride as in the method of Description 10 to give the title compound (0.18 g, 57%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].Cl.[C:25]1([CH:31]2[CH2:36][CH2:35][N:34]([C:37]3([C:40](O)=[O:41])[CH2:39][CH2:38]3)[CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:40]([C:37]2([N:34]3[CH2:33][CH2:32][CH:31]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:36][CH2:35]3)[CH2:39][CH2:38]2)=[O:41])[C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9]
Reactant: O=C(O)C1(N2CCC(c3ccccc3)CC2)CC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2(N3CCC(c4ccccc4)CC3)CC2)CC1
Yield: 52 %

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H with 1-(4-phenylpiperidin-1-yl)cyclopropanecarboxylic acid hydrochloride 16H carried out according to the general procedure L yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(4-phenylpiperidin-1-yl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide as an off-white solid (52%). MS ISP (m/e): 581.2 (100) [(M+H)]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([O:18][CH3:19])=[C:9]([O:16][CH3:17])[C:10]=2[O:14][CH3:15])[CH:5]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].Cl>N1C=CC=CC=1>[CH3:20][S:21]([O:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([O:18][CH3:19])=[C:9]([O:16][CH3:17])[C:10]=2[O:14][CH3:15])[CH:5]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc2cc(CCO)ccc2c(OC)c1OC
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc2cc(CCOS(C)(=O)=O)ccc2c(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(2-Hydroxyethyl)-5,6,7-trimethoxynaphthalene (1.26 g) was dissolved in pyridine (5 mL), methanesulfonyl chloride (715 mg) was added at 0° C. to the solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The resultant extract was washed with water and saturated brine. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:5) to obtain the title compound.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH:12]=[C:11]([C:13]3[CH:36]=[CH:35][C:16]4[N:17]([C:20]5[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[O:28])[CH:23]=[CH:24][CH:25]=5)[CH:18]=[N:19][C:15]=4[CH:14]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.[N:37]([C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1)=[C:38]=[O:39]>>[N:42]1[CH:43]=[CH:44][CH:45]=[C:40]([NH:37][C:38]([N:2]2[CH2:3][CH2:4][CH:5]([N:8]3[CH:12]=[C:11]([C:13]4[CH:36]=[CH:35][C:16]5[N:17]([C:20]6[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:33])([F:32])[F:34])=[O:28])[CH:21]=6)[CH:18]=[N:19][C:15]=5[CH:14]=4)[CH:10]=[N:9]3)[CH2:6][CH2:7]2)=[O:39])[CH:41]=1
Reactant: O=C=Nc1cccnc1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cnn(C5CCNCC5)c4)ccc32)c1
Agent: Cl
Product: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cnn(C5CCN(C(=O)Nc6cccnc6)CC5)c4)ccc32)c1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 24 starting from N-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea HCl salt (prepared from the procedure for Example 21, step 4) and 3-isocyanatopyridine (Oakwood, Cat. No. 022077), LCMS (M+H)+: m/z=604.3.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:20][C:19](=[O:21])[C:18]2[C:13](=[C:14](I)[CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH2:2][CH3:3].[C:23]1([CH2:29][CH2:30][CH:31]=[CH2:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:20][C:19](=[O:21])[C:18]2[C:13](=[C:14]([CH:32]=[CH:31][CH2:30][CH2:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH2:2][CH3:3]
Reactant: C=CCCc1ccccc1
Reactant: CCCOc1ccccc1-c1nc2c(I)cccc2c(=O)[nH]1
Product: CCCOc1ccccc1-c1nc2c(C=CCCc3ccccc3)cccc2c(=O)[nH]1
Yield: 49.9 %

Procedure:
The title compound is prepared analogously to the method of Example 2, starting with the compound from Example III and 4-phenyl-1-butene.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2.[NH2-].[Na+].[O:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1>C1COCC1>[O:18]1[CH:22]2[C:2]3[C:3]4[C:8]([C:9]5[C:14]([C:15]=3[CH:19]1[CH:20]=[CH:21]2)=[CH:13][CH:12]=[CH:11][CH:10]=5)=[CH:7][CH:6]=[CH:5][CH:4]=4
Reactant: c1ccoc1
Reactant: Brc1cc2ccccc2c2ccccc12
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C1=CC2OC1c1c2c2ccccc2c2ccccc12
Temperature: 70 °C

Procedure:
9-Bromophenanthrene (18.6 g, 72.3 mmol), sodium amide (8.47 g, 217.0 mmol) were charged in a two-necked bottle. The bottle was then vacuumed and purged with nitrogen, and dried THF (120 mL) and furan (78.1 mL, 1.07 mmol) were added to the bottle. The mixture in the bottle was heated to 70° C. for reaction for 24 hours, and the resulting was filtered to remove metal. The filtrate was condensed to remove the solvent, and then purified by chromatography with hexanes to yield A (14.7 g, 83%) as white solid powder.