Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P(Cl)(Cl)Cl.[C:6](N1CCOCC1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:20]([O:22][C:23]([C:25]1([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:32]2[N:28]([CH:29]=[CH:30][CH:31]=2)[CH2:27][CH2:26]1)=[O:24])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>ClC(Cl)C>[C:6]([C:29]1[N:28]2[C:32](=[CH:31][CH:30]=1)[C:25]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([C:23]([O:22][CH2:20][CH3:21])=[O:24])[CH2:26][CH2:27]2)(=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)C1(C(=O)OCC)CCn2cccc21
Reactant: O=C(c1ccccc1)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: CCOC(=O)C1(C(=O)OCC)CCn2c(C(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 10 h
Yield: 100.2 %

Procedure:
A mixture of POCl3 (166 mg, 1.08 mmole) and N-benzoylmorpholine (96 mg, 0.5 mmole) was maintain for 6 hours at 25° C. A solution of diethyl-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylate (126 mg, 05 mmole) in dichloroethane (2 ml) was added. Then, the mixture was maintained at 50° C. for 3 days. The reacted mixture was poured with 2.5 ml of 10% aqueous sodium carbonate solution. The mixture was stirred at room temperature for 10 hours, and refluxed for 2 hours. The organic layer was separated, and the aqueous layer was washed with 1,2-dichloroethane. The organic layer was dried using sodium carbonate, and the solvent was removed. Finally, the residue was purified by silica gel column chromatography using ethyl acetate-hexane (1:9) as an eluting solvent and 178 mg of the product diethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylate (84%) was obtained. The IR and NMR spectral properties were identical to those of an authentic sample.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[O:14])[N:8]=1)=[O:5].[CH:27](=O)[CH3:28].C([BH3-])#N.[Na+].FC(F)(F)C(O)=O>CO>[F:26][C:21]1[CH:22]=[C:23]([F:25])[CH:24]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH:15]2[CH2:16][CH2:17][N:18]([CH2:27][CH3:28])[CH2:19][CH2:20]2)=[O:14])[N:8]=1)=[O:5]
Reactant: CC=O
Reactant: O=C(Nc1cccc(C(=O)C2CCNCC2)n1)c1c(F)cc(F)cc1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCN1CCC(C(=O)c2cccc(NC(=O)c3c(F)cc(F)cc3F)n2)CC1
Temperature: 90 °C
Yield: 30 %

Procedure:
Mix 2,4,6-trifluoro-N-[6-(piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide (26 mg), acetaldehyde (42 mg), sodium cyanoborohydride (10 mg) and trifluoroacetic acid (16.4 mg) in methanol (2 mL) in a sealed tube and heat in an oil bath at 90° C. overnight. Dilute with methanol and load on a SCX column (10 g), wash with methanol, elute the product with 2M NH3-methanol, evaporate, purify on a silica gel column (4 g, solvent: dichloromethane-2M NH3 in methanol, gradient) to obtain the title compound (8.4 mg). Mass spectrum (electrospray) m/z=392 (M+1); 1H NMR (CDCl3): 8.51 (d, 1H), 8.42 (br, 1H), 7.92 (t, 1H), 7.82 (dd, 1H), 6.84 (m, 2H), 3.63 (m, 1H), 3.02 (m, 2H), 2.44 (m, 2H), 2.04 (m, 2H), 1.87 (m, 4H), 1.60 (m, 5H), 1.11 (t, J=6.8 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[CH:17]=O>C(O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:17][C:16]2[CH:19]=[C:20]([Cl:22])[CH:21]=[C:14]([Br:13])[CH:15]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: O=Cc1cc(Cl)cc(Br)c1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CCO
Product: CCOC(=O)c1ccc(N=Cc2cc(Cl)cc(Br)c2)cc1
Temperature: 25 °C
Yield: 34.7 %

Procedure:
A mixture of 4-amino-benzoic acid ethyl ester (8.3 g, 50.3 mmol) and 3-bromo-5-chloro-benzaldehyde (11.0 g, 50.3 mmol) in ethanol (100 mL) was heated to reflux for 2 hours. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-{[1-(3-bromo-5-chloro-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (6.4 g, 35%) as a white solid: LC/MS m/e calcd for C16H13BrClNO2 M+: 366.6, observed: 366.6.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH2:21][C:22](O)=[O:23])=[CH:11][CH:12]=2)[CH:7]=[N:6]1)[CH:2]([CH3:4])[CH3:3].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:67]1([C:73]2[CH:78]=[CH:77][C:76]([NH2:79])=[CH:75][CH:74]=2)[CH2:72][CH2:71][O:70][CH2:69][CH2:68]1.C(O)C(N)(CO)CO>C(Cl)(Cl)Cl>[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH2:21][C:22]([NH:79][C:76]3[CH:75]=[CH:74][C:73]([N:67]4[CH2:68][CH2:69][O:70][CH2:71][CH2:72]4)=[CH:78][CH:77]=3)=[O:23])=[CH:11][CH:12]=2)[CH:7]=[N:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cn1ncc2cc(Oc3ccccc3CC(=O)O)ccc21
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC(CO)(CO)CO
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Cn1ncc2cc(Oc3ccccc3CC(=O)Nc3ccc(N4CCOCC4)cc3)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.3 %

Procedure:
To a solution of (15p) (0.04 g, 0.123 mmol), PyBOP (0.135 g, 0.26 mmol) and DIEA (0.02 mL, 0.12 mmol) in CHCl3 (2 ml), 4-morpholin-4-yl-phenylamine (0.044 g, 0.247 mmol) were added. The mixture was stirred at room temperature for 16 hours, treated with AP-trisamine resin (0.25 g, 2.49 mmol/g), and finally the solvent was removed under reduced pressure after filtration from the resin. The resulting residual was purified by chromatography (Sep-Pak, 10 g) with ether to provide the desired product (16p) (0.024 g, 40%). 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.50 (br s, 1H), 7.45 (dd, J=7.83, 1.57 Hz, 1H), 7.39 (d, J=9.39 Hz, 2H), 7.31-7.26 (m, 3H), 7.23 (dd, J=7.83, 1.57 Hz, 1H), 7.15-7.09 (m, 2H), 6.86-6.79 (m, 3H), 4.17 (d, J=7.04 Hz, 2H), 3.86-3.82 (m, 4H), 3.80 (s, 2H), 3.11-3.06 (m, 4H), 2.41-2.29 (m, 1H), 0.95 (s, CH3), 0.94 (s, CH3); MS (APCI+) m/z 485.2 (M+H) was detected.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22]CC4C=CC=CC=4)=[O:21])[CH:18]=3)[NH:13][CH:12]=2)=[C:6]([O:30][CH3:31])[CH:5]=1>CN(C)C=O.C(O)=O.[Pd]>[CH3:31][O:30][C:6]1[CH:5]=[C:4]([C:3]([O:2][CH3:1])=[O:32])[CH:9]=[CH:8][C:7]=1[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([OH:22])=[O:21])[CH:18]=2)[NH:13][CH:12]=1
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc(C(=O)OCc4ccccc4)cc23)c(OC)c1
Agent: [Pd]
Solvent: O=CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cc2c[nH]c3ccc(C(=O)O)cc23)c(OC)c1
Reaction time: 1.5 h
Yield: 72 %

Procedure:
To a solution of 4-[5-benzoxycarbonyl-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid methylester (3.46 grams, 8.06 mmol) in dimethylformamide (40 mL) and formic acid (2 mL) was added 10% palladium on carbon (1.5 grams). The resulting mixture was hydrogenated at 30 psi for 1.5 hours. The mixture was filtered through celite and the filtrate diluted with ethyl acetate. This solution was washed several times with 1 M hydrochloric acid (aq). The organics were then dried over magnesium sulfate and concentrated. Recrystallization from methylene chloride gave 3-(2-methoxy-4-methoxycarbonyl-benzyl)-1H-indole-5-carboxylic acid (1.97 grams, 73% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)[CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([S:14][CH2:15][CH3:16])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: CCSc1ccc(-c2cc(Cl)ccc2OCC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCSc1ccc(-c2cc(Cl)ccc2OCC(=O)O)cc1

Procedure:
The title compound was prepared by stirring a mixture of the product from step (ii) (0.3 g) and trifluoroacetic acid (4 ml) in DCM (10 ml) at RT for 5 h. The solvent was evaporated under reduced pressure, the residue triturated with diethylether then purified by reverse phase HPLC. Yield 0.106 g
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:21])[C:18]=3[F:20])[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[F:21][C:17]1[C:18]([F:20])=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([NH:1][CH2:34][C:32]3[CH:31]=[CH:30][C:27]4[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=4[N:33]=3)[CH2:3][CH2:4]2)=[CH:15][CH:16]=1
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)c(F)c32)CC1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=C1COc2ccc(CNC3CCN(CCn4c(=O)cnc5ccc(F)c(F)c54)CC3)nc2N1
Yield: 41.5 %

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-7,8-difluoroquinoxalin-2(1H)-one (Intermediate 153, 130 mg, 0.42 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (70 mg, 0.42 mmol), and sodium triacetoxy borohydride (270 mg, 1.30 mmol) were reacted as described for Example 69 to give 82 mg (41%) of the free base of the product.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[C:6]([CH3:12])[O:5][N:4]=1)[CH3:2].C([Li])CCC.CCCCCC.[CH:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[CH2:1]([C:3]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[C:6]([CH2:12][CH:24]([OH:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc(C)c1C(=O)NC
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1noc(CC(O)c2ccccc2)c1C(=O)NC
Temperature: -30 °C
Reaction time: 2 h

Procedure:
A suspension of 58.5 g. (0.348 mole) of 3-ethyl-N,5-dimethyl-isoxazole-4-carboxamide and 1 liter of tetrahydrofuran is cooled to -65° C. and 478 ml. of 1.6M n-butyllithium in hexane (0.765 mole) is added dropwise maintaining the temperature between -60° and -70° C. After the addition is complete, the suspension is stirred for 11/2 hours at -60° to -70° C., and then 37.2 g. (0.350 mole) of benzaldehyde in 375 ml. tetrahydrofuran is added dropwise maintaining the temperature between -60° and -70° C. After addition is complete, the mixture is stirred for 11/2 hours at -60° to - 70° C. and then warmed to -30° C. and quenched by the addition of saturated ammonium chloride solution. The mixture is further diluted with tetrahydrofuran and the layers are separated. The tetrahydrofuran layer is washed twice with 50% brine, and once with brine, dried over anhydrous mangesium, sulfate, filtered and evaporated in vacuo. The solid residue is triturated with ether and filtered to give 3-ethyl-5-(β-hydroxyphenethyl)N-methyl-isoxazole-4-carboxamide, m.p. 135° to 137° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:19]([O:22][CH3:23])[C:20]#[CH:21]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:21]#[C:20][CH2:19][O:22][CH3:23])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(I)ncn2-c2cccc(Cl)c2C1=O
Reactant: C#CCOC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: COCC#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2

Procedure:
10.0 g (26.7 mmol) of 7-chloro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one, 140 mg of bis-(triphenylphosphine)-palladium(II) dichloride, 40 mg of copper(I) iodide and 3.4 ml (40.3 mmol) of methyl propargyl ether in 100 ml of diethylamine were heated to boiling under reflux for 3.5 hours. The reaction mixture was evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate. After recrystallization from ethyl acetate there was obtained 7-chloro-4,5-dihydro-3-(3-methoxy-1-propynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 154°-156°.
Reaction SMILES: C([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:14]=[N:13][C:12]2=[O:23])[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:26]CCCl.ClC(OC(Cl)C)=O>CO>[ClH:26].[F:22][C:19]1[CH:20]=[CH:21][C:16]([N:15]2[C:11]3([CH2:10][CH2:9][NH:8][CH2:25][CH2:24]3)[C:12](=[O:23])[N:13]=[CH:14]2)=[CH:17][CH:18]=1
Reactant: ClCCCl
Reactant: O=C1N=CN(c2ccc(F)cc2)C12CCN(Cc1ccccc1)CC2
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Product: Cl
Product: O=C1N=CN(c2ccc(F)cc2)C12CCNCC2
Temperature: 25 °C

Procedure:
Combine 8-benzyl-1-(4-fluoro-phenyl)-1,3,8-triazaspiro[4.5]dec-2-en-4-one (10 mmol) and 1,2-dichloroethane (70 mL). Cool using an ice bath. Add in dropwise fashion, 1-chloroethyl chloroformate (48.6 mmol). Warm to ambient temperature and maintain for 1 h. Extract using saturated NaHCO3 (120 mL). Extract the aqueous phase using dichloromethane (120 mL). Combine the organic layers, extract with saturated NaCl, dry over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Add anhydrous methanol (70 mL) and heat at reflux for 1 h. Concentrate in in vacuo to obtain a residue and purify to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[C:4]([C:15]([F:18])([F:17])[F:16])=[CH:5][C:6]([N+:12]([O-])=O)=[C:7]([CH2:9][C:10]#N)[CH:8]=1.C(O)C.C(O)(=O)C>[C].[Pd].O>[CH3:1][N:2]([CH3:19])[C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][C:4]=1[C:15]([F:18])([F:17])[F:16])[NH:12][CH:10]=[CH:9]2
Reactant: CN(C)c1cc(CC#N)c([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CN(C)c1cc2cc[nH]c2cc1C(F)(F)F
Temperature: 35 °C
Reaction time: 16 h
Yield: 119.7 %

Procedure:
To a solution of (5-dimethylamino-2-nitro-4-trifluoromethylphenyl)acetonitrile (0.058 g) in a mixed solvent of ethanol (1 mL), acetic acid (0.1 mL) and water (0.1 mL) was added palladium-carbon powder (0.0058 g), and this mixture was stirred at 35° C. for 16 hours. The insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound (0.058 g).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([OH:18])=O)[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]1([NH:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:21][CH2:20]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:23]1([N:22]([CH:19]2[CH2:21][CH2:20]2)[C:16]([CH:12]2[CH2:13][CH2:14][CH2:15][N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])[CH2:11]2)=[O:18])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCC(NC2CC2)CC1
Reactant: O=C(O)C1CCCN(S(=O)(=O)c2ccccc2)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(C1CCCN(S(=O)(=O)c2ccccc2)C1)N(C1CCCCC1)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(phenylsulfonyl)piperidine-3-carboxylic acid (20 mg), N-cyclopropylcyclohexanamine (10 mg) and benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (36 mg) in DMF (200 μL) was added N,N-diisopropylethylamine (26 μL). The resulting solution was stirred at r.t. for 2 hours and directly purified with prep HPLC. LCMS m/z 391.1 (M+H)+; 803.2 (2M+Na)+.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:20]1([CH2:30][NH2:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[C:20]1([CH2:30][NH:31][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: NCc1cccc2ccccc12
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: c1ccc2c(CNc3nccc(-n4cnc5ccccc54)n3)cccc2c1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 1-naphthalenemethylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 352.0 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.60 (s, 1H); 8.44 (br s, 1H); 8.12 (m, 1H); 7.94 (m, 1H); 7.85 (m, 2H); 7.59 (m, 2H); 7.48 (m, 1H); 7.32 (br s, 1H); 6.86 (br s, 1H); 5.20 (d, J=5.5 Hz, 2H).
Reaction SMILES: Cl.C([N:5]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:7]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6]1)(=O)C.FC(F)(F)S(O[CH2:25][C:26]([F:29])([F:28])[F:27])(=O)=O.C(N(CC)CC)C>CC(C)=O>[F:27][C:26]([F:29])([F:28])[CH2:25][N:10]1[CH2:9][CH2:8][C:7]2([C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:5][CH2:6]2)[CH2:12][CH2:11]1
Reactant: CC(=O)N1CC2(CCNCC2)c2ccccc21
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: FC(F)(F)CN1CCC2(CC1)CNc1ccccc12

Procedure:
A mixture of 1-acetyl-1,2-dihydrospiro[indole-3,4′-piperidine] hydrochloride, [Chen et al. Tetrahedron Lett. 1996, 37(30), 5233-5234] (200 mg, 0.750 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.128 mL, 0.900 mmol), and triethylamine (0.522 mL, 3.75 mmol) in acetone (2 mL) was heated at reflux for 15 h. The mixture was allowed to cool, and the solvent removed under reduced pressure. The residue was taken up in CH2Cl2 (10 mL) and washed with saturated aqueous NaHCO3 (10 mL). The aqueous layer was further extracted with CH2Cl2 (2×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 50:50, to provide the title compound. MS: m/z=271 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=O.CCN(C(C)C)C(C)C.Cl.Cl.[NH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][NH:36][S:37]([C:40]([F:43])([F:42])[F:41])(=[O:39])=[O:38])[CH2:30][CH2:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][NH:36][S:37]([C:40]([F:43])([F:42])[F:41])(=[O:39])=[O:38])[CH2:30][CH2:29]1)=[O:7]
Reactant: NCC1CCN(CCNS(=O)(=O)C(F)(F)F)CC1
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCN(CCNS(=O)(=O)C(F)(F)F)CC1)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)benzoic acid (0.1 g, 0.37 mmol) in CH2Cl2 (4 mL) was added DIPEA (0.3 mL, 1.8 mmol), N-(2-(4-(aminomethyl) piperidin-1-yl)ethyl)-1,1,1-trifluoromethanesulfonamide dihydrochloride salt (0.1 g, 0.3 mmol) and HATU (0.17 g, 0.4 mmol). The reaction mixture was stirred at room temperature for 2 h. The organic layer was washed with sat. NaHCO3 aq. (8 mL), dried over Na2SO4, and concentrated to give crude product as gummy solid. Purification of the crude material was done using High Throughput Purification System (HiTOPs).
Reaction SMILES: [H-].[Na+].[C:3]([N:10]1[CH2:15][CH2:14][C:13]([CH2:22][NH:23][S:24]([CH3:27])(=[O:26])=[O:25])([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:28]I>CN(C)C=O.C(OCC)(=O)C>[CH3:28][N:23]([CH2:22][C:13]1([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:12][CH2:11][N:10]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:15][CH2:14]1)[S:24]([CH3:27])(=[O:26])=[O:25]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(CNS(C)(=O)=O)(C2CCCCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CC1(C2CCCCC2)CCN(C(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.28 h
Yield: 72.2 %

Procedure:
A 10-mL, round-bottomed flask was purged with nitrogen and then charged with a 60% sodium hydride dispersion in mineral oil (0.005 g, 0.125 mmol), and the flask was cooled at 0° C. in an ice-water bath. A solution of the sulfonamide from Step B (0.040 g, 0.107 mmol) in 0.8 mL of dimethylformamide was then added dropwise via syringe. The resulting mixture was stirred at 0° C. for 17 min, warmed to room temperature, and stirred for 10 min. The resulting thick mixture was then charged with methyl iodide (0.033 mL, 0.535 mmol), and the clear mixture was then stirred at room temperature for 5 days. The reaction mixture was then diluted with ethyl acetate and washed with two portions of 1 N HCl solution, saturated sodium bicarbonate solution, water, and saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated to give the title compound (0.030 g) as a light yellow oil.
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:8][CH:9]=[C:10]([Br:12])[CH:11]=1.[N:13]1[O:14][CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][C:17]=12.[Cl-].[NH4+]>C1(C)C=CC=CC=1.C1COCC1>[Br:12][C:10]1[CH:11]=[C:7]([C@@:17]23[CH2:18][O:19][CH2:20][CH2:21][C@H:16]2[CH2:15][O:14][NH:13]3)[S:8][CH:9]=1
Reactant: Brc1csc(Br)c1
Reactant: C1CC2CON=C2CO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Brc1csc([C@@]23COCC[C@H]2CON3)c1
Reaction time: 1 h

Procedure:
n-Butyllithium (2.63 M, 2.99 ml) was added dropwise to a solution of 2,4-dibromothiophene (2.00 g) in toluene-THF (10:1) (22 ml) at −78° C. After stirring at the same temperature for one hour, a solution of (±)-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c]isoxazole obtained in Preparation Example 1-(2) (500 mg) in toluene-THF (10:1) (10 ml) and a boron trifluoride-diethyl ether complex (990 μl) were added dropwise at the same time. After stirring at the same temperature for two hours, an ammonium chloride solution was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (700 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])=[N:8]3.C(N(CC)CC)C.CC[O:29][C:30]([C:32]([F:35])([F:34])[F:33])=O>C(#N)C>[CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:30](=[O:29])[C:32]([F:35])([F:34])[F:33])=[N:8]3
Reactant: CCOC(=O)C(F)(F)F
Reactant: Cc1nc2cccc3nc(SCCCCCN)c1n23
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc2cccc3nc(SCCCCCNC(=O)C(F)(F)F)c1n23
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 275 mg (1.00 mmol) of 3-methyl-2-[5-(amino)pentan-1-ylthio]-1,4,7b-triazacyclopent[cd]indene in 30 ml of acetonitrile were added 0.19 ml (1.36 mmol) of triethylamine and 171 mg (1.20 mmol) of ethyl ester of trifluoroacetic acid. The mixture was stirred for 15 hours at room temperature. The solvent was distilled off. To the residue was added ethyl acetate, which was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to afford 267 mg (72.0%, a pale yellow solid) of the desired compound.