Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24](O)=[O:25])=[O:21])[CH3:19])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:41]([O:48][C:49](=[O:55])[C@H:50]1[CH2:54][CH2:53][CH2:52][NH:51]1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:41]([O:48][C:49](=[O:55])[C@H:50]1[CH2:54][CH2:53][CH2:52][N:51]1[C:24](=[O:25])[C@@H:23]1[CH2:27][CH2:28][CH2:29][N:22]1[C:20](=[O:21])[C@H:18]([CH3:19])[NH:17][P:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9])[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Reactant: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 3 h

Procedure:
Dibenzylphosphoryl-L-alanyl-L-proline (1.4 g, 3.2 m mole), HOBt (476 mg, 3.5 m mole) and oily D-proline benzylester hydrochloride (968 mg, 4 m mole) were dissolved in DMF (5 ml) and WSC (0.64 ml, 3.5 m mole) were added thereto while cooling to -15° C. The reaction was carried out for 3 hours under cooling and then overnight at room temperature, and ethyl acetate (100 ml) was added to the reaction solution. The mixture was washed with 1N hydrochloric acid, 5% sodium bicarbonate and water in order, and then dried with anhydrous sodium sulfate. The solution was distilled under reduced pressure leaving an oily dibenzylphosphoryl-L-alanyl-L-prolyl-D-proline benzylester material.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[NH:17][CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:25]1[N:30]=[C:29]([CH3:31])[C:28]([N+:32]([O-:34])=[O:33])=[CH:27][CH:26]=1>>[CH3:31][C:29]1[N:30]=[C:25]([N:20]2[CH2:21][CH2:22][CH2:23][C@H:18]([NH:17][C@@H:12]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]3[NH:10][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:9])[CH2:19]2)[CH:26]=[CH:27][C:28]=1[N+:32]([O-:34])=[O:33]
Reactant: Cc1nc(F)ccc1[N+](=O)[O-]
Reactant: O=C(Nc1ccccc1)N[C@@H]1CCCC[C@H]1NC1CCCNC1
Product: Cc1nc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3NC(=O)Nc3ccccc3)C2)ccc1[N+](=O)[O-]

Procedure:
1-((1R,2R)-2-((S)-1-(6-Methyl-5-nitropyridin-2-yl)piperidin-3-ylamino)cyclohexyl)-3-phenylurea was synthesized using 1-phenyl-3-((1R,2R)-2-(piperidin-3-ylamino)cyclohexyl)urea (from intermediate C, Example 1) (100 mg, 0.32 mmol) and 6-fluoro-2-methyl-3-nitropyridine (54.3 mg, 0.35 mmol) according to General Procedure A to give 20 mg (14%) of yellow solid. Anal. Calcd. for C24H32N6O3 m/z 452.2, found: 453.2 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 7.82 (d, J=9.4 Hz, 1H), 7.17 (m, 4H), 6.98 (m, 1H), 6.59 (d, J=9.4 Hz, 1H), 6.02 (d, J=4.6 Hz, 1H), 4.74 (m, 1H), 4.16 (m, 1H), 3.68 (m, 1H), 3.54 (m, 2H), 3.26 (m, 2H), 2.57 (s, 3H), 2.39 (m, 1H), 2.12 (m, 3H), 1.92 (m, 4H), 1.47 (m, 4H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]([C:11]1[N:12]=[C:13]([CH2:27][CH2:28][CH3:29])[NH:14][C:15]=1[C:16]([O:18][CH2:19][C:20]1[O:21][C:22](=[O:26])[O:23][C:24]=1[CH3:25])=[O:17])([CH3:10])[CH3:9].[C:30]([N:49]1[C:53]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[C:60]2[CH:67]=[CH:66][C:63]([CH2:64]Br)=[CH:62][CH:61]=2)=[N:52][N:51]=[N:50]1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C(=O)C.C(OCC)(=O)C>[OH:7][C:8]([C:11]1[N:12]=[C:13]([CH2:27][CH2:28][CH3:29])[N:14]([CH2:64][C:63]2[CH:62]=[CH:61][C:60]([C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=3[C:53]3[N:49]([C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:50]=[N:51][N:52]=3)=[CH:67][CH:66]=2)[C:15]=1[C:16]([O:18][CH2:19][C:20]1[O:21][C:22](=[O:26])[O:23][C:24]=1[CH3:25])=[O:17])([CH3:9])[CH3:10]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 60 °C
Yield: 49.7 %

Procedure:
A suspension of 0.97 g of potassium carbonate in 100 ml of N,N-dimethylacetamide was warmed at 60° C., and then a solution of 1.14 g of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (prepared as described in Preparation 31) and 2.35 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide in 50 ml of N,N-dimethylacetamide was added dropwise to the warm suspension, whilst stirring. The reaction mixture was stirred at 60° C. for 3.5 hours, and it was then diluted with ethyl acetate. The ethyl acetate layer was separated, washed with water and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.4 g of the title compound as an amorphous solid. This product was crystallized from diisopropyl ether, to give pure title compound, melting at 98°-99° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([CH2:10]Br)[C:6]=2[CH:12]=1.CN(C)C([N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1)=O.N>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([CH2:10][N:19]3[C:20]([CH3:22])=[CH:21][N:17]=[CH:18]3)[C:6]=2[CH:12]=1
Reactant: Cc1cn(C(=O)N(C)C)cn1
Reactant: Clc1ccc2onc(CBr)c2c1
Agent: N
Solvent: CC#N
Product: Cc1cncn1Cc1noc2ccc(Cl)cc12
Reaction time: 1 h

Procedure:
A solution containing 5-chloro-3-bromomethyl-1,2-benzisoxazole (2.5 g, 0.010 mole) and 1-dimethylcarbamoyl-4-methyl-imidazole (1.84 g, 0.012 mole) in anhydrous acetonitrile (25 mL) is stirred at reflux for 72 hours. The solution is cooled to 5° C. (ice-bath) and ammonia gas is bubbled through the solution for 5 minutes after which the solution is allowed to stand at ambient temperature for 1 hour. The solvent is evaporated and the residue is taken up in methylene chloride (25 mL). This solution is washed with water (2×20 mL), dried over anhydrous sodium sulphate, filtered and evaporated to give 5-chloro-3-[(5-methyl-1H-imidazol-1-yl)-methyl]-1,2-benzisoxazole as an oil. A solution of this product in acetone is treated with a slight excess of ethereal hydrogen chloride to afford the hydrochloride salt, m.p. 245°-247° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li][C:11](C)([CH3:13])[CH3:12].IC(C)C>C1COCC1>[CH:11]([C:5]1[S:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=1)([CH3:13])[CH3:12]
Reactant: c1ccc2sccc2c1
Reactant: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CC(C)I
Product: CC(C)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
2-i-Propylbenzo[b]thiophene was prepared by the method of Example 40A with benzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 M, 11.2 mmoles, 6.6 ml), 2-iodopropane (11.2 mmoles, 1.12 ml) and THF (20 ml) with stirring at ambient temperature for 24 hrs. It was isolated as a yellow oil (1.11 g; 85% yield).
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([CH3:18])[CH:10]=3)=[N:7][N:6]=[N:5]2)[CH2:3][CH2:2]1.[H][H]>C(O)C.[C].[Pd]>[CH:1]1([N:4]2[C:8]([C:9]3[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([CH3:18])[CH:10]=3)=[N:7][N:6]=[N:5]2)[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: Cc1cc(-c2nnnn2C2CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(-c2nnnn2C2CC2)ccc1N
Yield: 71.5 %

Procedure:
0.4 g of 5% palladium carbon was added to a solution of 1.6 g (6.5 mmol) of 4-(1-cyclopropyltetrazol-5-yl)-2-methylnitrobenzene in 70 ml of ethanol and the mixture was stirred under 3 atm hydrogen atmosphere overnight. The reaction mixture was filtered and concentrated under reduced pressure and the residual substance was purified with silica gel column chromatography to obtain 1.0 g of the desired compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[Cl:21][C:22]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25]>>[Cl:21][C:22]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:23]=1[C:24]([NH:2][CH2:3][C:4](=[O:5])[NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:25]
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Agent: Cl
Product: O=C(CNC(=O)c1ccc(Cl)cc1Cl)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 2,4-dichlorobenzoic acid.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[F:21][C:22]([F:37])([F:36])[C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:20][C:4]1[N:3]=[C:2]([C:25]2[CH:26]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:28]=[C:23]([C:22]([F:21])([F:37])[F:36])[CH:24]=2)[N:19]=[C:18]2[C:5]=1[N:6]=[CH:7][N:8]2[C@H:9]1[C@H:10]([OH:11])[C@H:12]([OH:13])[C@@H:14]([CH2:15][OH:16])[O:17]1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Nc1nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 30 %

Procedure:
A solution of 2-iodo adenosine (1.00 g, 2.53 mmol), 3,5-bis(trifluoromethyl)phenylboronic acid (784 mg, 3.04 mmol), cesium carbonate (1.81 g, 6.08 mmol) and Pd(PPh3)4 (293 mg, 0.25 mmol) in toluene (2.4 mL) and ethanol (4.8 mL) was heated in a Biotage microwave (120° C., absorption high, pre-stirring 30 s) for 40 min in 2 batches and the crude reaction mixtures were combined. The solvents were then removed in vacuo and the residue dissolved in EtOAc (200 mL) and washed with sat. aq. NaHCO3 (100 mL) and brine (100 mL). Purification by flash column chromatography (normal phase, ICN silica, 50 g, 18-32μ, gradient 5-25% ethanol in DCM, residue dry loaded, product eluted in 25% ethanol) afforded (2R,3R,4S,5R)-2-{6-amino-2-[3,5-bis(trifluoromethyl)phenyl]-9H-purin-9-yl}-5-(hydroxymethyl)tetrahydrofuran-3,4-diol 11 as an off-white glass (364 mg, 30%).
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:30])[O:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([NH:17][C:18]2[N:23]=[C:22]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[N:21]=[C:20](Cl)[N:19]=2)[CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:31]([NH:35][CH2:36][CH2:37][CH2:38][CH2:39][OH:40])[CH2:32][CH2:33][CH3:34].O1CCCC1>O>[C:1]1([C:7]2[C:8](=[O:30])[O:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([NH:17][C:18]2[N:23]=[C:22]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[N:21]=[C:20]([N:35]([CH2:36][CH2:37][CH2:38][CH2:39][OH:40])[CH2:31][CH2:32][CH2:33][CH3:34])[N:19]=2)[CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)c1nc(Cl)nc(Nc2ccc3cc(-c4ccccc4)c(=O)oc3c2)n1
Reactant: CCCCNCCCCO
Solvent: C1CCOC1
Solvent: O
Product: CCCCN(CCCCO)c1nc(Nc2ccc3cc(-c4ccccc4)c(=O)oc3c2)nc(N(CC)CC)n1

Procedure:
21.1 Parts of 3-phenyl-7-[(6-chloro-4-diethylamino-s-triazine-2-yl)amino]coumarin and 14.2 parts of N-butylamino-4-butanol were added to 20 parts of tetrahydrofuran and reacted for 6 hours under reflux. The reaction product was poured into water, and the crystals thus precipitated were collected by filtration. The product was recrystallized from a mixed solvent of chloroform:ethyl acetate (1:1 by volume) to obtain 20 parts of 3-phenyl-7-[[6-(4-hydroxybutylbutylamino)-4-diethylamino-s-triazine-2-yl]amino]coumarin. The resulting compound had a melting point of from 124° to 126° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[C:14]3=[N:15][C:16]([Sn](C)(C)C)=[CH:17][N:18]=[C:13]3[NH:12][CH2:11][C:10]2=[O:23])[CH2:3][CH2:2]1.C(OC([N:31]1[C:35]2=[N:36][CH:37]=[CH:38][C:39](Br)=[C:34]2[CH:33]=[CH:32]1)=O)(C)(C)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>O1CCOCC1>[NH:31]1[C:35]2=[N:36][CH:37]=[CH:38][C:39]([C:16]3[N:15]=[C:14]4[N:9]([CH2:8][CH2:7][CH:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)[C:10](=[O:23])[CH2:11][NH:12][C:13]4=[N:18][CH:17]=3)=[C:34]2[CH:33]=[CH:32]1
Reactant: C[Sn](C)(C)c1cnc2c(n1)N(CCC1CCOCC1)C(=O)CN2
Reactant: CC(C)(C)OC(=O)n1ccc2c(Br)ccnc21
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C1CNc2ncc(-c3ccnc4[nH]ccc34)nc2N1CCC1CCOCC1
Temperature: 95 °C
Reaction time: 3.5 h
Yield: 35 %

Procedure:
A mixture of 1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (See Example 15.C) (1 equiv), 4-bromo-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (1 equiv), tris(dibezylideneacetone) palladium (0.13 equiv), tri-o-tolylphosphine (0.25 equiv) and triethylamine (2.8 equiv) in anhydrous dioxane was purged, degassed for 2 min and stirred at 95° C. under nitrogen for 3-4 h. Upon completion of the reaction as indicated by TLC, the volatiles were removed under reduced pressure and the residue was purified by column chromatography to give the desired product in 35% yield. MS (ESI) m/z 479.7 [M+1]+. tert-Butyl 4-(7-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate was stirred in methanolic hydrochloride solution at room temperature. Upon completion of the reaction as indicated by TLC, the solvent was removed under reduced pressure and the residue was purified on silica gel to give the title compound in 63% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 11.72 (s, 1H), 8.38 (s, 1H), 8.25 (d, J=4.8 Hz, 1H), 7.79 (s, 1H), 7.53-7.51 (m, 2H), 6.97 (q, J=1.6 Hz, 1H), 4.23 (s, 2H), 4.14 (t, J=7.6 Hz, 2H), 3.81 (dd, J1=2.4 Hz, J2=11.2 Hz, 2H), 3.25 (d, J=10.8 Hz, 2H), 1.67 (d, J=13.2 Hz, 2H), 1.61 (m, 3H), 1.22 (m, 2H); MS(ESI): m/z 379.2 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl.[CH3:38][N:39]1[CH:43]=[C:42]([C:44](Cl)=[O:45])[N:41]=[CH:40]1>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[CH2:14][N:15]([C:44]([C:42]2[N:41]=[CH:40][N:39]([CH3:38])[CH:43]=2)=[O:45])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:25])[F:26])[CH:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2C(CNCc3cccc(OC(F)(F)F)c3)C2C1
Reactant: Cn1cnc(C(=O)Cl)c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cnc(C(=O)N(Cc2cccc(OC(F)(F)F)c2)CC2C3CN(C(=O)OC(C)(C)C)CC32)c1
Reaction time: 24 h

Procedure:
To a stirring solution of 6-[(3-Trifluoromethoxy-benzylamino)-methyl]-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester prepared above (5.9 gm, 15.4 mmol) in 192 mL of CH3CN at room temperature under N2 was added DIEA (8.0 mL, 46.1 mmol) and 1-Methyl-1H-imidazole-4-carbonyl chloride HCL (5.6 gm, 30.7 mmol). After 24 hours, reaction was quenched with H2O, extracted with EtOAc. Organic layer was then washed with a 10% Citric acid solution, H2O, NaHCO3, and brine. The combined extracts were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure, to yield 6.7 gm of 6-{[(1-Methyl-1H-imidazole-4-carbonyl)-(3-trifluoromethoxy-benzyl)-amino]-methyl}-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 400 MHz 1H NMR (CDCl3) δ 7.8 (d, J=1.2 Hz, 1H), 7.3-7.1 (m, 5H), 5.4 (s, 1H), 4.8-4.7 (m, 1H), 4.2 (m, 1H), 3.7 (s, 1H), 3.7 (s, 3H), 3.4-3.2 (m, 3H), 1.4 (s, 9H), 1.3 (m, 2H), 0.8 (m, 1H); MS (M+1) 495.3.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:17]2[C:25]3[C:20](=[C:21]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)([C:15]#[N:16])[CH2:13][CH3:14])=[CH:8][CH:7]=1.[Cl-].[NH4+]>CN(C=O)C>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:17]2[C:25]3[C:20](=[C:21]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)([C:15]2[N:1]=[N:2][NH:3][N:16]=2)[CH2:13][CH3:14])=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCC(C#N)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(c1ccc(Cl)cc1)(c1nn[nH]n1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 130 °C

Procedure:
Sodium azide (117.6m g, 1.809 mmol) was added to a stirred solution of N-(1-(1-(4-chlorophenyl)-1-cyanopropyl)-1H-indol-4-yl)methanesulfonamide (100 mg, 0.258 mmol) and ammonium chloride (110.6 g, 2.067 mmol) in DMF (2 mL) was heated at 130° C. for 3 h in microwave reactor. The reaction was quenched with water, and extracted with ethyl acetate (100 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with PE/EA (5/1 to 1/1, v/v) to afford the title compound as a yellow solid. LC/MS m/z=431.0 [M+H]+.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=[CH:9][C@H:10]([C@H:12]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[OH:13])[OH:11]>ClCCl>[CH2:4]1[CH2:5][CH2:6][C:1]2([O:11][C@@H:10]([C@H:12]3[O:13][C@@H:18]4[O:19][C:1]5([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[O:17][C@H:16]4[C@H:14]3[OH:15])[CH2:9][O:7]2)[CH2:2][CH2:3]1
Reactant: O=C1CCCCC1
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: ClCCl
Product: O[C@@H]1[C@@H]2OC3(CCCCC3)O[C@H]2O[C@@H]1[C@H]1COC2(CCCCC2)O1
Reaction time: 9 h
Yield: 95 %

Procedure:
To a mixed solution of 150 ml of cyclohexanone and 120 ml of dichloromethane were added 10.0 g of D-mannose and 125 mg of anhydrous cupric chloride, and the mixture was stirred for 9 hours under reflux in a warm-water bath at 63° to 65° C. The refluxing solvent was continuously dried with 20 g of molecular sieves 3A which was placed between the reaction vessel and cooling tube. The reaction solution was diluted with benzene, washed with aqueous sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. When the solvent and cyclohexanone were distilled off under reduced pressure, there was obtained 17.9 g (95%) of 2,3:5,6-di-O-cyclohexylidene-α-D-mannofuranose (purity of not less than 95%) as a residue. The compound, when recrystallized from n-hexane, showed a melting point of 122° to 124° C.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([NH2:15])[CH:3]=1.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1/[CH:21]=[CH:22]/[C:23](Cl)=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:49]([OH:54])(=[O:53])[C:50]([OH:52])=[O:51]>C(OCC)(=O)C>[C:49]([OH:54])(=[O:53])[C:50]([OH:52])=[O:51].[CH3:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[C:23](/[CH:22]=[CH:21]/[C:17]3[S:16][CH:20]=[CH:19][CH:18]=3)=[N:15][C:4]=2[CH:3]=1
Reactant: O=C(Cl)/C=C/c1cccs1
Reactant: Cc1ccc(Nc2ccccn2)c(N)c1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)nc(/C=C/c1cccs1)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-methyl-2-amino-N-(2-pyridyl)aniline and (E)-3-(2-thienyl)acryloyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound. MW: 417.42; mp: 181.5-182.0° C.; 1H-NMR (DMSO) δ: 8.78-8.72 (1H, m), 8.16 (1H, t, J=7.7 Hz), 8.00 (1H, d, J=15.8 Hz), 7.69 (1H, d, J=8.1 Hz), 7.62-7.50 (3H, m), 7.39 (1H, br.s), 7.31 (1H, d, J=8.1 Hz), 7.15-7.05 (2H, m), 6.86 (1H, d, J=15.8 Hz), 2.42 (3H, s).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[NH:9][C:8](=[O:10])[C:7]([C:11]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:16]2)=[O:12])=[CH:6][C:5]=1[Cl:25].[H-].[Na+].I[CH3:29].O>CN(C)C=O>[NH2:3][C:4]1[N:9]([CH3:29])[C:8](=[O:10])[C:7]([C:11]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:16]2)=[O:12])=[CH:6][C:5]=1[Cl:25]
Reactant: CI
Reactant: CCCCN1CCC(CNC(=O)c2cc(Cl)c(N)[nH]c2=O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCN1CCC(CNC(=O)c2cc(Cl)c(N)n(C)c2=O)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 5.9 %

Procedure:
To a solution of 6-amino-N-[(1-butyl-4-piperidinyl)methyl]-5-chloro-2-oxo-1,2-dihydro-3-pyridinecarboxamide dihydrochloride (step 2 in example 3, 80 mg, 0.19 mmol) in N,N-dimethylformamide (3 ml), sodium hydride (60% dispersion in mineral oil, 39 mg, 0.97 mmol) was added at 0° C. and the mixture was stirred for 15 min at room temperature. The mixture was cooled to 0° C. and iodomethane (1.0 M in N,N-dimethylformamide, 0.19 ml, 0.19 mmol) was added. After stirring for 18 h at room temperature, the mixture was poured into water, extracted with ethyl acetate (50 ml×2), washed with water (50 ml) and brine (50 ml) and dried over magnesium sulfate. Removal of solvent gave pale yellow oil, which was chromatographed on a column of silica gel eluting with 25% ammonium hydroxide/methanol/dichloromethane (0.2:1:12) to give 4 mg (6%) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[C:21](=[C:22]3[CH2:27][CH2:26][N:25](C)[CH2:24][CH2:23]3)[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH2:14][CH2:13][C:12]=2[CH:29]=1>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[C:21](=[C:22]3[CH2:23][CH2:24][N:25]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:26][CH2:27]3)[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH2:14][CH2:13][C:12]=2[CH:29]=1
Reactant: CCOC(=O)Cl
Reactant: CN1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Temperature: 80 °C

Procedure:
Ethyl chloroformate (40.4 mL; 45.9 g; 0.423 mol) was added slowly to a hot (-80° C) toluene solution (320 mL) of the 8-chloro-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (45.7 g; 0.141 mol) from Example 1E containing the two corresponding fluoro-substituted compounds of the invention. Following complete addition, the temperature was maintained at 80° C. for 1 h. The reaction mixture was cooled to ambient temperature and the toluene solution washed with water which was adjusted to pH 10 with aqueous sodium hydroxide. The organic layer was concentrated to a residue which was dissolved in hot acetonitrile and decolorized with charcoal. The solution was concentrated to a crystalline slurry which was cooled (5° C). 8-chloro-6,11-dihydro-11-(1-ethoxycarbonyl-4-piperidylidene)-5H-benzo[5,6]cyclohepta [1,2-b]pyridine containing the two corresponding fluoro-substituted compounds of the invention as discussed in Examples 1G below was isolated by filtration yielding 42.4 g: m.p. 134.5°-136° C.; NMR (400 MHz, CDCl3)δ1.25 (t,3H,J=8 Hz), 2.3-2.4 (m,3H), 2.4-2.5 (m,1H), 2.7-2.9 (m,2H), 3.1-3.2 (m,2H), 3.3-3.4 (m,2H), 3.81 (br s, 2H), 4.13 (q,2H,J=8 Hz), 7.1-7.3 (m,4H), 7.43 (dd,1H,J=9,2 Hz), 8.40 (d,1H,J=5 Hz); mass spectrum, m/e (relative intensity) 385M+3 (35), 383 M+1 (100). Anal. Calcd. for C22H23N2ClO2 : C,69.00; H,6.05; N,7.32; Cl9.26. Found: C,69.37; H,6.09; N,7.35; Cl 9.37.