Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34](O)=[O:35])[CH2:29][CH2:28]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:34](=[O:35])[CH2:33][N:30]5[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: CN1CCN(CC(=O)O)CC1
Agent: Cl
Product: CN1CCN(CC(=O)N[C@H]2CC[C@H](CCN3CCC(c4cccc5c4OCO5)CC3)CC2)CC1

Procedure:
The title compound, white solid (13.5 mg, 35.1%), MS (ISP) m/z=471.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0818 mmol) and 2-(4-methylpiperazin-1-yl)acetic acid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:27]=[CH:26][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1.[Si]([O:35][CH2:36][CH:37]=O)(C(C)(C)C)(C)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[OH-].[Na+]>C(Cl)Cl>[CH:23]([N:18]1[C:17]([C:11]2[S:12][C:13]3[CH2:14][CH2:15][O:16][C:7]4[CH:6]=[C:5]([CH:3]5[CH2:4][N:1]([CH2:37][CH2:36][OH:35])[CH2:2]5)[CH:27]=[CH:26][C:8]=4[C:9]=3[N:10]=2)=[N:21][C:20]([CH3:22])=[N:19]1)([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CNC4)ccc2-3)n(C(C)C)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CN(CCO)C4)ccc2-3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.8 %

Procedure:
To a solution of 8-azetidin-3-yl-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.300 g, 0.000786 mol) in methylene chloride (4.33 mL) was added 2-(tert-butyldimethylsilyloxy)acetaldehyde (0.449 mL, 0.00236 mol) and acetic acid (2.68 mL, 0.0472 mol) followed by sodium triacetoxyborohydride (1.000 g, 0.004718 mol). The reaction was stirred at room temperature for 3 hours. The reaction was quenched with 1N NaOH. Methylene chloride was added and the mixture was extracted 3 times with methylene chloride. The organic phases were combined, dried with MgSO4 and concentrated. The crude material was redissolved in methanol (6.69 mL). Hydrogen chloride (0.000786 mol, 4N in dioxanes, 0.2 mL) was added dropwise and the reaction was stirred at room temperature for 2 hours. 1N NaOH was added until the solution was basic. The mixture was extracted 3 times with methylene chloride. The organic phases were combined, dried with MgSO4 and concentrated. The crude was purified by reverse-phase HPLC to give 519 as a white solid (89.6 mg). m+1 426.2 MS (ESI+) 426.2. 1H NMR (400 MHz, DMSO) δ 8.28 (d, J=8.2 Hz, 1H), 7.19 (dd, J=8.2, 1.5 Hz, 1H), 7.03 (d, J=1.4 Hz, 1H), 5.85-5.66 (m, 1H), 4.39-4.32 (m, 3H), 3.67-3.53 (m, 3H), 3.41 (t, J=5.1 Hz, 2H), 3.39-3.34 (m, 2H), 3.15-3.08 (m, 2H), 2.54-2.50 (m, 2H), 2.32 (s, 3H), 1.52 (d, J=6.6 Hz, 6H)
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:8]=[C:7]([CH2:9][O:10][CH3:11])[N:6]([CH2:12][CH2:13][N:14]([CH2:21][CH2:22][N:23]2[C:27]([CH2:28][O:29][CH3:30])=[CH:26][C:25]([CH2:31][O:32][CH3:33])=[N:24]2)[CH2:15][C:16](OCC)=[O:17])[N:5]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][O:2][CH2:3][C:4]1[CH:8]=[C:7]([CH2:9][O:10][CH3:11])[N:6]([CH2:12][CH2:13][N:14]([CH2:21][CH2:22][N:23]2[C:27]([CH2:28][O:29][CH3:30])=[CH:26][C:25]([CH2:31][O:32][CH3:33])=[N:24]2)[CH2:15][CH2:16][OH:17])[N:5]=1
Reactant: CCOC(=O)CN(CCn1nc(COC)cc1COC)CCn1nc(COC)cc1COC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCc1cc(COC)n(CCN(CCO)CCn2nc(COC)cc2COC)n1
Yield: 60 %

Procedure:
This compound has been obtained by reacting a solution of ethyl 2-(bis(2-(3,5-bis(methoxymethyl)-1H-pyrazol-1-yl)ethyl)amino)acetate (280 mg; 0.6 mmol) in dry THF (10 mL) with LiAlH4. The title compound was isolated following the same methodology above described for the synthesis of other (hydroxymethyl)pyrazoles (see example 6). Yield: 60% (170 mg, 0.4 mmol).
Reaction SMILES: Cl.[CH:2]1([NH:7][C:8]([NH2:10])=[NH:9])[CH2:6][CH2:5][CH2:4][CH2:3]1.[O-]CC.[Na+].[Cl:15][C:16]1[N:21]2[N:22]=[C:23]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=3)[C:24]([C:25](=O)/[C:26](/[CH3:29])=[CH:27]/[CH3:28])=[C:20]2[CH:19]=[CH:18][CH:17]=1.ClC1N2N=C(C3C=CC=C(C)C=3)C(C(=O)/C(/C)=C\C)=C2C=CC=1>C(O)C.[Pd]>[Cl:15][C:16]1[N:21]2[N:22]=[C:23]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=3)[C:24]([C:25]3[C:26]([CH3:29])=[C:27]([CH3:28])[N:10]=[C:8]([NH:7][CH:2]4[CH2:6][CH2:5][CH2:4][CH2:3]4)[N:9]=3)=[C:20]2[CH:19]=[CH:18][CH:17]=1
Reactant: C/C=C(\C)C(=O)c1c(-c2cccc(C)c2)nn2c(Cl)cccc12
Reactant: N=C(N)NC1CCCC1
Agent: [Pd]
Agent: C/C=C(/C)C(=O)c1c(-c2cccc(C)c2)nn2c(Cl)cccc12
Agent: CC[O-]
Solvent: CCO
Product: Cc1cccc(-c2nn3c(Cl)cccc3c2-c2nc(NC3CCCC3)nc(C)c2C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
To a suspension of N-cyclopentylguanidine hydrochloride (261 mg, 1.60 mmol) in ethanol (2 mL) was added sodium ethoxide (530 μL, 3 M in ethanol, 1.6 mmol). The mixture was stirred at room temperature for 10 minutes. To this suspension was added a mixture of (2E)-1-[7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-methyl-2-buten-1-one and (2Z)-1-[7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-methyl-2-buten-1-one (200 mg, 0.616 mmol) portionwise. The reaction mixture was stirred at 70° C. for 16 hours then cooled to room temperature. Palladium on carbon (10%, 230 mg) was added and the reaction mixture was stirred at 60° C. for 24 hours. The reaction mixture was diluted with ethanol (15 mL) and filtered through Celite. The filtrate was concentrated in vacuo and chromatographed (39:1 dichloromethane:methanol) to provide 4-[7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-5,6-dimethyl-2-pyrimidinamine (80 mg, 30%) as a light brown solid. Rf 0.47 (29:1 dichloromethane:methanol); 1H NMR (CDCl3) δ 7.60 (s, 1H), 7.55 (d, 1H), 7.32 (d, 1H), 7.21–7.11 (m, 3H), 6.96 (d, 1H), 4.99 (broad, 1H), 4.28 (m, 1H); 2.35 (s, 3H), 2.30 (s, 3H), 2.01 (m, 2H), 1.74–1.42 (9 H); MS m/z 432 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(Cl)(Cl)Cl.O>[OH:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:9][CH2:10]1
Reactant: CCOC(=O)Cl
Reactant: OCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)N1CCC(CO)CC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
168.3 g (1.22 mol) of potassium carbonate are added to a solution of 61.6 g (406 mmol) of 4-piperidinemethanol hydrochloride in a mixture of 406 ml of chloroform and 406 ml of water, followed by 42.55 ml (440 mmol) of ethyl chloroformate dissolved in 160 ml of chloroform. The mixture is stirred for 3 h at 20° C., the organic phase is separated off, the aqueous phase is extracted with dichloromethane, the organic phases are combined to form a single phase, washed with water and dried over magnesium sulphate, and the solvents are evaporated off under reduced pressure. 76 g of an oil is obtained, this being used without further treatment in the following stage.
Reaction SMILES: [CH3:1][N:2]([CH3:35])[CH2:3][CH2:4][N:5]([C@H:28]1[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]1)[C:6]([CH:8]=[CH:9][CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]CC2C=CC=CC=2)=[C:14]([O:26][CH3:27])[CH:13]=1)=[O:7].[H][H]>CO.[C].[Pd]>[CH3:35][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([C@H:28]1[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]1)[C:6](=[O:7])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:26][CH3:27])[CH:13]=1
Reactant: [H][H]
Reactant: COc1cc(C=CC=CC(=O)N(CCN(C)C)[C@H]2CC[C@H](C)CC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCCCC(=O)N(CCN(C)C)[C@H]2CC[C@H](C)CC2)ccc1O
Reaction time: 18 h

Procedure:
3.81 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-4-(4-benzyloxy-3-methoxyphenyl)-1,3-butadiene-1-carboxamide (Example 113) was dissolved in 100 ml of methanol. 0.2 g of 10% palladium-carbon was added to the solution. The solution was vigorously stirred at room temperature under normal-pressure hydrogen gas. After 18 hours, the reaction was ceased, and the catalyst was filtered out. The solvent was removed in vacuo from the filtrate, yielding 2.1 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-5-(4-hydroxy-3-methoxyphenyl)valeramide (a compound of the present invention) as a pale yellow oil, which had the following physiochemical properties:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)(=O)C>[O:12]([CH2:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][CH2:2][NH:26][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCCCOCCOCCCOc1ccccc1
Reactant: NCc1ccccc1
Solvent: CCOC(C)=O
Product: c1ccc(CNCCCOCCOCCCOc2ccccc2)cc1
Reaction time: 2 h
Yield: 69.8 %

Procedure:
[3-[2-(3-Bromopropoxy)ethoxy]propoxy]benzene (1.6 g) was added dropwise with stirring to benzylamine (2.70 g) at 130° under nitrogen. The solution was stirred at 130° under nitrogen for 2 h, cooled and diluted with ethyl acetate (150 ml), and washed with 2N hydrochloric acid (100 ml). The aqueous phase was re-extracted with ethyl acetate (2×100 ml) and the combined organic phases washed with 8% sodium bicarbonate solution (150 ml), dried and evaporated in vacuo to give the title compound (1.21 g) as an oil. T.l.c. (System E 40:10:1) Rf 0.52
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:23])[C:20]=1[O:21]C)[C:5]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:17])(=[O:16])[CH2:8]1)=[O:6].[Cl-].[Li+].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:23])[C:20]=1[OH:21])[C:5]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:16])(=[O:17])[CH2:8]1)=[O:6]
Reactant: COc1c(Cl)cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(c1cc(Cl)c(O)c(Cl)c1)N1CS(=O)(=O)c2ccccc21
Temperature: 130 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
3-(3,5-dichloro-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (1.00 g) was dissolved in N,N-dimethylformamide (5 mL), and lithium chloride (570 mg) was added, and then the mixture was stirred at 130° C. for 2 hours. To the reaction solution, 1N hydrochloric acid was added, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was crystallized from ethanol to obtain the title compound (749 mg) as a colorless crystal.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:12](=[O:21])[N:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=[C:5]3[C:4]=2[N:3]=1.C(OC(C1C=NC2C(C=1[Cl:37])=NC(F)=CC=2)=O)C>>[Cl:37][C:4]1[C:9]2[NH:8][CH:7]=[C:6]3[C:12](=[O:21])[N:13]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:14]=[C:5]3[C:10]=2[CH:11]=[CH:2][N:3]=1
Reactant: O=c1c2c[nH]c3ccc(F)nc3c-2nn1-c1ccccc1
Reactant: CCOC(=O)c1cnc2ccc(F)nc2c1Cl
Product: O=c1c2c[nH]c3c(Cl)nccc3c-2nn1-c1ccccc1

Procedure:
The title compound was prepared following the procedure described in Step 3 for synthesis for 5a using 15 instead of 4a. 1H-NMR (DMSO-d6) δ (ppm): 7.16 (1H, m), 7.44 (2H, dd, J=8.6, 7.6 Hz), 8.09 (1H, d, J=5.3 Hz), 8.14 (2H, dd, J=8.5, 1.1 Hz), 8.37 (1H, d, J=5.2 Hz), 8.51 (1H, s). m/z 297.7 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C([BH3-])#N.[Na+]>C(O)(C)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(=O)Nc1cccc(N)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)O
Product: CC(=O)Nc1cccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 120 °C
Yield: 49 %

Procedure:
A mixture of N-(3-amino-phenyl)-acetamide (0.19 g, 1.25 mmol, 1.0 equiv; commercially available) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.3 g, 1.50 mmol, 1.2 equiv; commercially available) in isopropanol (2 mL) was heated by microwave irradiation to 120° C. for 20 min. Sodium cyanoborohydride (0.16 g, 2.50 mmol, 2.0 equiv), dissolved in isopropanol (2 mL), was added and the reaction mixture heated by microwave irradiation to 120° C. for an additional time period of 20 min. The crude reaction material was purified by silica column chromatography eluting with heptane/ethyl acetate (1:2) providing 0.21 g (49%) of the title compound. MS (ISP): 334.3 [M+H]+.
Reaction SMILES: [N+:1]([O-])([O-])=O.[Na+].[NH:6]([C:8]1[C:17]2[N:18]=[CH:19][N:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1)[NH2:7]>O.C(O)(=O)C>[CH3:23][CH:22]([CH3:24])[CH2:21][N:20]1[C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]3[N:1]=[N:7][N:6]=[C:8]3[C:17]=2[N:18]=[CH:19]1
Reactant: CC(C)Cn1cnc2c(NN)nc3ccccc3c21
Reactant: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Cn1cnc2c1c1ccccc1n1nnnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 375.5 %

Procedure:
A solution of sodium nitrate (2.0 g, 3 mmole) in water (5 mL) was added to a solution of 4-hydrazino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (4.0 g, 15.7 mmole, Example 7) in a mixture of acetic acid (5 mL) and water (50 mL). The reaction mixture was stirred at ambient temperature for 15 minutes. A precipitate was isolated by filtration, washed with water then air dried to provide 4.1 g of crude product. This material was recrystallized from dichloromethane/ethanol to provide 3.0 g of 6-(2-methylpropyl)-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline as a cream colored crystalline solid, m.p. 208-212° C. Analysis: Calculated for C14H14N6: %C, 63.14; %H, 5.30; %N, 31.56; Found: %C, 62.60; %H, 5.2; %N, 31.5.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[O:11][C:12]3[C:13](=[C:15]([C:19]([OH:21])=O)[CH:16]=[CH:17][CH:18]=3)[N:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1C=CC2N(O)N=[N:28]C=2C=1.[NH4+].[Cl-].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.O>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[O:11][C:12]3[C:13](=[C:15]([C:19]([NH2:28])=[O:21])[CH:16]=[CH:17][CH:18]=3)[N:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cccc2oc(-c3cccc([N+](=O)[O-])c3)nc12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cccc2oc(-c3cccc([N+](=O)[O-])c3)nc12
Temperature: 30 °C
Reaction time: 17 h
Yield: 49.4 %

Procedure:
To a solution of 2-(3-nitrophenyl)benzo[d]oxazole-4-carboxylic acid (1.42 g, 5 mmol) in DMF (70 mL) was added HOBt (0.75 g, 5.5 mmol), NH4Cl (0.27 g, 5.0 mmol), DIPEA (1.94 g, 15.0 mmol) and EDCI (1.15 g, 6.0 mmol). The mixture was stirred at 30° C. for 17 hr. To the resulting mixture, water (10 mL) was added and 1N aqueous hydrochloric acid to pH=3, then filtered, the filtrate was washed with saturated sodium bicarbonate solution (100 mL×2), brine (100 mL×2) and dried in vacuum to get a crude product. The crude product was re-crystallized in THF to obtain 2-(3-nitrophenyl)benzo[d]oxazole-4-carboxamide as a yellow solid (700 mg, yield 49%); LC-MS (ESI) m/z 284 [M+1]−.
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]3[CH2:23][N:22]([C:24]([O:26]C(C)(C)C)=O)[C@H:21]([CH2:31][O:32][C:33](=[O:43])[NH:34][C:35]4[CH:40]=[CH:39][C:38]([CH2:41][CH3:42])=[CH:37][CH:36]=4)[CH2:20]3)=O)C3C(=CC=CC=3)C=2C=CC=1.Cl.CCN(C(C)C)C(C)C.[Cl:54][C:55]1[CH:64]=[CH:63][CH:62]=[CH:61][C:56]=1[CH2:57][N:58]=C=O>CO>[CH2:41]([C:38]1[CH:37]=[CH:36][C:35]([NH:34][C:33](=[O:43])[O:32][CH2:31][C@@H:21]2[CH2:20][C@@H:19]([NH2:18])[CH2:23][N:22]2[C:24](=[O:26])[NH:58][CH2:57][C:56]2[CH:61]=[CH:62][CH:63]=[CH:64][C:55]=2[Cl:54])=[CH:40][CH:39]=1)[CH3:42]
Reactant: O=C=NCc1ccccc1Cl
Reactant: CCc1ccc(NC(=O)OC[C@@H]2C[C@@H](NC(=O)OCC3c4ccccc4-c4ccccc43)CN2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(NC(=O)OC[C@@H]2C[C@@H](N)CN2C(=O)NCc2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of crude (2S,4R)-tert-butyl 4-(((9H-fluoren-9-yl)methoxy)carbonylamino)-2-((4-ethylphenylcarbamoyloxy)methyl)pyrrolidine-1-carboxylate in MeOH was added HCl (4 N in dioxane). The reaction was stirred at rt for 1 h and concentrated. The residue was dissolved in THF (10 mL). To this solution were added DIEA (469 μL, 2.7 mmol) and 2-chlorobenzylisocyanate. The mixture was stirred at rt for 1 h and concentrated. The residue was dissolved in 10 ml of 20% piperidine in DCM. The reaction mixture was stirred at rt for 15 min, concentrated and purified on RP-HPLC using a mixture of acetonitrile and H2O to give ((2S,4R)-4-amino-1-(2-chlorobenzylcarbamoyl)pyrrolidin-2-yl)methyl 4-ethylphenylcarbamate (210 mg, 53% for 4 steps). LRMS (M+H+) m/z 431.1.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[CH:12]=[C:11]([CH3:18])[N:10]=2)=CC=1.S(=O)(=O)(O)O.O.N>FC(F)(F)C(O)=O>[NH2:8][C:9]1[C:14]2[CH:15]=[CH:16][S:17][C:13]=2[CH:12]=[C:11]([CH3:18])[N:10]=1
Reactant: COc1ccc(CNc2nc(C)cc3sccc23)cc1
Agent: N
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc2sccc2c(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 108.2 %

Procedure:
To a solution of 24 g of 4-(4-methoxybenzyl)amino-6-methylthieno[3,2-c]pyridine in 80 ml of trifluoroacetic acid was added 15 ml of concentrated sulfuric acid, and the mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was poured into ice water, rendered alkaline by the addition of 28% ammonia water and extracted with chloroform. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel and recrystallized from chloroform/petroleum ether to give 15 g of the title compound as a white powder.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[C:6]([CH2:14]Br)=[N:5]1)(=[O:3])[CH3:2].[CH2:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][NH:17]1.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[C:6]([CH2:14][N:17]2[CH2:18][CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16]2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1nc(CBr)c2ccc(F)cc21
Reactant: c1ccc2c(c1)CCNC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)n1nc(CN2CCc3ccccc3C2)c2ccc(F)cc21
Temperature: 20 °C
Reaction time: 16 h
Yield: 74.9 %

Procedure:
1-Acetyl-3-bromomethyl-6-fluoro-1H-indazole (0.53 g, 1.96 mmol) in CH2Cl2 (10 mL) was treated with 1,2,3,4-tetrahydroisoquinoline (0.261 g, 1.96 mmol) and Hunig's base (0.44 mL, 2.5 mmol) and the mixture stirred at 20° C. for 16 h. The mixture was poured into saturated aqueous sodium bicarbonate solution (25 mL) and extracted with CH2Cl2 (3×25 mL). The combined organic extracts were dried (MgSO4), concentrated and the residue purified by flash chromatography (7%→12% EtOAc in hexane) to give the title compound as a white solid (475 mg, 53%); mp 106°-107° C. (from Et2O/hexane); 1H NMR (360 MHz, d6 -DMSO) δ 8.08 (dd, J=8.8, 5.4 Hz, 1H, indazole), 8.00 (dd, J=9.6, 2.2 Hz, 1H, indazole), 7.29 (dt, J=9.1, 2.5 Hz, 1H, indazole), 7.10 (m, 3H, tetrahydroisoquinoline), 7.02 (m, 1H, tetrahydroisoquinoline), 4.05 (s, 2H, Ar--CH2N), 3.68 (s, 2H, Ar--CH2N)), 2.79 (m, 4H, tetrahydroisoquinoline)2.72 (s, 3H, Ac); MS (CI+) m/e 324 (M+H+); Anal. calcd for C19H18FN3O: C, 70.57; H, 5.61; N, 12.99. Found: C, 70.28; H, 5.32; N, 12.84.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([C:38]#[N:39])[C:21]=1[C:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:23]=1[F:37]>>[F:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([C:38]#[N:39])[C:21]=1[C:22]1[CH:27]=[C:26]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)[CH:25]=[CH:24][C:23]=1[F:37]
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3c(F)cccc3C#N)c2)OC1(C)C
Product: N#Cc1cccc(F)c1-c1cc(-c2cnc3nc(C(F)(F)F)ccn23)ccc1F

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 6,2′-difluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 6,2′-difluoro-5′-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile as an off-white solid: δH (400 MHz, CDCl3) 7.29 (1H, d, J 7), 7.44-7.71 (6H, m), 8.11 (1H, s), 9.00 (1H, d, J 7); m/z (ES+) 401 (M++H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH2:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][S:37](Cl)(=[O:39])=[O:38]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH:28][S:37]([CH2:36][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[Cl:29])(=[O:38])=[O:39])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN)cc3)cc2)CC1
Reactant: O=S(=O)(Cl)Cc1ccccc1Cl
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNS(=O)(=O)Cc4ccccc4Cl)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-[4′-(4-aminomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and (2-chloro-phenyl)-methanesulfonyl chloride.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:9][CH:8]=1)=[O:6].NOS(O)(=O)=O.C([O-])(O)=O.[Na+]>CO>[N:13]1([C:10]2[CH:11]=[CH:12][C:7]([C:5]3[O:6][N:2]=[CH:3][CH:4]=3)=[CH:8][CH:9]=2)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: CN(C)C=CC(=O)c1ccc(-n2ccnc2)cc1
Agent: NOS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: c1cn(-c2ccc(-c3ccno3)cc2)cn1
Reaction time: 3 h

Procedure:
5-(4-imidazol-1-ylphenyl)isoxazole was prepared by treating a solution of 3-dimethylamino-1-[(4-imidazol-1-yl)phenyl]propen-1-one (1.64 g, 6.8 mmol) in MeOH with hydroxylamine-O-sulphonic acid (831 mg, 7.35 mmol) at ambient temperature for 16 h. A further quantity of hydroxylamine-O-sulphonic acid (831 mg, 7.35 mmol) was added and stirring continued for 3 h. The reaction was then treated with saturated NaHCO3 solution, the resulting solution being collected by filtration and washed with water and diethyl ether to give the desired material (1.08 g) as a pink solid, m.p. 168°._δH (d6 DMSO) 8.67 (1H, d, J 1.8 Hz), 3.89 (1H, s), 8.03-7.99 (2H, m), 7.86-7.84 (3H, m), 7.14 (1H, s) and 7.10 (1H, d, J 1.9 Hz).