Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[C:7][C:8]1[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=1)[O:11][CH2:12][CH2:13][NH:14]C(=O)OC(C)(C)C.[ClH:25].O1CCOCC1>>[ClH:25].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[C:7][C:8]1[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=1)[O:11][CH2:12][CH2:13][NH2:14]
Reactant: CC(C)(C)OC(=O)NCCOc1cccc(C#Cc2cccs2)c1
Agent: Cl
Solvent: C1COCCO1
Product: NCCOc1cccc(C#Cc2cccs2)c1

Procedure:
Deprotection of tert-butyl 2-(3-(thiophen-2-ylethynyl)phenoxy)ethylcarbamate with HCl-dioxane following the method used in Example 13 gave 2-(3-(thiophen-2-ylethynyl)phenoxy)ethanamine hydrochloride as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (br s, 3H), 7.66 (dd, J=5.2, 1.2 Hz, 1H), 7.40 (dd, J=3.6, 1.2 Hz, 1H), 7.14 (dd, J=7.6, 1.2 Hz, 1H), 7.10-7.12 (m, 2H), 7.03 (ddd, J=8.4, 2.4, 1.2 Hz, 1H), 4.19 (t, J=5.2 Hz, 2H), 3.17 (t, J=5.2, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[N:4][N:5]([CH2:7]Cl)[CH:6]=1.[F:13][C:14]([F:23])([F:22])[CH2:15][CH2:16][CH:17]([C:20]#[N:21])[C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[N:4][N:5]([CH2:7][C:17]([CH2:16][CH2:15][C:14]([F:13])([F:22])[F:23])([C:18]#[N:19])[C:20]#[N:21])[CH:6]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: FC(F)(F)c1nn(CCl)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cc(Br)c(C(F)(F)F)n1
Yield: 39.3 %

Procedure:
1.67 g of 4-bromo-1-(chloromethyl)-3-trifluoromethyl-1H-pyrazole and 1.03 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 18 ml of N,N-dimethylformamide. 1.74 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.97 g of [(4-bromo-3-trifluoromethyl-1H-pyrazole-1-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (15), hereinafter) shown by below formula.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:20])[C:14]=1[O:15][CH2:16][CH:17]1[CH2:19][CH2:18]1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:21][C:22]1[N:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25].C([O-])(=O)C.[NH4+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:20][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][CH:29]=[N:30][C:22]=3[CH3:21])[C:14]=1[O:15][CH2:16][CH:17]1[CH2:19][CH2:18]1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: Cc1ncccc1C(=O)O
Reactant: Nc1c(OCC2CC2)c(Cl)cc2c1[nH]c1cnccc12
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: Cc1ncccc1C(=O)Nc1c(OCC2CC2)c(Cl)cc2c1[nH]c1cnccc12
Yield: 40 %

Procedure:
The desired compound was prepared according to Method A from 6-chloro-7-cyclopropylmethoxy-9H-β-carbolin-8-ylamine and 2-methylnicotinic acid in a 40-60% yield. 1H-NMR (300 MHz, MeOH-d4): 60.29 (m, 2H), 0.55 (m, 2H), 1.29 (m, 1H), 2.78 (s, 3H), 3.95 (m, 2H), 7.46 (dd, 1H), 8.08 (m, 1H), 8.30 (m, 3H), 8.59 (m, 1H), 8.81 (s, 1H). Retention Time (LC, method: ammonium acetate standard): 2.18 min. MS (M+H+): 405.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14](N(OC)C)=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([CH:14]=[O:15])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)C1CCN(c2ccc(Cl)cc2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=CC1CCN(c2ccc(Cl)cc2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 105.6 %

Procedure:
A solution of 1-(4-chlorophenyl)-N-methoxy-N-methylpiperidine-4-carboxamide (200 mg, 0.707 mmol) in anhydrous THF (2 mL) was placed under nitrogen, cooled to −78° C., and treated with diisobutylaluminum hydride (1.061 mL of a 1.0 M solution in toluene, 1.061 mmol). The reaction mixture was stirred at −78° C. for 1 h. After this time, the reaction mixture was quenched with 10% Rochelle's salt and warmed to RT before being extracted several times with Et2O. The extract was dried over MgSO4 and concentrated to give the title compound (167 mg, 106% yield) as a yellow oil, which was used in the subsequent step without additional purification. 1H NMR (400 MHz, CDCl3) δ ppm 9.69 (1H, s), 7.16-7.21 (2H, m), 6.81-6.88 (2 H, m), 3.55 (2H, ddd, J=12.63, 3.74, 3.63 Hz), 2.80-2.87 (2H, m), 2.35-2.43 (1H, m), 1.98-2.07 (2H, m), 1.72-1.82 (2H, m).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][NH:17][CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(O[N:25]([CH:34]=C=O)[C@@H:26]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:27](O)=[O:28])(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.Cl>CN(C)C=O.O1CCOCC1>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][N:17]([C:27](=[O:28])[C@@H:26]([NH:25][CH3:34])[CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: CC(C)C[C@@H](C(=O)O)N(C=C=O)OC(C)(C)C
Reactant: c1nc(C2CC2)cnc1O[C@@H]1C[C@H]2CNCCN2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN[C@@H](CC(C)C)C(=O)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the product from Example 54F and (5)-2-(tert-butoxy-carbonyl(methyl)amino)-4-methylpentanoic acid (51.8 mg, 0.211 mmol) in anhydrous N,N-dimethylformamide (2.5 mL) was added 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (110 mg, 0.288 mmol) and 4-methylmorpholine (0.042 mL, 0.384 mmol). The resulting mixture was stirred at room temperature for 90 minutes and then was partitioned between water and ethyl acetate (3×). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in a mixture of 1,4-dioxane (1 mL) and hydrogen chloride (4 N in 1,4-dioxane, 1 mL, 4.00 mmol), and the resulting mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was partitioned between saturated aqueous NaHCO3 solution and dichloromethane (3×). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-10% methanol in dichloromethane. The title compound was obtained as a colorless solid (53 mg, 71%). 1H NMR (300 MHz, CDCl3) δ ppm 0.87-1.03 (m, 10 H), 1.23-1.52 (m, 2 H), 1.76-2.06 (m, 4 H), 2.17-2.49 (m, 6.5 H), 2.74-2.96 (m, 1 H), 2.98-3.10 (m, 1 H), 3.12-3.26 (m, 0.5 H), 3.36-3.52 (m, 1 H), 3.73 (dd, J=9.83, 6.78 Hz, 1 H), 3.88 (d, J=13.22 Hz, 0.5 H), 4.00 (d, J=12.55 Hz, 0.5 H), 4.66 (d, J=13.56 Hz, 0.5 H), 4.81 (d, J=11.87 Hz, 0.5 H), 5.31-5.42 (m, 1 H), 7.92-7.97 (m, 1 H), 8.00-8.06 (m, J=7.80 Hz, 1 H); MS (ESI) m/z 388 (M+H)+.
Reaction SMILES: C(O[C:4](=[O:30])[CH2:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH:10]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:33]O.Cl>CO.O>[CH3:29][N:27]1[N:26]=[N:25][C:24]([CH:10]2[CH2:9][CH:8]([C:6]3[O:7][NH:33][C:4](=[O:30])[CH:5]=3)[CH2:13][CH2:12][N:11]2[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[N:28]1
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OCc2ccccc2)C(c2nnn(C)n2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1nnc(C2CC(c3cc(=O)[nH]o3)CCN2C(=O)OCc2ccccc2)n1
Temperature: -40 °C
Reaction time: 0.67 h
Yield: 70.9 %

Procedure:
Benzyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-methyl-2H-tetrazol-5-yl)piperidine-1-carboxylate (0.499 g, 1.20 mmol) was dissolved in MeOH (6 mL) and cooled to −40° C. 3.8 M NaOH (0.316 mL, 1.20 mmol) dissolved in water (0.6 mL) was added and the reaction stirred at −40° C. for 40 min. Hydroxylamine (50% by weight in water, 0.074 mL, 1.20 mmol) was added and stirring continued for 3.5 h at −40° C. The reaction mixture was then added to a preheated 80° C. solution of 6 M HCl (6.01 mL, 36.03 mmol) and stirred for 20 min. The reaction mixture was partitioned between water and DCM. The aqueous phase was extracted twice with DCM and the combined organic phase was dried and evaporated. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 15-55% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Benzyl 2-(2-methyl-2H-tetrazol-5-yl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (327 mg, 71%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.96-2.15 (m, 2H), 2.41 (dt, 1H), 2.64-2.74 (m, 1H), 3.12-3.19 (m, 1H), 3.61-3.72 (m, 1H), 4.07-4.20 (m, 4H), 5.13 (s, 2H), 5.43 (s, 1H), 5.58-5.64 (m, 1H), 7.25-7.41 (m, 5H). MS m/z 385 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8].[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][C:11]([CH3:13])=O.Cl[Sn](Cl)(Cl)Cl>C1(C)C=CC=CC=1>[NH2:8][C:7]1[C:10]([C:9]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([CH3:13])[N:1]=[C:2]2[S:3][CH:4]=[CH:5][C:6]=12
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1ccsc1N
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2sccc2c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.2 %

Procedure:
A mixture of 2-amino-3-thiophenecarbonitrile (2 g, 16.11 mmol), ethyl acetoacetate (2.24 mL, 17.72 mmol) and SnCl4 (3.78 mL, 32.2 mmol) in toluene (120 mL) was stirred at RT for 30 min and then at reflux for ca. 4 h. After cooling to RT, the mixture was quenched with 6M NaOH (ca. 80 mL), diluted with ethyl acetate (80 mL) and then filtered through celite. The organic layer of the filtrate was separated and the aqueous layer was re-extracted with ethyl acetate (50 mL×5). The combined organics were dried and concentrated. Purification by chromatography on silica, eluting with a gradient of 0-50% ethyl acetate in cyclohexane, to give the title compound (960 mg). LCMS (A) m/z: 237 [M+1]+, Rt 0.67 min (acidic).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[O:24]=[C:25]1[N:29]=[C:28]([NH:30][C@H:31]2[C@H:36]([OH:37])[CH2:35][CH2:34][O:33][CH2:32]2)[CH2:27][S:26]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:27]2/[C:28]([NH:30][C@H:31]3[C@H:36]([OH:37])[CH2:35][CH2:34][O:33][CH2:32]3)=[N:29][C:25](=[O:24])[S:26]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: O=C1N=C(N[C@@H]2COCC[C@H]2O)CS1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(N[C@@H]2COCC[C@H]2O)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 75 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (941 mg) in 2-propanol (20 mL) were added 1,5-anhydro-2,4-dideoxy-2-[(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)amino]-threo-pentitol (900 mg) and piperidinium acetate (411 mg). The reaction mixture was stirred at 75° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (806 mg). Absolute configuration undetermined.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([NH2:11])=[S:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:13][C:14](=O)[S:15][CH3:16]>C(O)C>[CH3:16][S:15][C:14]1[N:11]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[S:10][CH:13]=1
Reactant: CC(C)(C)OC(=O)NC(N)=S
Reactant: CSC(=O)CBr
Solvent: CCO
Product: CSc1csc(NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Yield: 50 %

Procedure:
N-tert-butoxycarbonylthiourea (503, 0.841 g, 4.77 mmol, prepared according to Schiavi, B.; Ahond, A.; Poupat, C.; Potier, P. Synth. Commun. 2002, 32, 1671) was suspended in ethanol (7.0 mL) and cooled in an ice bath. A solution of S-methyl bromoethanethioate (1.371 g, 5.0582 mmol, prepared according to Praveen Rao, P. N.; Amini, M.; Li, H.; Habeeb, A. G.; Knaus, E. E. J. Med. Chem. 2003, 46, 4872-82) in ethanol (7.0 mL) was added dropwise over 3 minutes. The suspension turned homogeneous at the end of the addition, the bath was removed, and the reaction was stirred at room temperature. The solvent was removed, and the crude material was partitioned between dichloromethane and water. The organics were washed with water and brine. The combined aqueous layers were back-extracted with dichloromethane, and the combined organics were dried with anhydrous MgSO4, filtered, and concentrated in vacuo to an orange glass (stench). The crude material was adsorbed onto ca. 5 g silica gel with ethyl acetate, and flushed through a plug of silica gel with hexanes (discarded) followed by 9:1 hexanes:ethyl acetate. The eluent was evaporated in vacuo to yield 504 (589 mg, 50%) as a colorless solid.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[OH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:23][CH:22]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:29][C:28]([CH3:31])([CH3:30])[C:27]([C:24]1[CH:23]=[CH:22][C:21]([O:20][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=2)=[CH:26][CH:25]=1)=[O:32]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: CC(C)(C)C(=O)c1ccc(O)cc1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccc(C(=O)C(C)(C)C)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 1-(4-hydroxy-phenyl)-2,2-dimethyl-propan-1-one via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil. MS (ES) for C23H28O6 [M+H]+: 401.4.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[NH:4][C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=2[C:13]([OH:15])=O.[CH3:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=1[C:26]1[CH:27]=[N:28][CH:29]=[N:30][CH:31]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:13]([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[NH:4][C:3]([C:2]([F:1])([F:17])[F:16])=[C:11]3[CH3:12])=[O:15])=[CH:21][C:20]=1[C:26]1[CH:31]=[N:30][CH:29]=[N:28][CH:27]=1
Reactant: Cc1c(C(F)(F)F)[nH]c2c(C(=O)O)cccc12
Reactant: Cc1ccc(N)cc1-c1cncnc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc3c(C)c(C(F)(F)F)[nH]c23)cc1-c1cncnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.3 %

Procedure:
To a suspension of 2-trifluoromethyl-3-methylindole-7-carboxylic acid (122 mg) and 4-methyl-3-(pyrimidin-5-yl)aniline (93 mg) in dichloromethane (5 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (144 mg) and 4-dimethylaminopyridine (30 mg). The mixture was stirred at ambient temperature for 24 hours and diluted with dichloromethane. The solution was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by a silica gel column chromatography eluting with 2% methanol in dichloromethane to give N-[4-methyl-3-(pyrimidin-5-yl)-phenyl]-3-methyl-2-trifluoromethyl-1H-indole-7-carboxamide (155 mg, 75.6%).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].CO[CH:11]=[CH:12][C:13]#[N:14].[O-]CC.[Na+]>C(O)C>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[N:1]1[CH:11]=[CH:12][C:13]([NH2:14])=[N:2]1
Reactant: NNc1ccccn1
Reactant: COC=CC#N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1ccn(-c2ccccn2)n1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2-Hydrazinylpyridine (100 mg, 0.92 mmol), 3-methoxyacrylonitrile (0.077 mL, 0.92 mmol) and sodium ethoxide (62 mg, 0.92 mmol) were dissolved in ethanol (4.5 mL) and stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel chromatography (ethyl acetate/hexanes, linear gradient) to afford 1-(pyridin-2-yl)-1H-pyrazol-3-amine. The purified material contained impurities and was used without further purification. MS ESI calc'd. for C8H9N4 [M+H]+ 161. found 161.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=1[NH:22][NH2:23])[C:15](OC)=[O:16].O>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([CH2:15][OH:16])[CH:19]=[CH:20][C:21]=1[NH:22][NH2:23]
Reactant: COC(=O)c1ccc(NN)c(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: NNc1ccc(CO)cc1Cl
Temperature: -73 °C
Reaction time: 0.5 h

Procedure:
Diisobutylaluminium hydride (1M in toluene, 190 ml) is added dropwise, under a nitrogen atmosphere and at −73° C., to a solution of methyl 3-chloro-4-hydrazino-benzoate (9.5 g, 47 mmol) in 1 l of toluene in such a way that the temperature does not rise above −70° C. The reaction mixture is stirred at −73° C. for 30 min and then warmed to −5° C. Following hydrolysis with 500 ml of water, the precipitate is filtered off and washed with ethyl acetate (5×500 ml). The organic phase is evaporated, after which the residue is taken up in a little ethyl acetate and precipitated with petroleum ether/diethyl ether and filtered off. The solid which is obtained in this way is purified chromatographically on silica gel using cyclohexane/ethyl acetate. Yield: 2.9 g
Reaction SMILES: C(OC1N=NC(C#CC2C=CC(C(F)(F)F)=CN=2)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[CH2:35]([O:42][C:43]1[N:44]=[N:45][C:46]([C:57]#[CH:58])=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.Br[C:60]1[C:65]([F:66])=[CH:64][CH:63]=[CH:62][C:61]=1[F:67]>>[CH2:35]([O:42][C:43]1[N:44]=[N:45][C:46]([C:57]#[C:58][C:60]2[C:65]([F:66])=[CH:64][CH:63]=[CH:62][C:61]=2[F:67])=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Fc1cccc(F)c1Br
Reactant: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)nc1
Product: Fc1cccc(F)c1C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridazine (Intermediate 6) from 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5) and 2-bromo-1,3-difluorobenzene.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O>CCOC(C)=O.[Pd]>[N:9]1([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:15][CH:14]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=[N+]([O-])c1ccc(CN2CCCC2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(CN2CCCC2)cc1
Reaction time: 2 h

Procedure:
10% Pd/C (500 mg) was added to a solution of 1-(4-nitrobenzyl)-pyrrolidine Compound 1n3 (4.56 g, 22.1 mmol) in EtOAc (20 mL). The mixture was hydrogenated at 50 PSI for a period of 2 hrs and filtered through Celite. The filtrate was evaporated and the residue was dissolved in 10% NH4Cl and washed with ethyl ether. The aqueous layer was then adjusted to pH 10 with NaOH and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and evaporated in vacuo to give 4-pyrrolidin-1-ylmethyl-phenylamine Compound 1n (3.05 g) as a light brown oil. 1H NMR (CDCl3) δ 7.10 (d, J=8.5 Hz, 2H); 6.63 (d, J=8.5 Hz, 2H); 3.60 (br s, 2H); 3.50 (s, 2H); 2.52-2.42 (m, 4H); 1.83-1.69 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16]S(C3C=CC(C)=CC=3)(=O)=O)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[C:29]([F:37])[CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:38][C:39]1[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=1.N>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][C:42]3[CH:43]=[CH:44][C:39]([F:38])=[CH:40][CH:41]=3)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[C:29]([F:37])[CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)c(F)c3)cnn(-c3ccc(F)c(F)c3)c2=O)cc1
Reactant: Oc1ccc(F)cc1
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2Oc2ccc(F)cc2)cc1F

Procedure:
The title compound was prepared according to the method of Example 346, starting with 2-(3,4-difluorophenyl)-4-tosyloxy-5-[3-fluoro-4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 4-fluorophenol in place of isobutanol mp 168-170° C. 1H NMR (300 MHz, DMSO-d6) δ 3.39 (s, 3H), 7.15 (d, 4H), 7.51 (m, 1H), 7.6 (m, 1H), 7.6 (m, 1H) 7.75 (m, 3H), 7.97 (t, 1H); 8.4 (s, 1H). MS (DCI/NH3) m/z 491 (M+H)+, 508 (M+NH4)+. Anal. calc. for C23H14F4N2O4S: C, 56.33; H, 2.88; N, 5.71. Found, C, 56.07; H, 2.94; N, 5.33.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[S:15])=[CH:9][CH:8]=2)[CH:6]=1.Br[CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]1=O>C(O)C>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[S:15][C:26]4[CH2:27][CH2:28][CH2:29][CH:24]([C:20]5[CH:21]=[CH:22][CH:23]=[CH:18][CH:19]=5)[C:25]=4[N:16]=3)=[CH:11][CH:12]=2)[CH:6]=1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Reactant: Cc1cn(-c2ccc(NC(N)=S)cc2)cn1
Solvent: CCO
Product: Cc1cn(-c2ccc(Nc3nc4c(s3)CCCC4c3ccccc3)cc2)cn1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
A suspension of [4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (29.2 mg, 0.13 mmol) and of 2-bromo-6-phenyl-cyclohexanone (65.5 mg, 0.26 mmol) in ethanol (2 mL) was stirred at room temperature for 30 minutes and then heated for two days to reflux under an atmosphere of nitrogen. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified on silica gel using dichloromethane then dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound (50 mg, 100%) as an colourless oil. MS ISP (m/e): 387.4 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.12 (s, 1H), 7.95 (s, 1H), 7.52 (d, 2H), 7.39 (d, 2H), 7.29 (m, 3H), 7.11-7.20 (m, 3H), 4.02 (m, 1H), 2.71 (m, 2H), 2.13 (s, 3H), 2.12 (m, 1H), 1.70-1.94 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH3:14])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1.[CH:16]1(CO)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([CH2:1][O:2][C:3](=[O:15])[C@H:4]([CH3:14])[NH:5][C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: OCC1CCCCC1
Reactant: COC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1
Product: C[C@H](Nc1ccc(Cl)c(Cl)c1)C(=O)OCC1CCCCC1

Procedure:
Following transesterification General Procedure AB above and using N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9 above) and cyclohexylmethanol (Aldrich), the title compound was prepared.