Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:15](=[O:32])[NH:16][C@H:17]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:18]1=[O:31])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:40][C@H:41]1[CH2:47][CH2:46][S:45][C@H:44]2[CH2:48][CH2:49][CH2:50][C@@H:51]([CH3:52])[N:43]2[C:42]1=[O:53]>>[CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:15]([NH:16][C@H:17]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:18]1=[O:31])=[O:32])[C:9]([NH:40][C@H:41]1[CH2:47][CH2:46][S:45][C@H:44]2[CH2:48][CH2:49][CH2:50][C@@H:51]([CH3:52])[N:43]2[C:42]1=[O:53])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N12
Reactant: Cc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)O)Cc2ccccc2)C1=O
Product: Cc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)N[C@H]2CCS[C@H]3CCC[C@@H](C)N3C2=O)Cc2ccccc2)C1=O

Procedure:
(2R,5R)-2,5-Dibenzyl-N1-((4S,7R,10aS)-7-methyl-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)-N6-((S)-2-oxo-1-o-tolylazepan-3-yl)hexanediamide was synthesized as described in General Procedure H using Intermediate 71 (17 mg, 0.031 mmol) and Intermediate 72 (7.5 mg, 0.035 mmol) to give a white solid (18 mg, 69% yield). Anal. Calcd. for C43H54N4O4S m/z 722.7. found: 723.5 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.37-6.88 (m, 14H), 5.28 (d, J=5.2 Hz, 1H), 4.99-4.85 (m, 1H), 4.83-4.70 (m, 1H), 4.66-4.56 (m, 1H), 4.09-3.83 (m, 2H), 3.53 (d, J=14.5 Hz, 1H), 3.31 (dd, J=15.0, 5.0 Hz, 1H), 3.15-2.93 (m, 4H), 2.90-2.64 (m, 4H), 2.63-2.49 (m, 2H), 2.48-2.30 (m, 3H), 2.19 and 2.13 (s, 3H), 2.09-1.43 (m, 11H), 1.32 (d, J=6.9 Hz, 3H), 1.44-1.16 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:38])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:33][CH3:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[O:41]=[S:42]1(=[O:54])[CH2:47][CH2:46][CH:45]([N:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[CH2:44][CH2:43]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:38])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:51]3[CH2:52][CH2:53][N:48]([CH:45]4[CH2:44][CH2:43][S:42](=[O:41])(=[O:54])[CH2:47][CH2:46]4)[CH2:49][CH2:50]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:33][CH3:34])([CH3:31])[CH3:32])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCC(N2CCNCC2)CC1
Reactant: CCOc1cc(C(C)(C)OC)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)OC)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C2CCS(=O)(=O)CC2)CC1

Procedure:
In a manner analogous to the method described in example 5, 4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(1-methoxy-1-methyl-ethyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(1,1-dioxo-tetrahydro-2H-thiopyran-4-yl)-piperazine dihydrochloride (example 22) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C39H49N4O5SCl2 [(M+H)+] 755.2795, observed 755.2792.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[C:16]([C:20]1[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([N+:29]([O-])=O)=[C:24]([F:32])[CH:23]=2)([CH3:19])([CH3:18])[CH3:17]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:29][C:25]4[CH:26]=[C:27]5[C:22](=[CH:23][C:24]=4[F:32])[N:21]([CH2:6][C@@H:5]([OH:1])[CH2:4][OH:3])[C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:28]5)=[O:15])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: CC(C)(C)c1cc2cc([N+](=O)[O-])c(F)cc2[nH]1
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)c(F)cc2n1C[C@@H](O)CO

Procedure:
(R)-1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(2,3-dihydroxypropyl)-6-fluoro-1H-indol-5-yl)cyclopropanecarboxamide was prepared using an experimental procedure similar to example 72 from 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid and 2-tert-butyl-6-fluoro-5-nitro-1H-indole.
Reaction SMILES: FC(F)(F)C(O)=O.O[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:10][CH2:11][N:12]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C(Cl)Cl>[OH:31][C:27]1[CH:26]=[C:25]([C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][CH2:11][N:12]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:30]=[CH:29][CH:28]=1
Reactant: Oc1cccc(C(O)(CCN2CCCNCC2)c2ccccc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Oc1cccc(C(=CCN2CCCNCC2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Trifluoroacetic acid (4.75 mL) was added to a solution of 1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295, 60 mg, 0.184 mmol) in CH2Cl2 (0.25 mL). The reaction mixture was stirred at room temperature for 2.5 h. The trifluoroacetic acid was evaporated to afford 1-[3-(3-hydroxyphenyl)-3-phenyl-2-propenyl]homopiperazine as a colorless oil used without further purification.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21]COC)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:25][CH2:26][CH2:27][CH3:28])[CH:10]=2)[CH:5]1[C:29]1[CH:34]=[CH:33][C:32]2[O:35][CH2:36][O:37][C:31]=2[CH:30]=1)#[N:2]>CCO.Cl>[C:1]([CH2:3][CH:4]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[OH:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:25][CH2:26][CH2:27][CH3:28])[CH:10]=2)[CH:5]1[C:29]1[CH:34]=[CH:33][C:32]2[O:35][CH2:36][O:37][C:31]=2[CH:30]=1)#[N:2]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCOC)C(CC#N)C2c1ccc2c(c1)OCO2
Agent: Cl
Solvent: CCO
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1O)C(CC#N)C2c1ccc2c(c1)OCO2

Procedure:
1RS,2RS,3RS)-2-Cyanomethyl-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane (300 mg, 0.60 mmol) was dissolved in EtOH (4 ml) with concentrated HCl (0.1 ml) then refluxed for 1 h. the mixture was cooled then partitioned between EtOAc and 3N HCl. The organic extract was washed with H2O, saturated NaHCO3 solution, H2O, then brine, dried (Na2SO4) and solvent removed in vacuo to afford the title compound as a solid foam (250 mg, 91%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[C:20]1[O:24][C:23]([CH3:25])=[N:22][CH:21]=1)[C:15]#[N:16]>CN(C=O)C.O>[CH2:3]([O:10][C:18]1[CH:17]=[C:14]([CH:13]=[CH:12][C:19]=1[C:20]1[O:24][C:23]([CH3:25])=[N:22][CH:21]=1)[C:15]#[N:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1ncc(-c2ccc(C#N)cc2F)o1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncc(-c2ccc(C#N)cc2OCc2ccccc2)o1
Reaction time: 0.5 h
Yield: 103.5 %

Procedure:
To a mixture of sodium hydride (60%, 2.1 g) in DMF (35 mL) was added benzylalcohol (5.61 g) at 0° C., and the mixture was stirred for 30 min. 3-Fluoro-4-(2-methyl-1,3-oxazol-5-yl)benzonitrile (3.50 g) was added to this reaction mixture at 0° C., and the mixture was stirred at room temperature for 1 hr, and diluted with water. The resultant precipitate was collected by filtration and washed with water to give the title compound (5.20 g).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1[C:22](=[O:38])[N:23]([C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][C:28]=2[O:36][CH3:37])[CH:24]=[CH:25][CH:26]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:33][C:30]1[CH:31]=[CH:32][C:27]([N:23]2[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:22]2=[O:38])=[C:28]([O:36][CH3:37])[CH:29]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(N)ccc1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
25 g (48 mmol) of the compound from Example 22A are dissolved in 800 ml of a 1:1 mixture of ethanol and ethyl acetate, and 18 g (286 mmol) of ammonium formate and 800 mg of palladium on carbon are added. The mixture is heated at 80° C. After 60 min, the mixture is allowed to cool and filtered through silica gel. The filter cake is washed with ethyl acetate, and the filtrate is concentrated to dryness under reduced pressure. This gives 27 g (98% of theory) of the desired product.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C@H:9]([NH:11][S@@](C(C)(C)C)=O)[CH3:10])[CH:4]=1.[ClH:20].O1CCOCC1>CO>[ClH:20].[ClH:20].[F:18][C:2]([F:1])([F:19])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C@H:9]([NH2:11])[CH3:10])[CH:4]=1
Reactant: C[C@@H](N[S@](=O)C(C)(C)C)c1cc(C(F)(F)F)ccn1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@H](N)c1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-2-methyl-propane-2-sulfinic acid [(R)-1-(4-trifluoromethyl-pyridin-2-yl)-ethyl]-amide (225 mg, 0.76 mmol) in MeOH (4 mL) was added 4.0 M hydrogen chloride in dioxane (0.48 mL, 1.9 mmol). The reaction mixture was stirred at room temperature for 30 min then concentrated and dried under high vacuum to afford 225 mg of (R)-1-(4-trifluoromethyl-pyridin-2-yl)-ethylamine dihydrochloride as a viscous colorless oil which was used without further purification.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([N:11]2[C:15]([CH2:16][CH2:17][CH3:18])=[C:14]([CH2:19]O)[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(Cl)(Cl)Cl>C=CCCC>[C:5]1([N:11]2[C:15]([CH2:16][CH2:17][CH3:18])=[C:14]([CH2:19][NH:11][CH2:5][CH2:6][CH2:7][CH3:8])[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCCc1c(CO)c(-c2ccccc2)nn1-c1ccccc1
Solvent: C=CCCC
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCNCc1c(-c2ccccc2)nn(-c2ccccc2)c1CCC
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Thionyl chloride (1 mL) is added to a solution of 165 (289 mg) in pentene stabilized chloroform (8 mL) and the mixture heated to 60° C. for 2 hours. The resulting mixture is cooled, washed with saturated sodium bicarbonate solution, dried (Na2SO4), and concentrated. The resulting crude chloride is taken up in dimethylformamide (3 mL) and added dropwise to a solution of butylamine (1.0 g) in dimethylformamide (10 mL) containing 2g of powdered potassium carbonate. After the addition is complete, the resulting mixture is stirred for an additional 3 h and partitioned between water (20 mL) and ether (10 mL). The ether layer is washed 2 times with water, dried (Na2SO4), and concentrated. The resulting material is purified by chromatography on silica eluting with 10% CH3OH/CHCl3 to give the desired secondary amine 166. LC-MS (M+1): 348.3; 1H NMR (δ, CDCl3), 7.87 (dd, J=8.0, 1.6 Hz, 2H), 7.32-7.48 (m, 1H), 3.77 (s, 2H), 2.70 (m, 4H), 1.48 (m, 4H), 1.34 (m, 2H), 0.91 (t, J=7.6 Hz, 3H), 0.87 (t, J=7.6 Hz, 3H) ppm.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1I)[CH3:2].FC1C=CC(B(O)O)=CC=1.[CH:31]([C:33]1[O:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:32]>>[CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1[C:36]1[O:37][C:33]([CH:31]=[O:32])=[CH:34][CH:35]=1)[CH3:2]
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OCc1ccccc1
Reactant: O=Cc1ccc(B(O)O)o1
Agent: OB(O)c1ccc(F)cc1
Product: CCc1c(-c2ccc(C=O)o2)[nH]c(C=O)c1C(=O)OCc1ccccc1

Procedure:
Following the procedures described in Example 5, replacing methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate with benzyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate and 4-fluorophenylboronic acid with 5-formyl-2-furylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the title compound. HRMS (ES) exact mass calculated for C20H18NO5 (M+H): 352.1180. Found 352.1183
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH2:28][C:29]#[C:30][CH3:31])[C@H:3]([O:21]C1CCCCO1)/[CH:4]=[CH:5]/[C@@H:6]1[C@@H:10]([CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:9](=[O:20])[CH2:8][CH2:7]1>C(O)(=O)C.O.C1COCC1>[CH3:1][C:2]([CH3:32])([CH2:28][C:29]#[C:30][CH3:31])[C@H:3]([OH:21])/[CH:4]=[CH:5]/[C@@H:6]1[C@@H:10]([CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:9](=[O:20])[CH2:8][CH2:7]1
Reactant: CC#CCC(C)(C)[C@@H](/C=C/[C@H]1CCC(=O)[C@@H]1C/C=C\CCCC(=O)O)OC1CCCCO1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC#CCC(C)(C)[C@H](O)/C=C/[C@H]1CCC(=O)[C@@H]1C/C=C\CCCC(=O)O

Procedure:
At 20°, 390 mg. of (5Z,13E)-(15R)-16,16-dimethyl-9-oxo-15-(tetrahydropyran-2-yloxy)-5,13-prostadien-18-ynoic acid is agitated for 16 hours with 10 ml. of a mixture of glacial acetic acid/water/THF (65/35/10); the mixture is evaporated under vacuum and the residue purified by column chromatography on silica gel. With methylene chloride/5% methanol, 305 mg. of the title compound is obtained as a colorless oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19](=[S:21])[NH2:20])=[CH:15]2)(=[O:8])=[O:7].[C:22]([O:27][CH2:28][CH3:29])(=[O:26])[C:23]#[C:24][CH3:25].C(P(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>O1CCCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:21][CH:24]([CH2:23][C:22]([O:27][CH2:28][CH3:29])=[O:26])[CH2:25][N:20]=1)=[CH:15]2)(=[O:7])=[O:8]
Reactant: CC#CC(=O)OCC
Reactant: NC(=S)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CN=C(c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)S1
Temperature: 60 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
A solution of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (4.3 g), ethyl but-2-ynoate (3.2 mL) and tributylphosphine (3.2 mL) in tetrahydrofuran (40 mL)-toluene (40 mL) was stirred at room temperature for 2 days ethyl but-2-ynoate (1.6 mL) was added to the reaction solution again, and the mixture was stirred at 60° C. for 2 hr. The reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=2:8-4:6) to give the title compound (1.6 g, yield: 28%) as a pale-brown oil.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH:30]=O)=[CH:22]1>>[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:22]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: Cn1cc(C=O)c2ccccc21
Product: Cn1cc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c2ccccc21

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1-methylindole-3-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(1-methylindol-3-yl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])=[CH:17][C:16]=2[NH:27][C:28](=[O:31])[CH2:29]Br)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:21]([C:18]1[CH:17]=[C:16]2[C:15](=[CH:20][CH:19]=1)[N:14]([CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)[CH2:29][C:28](=[O:31])[NH:27]2)=[O:22])[CH:25]=[CH2:26]
Reactant: C=CCOC(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(NC(=O)CBr)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: C=CCOC(=O)c1ccc2c(c1)NC(=O)CN2C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h
Yield: 51.9 %

Procedure:
A mixture of 4-[4-allyloxycarbonyl-2-(2-bromo-acetylamino)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (23.0 g, 46.33 mmol, 1.0 equiv) and N-ethyldiisopropylamine (11.98 g, 92.67 mmol,2.0 equiv) in toluene (250 mL) was heated to reflux. After 8 h, the reaction mixture was cooled, washed with water and concentrated by evaporation under reduced pressure and purified with silica column chromatography eluting with dichloromethane/acetone (95:5) to obtain 10.0 g (52%) of the title compound as yellow solid. 1H NMR (400 MHz, DMSO): δ 1.41 (s, 9H), 1.65 (br s, 4H), 2.89 (s, 2H), 3.74 (s, 2H), 3.90 (br s, 1H), 4.05 (br s, 2H), 4.73 (d, J=5.1, 2H), 5.25 (d, J=10.4, 1H), 5.36 (dd, J=17.2 Hz, J=1.1 Hz, 1H), 5.98-6.05 (m, 1H), 6.95 (d, J=8.7 Hz, 1H), 7.44 (d, J=1.4 Hz, 1H), 7.53 (dd, J=17.2 Hz, J=1.1 Hz, 1H), 10.58 (s, 1H). 13C-NMR (100 MHz, DMSO): δ 26.87, 28.02, 45.15, 53.36, 64.35, 78.67, 110.81, 115.77, 117.36, 118.04, 125.21, 126.61, 132.95, 132.99, 138.63, 153.70, 164.94, 165.00. MS (ISP): 416.2 [M+H]+.
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:33]=[CH:32][C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]=[C:19]4[S:23][C:22]([N:24]5[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]5)=[N:21][C:20]4=[O:31])=[CH:15][CH:16]=3)[CH:11]=[N:10]2)=[C:6](I)[CH:5]=1.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.C([Sn](CCCC)(CCCC)[C:61]([O:63]CC)=[CH2:62])CCC.Cl>CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[C:61]([C:6]1[CH:5]=[C:4]([Cl:3])[CH:33]=[CH:32][C:7]=1[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH:18]=[C:19]3[S:23][C:22]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)=[N:21][C:20]3=[O:31])=[CH:15][CH:16]=2)[CH:11]=[N:10]1)(=[O:63])[CH3:62]
Reactant: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4I)c3)S2)CC1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)c1cc(Cl)ccc1Cn1ncc2cc(C=C3SC(N4CCN(C)CC4)=NC3=O)ccc21
Temperature: 90 °C

Procedure:
To a N2 flushed vial was added 5-[1-(4-chloro-2-iodo-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)thiazol-4-one (100 mg, 0.15 mmol), Pd2(dba)3 (10 mg, 0.011 mmol), biphenyl-2-yl-di-t-butyl-phosphane (12 mg, 0.04 mmol), Tributyl-(1-ethoxy-vinyl)-stannane (86 mg, 0.23 mmol) and dioxane (2 mL). The resulting mixture was heated at 90° C. for 16 h. The resulting mixture was poured into water and extracted with EtOAc. The organic layer was dried and concentrated, and the residue was purified by preparative HPLC to yield a white solid which was treated 1 N hydrochloric acid in MeOH to yield the title compound.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][C@H:26]([CH3:31])[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].Cl>CN(C)C=O.O.ClCCl>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][C@H:26]([CH3:31])[CH2:27][C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: C[C@@H](N)CC(=O)O
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H](CC(=O)O)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 140 °C
Yield: 75 %

Procedure:
1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (75 mg, 0.234 mmol) and 3-(R)-amino-butyric acid (103 mg, 1.0 mmol) were placed in a CEM 10 mL Microwave vessel and dissolved in anhydrous N,N-dimethylformamide (2 mL.) Sodium methoxide (54 mg, 1.0 mmol) was added to solution and the vessel was sealed. The reaction was heated to 140° C. in a CEM microwave apparatus for four hours. Upon completion, the reaction mixture was diluted with water and treated with 1N hydrochloric acid. The precipitate was dissolved in dichloromethane and dried over anhydrous sodium sulfate. The crude product was purified by MPLC (methylene chloride-ethyl acetate) to provide the title compound as a light-yellow solid in 75% yield. MS ESI(−) m/e: 390.091 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH2:43][CH2:42][CH2:41][CH:40]([OH:44])[CH2:39]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:38]3[CH2:43][CH2:42][CH2:41][CH:40]([OH:44])[CH2:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: OC1CCCNC1
Product: O=C(Nc1ccc(Oc2ccnc(N3CCCC(O)C3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and piperidin-3-ol according to conditions described in general procedure C. Mp: 93-95° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.24-1.26 (m, 2 H), 1.58-1.60 (m, 7 H), 1.75-1.85 (m, 1 H), 2.68-2.80 (m, 2 H), 3.27-3.36 (m, 6 H), 4.80 (d, J=4.0 Hz, 1 H), 6.14 (d, J=5.5 Hz, 1 H), 6.95 (d, J=12.8 Hz, 1 H), 7.14 (d, J=9.1 Hz, 1 H), 7.40 (d, J=8.0 Hz, 1 H), 7.46 (s, 1 H), 7.55-7.61 (m, 3 H), 7.82-7.84 (m, 1 H), 7.97 (d, J=7.3 Hz, 1 H), 8.22 (d, J=5.4 Hz, 1 H), 10.44 (s, 1 H).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].Br[CH2:10][C:11]#[N:12].C([N-]C(C)C)(C)C.[Li+]>C1COCC1>[C:11]([CH2:10][C:2]([CH3:1])([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4])#[N:12]
Reactant: CCC(C)C(=O)OC
Reactant: N#CCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(C)(CC#N)C(=O)OC
Yield: 60.8 %

Procedure:
The reaction of methyl 2-methylbutyrate (13.34 g, 115 mmol) with bromoacetonitrile (16.56 g, 138 mmol) in the presence of lithium diisopropylamide (prepared by treating diisopropylamine (12.78 g, 126.5 mmol) with butyllithium in hexanes (2.5 M, 50.6 mL, 126.5 mmol)) in THF (175 mL), as described above in the preparation of Example 1, gave 16.57 g of the crude product as a dark colored liquid. The crude product was vacuum distilled to give the nitrile (10.85 g, 61%) as a colorless liquid: bp 83-85° C. (10 mmHg).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH:9]2[CH2:14][CH2:13][CH:12]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: CNc1cccc(C2CCC(=O)CC2)n1
Product: CNc1cccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)n1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(6-methylamino-pyridin-2-yl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.