Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([CH2:11][C:12]3[CH:13]=[CH:14][N:15]4[C:20]=3[C:19]([NH:21][C:22]3[CH:23]=[C:24]5[C:28](=[CH:29][CH:30]=3)[N:27]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)[N:26]=[CH:25]5)=[N:18][CH:17]=[N:16]4)[CH2:7][CH2:6]2)[O:4]CC1>C1COCC1.Cl.C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:38][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=1)[CH2:31][N:27]1[C:28]2[C:24](=[CH:23][C:22]([NH:21][C:19]3[C:20]4=[C:12]([CH2:11][N:8]5[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]5)[CH:13]=[CH:14][N:15]4[N:16]=[CH:17][N:18]=3)=[CH:30][CH:29]=2)[CH:25]=[N:26]1
Reactant: Fc1cccc(Cn2ncc3cc(Nc4ncnn5ccc(CN6CCC7(CC6)OCCO7)c45)ccc32)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Temperature: 25 °C
Reaction time: 168 h
Yield: 38.5 %

Procedure:
A solution of [5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-[1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine (54 mg, 0.105 mmole) in a mixture of THF (1 mL) and 1 N aq. HCl (1 mL) containing 16 drops of conc. HCl was left stirring a RT for 7 days. The reaction was diluted with DCM and neutralized with sat. aq. NaHCO3 solution. After drying (Na2SO4), the solvent was removed to leave the title compound as an oil (19 mg, 39%). MS: 488 (M+H2O+H)+; HPLC Ret Time: 2.35 min (YMC Xterra ODS S7 C18, 3.0×50 mm column, 5 min gradient (component B was varied from 20 to 60%), 5 mL/min).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:16])[CH:10]=3.Cl[CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[CH:35]=1>>[C:38]([O:37][CH2:36][C:34]1[CH:35]=[C:30]([CH2:29][O:16][C:9]2[CH:10]=[C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]4[CH:3]=[C:2]([Br:1])[CH:15]=[CH:14][C:13]=4[S:12]3)[CH:8]=2)[CH:31]=[N:32][CH:33]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)OCc1cncc(CCl)c1
Reactant: O=c1c(Cc2cccnc2)cn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Product: CC(=O)OCc1cncc(COc2cc3c4c(c2)c(=O)c(Cc2cccnc2)cn4-c2cc(Br)ccc2S3)c1
Yield: 75.7 %

Procedure:
According to Example 34, the compound (250 mg) produced in Example 37 was reacted with 3-chloromethyl-5-acetoxymethylpyridine (175 mg) to obtain the title compound (260 mg; 77%).
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH2:28]([O:30][C:31]([C:33]1([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[O:32])[CH3:29].C(N(CC)CC)C>C1C=CC=CC=1.CCCCC>[CH2:28]([O:30][C:31]([C:33]1([C:39]2[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=2)[CH2:34][CH2:35][N:36]([C:9](=[O:10])[CH2:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:37][CH2:38]1)=[O:32])[CH3:29]
Reactant: CCOC(=O)C1(c2ccc(Cl)cc2)CCNCC1
Reactant: O=C(O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCCCC
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCOC(=O)C1(c2ccc(Cl)cc2)CCN(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reaction time: 16 h

Procedure:
A solution of 3.3 parts of 3,3,3-triphenylpropionic acid in 108 parts of dry benzene is treated with 1.8 parts of thionyl chloride. The mixture is refluxed for 2 hours before it is cooled and volatile material is removed under reduced pressure. The residue is dissolved in 88 parts of dry benzene and the solvent is removed again under reduced pressure to again give a residual oil. This is again dissolved in 88 parts of dry benzene and a solution of 2.9 parts of 4-(4-chlorophenyl)-4-piperidinecarboxylic acid ethyl ester and 1.1 part of triethylamine in 27 parts of dry benzene is added at 15°-25° C with stirring. The mixture is then allowed to stand for 16 hours before it is washed successively with dilute hydrochloric acid, water, and dilute aqueous potassium carbonate solution. It is then dried over sodium sulfate and the solvent is evaporated under reduced pressure to leave a residual gum. Upon trituration with pentane the gum solidifies and it is filtered, washed with pentane and air dried to give 1-(3,3,3-triphenylpropionyl)-4-(4-chlorophenyl)-4-piperidinecarboxylic acid ethyl ester melting at about 95°-98° C. 3.8 Patts of this compound is continuously extracted into a suspension of 1.1 part of lithium aluminum hydride in ether with stirring at reflux under nitrogen over a period of one hour. Stirring is continued for an additional 50 minutes and the mixture is decomposed by the successive addition of 1.1 part of water, 0.8 part of 20% aqueous sodium hydroxide solution and 3.9 parts of water. The mixture is filtered and the inorganic material is extracted woth ether. The combined ether solutions are concentrated and diluted with pentane. The solid material which forms is separated by filtration, washed with a mixture of ether and pentane, and dried under reduced pressure to give 1-(3,3,3-triphenylpropyl)-4-(4-chlorophenyl)-4-piperidinemethanol melting at about 156.5°-157.5° C and having the following structural formula ##STR23##
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=2[F:17])[CH:5]=[CH:4][N:3]=[CH:2]1.C[Al](C)C.[NH:22](/[C:26](/[CH3:32])=[CH:27]\[C:28](OC)=[O:29])[C:23]([CH3:25])=O>C(Cl)Cl>[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:28](=[O:29])[CH:27]=[C:26]([CH3:32])[N:22]=[C:23]3[CH3:25])=[CH:12][C:11]=2[F:17])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Nc1ccc(NCCCn2ccnc2)c(F)c1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(NCCCn3ccnc3)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.1 %

Procedure:
To a solution of N1-(3-(1H-imidazol-1-yl)propyl)-2-fluorobenzene-1,4-diamine (1.00 g, 4.27 mmol) in CH2Cl2 (30 mL) was added trimethylaluminium (16.4 mL, 32.8 mmol, 2 M in toluene) slowly. The mixture was stirred at rt for 0.5 h, followed by the addition of a solution of methyl 3-acetaminocrotonate (1.00 g, 6.36 mmol) in CH2Cl2 (8 mL). The reaction mixture was stirred at rt for 24 h, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (50 mL×3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V)=20:1) to give the title compound as pale yellow oil (0.22 g, 15%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH:14]=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23].C(Cl)(Cl)Cl.[I:30]N1C(=O)CCC1=O.C(Cl)Cl>O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([I:30])=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:21][S:22]([CH3:25])(=[O:23])=[O:24]
Reactant: CC(=O)Nc1cn2nc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)ccc2n1
Reactant: O=C1CCC(=O)N1I
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)nn2c1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.1 %

Procedure:
To a 50 mL round-bottomed flask was added N-(6-(6-chloro-5-(methylsulfonamido)pyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide (Example 19) (0.404 g, 1.06 mmol), chloroform (20 mL) and N-iodosuccinimide (0.48 g, 2.1 mmol). The mixture was stirred at 25° C. for 1 h then poured into CH2Cl2 (200 mL) and water (200 mL). The solution contained a precipitate. This was filtered and the filtercake was washed with water and then dried under vacuum. The solid was taken up in MeOH/CH2Cl2 and concentrated onto Celite® (diatomaceous earth). Purification by silica gel chromatography (2.0 to 10% MeOH/CH2Cl2) afforded the title compound as a yellow solid (0.199 g, 37%). MS (ESI, positive ion) m/z: 506.4 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.07 (s, 3H), 3.20 (s, 3H), 7.96 (d, J=9.6 Hz, 1H), 8.20 (d, J=9.4 Hz, 1H), 8.55 (d, J=2.2 Hz, 1H), 8.98 (d, J=2.2 Hz, 1H), 9.98 (s, 1H), 10.13 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]([S:4]([NH:7][C@@H:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([O:19]C)=[O:18])[CH:14]=2)[CH2:9]1)(=[O:6])=[O:5])[CH3:3].[OH-].[Li+].CCOC(C)=O.Cl>O.CO>[CH3:3][CH:2]([S:4]([NH:7][C@@H:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([OH:19])=[O:18])[CH:14]=2)[CH2:9]1)(=[O:6])=[O:5])[CH3:1]
Reactant: COC(=O)c1ccc2c(c1)C[C@@H](NS(=O)(=O)C(C)C)C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(C(=O)O)cc2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 78.2 %

Procedure:
A mixture of (S)-methyl 2-(1-methylethylsulfonamido)-2,3-dihydro-1H-indene-5-carboxylate (2.320 mmol, 690 mg) and lithium hydroxide (5.10 mmol, 122 mg) in H2O (25 mL) and MeOH (25 mL) was stirred at room temp for 2 days. EtOAc was added followed by 2M aq HCl and the reaction mixture extracted with EtOAc (×3). The EtOAc layers were combined and washed with brine, dried over MgSO4, filtered and the solvent removed in vacuo to give desired product as a white solid (514 mg, 78%). MS (ESI): m/z [M−H]− 282.2
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:25](=[O:26])[CH:24]=[C:23]([CH3:27])[NH:22]2)=[CH:17][C:16]=1[CH3:28]>C(#N)C>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([NH:6][C:7]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:25](=[O:26])[CH:24]=[C:23]([CH3:27])[NH:22]2)=[CH:17][C:16]=1[CH3:28])=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1ccc(F)cc1Cl
Reactant: Cc1cc(=O)n(-c2ccc(N)c(C)c2)[nH]1
Solvent: CC#N
Product: Cc1cc(=O)n(-c2ccc(NC(=O)NC(=O)c3ccc(F)cc3Cl)c(C)c2)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The solution of equivalent amounts of 2-chloro-4-fluorobenzoyl isocyanate in acetonitrile was added dropwise to the solution of 71 mg of 2-(4-amino-3-methylphenyl)-5-methyl-1,2-dihydropyrazol-3-one in 6 ml of acetonitrile and the mixture was stirred at room temperature overnight. The solid formed was filtered off with suction and dried under reduced pressure.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[F:23][C:24]([F:39])([F:38])[C:25]1[CH:26]=[C:27]([N:35]=[C:36]=[S:37])[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1>>[F:23][C:24]([F:38])([F:39])[C:25]1[CH:26]=[C:27]([NH:35][C:36]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[N:12]=[CH:13][C:8]4[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=4[N:10]=3)[CH2:15][CH2:16]2)=[S:37])[CH:28]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:30]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Reactant: FC(F)(F)c1cc(N=C=S)cc(C(F)(F)F)c1
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC3)nc21

Procedure:
Pipemidic acid (40 mg, 0.132 mmol) and 3,5-bis(trifluoromethyl)phenyl isothiocyanate (20 μL, 0.110 mmol) were used. Purification on silica yielded compound 18 in Table 1, below (61 mg, 97%). 1H NMR (300 MHz, CDCl3) δ 9.30 (s, 1H), 8.68 (s, 1H), 8.62 (s, 1H), 7.94 (s, 2H), 7.62 (s, 1H), 4.42-4.05 (m, 10H), 1.51 (t, J=7.07 Hz, 3H) ppm.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[O:6][CH:7]=1.[F:16][C:17]1[C:25]([OH:26])=[CH:24][CH:23]=[C:22]([F:27])[C:18]=1[C:19]([NH2:21])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:16][C:17]1[C:25]([O:26][CH2:2][C:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=3)[O:6][CH:7]=2)=[CH:24][CH:23]=[C:22]([F:27])[C:18]=1[C:19]([NH2:21])=[O:20]
Reactant: NC(=O)c1c(F)ccc(O)c1F
Reactant: COc1ccc(-c2nc(CCl)co2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)co2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.5 %

Procedure:
To a solution of 4-Chloromethyl-2-(4-methoxy-phenyl)-oxazole (0.100 g, 0.4 mmol) in 2 ml of anhydrous DMF was added 2,6-Difluoro-3-hydroxy-benzamide (0.077 g, 0.40 mmol) and potassium carbonate (0.216 g, 1.50 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.044 g, 27%). 1H NMR (DMSO-d6, 400 MHz): δ 4.01 (s, 3H), 5.12 (s, 2H), 7.10 (m, 3H), 7.40 (m, 1H), 7.85 (br s, 1H), 7.93 (d, J=8.80 Hz, 2H), 8.13 (br s, 1H) and 8.25 (s, 1H). MS ES+ (361.16), HPLC (method I) Rt=15.47 min.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27].C(#N)C.I.[Na]>>[F:19][C:18]([F:21])([F:20])[C:16]1[CH:15]=[CH:14][N:13]=[C:12]([N:9]2[CH2:10][CH2:11][C:3]3[C:2]([NH:27][C:26]4[CH:28]=[CH:29][CH:30]=[C:24]([O:23][CH3:22])[CH:25]=4)=[N:7][CH:6]=[N:5][C:4]=3[CH2:8]2)[CH:17]=1
Reactant: COc1cccc(N)c1
Reactant: FC(F)(F)c1ccnc(N2CCc3c(Cl)ncnc3C2)c1
Agent: I
Agent: [Na]
Solvent: CC#N
Product: COc1cccc(Nc2ncnc3c2CCN(c2cc(C(F)(F)F)ccn2)C3)c1
Temperature: 160 °C
Yield: 24.9 %

Procedure:
A mixture of 4-chloro-7-(4-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (0.041 g, 0.00013 mol), 3-methoxyaniline (0.018 mL, 0.00016 mol) in acetonitrile (1.00 mL, 0.0191 mol) and 47% HI (0.11 mL, 0.001 mol) was heated at 160° C. for 10 minutes in in a sealed tube via microwave. After cooling to r.t., the mixture was poured into saturated aqueous sodium bicarbanate (5 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with brine and dried over magnesium sulfate. Concentrated to leave a brown solid. Residue was purified by flash chromatography over silica gel (ethyl acetate/hexane gradient 0 to 100%) to give a white foam (0.013 g)
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH3:25][CH:26]1[CH2:31][CH2:30][CH2:29][C:28](=O)[CH2:27]1>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[C:28]3[CH2:29][CH2:30][CH2:31][CH:26]([CH3:25])[CH2:27]3)[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: CC1CCCC(=O)C1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Solvent: CC(=O)N(C)C
Product: CC1CCCC(=Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3sccc32)C1
Temperature: 25 °C

Procedure:
The product of Example 268D (0.054 g, 0.15 mmol) was reacted with 3-methylcyclohexanone (1.26 g, 11.25 mmol) in N,N-dimethylacetamide (1 mL) in a sealed tube at 135° C. for 45 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether (3 mL) and filtered to give the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([C:8]2[NH:13][C:12]3=[CH:14][CH:15]=[N:16][C:11]3=[CH:10][N:9]=2)[CH2:5][CH:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[NH:3]1.CC[O:31]C(C)=O.[ClH:35]>CO>[OH2:31].[ClH:35].[CH3:1][CH:2]1[CH2:7][CH:6]([C:8]2[NH:13][C:12]3=[CH:14][CH:15]=[N:16][C:11]3=[CH:10][N:9]=2)[CH2:5][CH:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[NH:3]1
Reactant: CCOC(C)=O
Agent: CC1CC(c2ncc3nccc-3[nH]2)CC(c2ccc(-c3ccccc3)cc2)N1
Agent: Cl
Solvent: CO
Product: O

Procedure:
Using the method described in Example 30 by employing [1-(4-phenylphenyl)vinyl]pyrrolidine (freshly prepared before use) (1.35 g, 5.42 mmol), 2-methyl-4,6-dichloro-5-nitropyrimidine (Example 76(b)) (1.21 g, 5.42 mmol), N,N-diisopropylethyl amine (Aldrich Chemical Company) (0.9 mL, 5.42 mmol), piperidine (Aldrich Chemical Company) (0.9 mL, 8.67 mmol), NEt3 (Aldrich Chemical Company) (1.0 mL) and SnCl2 (Aldrich Chemical Company) (16 mL of a 2M solution in DMF). The residue was purified by flash chromatography on silica gel with 95:5 CHCl3:MeOH as elutant to give 220 mg (11%) of the free base as a beige colored solid. 1H NMR (DMSO-d6; 400 MHz): δ 1.67 (br s, 6), 2.43 (s, 3), 3.74 (br s, 4), 6.80 (s, 1), 7.39 (t, 1, J=7.2), 7.50 (t, 2, J=7.7), 7.75 (d, 2, J=7.5), 7.78 (d, 2, J=7.6), 8.00 (d, 2, J=8.2), 11.01 (s, 1). MS m/z: 369 (M+1). To a hot solution of 2-methyl-6-(4-phenylphenyl)-4-piperidyl pyrrolo[3,2-d]pyrimidine (0.22 g, 0.59 mmol) in 10:1 EtOAc:MeOH (40 mL) was added 1N etheral HCl (Aldrich Chemical Company) (600 mL, 0.60 mmol). Crystallization occurred as the mixture cooled and the precipitate was collected by filtration, washed with Et2O (3×5 mL) and dried under vacuum to give 205 mg (86%) of the title compound as a pale yellow colored solid. Mp:>280° C. 1H NMR (DMSO-d6; 500 MHz): δ 1.72 (br s, 6), 2.58 (s, 3), 4.07 (br s, 4), 6.96 (s, 1), 7.43 (t, 1, J=7.2), 7.42 (t, 2, J=7.7), 7.77 (d, 2, J=7.9), 7.86 (d, 2, J=8.1), 8.06 (d, 2, J=8.1), 12.00 (s, 1), 14.29 (s, 1). MS m/z: 369 (M+1). Anal. Calcd for C24H24N4.HCl.1.0H2O: C, 67.92; H, 6.45; N, 13.21; Cl, 8.35. Found C, 67.92; H, 6.43; N, 13.17; Cl, 8.46.
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][O:9][C:10](=[O:27])[C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16](=[O:26])[CH2:17][NH:18]C(OC(C)(C)C)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>C(Cl)Cl>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[N+:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][O:9][C:10](=[O:27])[C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16](=[O:26])[CH2:17][NH2:18])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC(=O)N1CCC[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
To a solution of 4.10 g of Compound (22) obtained in the step (a) in 5 ml of methylene chloride was added 2.5 ml of trifluoroacetic acid under ice-cooling and the reaction mixture was stirred for 1 hour, then, 4 ml of trifluoroacetic acid was added to the reaction mixture and the stirring was continued for 2 hours. After reaction, the solvent was removed to give 5.82 g of glycyl-L-proline p-nitrobenzyl ester trifluoroacetic acid salt as pale brownish oil.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH3:54].C(=O)([O-])[O-].[Cs+].[Cs+].[F:61][C:62]([F:81])([F:80])[C:63]1[CH:68]=[CH:67][C:66]([NH:69][C:70]2[C:71]3[CH2:79][CH2:78][NH:77][CH2:76][C:72]=3[N:73]=[CH:74][N:75]=2)=[CH:65][CH:64]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[C:49]1([CH3:54])[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[N:77]1[CH2:78][CH2:79][C:71]2[C:70]([NH:69][C:66]3[CH:65]=[CH:64][C:63]([C:62]([F:81])([F:61])[F:80])=[CH:68][CH:67]=3)=[N:75][CH:74]=[N:73][C:72]=2[CH2:76]1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CCNC3)cc1
Reactant: Cc1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccccc1N1CCc2c(ncnc2Nc2ccc(C(F)(F)F)cc2)C1
Temperature: 160 °C
Reaction time: 3 h
Yield: 8.2 %

Procedure:
To 2 mL of dioxane was added 10 mol % of palladium(II)acetate (12 mg) and 20 mol % rac-BINAP (58 mg). After stirring for 3 hours, 2-bromotoluene (0.064 ml, 0.53 mmol), cesium carbonate (682 mg, 2.12 mmol), N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (150 mg, 0.51 mmol) and activated molecular sieves (340 mg) were added. The mixture was sonicated for 10 minutes and heated in a sealed tube via microwave at 160° C. for 3 h in a Personal Chemistry Microwave (Smith Creator). After completion, the mixture was filtered through celite, evaporated and purified by flash chromatography over silica gel using a 0-100% gradient of ethyl acetate/hexanes to give the desired product as a white solid (16 mg).
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:1][C:2]1[N:29]=[C:5]2[N:6]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(Cc2ccc(F)cc2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
A mixture of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.7 g), 1-(bromomethyl)-4-fluorobenzene (0.27 mL), potassium carbonate (0.51 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.56 g, 62%).
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:5].[OH2:17].[OH-].[Na+]>CO>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH:7]2[CH2:8][CH:6]2[C:4]([OH:17])=[O:5])=[CH:10][CH:11]=1
Reactant: CON(C)C(=O)C1CC1c1ccc(Cl)cc1
Reactant: O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CC1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of 2-(4-chloro-phenyl)-cyclopropanecarboxylic acid methoxy-methyl-amide (9.6 g), water (20 mL), and NaOH (3.2 g) in MeOH (40 mL) was refluxed for 3 h. The reaction mixture was cooled down to room temperature and concentrated in vacuo. The residue was acidified by 6 N HCl followed by extraction with CH2Cl2. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound (7.3 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12](=[O:21])[NH:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([CH3:10])([CH3:9])[CH3:8].Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=1>CO>[C:7]([O:11][C:12](=[O:21])[NH:13][CH2:14][CH:15]1[CH2:16][CH2:17][N:18]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=2)[CH2:19][CH2:20]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 120 °C
Yield: 80.8 %

Procedure:
In a 5-ml microwave vial equipped was placed potassium carbonate (1.38 g), tert-butyl(piperidin-4-ylmethyl)carbamate (1.07 g), and 2-bromo-5-trifluoromethylpyridine (1.13 g) in methanol. This was heated to 120° C. for 30 min in a microwave reactor. The mixture was cooled and concentrated in vacuo, and the residue was taken up in ethyl acetate. This was filtered through a plug of silica gel, and the eluent was concentrated in vacuo to provide tert-butyl({1-[5-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}methyl)carbamate (1.45 g, 81%). This compound was taken up in 15 ml of dichloromethane and 15 ml of trifluoroacetic acid. The resultant mixture was stirred at room temperature for 2 h, and then concentrated and taken up in dichloromethane (20 ml) and saturated aqueous sodium bicarbonate. The mixture was extracted and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to provide 1.31 g (87%) of the title compound. Mass spectrum (ESI) 260.1 (M+1).