Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][S:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:27]=[C:28]([NH2:32])[CH2:29][CH2:30][OH:31]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:25][N:32]=[C:28]([CH2:29][CH2:30][OH:31])[N:27]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][S:20][CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCSCC3)C2)cc1
Reactant: NC(CCO)=NO
Product: CCc1ccc(C2CC(c3nc(CCO)no3)CN(C(=O)N3CCSCC3)C2)cc1

Procedure:
According to General Method 6A, 300 mg (0.828 mmol) of the compound from Example 7A and 112 mg (1.08 mmol) of N′,3-dihydroxypropanimidamide [Graham A. Showell et al., J. Med. Chem., 1991, 34, 1086-1094] were reacted. Yield: 248 mg (66% of theory)
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:5]=2[N:4]=[C:3]1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[S:21][CH3:22].I([O-])(=O)(=O)=[O:24].[Na+].C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O.CO>[CH3:22][S:21]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:15]=1[C:3]1[N:2]([CH3:1])[C:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:5]=2[N:4]=1)=[O:24]
Reactant: CSc1cnccc1-c1nc2cc(C(F)(F)F)ccc2n1C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cn1c(-c2ccncc2S(C)=O)nc2cc(C(F)(F)F)ccc21
Temperature: 40 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
To a mixture of 0.49 g of 1-methyl-2-(3-methylthiopyridine-4-yl)-5-trifluoromethyl-1H-benzimidazole, 5 ml of methanol and 10 ml of water was added 0.65 g of sodium periodate under ice cool, then, the mixture was stirred for 1 hour at 40° C. After cooling down to room temperature, a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium thiosulfate aqueous solution were poured, and the mixture was extracted three times with chloroform. The combined organic layers were dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.48 g of 2-(3-methanesulfinylpyridin-4-yl)-1-methyl-5-trifluoromethyl-1H-benzimidazole (hereinafter, referred to as present active compound 18).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](Cl)=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH3:14]>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH2:14])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: O=C(Cl)c1ccc2ncccc2c1
Solvent: C1CCOC1
Product: NC(=O)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of quinoline-6-carbonyl chloride (0-2) (2.2 g, 10.5 mmol) in THF (100 mL) was added ammonia (5 mL) at 0° C. The mixture was stirred at room temperature for 1 h, then concentrated and washed with water (15 mL) to afford the title compound (1.5 g). MS (m/z): 173 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([F:15])([F:14])[F:13])=[C:6]2C(O)=O)#[N:2].O>CN1C(=O)CCC1>[F:15][C:12]([F:13])([F:14])[C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2
Reactant: N#Cc1ccc2[nH]c(C(F)(F)F)c(C(=O)O)c2c1
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2[nH]c(C(F)(F)F)cc2c1
Temperature: 135 °C
Reaction time: 0.67 h
Yield: 82.2 %

Procedure:
5-cyano-2-(trifluoromethyl)-1H-indole-3-carboxylic acid (Intermediate 13, 2.09 g) was dissolved in NMP (10 mL) and H2O (1 mL) was then added. The mixture was heated to 130-140° C. overnight under nitrogen. The solution was cooled to room temperature and H2O (30 mL) was added and the solution stirred for 40 min. and then filtered. The cake was washed with H2O. The product is then dried under vacuum at 40° C. to give the title compound (1.42 g);
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-])=O)=[CH:11][CH:10]=1.[H][H]>CO.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(COC2CCCCO2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1-c1ccc(COC2CCCCO2)cc1
Reaction time: 2 h
Yield: 95.4 %

Procedure:
A solution of 4-(tetrahydropyranyloxy)methyl-2'-nitro-1,1'-biphenyl (4.12 g, 13.2 mmol) in 100 mL of methanol was hydrogenated at 40 psi in the presence of 5% palladium on carbon. After 2 hours, uptake of hydrogen was complete. The reaction mixture was filtered through diatomacious earth, and the filter cake washed with methanol. The filtrate was evaporated under vacuum to yield 3.57 g of the product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([C@@H:25]([NH2:27])[CH3:26])=[N:23][CH:24]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:17][C:5]1[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)=[N:7][C:2]([NH:27][C@H:25]([C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:24][N:23]=2)[CH3:26])=[N:3][CH:4]=1
Reactant: Clc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Reactant: C[C@H](N)c1ccc(F)cn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(F)cn1
Temperature: 175 °C
Yield: 75 %

Procedure:
A mixture of 2,5-dichloro-4-(5-cyclopropyl-1H-pyrazole-3-ylamino)pyrimidine (Method 7; 0.064 g, 0.235 mmol), (S)-1-(5-fluoropyridin-2-yl)ethanamine (Method 6; 0.030 g, 0.214 mmol), and DIEA (0.045 ml, 0.257 mmol) in n-BuOH (2 ml) was heated in a sealed tube at 175° C. for 20 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane:EtOAc=1:1) to give the title compound as a white solid (0.060 g, 75%). 1H NMR (400 MHz) 12.51 and 12.09 (s, 1H), 9.70 and 9.64 (s, 1H), 8.49 (s, 1H), 8.38 (s, 1H), 8.02 and 7.93 (b, 1H), 7.63 (m, 1H), 7.40 (m, 1H), 5.93 and 5.80 (s, 1H), 5.06 (m, 1H), 1.83 (m, 1H), 1.45 (d, J=6.8 Hz, 3H), 0.94 (m, 1H), 0.84 (m, 1H), 0.74 (m, 1H), 0.63 (m, 1H). MS: Calcd.: 373. Found: [M+H]+374.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:12][C@@H:13]([CH:21]([CH3:23])[CH3:22])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CS(C)=O>[CH3:22][CH:21]([CH3:23])[C@H:13]([NH:12][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)[C@H](Nc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 1-fluoro-4-nitrobenzene (3.0 g, 21 mmol) and tert-butyl (2S)-2-amino-3-methylbutanoate hydrochloride (5.4 g, 26 mmol) in DMSO (20 mL) was added K2CO3 (8.8 g, 64 mmol). The reaction mixture was stirred at 100° C. for 8 h. EtOAc (200 mL) was added. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/petroleum ether (1:10 v/v)) to obtain compound 55a as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C15H22N2O4: 295.2 (M+H). Found 295.2.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH3:12])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[Br:21][CH2:22][CH2:23][CH2:24]Br>C(#N)C>[CH3:14][N:2]([CH3:1])[C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:24][CH2:23][CH2:22][Br:21])=[C:6]([O:11][CH3:12])[CH:5]=1
Reactant: COc1cc(C(=O)N(C)C)ccc1O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(=O)N(C)C)ccc1OCCCBr
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.7 %

Procedure:
To N,N-dimethyl-4-hydroxy-3-methoxybenzamide (5.64 g, 28.7 mmol) in acetonitrile (450 ml) was added potassium carbonate (7.9 g) followed by 1,3-dibromopropane (11.6 g). The resulting reaction mixture was refluxed for 3 hours and stirred at room temperature for 12 hours. The mixture was filtered and concentrated to an oil. Following purification by column chromatography, N,N-dimethyl-4-bromopropoxy-3-methoxybenzamide as a colorless oil (7.6 g) was obtained.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4].[CH3:22][NH:23][CH3:24]>C1COCC1.ClCCl>[CH3:22][N:23]([CH3:24])[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4]
Reactant: O=C(CCl)Nc1cccc(-c2cnc3ccccc3n2)c1
Reactant: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)CC(=O)Nc1cccc(-c2cnc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 36 %

Procedure:
To a solution of 2-chloro-N-(3-quinoxalin-2-ylphenyl)acetamide (67 mg, 0.225 mmol) in THF (3 mL), a 2 M solution of dimethylamine in THF (0.562 mL, 1.152 mmol) was added and the reaction mixture was stirred at room temperature for 48 hrs. The reaction mixture was diluted with dichloromethane (DCM, 5 mL) and solvents evaporated to afford N2,N2-dimethyl-N1-(3-quinoxalin-2-ylphenyl)glycinamide (25 mg, 36% yield). LCMS calculated for C18H18N4O (M+H): 307.37. found 307.20. 1H-NMR (MeOD, 400 Mhz) δH: 9.50 (1H, s), 8.65 (m, 1H), 8.30-8.15 (m, 3H), 8.00-7.87 (m, 3H), 7.60-7.55 (m, 1H), 4.30 (s, 2H), 3.15 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6](Cl)[N:5]=[C:4]([CH3:10])[N:3]=1.[OH-].[NH4+:12]>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([CH3:10])[N:5]=[C:6]([NH2:12])[C:7]=1[CH3:8]
Reactant: Cc1nc(Cl)c(C)c(Cl)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(N)c(C)c(Cl)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A microwave vial was charged with 4,6-dichloro-2,5-dimethylpyrimidine (523 mg, 2.95 mmol) and ammonium hydroxide (8 mL) in ethanol (4 mL). The vial was heated to 80° C. and stirred for 8 h. After concentration under reduced pressure, the reaction mixture was extracted with EtOAc (15 mL×8). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give 6-chloro-2,5-dimethylpyrimidin-4-amine as a yellow solid (411 mg). MS (ESI): m/z 158 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([NH:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:29][C:28]2=[O:37])[CH2:23][CH2:22]1)=[O:20])[CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[C:15]([CH3:17])[CH:16]=1)[NH:13][N:12]=[CH:11]2.[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CS(C)=O>[CH2:38]([N:3]1[CH:4]=[CH:5][N:1]=[C:2]1[CH:6]([NH:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:29][C:28]2=[O:37])[CH2:23][CH2:22]1)=[O:20])[CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[C:15]([CH3:17])[CH:16]=1)[NH:13][N:12]=[CH:11]2)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2ncc[nH]2)cc2cn[nH]c12
Reactant: BrCc1ccccc1
Solvent: CS(C)=O
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2nccn2Cc2ccccc2)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-(1-(1H-Imidazol-2-yl)-2-(7-methyl-1H-indazol-5-yl)ethyl)-4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamide (100 mg, 0.2 mmol) and benzyl bromide (25.0 μL, 1.1 equiv) were combined in dimethyl sulfoxide (0.6 mL). After stirring at room temperature for 16 h, the reaction mixture was poured into ice water and extracted with ethyl acetate (2×). The organic layer was washed with brine (2×), dried over sodium sulfate, concentrated, and purified by column chromatography to afford 14.0 mg (12%). 1H-NMR (CD3OD, 500 MHz) δ 1.58-1.70 (m, 4H), 2.48 (s, 3H), 2.75-2.84 (m, 2H), 3.36-3.43 (m, 2H), 4.02-4.14 (m, 3H), 4.23 (s, 2H), 4.86 (m, 1H), 5.23 (s, 2H), 5.29-5.38 (m, 1H), 6.85-7.01 (m, 3H), 7.10-7.84 (m, 10H), 7.96 (s, 1H). Mass spec.: 589.16 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31]C(=O)C(C)(C)C)=[CH:27][CH:26]=3)=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:9](=[O:13])[O:10]2)=[CH:5][C:4]=1[CH3:38].O[Li].O.C1COCC1>O>[OH:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C:7]2[C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([CH3:38])[CH:5]=3)[O:10][C:9](=[O:13])[C:8]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=2)=[CH:26][CH:27]=1
Reactant: COc1cc2oc(=O)c(-c3ccc(C(F)(F)F)cc3)c(Cc3ccc(OC(=O)C(C)(C)C)cc3)c2cc1C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2oc(=O)c(-c3ccc(C(F)(F)F)cc3)c(Cc3ccc(O)cc3)c2cc1C
Yield: 64.9 %

Procedure:
A mixture of 2,2-dimethyl-propionic acid 4-(7-methoxy-6-methyl-2-oxo-3-(4-trifluoromethyl-phenyl)-2H-chromen-4-ylmethyl)-phenyl ester (72 mg, 0.14 mmol) and LiOH.H2O (23 mg, 0.55 mmol) in an 8:1 mixture of THF:H2O (4.5 mL) was stirred at 30° C. for 4 h. THF was removed in vacuo and AcOEt was added. The pH of the aqueous layer was lowered to 5 by addition of aqueous 1N HCl. The layers were separated and the aqueous phase was extracted with AcOEt (2×). The combined organic layers were washed with brine, dried (MgSO4) and concentrated. The residue was purified using flash chromatography (99:1 CH2Cl2:MeOH) to provide the desired compound as a beige solid (40 mg, 67%). 1H NMR (300 MHz, CDCl3) δ 7.62 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 7.25 (d, J=1.0 Hz, 1H), 6.92–6.86 (m, 2H), 6.82 (s, 1H), 6.75–6.69 (m, 2H), 3.95 (s, 2H), 3.90 (s, 3H), 2.16 (s, 3H); MS (ESI) m/z 440.9 (M+H)+; HPLC tR 6.50 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([NH2:14])([CH3:13])[CH3:12])[CH:5]=1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C@@H:30]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:31]Br)=[CH:26][C:25]=1[CH2:41][OH:42])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[I-].[Na+].C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([NH:14][CH2:31][C@@H:30]([C:27]2[CH:28]=[CH:29][C:24]([O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:25]([CH2:41][OH:42])[CH:26]=2)[O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])([CH3:12])[CH3:13])[CH:5]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(CO)c1
Reactant: COC(=O)c1cccc(CC(C)(C)N)c1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c(CO)c2)c1

Procedure:
3-(2-amino-2-methylpropyl)benzoic acid methyl ester (Preparation 34) (1.36 g, 6.60 mmol), [2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]methanol (Preparation 23) (2.96 g, 6.60 mmol), sodium iodide (980 mg, 6.60 mmol) and diisopropylethylamine (3.44 ml, 19.7 mmol) in acetonitrile (10 ml) were heated to reflux for 48 hours under a nitrogen atmosphere. The solvent was then removed in vacuo and saturated aqueous sodium hydrogen carbonate solution (20 ml) added and the product extracted with ethyl acetate (3×30 ml). The combined organics were washed with brine (3×20 ml), dried (sodium sulfate) and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 by volume) to furnish the title compound, the purified product was dissolved in diethylether and evaporated (×3) to yield a white foam (1.70 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([CH:12]=O)[N:5]2[N:4]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([CH2:12][NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:5]2[N:4]=1
Reactant: Nc1ccccc1
Reactant: CSc1ncc2ccc(C=O)n2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CSc1ncc2ccc(CNc3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde (0.200 g, 1.04 mmol) and Aniline (0.104 mL, 1.14 mmol) were dissolved in a solution of Acetic acid (0.100 mL, 1.76 mmol) and Methylene chloride (10 mL, 200 mmol) and the reaction was allowed to stir at room temperature for 1 hour. Sodium triacetoxyborohydride (0.439 g, 2.07 mmol) was then added and the reaction was allowed to continue stirring at room temperature until HPLC showed consumption of starting material. The reaction mixture was poured over saturated sodium bicarbonate and organics were extracted with dichloromethane. Combined extracts were then dried over sodium sulfate, filtered and reduced. The crude reaction mixture was then purified by Isco flash column chromatography (hexanes/ethyl acetate eluent) and combined fractions were reduced and dried under vacuum to afford 0.280 g of (2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-ylmethyl)-phenyl-amine. 1H NMR (400 MHz, DMSO, d6) δ 8.92 (s, 1H), 7.06 (m, 2H), 6.90 (d, 1H, J=4.61 Hz), 6.83 (d, 1H, J=4.61 Hz), 6.65 (m, 2H), 6.54 (t, 1H, J=7.28 Hz), 6.13 (t, 1H, J=6.16 Hz), 4.61 (d, 2H, J=6.16 hz), 2.56 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.Cl.Cl.[Cl:15][C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C>C(O)CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:25]3[CH2:24][CH2:23][N:22]([C:18]4[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=4)[CH2:27][CH2:26]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: OCCO
Product: Clc1cccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)c1
Yield: 58.5 %

Procedure:
Following the general procedure of Example 11 and making noncritical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (Example 4, Step 1; 0.354 g), 1-(3-chlorophenyl)piperazine dihydrochloride (Aldrich; 0.475 g), triethylamine (0.552 g), and ethylene glycol (2 mL) give 0.372 g of the title compound after chromatography (silica gel, methanol/dichloromethane, 4/96) and crystallization from dichloromethane/hexane; mp 148-149° C.; MS m/z 360; IR (mineral oil) 1594, 1340, 1073, 1218, 1502 cm-1. 1H NMR (CDCl3) δ2.71, 3.23, 3.76, 6.79, 6.86, 7.14, 7.52, 7.53, 8.14.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15]([F:17])[C:14](F)=[C:13]([F:19])[CH:12]=3)[C:6]=2[N:7]=1.[CH3:21][NH2:22]>CO>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH3:21])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([F:19])[CH:14]=[C:15]([F:17])[CH:16]=3)[C:6]=2[N:7]=1
Reactant: Fc1cc(C2CCc3c(Cl)nc(Cl)nc32)cc(F)c1F
Reactant: CN
Solvent: CO
Product: CNc1nc(Cl)nc2c1CCC2c1cc(F)cc(F)c1
Yield: 13 %

Procedure:
A solution of 2,4-dichloro-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (498 mg, 1.561 mmol) and methanamine (1.561 mL, 3.12 mmol) in MeOH (10 mL) was stirred at rt for 1 h. Incomplete reaction was observed. Additional portions of methanamine (1.561 mL, 3.12 mmol) were added to the reaction mixture until the reaction was complete. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give 2-chloro-7-(3,5-difluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (60 mg, 0.203 mmol, 30.5% yield). LC-MS (M+H)+=314.0.
Reaction SMILES: P(Br)(Br)([Br:3])=O.O[C:7]1[CH:12]=[C:11]([CH3:13])[NH:10][C:9](=[O:14])[CH:8]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Br:3][C:7]1[CH:12]=[C:11]([CH3:13])[NH:10][C:9](=[O:14])[CH:8]=1
Reactant: O=P(Br)(Br)Br
Reactant: Cc1cc(O)cc(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Br)cc(=O)[nH]1
Temperature: 110 °C

Procedure:
16 mmol of phosphorus oxybromide are added under an argon atmosphere to a solution of 21 mmol of 4-hydroxy-6-methyl-1H-pyridin-2-one [3749-51-7] in 9 ml of N,N-dimethylformamide. The reaction mixture is heated to 110° C. for 30 minutes and subsequently cooled to room temperature, and 10 ml of water are added. The solution is brought to pH 7 by adding sodium carbonate and cooled to 0° C. The precipitate is filtered off and washed with water and diethyl ether. The title compound is identified on the basis of the Rf value.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>ClCCl.Cl>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([O:9][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)=[CH:7][CH:8]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: C1=COCCC1
Agent: Cl
Solvent: ClCCl
Product: FC(F)(F)c1ccc(OC2CCCCO2)cc1
Yield: 133.3 %

Procedure:
A solution of 4-(Trifluoromethyl)-phenol (40 g) in dichloromethane (100 ml) was added at 0° C. dropwise to a solution of dihydropyran (53 g) in dichloromethane (100 ml) and aqueous HCl (200 μl) The reaction was allowed to reach room temperature, then quenched with saturated sodium bicarbonate (×1). The organic layer was separated and dried (MgSO4), concentrated in vacuo to give the sub-title compound (81 g)
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)(=[O:18])=[O:17].[CH3:32][CH:33]([C:35]1[N:39]=[C:38]([N:40]2[CH2:45][CH2:44][CH:43]([CH2:46]O)[CH2:42][CH2:41]2)[O:37][N:36]=1)[CH3:34].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH3:34][CH:33]([C:35]1[N:39]=[C:38]([N:40]2[CH2:41][CH2:42][CH:43]([CH2:46][O:31][C:28]3[CH:27]=[CH:26][C:25]([C:22]4[CH:21]=[CH:20][C:19]([S:16]([CH3:15])(=[O:18])=[O:17])=[CH:24][CH:23]=4)=[N:30][CH:29]=3)[CH2:44][CH2:45]2)[O:37][N:36]=1)[CH3:32]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(O)cn2)cc1
Reactant: CC(C)c1noc(N2CCC(CO)CC2)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc(S(C)(=O)=O)cc4)nc3)CC2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.7 %

Procedure:
Diisopropyl azodicarboxylate (0.175 mL, 0.89 mmol) was added dropwise to a solution of 6-[4-(methylsulfonyl)phenyl]-3-pyridinol (150 mg, 0.59 mmol), {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol (prepared as in Example 20, Steps 1-3, 200 mg, 0.89 mmol), PPh3 (233 mg, 0.89 mmol), and THF (10 mL) at ambient temperature. The mixture was stirred at ambient temperature for 4 h. The mixture was concentrated, and the resulting crude was purified by reverse-phase preparative HPLC using a CH3CN:H2O gradient (10:90 to 100:0) with 0.05% TFA as a modifier, then taken up in CH2Cl2 and free-based with saturated NaHCO3 (aq) to give 5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridine (220 mg) as a white solid.