Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: II.[BH4-].[Na+].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([NH:15][CH3:16])=O.CO>C1COCC1>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][NH:15][CH3:16]
Reactant: CNC(=O)Cc1ccccc1Cl
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CNCCc1ccccc1Cl
Temperature: 0 °C
Yield: 18.8 %

Procedure:
At 0° C., a solution of iodine (29.9 g, 0.12 mol) in THF (100 ml) was added dropwise to a suspension of sodium borohydride (11.1 g, 0.29 mol) and 2-(2-chlorophenyl)-N-methylacetamide (21.6 g, 0.12 mol) in THF (150 ml). After the addition was completed, the reaction mixture was heated to reflux for 16 hours. It was cooled to 0° C. Methanol (150 ml) was added dropwise. The solvent was removed in vacuo. The residue was dissolved in a mixture of tert-butyl methyl ether (200 ml) and a 20% aqueous solution of sodium hydroxide (200 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (2×100 ml). The combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (300 g), using a mixture of DCM/methanol/25% aqueous ammonia (first: 100:10:1, then: 100:20:2, then 100:30:3) as eluent, to give 3.82 g of N-[2-(2-chlorophenyl)ethyl]-N-methylamine.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:13](O)=[O:14])[C:9](=[O:11])[CH:10]=1.[NH2:28][C:29]1[CH:33]=[CH:32][N:31]([CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[N:30]=1>>[F:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:2]([F:1])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:13]([NH:28][C:29]2[CH:33]=[CH:32][N:31]([CH2:34][C:35]([OH:37])([CH3:36])[CH3:38])[N:30]=2)=[O:14])[C:9](=[O:11])[CH:10]=1
Reactant: O=C(O)C(CC1CCOCC1)n1ncc(Oc2c(F)cccc2F)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCOCC2)n2ncc(Oc3c(F)cccc3F)cc2=O)n1
Yield: 37 %

Procedure:
Using the method described in Example 17, 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(tetrahydro-pyran-4-yl)-propionic acid (Intermediate 32) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide as a white solid (0.11 g, 37%); ES+-HRMS m/e calcd for C25H29N5O5F2 [M+H+] 518.2210 found 518.2210. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3H) 1.07 (s, 3H) 1.12-1.62 (m, 5H) 1.81-1.96 (m, 1H) 2.13-2.28 (m, 1H) 3.08-3.28 (m, 2H) 3.70-3.86 (m, 2H) 3.90 (s, 2H) 4.67 (s, 1H) 5.55 (dd, J=11.1, 4.3 Hz, 1H) 6.04 (d, J=3.0 Hz, 1H) 6.40 (d, J=2.3 Hz, 1H) 7.34-7.43 (m, 2H) 7.43-7.52 (m, 1H) 7.53 (d, J=2.3 Hz, 1H) 8.30 (d, J=3.0 Hz, 1H) 10.86 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)[CH:9]=2)[C:4](=O)[CH2:3]1.[CH2:23]([NH2:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:22])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)[CH:9]=2)[CH:4]([NH:31][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:3]1
Reactant: NCCc1ccccc1
Reactant: CC1(C)CC(=O)c2ccc(Oc3ccc(C(N)=O)cn3)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC1(C)CC(NCCc2ccccc2)c2ccc(Oc3ccc(C(N)=O)cn3)cc21
Yield: 66.5 %

Procedure:
Using a method similar to Example 14, using 6-(3,3-dimethyl-1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 11, 100 mg, 0.337 mmol), phenethylamine (49 mg, 0.405 mmol), Ti(iPrO)4 (192 mg, 0.675 mmol), TiCl4 (1.0M/DCM, 0.675 ml, 0.675 mmol), and NaBH3CN (42 mg, 0.675 mmol) gives the title compound (90 mg) as a white solid. Mass spectrum (ion spray): m/z=402 (M+1); 1HNMR (CDCl3): 8.60 (s, 1H), 8.14 (d, 1H), 7.32-7.19 (m, 6H), 6.95-6.88 (m, 3H), 6.25 (br. s, 2H), 4.31 (t, 1H), 3.02 (m, 2H), 2.86 (m, 2H), 2.33 (m, 1H), 1.68 (m, 1H), 1.31 (s, 3H), 1.17 (s, 3H).
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]([OH:8])=O)([CH3:3])[CH3:2].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:19])=[C:14]([N:16]=[C:17]=[S:18])[CH:15]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:19])=[C:14]([N:16]2[C:6](=[O:8])[CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[C:17]2=[S:18])[CH:15]=1
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: CC(C)NCC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(Cl)cc1N1C(=O)CN(C(C)C)C1=S
Yield: 54.7 %

Procedure:
A mixture of the crude N-isopropyl glycine (21.2 g), 5-chloro-2-methylphenylisothiocyanate (18.3 g), triethyl amine (21.0 g) and chloroform (300 mL) was heated at reflux for 4 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (400 mL) and water (300 mL). The organic phase was washed with 2N HCl (2×300 mL), then with water. The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. Crystallization from ethanol afforded the title compound (15.4 g) as a peach solid, m.p. 142°-144° C. Anal. Calcd. for. C13H15Cl N2O S: C, 55.21; H, 5.35; N, 9.91. Found: C, 55.07; H, 5.20; N, 9.82. Mass spectrum (+FAB, [M+H]+) m/z 283/285.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH:8]=[O:9].[C:10]([Mg]Cl)#[CH:11]>>[OH:9][CH:8]([C:4]1[S:5][CH:6]=[CH:7][C:3]=1[O:2][CH3:1])[C:10]#[CH:11]
Reactant: C#C[Mg]Cl
Reactant: COc1ccsc1C=O
Product: C#CC(O)c1sccc1OC

Procedure:
3-Methoxy-2-thiophenecarboxadlehyde was prepared by adding n-butyllithium (10.56 mmol, 2.5M solution in hexane)(Aldrich), without cooling, to a solution of 3-methoxythiophene (1 g,8.8 mmol) (Aldrich) in dry diethyl ether (5 mL) over a period of 5 min. The mixture was gently heated at reflux for 2 h at which time the organolithium compound was transferred, via cannula, to a solution of DMF (23 mmol) in diethyl ether (5 mL) which was cooled in an ice bath. The reaction was stirred at room temperature for 14 h, at which time 1N HCl (10 mL) was added and the layers were separated. The aqueous layer was extracted with diethyl ether (3×25 mL), and the combined organic extracts were dried over magnesium sulfate, and concentrated to yield 3-methoxy-2-thiophenecarboxaldehyde as a pale, yellow solid. The 3-methoxy-2-thiophenecarboxaldehyde was then added to ethynylmagnesium chloride (Aldrich) according to Method A above to yield 3-hydroxy-3-(3-methoxy-2-thiophenyl)-1-propyne. (Yield 151 mg, 0.9 mmol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[F:13][C:14]1[CH:21]=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]>CC#N.CCOC(C)=O>[F:13][C:14]1[CH:21]=[C:20]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: N#Cc1ccc(F)cc1F
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1ccc(N2CCNCC2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Piperazine (20.0 g, 232.3 mmol) and K2CO3 (16.0 g, 118.5 mmol) are dissolved in CH3CN (85 ml). 2,4-Difluoro-benzonitrile (8.5 g, 61.1 mmol) is added and the mixture is stirred for 2 h at rt, then diluted with AcOEt and washed with water. The organic layer is separated, dried over Na2SO4 and evaporated. Excess piperazine is removed by MPLC (100 g silica gel, eluent CH2Cl2:MeOH 85:15). A second chromatographic purification (300 g silica gel, eluent toluene:EtOH:AcOH 4:4:1) yields the acetate salt of 2-fluoro-4-(piperazin-1-yl)-benzonitrile that is crystallized from AcOEt, filtered off and washed with ether. The free base is isolated by extraction with sat. aq. Na2CO3 solution/AcOEt.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1.[C:20](N1C=CN=C1)(N1C=CN=C1)=[O:21]>C1COCC1>[O:21]=[C:20]1[N:8]([C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)c1ccc(Nc2ccccc2N)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-n2c(=O)[nH]c3ccccc32)cc1
Temperature: 75 °C

Procedure:
A mixture of ethyl 4-[(2-aminophenyl)amino]benzoate from Step B (442 mg, 1.72 mmol) and 1,1′-carbonyldiimidazole (652 mg, 4.02 mmol) in THF (10 mL) was heated at 75° C. for 3 h. The cooled mixture was partitioned between EtOAc (100 mL) and 10% aqueous citric acid (50 mL). The organic layer was washed with H2O (30 mL), then brine (30 mL), then dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane::EtOAc—95:5 to 75:25, to give the title compound, which was of sufficient purity for use in the next step. MS: m/z=283 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([N:17]2[CH:22]3[CH2:23][CH2:24][CH:18]2[CH2:19][O:20][CH2:21]3)[N:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[CH2:31][CH2:32][O:33][CH2:34][CH:35]=1)CCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[O:33]1[CH2:32][CH:31]=[C:30]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=3)[N:5]=[C:4]([N:17]3[CH:22]4[CH2:23][CH2:24][CH:18]3[CH2:19][O:20][CH2:21]4)[N:3]=2)[CH2:35][CH2:34]1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCOCC1
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)nc(N3C4CCC3COC4)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(-c2nc(C3=CCOCC3)nc(N3C4CCC3COC4)n2)cc1
Temperature: 100 °C
Yield: 85.6 %

Procedure:
A microwave vial was charged with 8-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.440 g, 1.27 mmoles). Toluene (6 mL) was then added and the solution was sparged with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.088 g, 0.076 mmol) and tributyl(3,6-dihydro-2H-pyran-4-yl)stannane (0.567 g, 1.52 mmol) were added. The vial was sealed and heated to 100° C. for 40 minutes via microwave. Additional tributyl(3,6-dihydro-2H-pyran-4-yl)stannane (0.283 g, 0.76 mmoles) and tetrakis(triphenylphosphine)palladium(0) (0.022 g, 0.019 mmol) were added and the suspension was heated to 110° C. by microwave for additional 90 minutes. The suspension was then cooled to room temperature and filtered through Celite™. The filter cake was washed with ethyl acetate and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with 0-2% methanol in methylene chloride, to provide 8-(4-(3,6-dihydro-2H-pyran-4-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.430 g, 86%) as a light yellow solid. HRMS 396.1666 (M+H, calc.), 396.1668 (M+H, obs.).
Reaction SMILES: [OH:1][C@H:2]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:3]([CH3:21])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18](O)=[O:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[CH:30]([NH2:33])([CH3:32])[CH3:31].ON1C2C=CC=CC=2N=N1>CN(C)C=O>[OH:1][C@H:2]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:3]([CH3:21])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([NH:33][CH:30]([CH3:32])[CH3:31])=[O:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1
Reactant: C[C@H](Oc1ccc(-c2ccc(CC(=O)O)cc2)cc1)[C@H](O)CCc1cccnc1
Reactant: CC(C)N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)NC(=O)Cc1ccc(-c2ccc(O[C@@H](C)[C@H](O)CCc3cccnc3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.9 %

Procedure:
(1S,2R)-[4′-(2-Hydroxy-1-methyl-4-pyridin-3-yl-butoxy)-biphenyl-4-yl]-acetic acid (Example 55, 0.07 g), isopropylamine (0.012 g), 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (0.038 g) and 1-hydroxybenzotriazole (0.027 g) were dissolved in dimethylformamide (2 ml) and stirred for 16 hours at room temperature. The dimethylformamide was removed by vacuum distillation, the residue dissolved in dichloromethane, filtered and purified by normal-phase HPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as a solid (0.061 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]([NH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]([O:22]CC)=O)=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[C:3]=1[CH:10]1[C:20](=[O:22])[C:19]2[C:14](=[CH:15][N:16]=[CH:17][CH:18]=2)[NH:13][C:11]1=[O:12]
Reactant: CCOC(=O)c1ccncc1NC(=O)Cc1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2cnccc2C(=O)C1c1c(F)cc(F)cc1F
Yield: 77.2 %

Procedure:
The product from Step 2 (3.0 g) and potassium carbonate (1.6 g) were stirred in dry DMF (100 ml) at 100° C. for 3 hours. The reaction was cooled and the excess DMF evaporated to give a black oil. Water (100 ml) was added and then washed with ethyl acetate. The aqueous fraction was filtered and acidified with 2M aqueous hydrochloric acid to neutral pH, and the water was evaporated to give a solid, which was then extracted with methanol. The methanol extract was evaporated to give the crude 3-(2,4,6-trifluorophenyl)-1H-[1,7]naphthyridine-2,4-dione as a dark brown crystalline solid (2.0 g), which was used for the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:25]#[C:26][CH2:27][CH2:28][CH2:29][CH:30]=[O:31])[CH:16]=[CH:17][C:18]=1[N:19]1[CH:23]=[N:22][C:21]([CH3:24])=[N:20]1.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]([OH:31])[CH2:29][CH2:28][CH2:27][C:26]#[C:25][C:15]2[CH:16]=[CH:17][C:18]([N:19]3[CH:23]=[N:22][C:21]([CH3:24])=[N:20]3)=[C:13]([O:12][CH3:11])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C#CCCCC=O)ccc1-n1cnc(C)n1
Reactant: Clc1ccc([Mg]Br)cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(C#CCCCC(O)c2ccc(Cl)c(Cl)c2)ccc1-n1cnc(C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3,4-Dichlorophenylmagnesium bromide (0.5 M THF solution, 13 mL) was added dropwise to a mixture of 6-[3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]hex-5-ynal (900 mg) in THF (32 mL) at −78° C., and the mixture was stirred for 1 hr under ice-cooling and at room temperature for 14 hr. 3,4-Dichlorophenylmagnesium bromide (0.5M THF solution, 13 mL) was added to the reaction mixture under ice-cooling, and the mixture was stirred for 1 hr under ice-cooling. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (349 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH:23]=[C:22]3[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[NH:9][C:10]([NH:12][CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[S:11])=[CH:4][CH:3]=1.IC.[C:38](=O)([O-])[O-].[K+].[K+]>CC(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH:23]=[C:22]3[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[NH:9][C:10]([S:11][CH3:38])=[N:12][CH2:13][CH:14]([O:15][CH3:16])[O:17][CH3:18])=[CH:6][CH:7]=1
Reactant: COC(CNC(=S)NC(c1ccc(Cl)cc1)c1ccc2[nH]c(=O)cc(-c3ccccc3)c2c1)OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(CN=C(NC(c1ccc(Cl)cc1)c1ccc2[nH]c(=O)cc(-c3ccccc3)c2c1)SC)OC
Temperature: 25 °C
Yield: 113.2 %

Procedure:
A mixture of intermediate (6-a) (15.3 g), iodomethane (2.27 ml) and potassium carbonate (5 g) in 2-propanone (50 ml) was stirred at room temperature for one night. The mixture was evaporated, the residue was taken up in DCM and washed with K2CO3 10%. The organic layer was dried (MgSO4), filtered off and evaporated, yielding 17.8 g (100%) of (±)-methyl N-[(4-chlorophenyl)(1,2-dihydro-2-oxo-4-phenyl-6-quinolinyl)-methyl]-N'-(2,2-dimethoxy-ethyl)carbamimidothioate (interm. 6-b), which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[N:5][C:6]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:7]([Cl:15])[N:8]=2)[N:3]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Cl:15][C:7]1[N:8]=[C:9]2[C:4](=[N:5][C:6]=1[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[N:3]=[C:2]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[N:11]=[C:10]2[N:12]([CH3:14])[CH3:13]
Reactant: CN(C)c1nc(Cl)nc2nc(NCc3ccccc3)c(Cl)nc12
Reactant: C1CNCCN1
Product: CN(C)c1nc(N2CCNCC2)nc2nc(NCc3ccccc3)c(Cl)nc12

Procedure:
This compound was prepared analogous to Example 1 from 2,6-dichloro-4-dimethylamino-7-benzylamino-pteridine and piperazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:35]([O:36][CH3:37])=[CH:34][C:6]2[S:7][C:8](/[CH:23]=[C:24](\[C:28]3[CH:33]=[CH:32]N=[CH:30][CH:29]=3)/[C:25]([O-:27])=[O:26])=[C:9]([O:10][C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=4)[CH:12]=3)[C:5]=2[CH:4]=1.[Na+].[CH3:39]OC1C(OC)=CC2SC(/C=C(\C3C=CC=CC=3)/C([O-])=O)=C(OC3C=CC(OC)=CC=3)C=2C=1.[Na+]>>[CH3:1][O:2][C:3]1[C:35]([O:36][CH3:37])=[CH:34][C:6]2[S:7][C:8](/[CH:23]=[C:24](\[C:28]3[CH:33]=[CH:32][CH:39]=[CH:30][CH:29]=3)/[C:25]([OH:27])=[O:26])=[C:9]([O:10][C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=4)[CH:12]=3)[C:5]=2[CH:4]=1
Reactant: COc1ccc2cc(Oc3c(/C=C(/C(=O)[O-])c4ccncc4)sc4cc(OC)c(OC)cc34)ccc2c1
Reactant: COc1ccc(Oc2c(/C=C(/C(=O)[O-])c3ccccc3)sc3cc(OC)c(OC)cc23)cc1
Agent: [Na+]
Product: COc1ccc2cc(Oc3c(/C=C(/C(=O)O)c4ccccc4)sc4cc(OC)c(OC)cc34)ccc2c1

Procedure:
The procedure is as for Example 1 using the reagent of Example 5 in Step E, and the reagent of Example 6 in Step F.
Reaction SMILES: [CH:1]1([CH2:5][OH:6])[CH2:4][CH2:3][CH2:2]1.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH:1]1([CH2:5][O:6][S:13]([C:10]2[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=2)(=[O:15])=[O:14])[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCC2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
A solution of cyclobutanemethanol (4.0 g, 46.4 mmol) in dichloromethane (28 mL) at 25° C. was treated with 4-dimethylaminopyridine (6.23 g, 50.9 mmol). The reaction was then cooled to 0° C. and was treated with para-toluenesulfonylchloride (8.95 g, 46.94 mmol). The reaction was allowed to slowly warm to 25° C. and was allowed to stir overnight. After this time, the reaction was partitioned between water (200 mL) and methylene chloride (2×200 mL). The combined organics were washed with a 1N aqueous hydrochloric acid solution and a saturated aqueous sodium chloride solution (1×200 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford toluene-4-sulfonic acid cyclobutylmethyl ester (10.87 g, 97%) as colorless oil which was used without further purification.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([C:15]3[C:16]([NH:27][C:28]4[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)=[N:17][CH:18]=[C:19]([C:21]4[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=4)[CH:20]=3)[N:12]=[C:11]([CH3:36])[N:10]=2)=CC=1>C(O)(C(F)(F)F)=O>[CH3:35][O:34][C:31]1[N:30]=[CH:29][C:28]([NH:27][C:16]2[C:15]([C:13]3[N:12]=[C:11]([CH3:36])[N:10]=[C:9]([NH2:8])[N:14]=3)=[CH:20][C:19]([C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)=[CH:18][N:17]=2)=[CH:33][CH:32]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(-c4cnn(C)c4)cnc3Nc3ccc(OC)nc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(-c3cnn(C)c3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 80 °C
Yield: 82.9 %

Procedure:
N,N-bis(4-Methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (140 mg, 0.222 mmol) was treated with TFA (10 mL) and heated at 80° C. with a reflux condenser for 18 h. The TFA was removed in vacuo and the residue was treated with 2 M NH3 in MeOH to pH 7 and dry-packed with silica gel. Purification on the ISCO (12 g column, 1-20% MeOH in DCM) gave 4-(2-(6-methoxypyridin-3-ylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (71.7 mg, 0.184 mmol, 83% yield) as an orange crystalline solid. m/z (ESI, +ve ion) 390.0 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.69 (1H, s); 8.87 (1H, d, J=2.5 Hz); 8.55 (2H, t, J=3.1 Hz); 8.18 (1H, dd, J=8.8, 2.7 Hz); 8.12 (1H, s); 7.90 (1H, s); 7.82 (1H, s); 7.77 (1H, s); 6.84 (1H, d, J=8.8 Hz); 3.88 (3H, s); 3.85 (3H, s); 2.46 (3H, s).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[CH:9][C:7]=2[CH:8]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH3:28][S:29]([O:1][CH2:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[CH:9][C:7]=2[CH:8]=1)(=[O:31])=[O:30]
Reactant: N#Cc1ccc(-c2ccc3oc(CCO)cc3c2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
To a solution of Example 1B (0.57 g, 2.2 mmol) and triethylamine (0.9 mL, 6.5 mmol) in dichloromethane (10 mL) at 20° C. was added methane sulfonyl chloride (0.79 g, 4.5 mmol). The mixture was stirred for 30 min., diluted with dichloromethane, washed with water, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was chromatographed on silica with dichloromethane to give the titled compound (0.66 g, 89%). MS (DCI) m/z 359 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19]([CH:21]3[CH2:23][CH2:22]3)=O)[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O>ClCCCl>[CH:21]1([C:19]2[N:12]3[C:13]([CH:14]=[N:15][C:10]([NH:9][C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)=[N:11]3)=[C:16]([CH3:17])[N:18]=2)[CH2:23][CH2:22]1
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)C3CC3)nn2)cc1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Nc2ncc3c(C)nc(C4CC4)n3n2)cc1
Yield: 54.4 %

Procedure:
Applying the Cyclization Procedure 1, using N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]cyclopropanecarboxamide (Intermediate 62) (103 mg, 0.33 mmol), 1,2-dichloroethane (5 mL) and phosphorus oxychloride (0.25 mL, 2.68 mmol), to afford 7-cyclopropyl-5-methyl-N-[4-(methyloxy)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (53 mg) as a yellow solid. MS m/z 296 (M+1).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C:5](=S)[CH2:4][N:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[N:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[C:22]([NH:24][NH2:25])=O>C(O)CCC>[CH3:1][C@H:2]1[CH2:7][N:6]2[C:22]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][N:16]=3)=[N:24][N:25]=[C:5]2[CH2:4][N:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: NNC(=O)c1cnccn1
Reactant: C[C@H]1CNC(=S)CN1C(=O)OC(C)(C)C
Solvent: CCCCO
Product: C[C@H]1Cn2c(nnc2-c2cnccn2)CN1C(=O)OC(C)(C)C
Temperature: 120 °C
Yield: 43.5 %

Procedure:
To a suspension of (S)-tert-butyl 2-methyl-5-thioxopiperazine-1-carboxylate (2.5 g, 10.9 mmol) in n-butanol (10 mL) was added pyrazine-2-carbohydrazide (1.6 g, 11.9 mmol) and the reaction mixture was heated to 120° C. for 12 hours. The reaction mixture as cooled to room temperature, concentrated onto silica gel and purified by flash column chromatography (0-20% MeOH in EtOAc) to provide the desired compound (1.5 g, 43%). 1H NMR (400 MHz, DMSO) δ 9.36 (d, J=1.4 Hz, 1H), 8.78-8.74 (m, 2H), 5.02 (d, J=17.4 Hz, 1H), 4.72 (d, J=12.6 Hz, 2H), 4.53 (d, J=17.4 Hz, 1H), 4.36-4.28 (m, 1H), 1.48 (s, 9H), 1.10 (d, J=6.9 Hz, 3H).