Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:11]=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=23)[CH:3]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C@@H:27]([NH2:29])[CH3:28]>CN1C(=O)CCC1>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C@@H:27]([NH:29][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=23)[N:5]=[C:6]([S:8][CH3:9])[N:7]=1)[CH3:28]
Reactant: C[C@H](N)c1ccc(F)cc1F
Reactant: CSc1nc(Cl)cc(-c2cnn3cccnc23)n1
Solvent: CN1CCCC1=O
Product: CSc1nc(N[C@@H](C)c2ccc(F)cc2F)cc(-c2cnn3cccnc23)n1
Yield: 58.6 %

Procedure:
A 7 ml NMP solution of 3-(6-chloro-2-(methylthio)pyrimidin-4-yl)pyrazolo[1,5-a]pyrimidine (7h, 1.30 g) and (S)-1-(2,4-difluoro-phenyl)ethanamine (1.47 g) was heated in a microwave reactor at 220° C. for 20 min. LC/MS indicated the major peak was the desired product. The reaction mixture was partitioned between ethyl acetate and sat. NH4OAc. The organic phase was dried with MgSO4, filtered and the solvent was removed under reduced pressure. The product was purified by chromatography (SiO2, EtOAc-Hex, 1:1) (1.09 g, 58.6% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])[C:6]([CH3:8])=O)[CH3:2].[CH3:18][N:19]1[C:23]([NH2:24])=[CH:22][C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:20]1.[ClH:31].CO>C(O)C>[ClH:31].[CH2:1]([O:3][C:4]([C:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[C:22]2[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:20][N:19]([CH3:18])[C:23]=2[NH:24][C:6]=1[CH3:8])=[O:17])[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccccc1C)C(C)=O
Reactant: Cn1nc(-c2ccccc2)cc1N
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CCOC(=O)C1=C(C)Nc2c(c(-c3ccccc3)nn2C)C1c1ccccc1C
Temperature: 25 °C

Procedure:
Ethyl-2-(2-methylbenzyliden)acetoacetate (0.050 mol) is added to 1-methyl-3-phenyl-5-pyrazolamine (0.050 mol) in ethanol (50 ml) and refluxed for 90 minutes. The mixture is then cooled to room temperature, further ethyl-2-(2-methylbenzyliden)acetoacetate (0.050 mol) is added thereto, and the mixture refluxed for further 90 minutes. The reaction mixture is then cooled, the solvent is evaporated, and the residue is taken up in ethyl ether, collected by filtration, and dried. The product is dissolved in methanol and a mixture of hydrochloric acid and methanol (45 mmol of HCl) is added thereto. The product of the title precipitates by adding ethyl ether. M.p. 187° C. (dec.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[CH2:24][CH2:25][C:26](=[O:28])[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[BH4-].[Na+].[Cl-].[Na+]>CCOCC>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:22])([CH3:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[CH2:24][CH2:25][CH:26]([OH:28])[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCC(C)(C)c1ccc(CCC(C)=O)c(OCc2ccccc2)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CCCCCCC(C)(C)c1ccc(CCC(C)O)c(OCc2ccccc2)c1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a -15° C. solution of 0.5 g. (1.31 mmols.) of 4-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-2-butanone (the product of Example 1) in 5 ml. of methanol is added 50 mg. (1.31 mmols.) of sodium borohydride. The reaction mixture is stirred for 30 minutes and is then added to 100 ml. of saturated sodium chloride-150 ml. ether. The ether extract is washed once with 100 ml. of saturated sodium chloride, dried over magnesium sulfate and evaporated to an oil. The oil is purified via column chromatography on 100 g. of silica gel eluted with 1:1 ether:cyclohexane to yield 419 mg. (84%) of the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][N:11]([CH3:13])[CH2:10]2)=[CH:4][N:3]=1.[NH2:14][C:15]1[C:16](=[O:23])[N:17]([CH3:22])[CH:18]=[C:19]([Br:21])[CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.O>[Br:21][C:19]1[CH:20]=[C:15]([NH:14][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH:9]3[CH2:12][N:11]([CH3:13])[CH2:10]3)=[CH:4][N:3]=2)[C:16](=[O:23])[N:17]([CH3:22])[CH:18]=1
Reactant: Cn1cc(Br)cc(N)c1=O
Reactant: CN1CC(Oc2ccc(Br)nc2)C1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CN1CC(Oc2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C1
Temperature: 100 °C
Yield: 41.5 %

Procedure:
To a solution of 2-Bromo-5-(1-methyl-azetidin-3-yloxy)-pyridine (0.327 g, 1.32 mmol) and 3-Amino-5-bromo-1-methyl-1H-pyridin-2-one (0.321 g, 1.58 mmol) in dioxane (5.5 mL) add Cs2CO3 (0.645 g, 1.98 mmol), xantphos (0.153 g, 0.264 mmol) and bubbled argon through reaction mixture for 15 min. Add Pd (OAc)2 (0.03 g, 0.132 mmol) in the end. The reaction was heated at 100° C. under argon for 3 h. TLC shows 2-Bromo-5-(1-methyl-azetidin-3-yloxy)-pyridine was gone. The reaction mixture was treated with water (30 mL) and extracted with dichloromethane (3×20 mL). Organic phase was concentrated and loaded onto silica gel column separation. Using 3-5% MeOH in DCM gave 5-bromo-1-methyl-3-[5-(1-methyl-azetidin-3-yloxy)-pyridin-2-ylamino]-1H-pyridin-2-one as green solid (200 mg, 40% yield).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([O:13][CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:10]=[C:9]([C:20]3[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[N:1]1([C:7]2[N:12]=[C:11]([O:13][CH:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:10]=[C:9]([C:20]3[CH:26]=[CH:25][C:23]([NH:24][C:34]([NH:33][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:35])=[CH:22][CH:21]=3)[N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(-c2nc(OC3CCOCC3)nc(N3CCOCC3)n2)cc1
Product: O=C(Nc1ccccc1)Nc1ccc(-c2nc(OC3CCOCC3)nc(N3CCOCC3)n2)cc1

Procedure:
1-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}-3-phenylurea was prepared by reacting the 4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]aniline and the corresponding phenylisocyanate. Product was purified by Gilson, HPLC. MS (ESI) m/z 476.5.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:15][C:14](=O)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:17][CH3:18])[CH:12]=2)[N:7]=1)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:21]>>[CH2:1]([O:3][C:4]([C:6]1[N:15]=[C:14]([Cl:21])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:17][CH3:18])[CH:12]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc2ccc(OC)cc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Cl)c2cc(OC)ccc2n1
Temperature: 100 °C

Procedure:
To 6-methoxy-4-oxo-3,4-dihydro-quinazoline-2-carboxylic acid ethyl ester (1.38 g, 5.438 mmol) was added POCl3 (25 mL) and the solution was heated at 100° C. for 1.5 h. The solution was concentrated under reduced pressure and the residue was dissolved in EtOAc and washed with water, brine, dried (Na2SO4) and concentrated under reduced pressure to give 1.22 g of 4-chloro-6-methoxy-quinazoline-2-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+]([O-])=O)[CH:6]=1)[CH3:3].C[N:15](CC1C=CC=CC=1[N+]([O-])=O)C.CN(CC1C=C(C=CC=1)N)C.CN(CC1C=CC=CC=1N)C>>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:15])=[CH:7][CH:6]=1)[CH3:3]
Reactant: CN(C)Cc1cccc([N+](=O)[O-])c1
Reactant: CN(C)Cc1ccccc1[N+](=O)[O-]
Agent: CN(C)Cc1cccc(N)c1
Agent: CN(C)Cc1ccccc1N
Product: CN(C)Cc1ccc(N)cc1

Procedure:
By using N,N-dimethyl-3-nitrobenzylamine or N,N-dimethyl-2-nitrobenzylamine in place of N,N-dimethyl-4-nitrobenzylamine, 3-dimethylaminomethylaniline and 2-dimethylaminomethylaniline are obtained, respectively.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[C:8]([N:15]2[C:19]3=[N:20][CH:21]=[N:22][C:23](O)=[C:18]3[CH:17]=[N:16]2)=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11]>>[Cl:6][C:7]1[C:8]([N:15]2[C:19]3=[N:20][CH:21]=[N:22][C:23]([Cl:3])=[C:18]3[CH:17]=[N:16]2)=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cccc(Cl)c1-n1ncc2c(O)ncnc21
Product: N#Cc1cccc(Cl)c1-n1ncc2c(Cl)ncnc21
Temperature: 100 °C
Reaction time: 4 h
Yield: 75.3 %

Procedure:
Phosphorus oxychloride (7.93 mL, 85.03 mmol) was added to 3-chloro-2-(4-hydroxy-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzonitrile (Intermediate AH5) (1.155 g, 4.25 mmol). The resulting mixture was heated to 100° C. and stirred for 4 hours. The reaction mixture was allowed to cool to ambient temperature. The reaction mixture was evaporated to near dryness. Poured onto ice/water with stirring. A solid precipitate was collected by filtration. This was dried overnight under vacuum to afford the product (0.928 g, 75%). 1H NMR (400 MHz, DMSO) δ 8.02-7.96 (1H, t), 8.26 (1H, d), 8.28 (1H, s), 9.05 (2H, d). m/z M+=289; GCMS tR=13.82 min.
Reaction SMILES: [CH3:1][C:2]([C:19]([O:21]C)=O)([CH3:18])[N:3]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].CO.C[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:18][C:2]1([CH3:1])[N:3]([C:4]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:5])[CH2:12][CH:13]([C:14]([O:16][CH3:17])=[O:15])[C:19]1=[O:21]
Reactant: COC(=O)CCN(C(=O)c1ccccc1)C(C)(C)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C1CN(C(=O)c2ccccc2)C(C)(C)C1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a solution of methyl 2-methyl-N-[3-(methyloxy)-3-oxopropyl]-N-(phenylcarbonyl)alaninate (3.5589 g, 11.58 mmol) in toluene (115 mL) was added MeOH (0.94 mL, 23.21 mmol), and NaOMe (1.25 g, 23.14 mmol). The mixture was heated at 60° C. and stirred for 2 h. An additional portion of MeOH (10 mL) was added, and the mixture was stirred for an additional 2 h at 60° C. The mixture was then concentrated in vacuo, and the residue was partitioned between DCM (200 mL) and 1 N aq. HCl (100 mL). The organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide crude methyl 5,5-dimethyl-4-oxo-1-(phenylcarbonyl)-3-pyrrolidinecarboxylate (2.746 g, 86% yield) as a colorless oil. LCMS: (M+H)+: 276.1.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.O[CH2:17][C@@H:18]1[O:22][CH2:21][C@@H:20]([S:23][C:24](=[O:26])[CH3:25])[CH2:19]1>C(Cl)Cl.N1C=CC=CC=1>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][CH2:17][C@@H:18]1[O:22][CH2:21][C@@H:20]([S:23][C:24](=[O:26])[CH3:25])[CH2:19]1)(=[O:8])=[O:9]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(=O)S[C@@H]1CO[C@@H](CO)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)S[C@@H]1CO[C@@H](COS(=O)(=O)C(F)(F)F)C1
Reaction time: 0.75 h

Procedure:
To a 0° C. solution of 0.535 ml of trifluoromethanesulfonic anhydride in 3.75 ml of methylene chloride is added, via a syringe, a 0° C. solution of 0.529 g of product from Example 6 in 0.75 ml of methylene chloride and 0.243 ml of pyridine. The reaction is stirred in an ice bath for 45 minutes; during which time the progress of reaction is checked by thin layer chromatography. The mixture is concentrated in vacuo, slurried with ethyl acetate and filtered. The filtrate is purified by chromatography (Silica Gel: 50% ethyl acetate/hexane) to give 0.799 g of the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][S:19](Cl)(=[O:21])=[O:20])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:30][C:31]([Cl:57])([Cl:56])[CH2:32][O:33][C:34]([N:36]1[C:48]2[CH2:47][N:46](C(OC(C)(C)C)=O)[CH2:45][CH2:44][C:43]=2[C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:35]>CCCCCCC.C(OCC)(=O)C>[Cl:57][C:31]([Cl:30])([Cl:56])[CH2:32][O:33][C:34]([N:36]1[C:48]2[CH2:47][N:46]([S:19]([CH2:18][CH:17]([CH:14]3[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])[CH2:12][CH2:13]3)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:21])=[O:20])[CH2:45][CH2:44][C:43]=2[C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(C(=O)OCC(Cl)(Cl)Cl)c3ccccc23)C1
Reactant: CC(C)(C)OC(=O)C(CS(=O)(=O)Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)C(CS(=O)(=O)N1CCc2c(n(C(=O)OCC(Cl)(Cl)Cl)c3ccccc23)C1)C1CCN(C(=O)OCc2ccccc2)CC1
Yield: 71.9 %

Procedure:
Prepared from 4-(1-tert-butoxycarbonyl-2-chlorosulfonyl-ethyl)-piperidine-1-carboxylic acid benzyl ester (640 mg) and 3,4-dihydro-1H-β-carboline-2,9-dicarboxylic acid 2-tert-butyl ester 9-(2,2,2-trichloro-ethyl) ester (500 mg) to give, after chromatography (SiO2, 2:1 heptane-ethyl acetate), the title compound (608 mg, 61%) as a white solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.N[C:11]([O:13][CH2:14][CH3:15])=[O:12].N>S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O.C1(C)C=CC=CC=1>[CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CCOC(N)=O
Agent: N
Agent: O=C1NS(=O)(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: CCOC(=O)N[Si](C)(C)C
Reaction time: 0.25 h
Yield: 129 %

Procedure:
15.6 ml of hexamethyldisilazane (0.075 mole) were added over 2 minutes to a refluxing mixture of 8.9 g (0.1 mole) of urethane, 183 mg (1 mmole) of saccharin and 10 ml of toluene and the theoretical amount of ammonia was evolved in 30 minutes. Refluxing was continued for 15 minutes and the solvent and excess hexamethyldisilazane were removed under reduced pressure. The residue was vacuum distilled to obtain 15.6 g (96.9%) of N-trimethylsilylurethane boiling at 73° C. at 12 mm Hg and nD 25=1.4268.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([N:28]5[CH2:33][C@H:32]([CH3:34])[NH:31][C@H:30]([CH3:35])[CH2:29]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.Br[CH2:37][CH2:38][F:39].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([N:28]5[CH2:33][C@H:32]([CH3:34])[N:31]([CH2:37][CH2:38][F:39])[C@H:30]([CH3:35])[CH2:29]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: FCCBr
Reactant: C[C@@H]1CN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C[C@H](C)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C[C@H](C)N1CCF
Temperature: 120 °C
Reaction time: 1 h
Yield: 27.7 %

Procedure:
A mixture of 2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (150 mg 0.3 mmol), 1-Bromo-2-fluoro-ethane (65 mg, 0.45 mmol) and Cesium carbonate (200 mg, 0.6 mmol) in N,N-Dimethyl-formamide (2 mL) was stirred at 120° C. for 1 h under the irradiation of microwave. The reaction mixture was filtered over celite and purified by pre-TLC (Hexanes/EtOAc=1:1) to afford 45 mg of 315 (yield: 28%). 1H NMR (CDCl3, 400 MHz): δ8.23 (s, 1H), 7.51-7.46 (m, 1H), 7.10-6.93 (m, 4H), 6.46 d, J=8.8 Hz, 1H), 4.52 (t, J=5.6 Hz, 2H), 4.40 (t, J=5.6 Hz, 2H), 4.18 (t, J=4.8 Hz, 2H), 3.85-3.82 (m, 2H), 3.07-2.94 (m, 4H), 2.70 (d, J=6.0 Hz, 2H), 2.55-2.49 (m, 2H), 1.22-1.34 (d, J=6.0 Hz, 6H). LC-MS (ESI): m/z=541 [M+H]+
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[N:5][NH:4][C:3]1=[S:17].Br[CH2:19][CH2:20][CH2:21][Cl:22].C(O)(=O)C>C(O)C>[Cl:22][CH2:21][CH2:20][CH2:19][S:17][C:3]1[N:2]([CH3:1])[C:6]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:12]=2)=[N:5][N:4]=1
Reactant: Cn1c(-c2ccc(C(F)(F)F)cc2)n[nH]c1=S
Reactant: ClCCCBr
Solvent: CCO
Solvent: CC(=O)O
Product: Cn1c(SCCCCl)nnc1-c1ccc(C(F)(F)F)cc1
Temperature: 90 °C

Procedure:
To 4-methyl-5-[4-(trifluoromethyl)phenyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (0.4 g, preparation reported in WO 02/40471) in ethanol (6 ml) sodium ethanolate (0.63 ml) was carefully added with stirring followed by 1-bromo-3-chloropropane (0.23 ml). The mixture was heated at 90° C. for 1 h. Acetic acid was added at room temperature until pH=4. After elimination of the solvent under reduced pressure the residue was partitioned between aqueous NaHCO3 (saturated) and DCM. The organic layer was collected and the aqueous phase extracted twice with DCM. The combined DCM layers were concentrated and submitted to column chromatography (EtOAc—acetone gradient) to provide the title compound as white solid (0.394 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)c1
Product: O=[N+]([O-])c1cccc(CNc2nc(-n3ccnc3)nc3sc(C(F)(F)F)cc23)c1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-trifluoromethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-trifluoromethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=[C:16]([NH:29][NH2:30])[CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1>C(O)C>[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[N:30][NH:29][C:16]2[CH:15]=[C:14]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=2)=[CH:34][CH:33]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccccc4)cc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
There was dissolved, in ethanol (2 mL), trifluoroacetic acid salt of (7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (28.5 mg, 0.0529 mM), then 4-chloro-benzaldehyde (7.4 mg, 0.053 mM) was added to the solution and the mixture was stirred at room temperature for one hour. This reaction liquid was filtered, the resulting solid was diluted with a saturated aqueous sodium bicarbonate solution and then the solution was extracted with methylene chloride. The extracts thus obtained were combined, dried over anhydrous sodium sulfate, then the solvent was distilled off and the resulting solid was washed with diethyl ether to thus give the title compound (13.0 mg, yield: 57%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:19][CH3:20].Cl.Cl[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:20][O:19][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)[N:9]=[CH:8][N:7]=[C:6]2[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCc1ccncc1
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1OCc1ccncc1
Temperature: 80 °C
Yield: 35 %

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-phenoxyquinazoline (95 mg, 0.35 mmol), 4-chloromethyl pyridine hydrochloride (120 mg, 0.74 mmol) and potassium carbonate (200 mg, 1.4 mmol) in DMF (5 ml) were heated at 80° C. for 2 hours. The reaction mixture was allowed to cool, water was added and the mixture extracted with ethyl acetate (3×50 ml). The combined extracts were then washed with water and dried (MgSO4). The solvent was removed by evaporation and the residue trituated with an ethyl acetate/hexane mixture to give 6-methoxy-4-phenoxy-7-(4-pyridylmethoxy)quinazoline (44 mg, 35%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:22][C:21]([C:23]([NH:25][CH:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])=[O:24])=[N:20][CH:19]=2)=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:22][C:21]([C:23]([NH:25][C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])=[O:24])=[N:20][CH:19]=3)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc(N)cc2)o1)C(C)C
Product: COC(=O)[C@@H](NC(=O)c1ncc(-c2ccc(NC(=O)Nc3ccc(Cl)cc3)cc2)o1)C(C)C

Procedure:
The title compound was synthesized analogous to Example 1, using 1-chloro-4-isocyanatobenzene (0.533 mmol) and intermediate 1. 1H NMR (DMSO-d6, 300 MHz): δ 9.011-8.983 (d, 2H), 8.919 (s, 1H), 7.813 (s, 1H), 7.792-7.763 (d, J=8.7 Hz, 2H), 7.624-7.595 (d, J=8.7 Hz, 2H), 7.518-7.488 (d, J=9 Hz, 2H), 7.357-7.327 (d, J=9 Hz, 2H), 4.327-4.276 (m, 1H), 3.680 (s, 3H), 2.285-2.216 (m, 1H), 0.979-0.957 (d, J=6.6 Hz, 6H); MS (ESI) m/z 471 (M+H)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:13]=[C:12]2[C:7]([N:8]=[C:9]([CH3:19])[C:10]([C:14]([O:16]CC)=O)=[N:11]2)=[CH:6][CH:5]=1.[C:20](#[N:22])[CH3:21].O>C1(C)C=CC=CC=1>[F:3][C:4]1[CH:13]=[C:12]2[C:7]([N:8]=[C:9]([CH3:19])[C:10]([C:14](=[O:16])[CH2:21][C:20]#[N:22])=[N:11]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1nc2cc(F)ccc2nc1C
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nc2ccc(F)cc2nc1C(=O)CC#N
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 12.0 g, 300 mmol) in toluene (450 mL) was added a solution of ethyl 7-fluoro-3-methylquinoxaline 2-carboxylate (35.1 g, 150 mmol) and acetonitrile (19.6 mL, 375 mmol) in toluene (40 mL) dropwise over 35 min at 85° C. After being stirred for 5 min at the same temperature, the reaction mixture was cooled to 0° C., and then added water (175 mL). The aqueous layer was separated and the organic layer was extracted with 1N aqueous sodium hydroxide (200 mL). The combined aqueous layer was acidified to pH 2 with conc. Hydrochloric acid (45.0 mL) at 0° C., and the resulting precipitate was collected and washed with water (150 mL). The solid was dissolved with chloroform (1000 mL) and water (500 mL). The aqueous layer was extracted with chloroform (300 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was triturated with ethanol to give 3-(7-fluoro-3-methylquinoxalin-2-yl)-3-oxopropanenitrile. MS (APCI): m/z 230 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH:15]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([CH3:17])[CH3:16]>CC(C)=O>[CH:15]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:20][CH2:19]1)([CH3:17])[CH3:16]
Reactant: Clc1cnccn1
Reactant: CC(C)N1CCNCC1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)N1CCN(c2cnccn2)CC1
Temperature: 120 °C

Procedure:
Chloropyrazine (2.3 g, 20 mmol) and triethylamine (3 g, 30 mmol) were mixed in acetone (8 mL) in a 20 mL microwave vessel. 1-Isopropylpiperazine (2.8 g, 22 mmol) was added and the reaction mixture was heated for 3300 seconds at 120° C. in a microwave oven. The reaction mixture was evaporated and the residue was purified on a silicagel column with dichloromethane/MeOH (9:1) as eluent. Yield: 1.64 g solid 4-isopropyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl.