Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([Cl:16])[N:3]=1.[CH2:17]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)CC(C)C>C(OCC)C>[ClH:16].[CH2:17]([CH:24]1[CH2:29][CH2:28][N:27]([C:4]2[N:3]=[C:2]([NH2:1])[C:11]3[C:6](=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[N:5]=2)[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: COc1ccc2c(N)nc(Cl)nc2c1OC
Solvent: CCOCC
Solvent: CC(C)CCO
Product: COc1ccc2c(N)nc(N3CCC(Cc4ccccc4)CC3)nc2c1OC
Product: Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
4-Amino-2-chloro-7,8-dimethoxyquinazoline (2.40 g., 10 mmole), 4-benzylpiperidine (1.93 g., 11 mmole) and 50 ml. of isoamyl alcohol were heated at reflux under a nitrogen atmosphere for two hours and cooled to room temperature. Diethyl ether (50 ml.) was added and the mixture allowed to stand in the refrigerator for two days. The precipitated solid was collected by filtration and recrystallized from ethanol/diethyl ether to afford 2.50 g. (60%) of the title compound, M.P. 216°-217° C.
Reaction SMILES: C[O:2][C:3]([CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:21](=[O:22])[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:14]2=[O:23])=[CH:9][C:8]=1[N+:24]([O-])=O)=O>C(O)(=O)C.C(OCC)(=O)C.O.[Fe]>[NH:24]1[C:8]2[C:7](=[CH:12][CH:11]=[C:10]([N:13]3[C:14](=[O:23])[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=4[C:21]3=[O:22])[CH:9]=2)[NH:6][CH2:5][C:3]1=[O:2]
Reactant: COC(=O)CNc1ccc(N2C(=O)C3=C(CCCC3)C2=O)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CNc2ccc(N3C(=O)C4=C(CCCC4)C3=O)cc2N1
Reaction time: 3 h
Yield: 76.3 %

Procedure:
2-(4-Methoxycarbonylmethylamino-3-nitrophenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (2.06 g) was dissolved in a mixture of acetic acid (20 ml) and ethyl acetate (20 ml), and the resultant solution was dropwise added to a mixture of 5% aqueous acetic acid (10 ml) and iron powder (4 g) at 70° to 80° C., followed by stirring at the same temperature for 3 hours. The reaction mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The extract was washed with sodium bicarbonate solution, dried and concentrated to give 2-(3,4-dihydro-2(1H)-quinoxalinon-7-yl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (1.3 g). m.p., 208°-209° C.
Reaction SMILES: [CH3:1][NH2:2].[N+:3]([C:6]1[CH:17]=[CH:16][C:9]2[CH2:10][CH2:11][CH:12]=[CH:13][C:14](=[O:15])[C:8]=2[CH:7]=1)([O-:5])=[O:4]>C1C=CC=CC=1.C(O)C>[N+:3]([C:6]1[CH:17]=[CH:16][C:9]2[CH2:10][CH2:11][CH:12]([NH:2][CH3:1])[CH2:13][C:14](=[O:15])[C:8]=2[CH:7]=1)([O-:5])=[O:4]
Reactant: CN
Reactant: O=C1C=CCCc2ccc([N+](=O)[O-])cc21
Solvent: c1ccccc1
Solvent: CCO
Product: CNC1CCc2ccc([N+](=O)[O-])cc2C(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 101.5 g of extemporaneously prepared monomethylamine in 700 ml of benzene was added at 20° C. with stirring to a mixture of 101.6 g of the product of Step B in 1 liter of ethanol and the mixture was stirred for 2 1/2 hours at room temperature and was allowed to stand for 12 hours. The mixture was evaporated to dryness under reduced pressure to obtain 125 g of 3-nitro-7-methylamino-6,7,8,9-tetrahydro [5H] benzocycloheptene-5-one in the form of a brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.[CH3:17][O:18][C:19]([C:21]1[C:26]([NH2:27])=[N:25][C:24]([NH:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[C:23]([Cl:35])[N:22]=1)=[O:20]>C(O)CC(C)C>[CH3:17][O:18][C:19]([C:21]1[C:26]([NH2:27])=[N:25][C:24]([NH:28][CH:29]2[CH2:34][CH2:33][N:32]([C:4]3[N:3]=[C:2]([NH2:1])[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=3)[CH2:31][CH2:30]2)=[C:23]([Cl:35])[N:22]=1)=[O:20]
Reactant: COC(=O)c1nc(Cl)c(NC2CCNCC2)nc1N
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: CC(C)CCO
Product: COC(=O)c1nc(Cl)c(NC2CCN(c3nc(N)c4cc(OC)c(OC)cc4n3)CC2)nc1N
Temperature: 120 °C
Yield: 49.5 %

Procedure:
4-Amino-2-chloro-6,7-dimethoxyquinazoline (0.74 g, 3.1 mmol) was added to a solution of (36) (1.0 g, 3.2 mmol) in isoamyl alcohol (20 mL) at 25° C. The mixture was heated to 120° C. and maintained at that temperature for 12 h. The reaction mixture was then cooled to room temperature and the desired product was filtered and rinsed with acetone to give 0.75 g (49%) of the compound (1): TLC (Rf =0.50; 10% MeOH/CH2Cl2); 1H NMR (CDCl3) δ 6.93 (s, 1H), 6.82 (s, 1H), 5.44 (d, 1H, J=7.8), 5.21 (br s, 2H), 4.77 (d, 2H, J=13.7), 4.19 (m, 1H), 3.97 (s, 3H), 3.92 (s, 3H), 3.90 (s, 3H), 3.12 (t, 2H, J=11.3), 2.12 (d, 2H, J=12.6), 1.56 (m, 2H); 13C NMR (CDCl3) δ 166.6, 160.7, 158.4, 155.6, 155.4, 150.8, 149.6, 146.1, 121.5, 110.6, 105.8, 102.8, 101.7, 56.3, 56.1, 51.9, 48.9, 43.0, 31.8; HRMS (FAB) m/z 621.0766 (M+Cs)+ (C21H25N8O4Cl requires 621.0742); Anal. (C21H25N8O4Cl·1/2HCl·1/4CH3OH) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](OS(C3C=CC(C)=CC=3)(=O)=O)=[N:13][C:12]=12.O.[NH:33]1[CH2:38][CH2:37][C:36](=[O:39])[CH2:35][CH2:34]1.C(N(CC)CC)C>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([N:33]3[CH2:38][CH2:37][C:36](=[O:39])[CH2:35][CH2:34]3)=[N:13][C:12]=12
Reactant: Cc1ccc(S(=O)(=O)Oc2nc3c(-c4ccccc4F)nnn3c3ccccc23)cc1
Reactant: O=C1CCNCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCN(c2nc3c(-c4ccccc4F)nnn3c3ccccc23)CC1
Yield: 76 %

Procedure:
A solution of 3-(2-fluorophenyl)-5-(4-methylbenzenesulfonyloxy)-[1,2,3]triazolo[1,5-α]quinazoline (Example 1, step b) (3.0 g, 6.91 mmol), 4-piperidone monohydrate, hydrochloride salt (1.28 g, 8.3 mmol) and triethylamine (3.0 ml, 21 mmol) in dry N,N-dimethylformamide (25 ml) was stirred at 60° C. under nitrogen for 4 h. The mixture was diluted with water (100 ml) and extracted with 10% methanol:dichloromethane (150 ml). The extract was dried (Na2SO4), filtered and concentrated. The residual solid was washed with diethyl ether-ethyl acetate and dried in vacuo to give 3-(2-fluorophenyl)-5-(4-oxopiperidin-1-yl)-[1,2,3]triazolo[1,5-α]quinazoline (1.90 g, 76%). δH (360 MHz; DMSO) 2.67 (4H, t, J=6), 3.99 (4H, t, J=6), 7.33-7.48 (3H, m), 7.78 (1H, dd, J=7 and 7), 8.05-8.11 (2H, m), 8.25 (1H, d, J=8), 8.58 (1H, d, J=8); m/z (ES+) 362 (M+H+).
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[CH2:16][C:15]([CH3:18])([CH3:17])[O:14][C:13]([CH3:20])([CH3:19])[CH2:12]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:19][C:13]1([CH3:20])[O:14][C:15]([CH3:17])([CH3:18])[CH2:16][N:11]([CH2:10][CH2:9][OH:8])[CH2:12]1
Reactant: [H][H]
Reactant: CC1(C)CN(CCOCc2ccccc2)CC(C)(C)O1
Agent: [Pd]
Solvent: CO
Product: CC1(C)CN(CCO)CC(C)(C)O1
Reaction time: 48 h

Procedure:
Dissolve 4-(2-benzyloxy-ethyl)-2,2,6,6-tetramethyl-morpholine (490 mg, 1.77 mmol) MeOH (40 mL). Add to a pressure vessel containing a slurry of 10% Pd/C (100 mg) in MeOH (20 mL). Pressurize with 45 psi hydrogen gas. Monitor the reaction by MS. After 48 h, add another portion of 10% Pd/C (100 mg) and re-pressurize to 45 psi hydrogen. Stir an additional 3 days. Filter the reaction mixture through Celite® eluting with MeOH. Concentrate to give the desired product in quantitative yield. MS (ES+) 188.3 (M+1)+.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].C(N(CC)CC)C.[CH3:14][C:15]([CH3:20])([CH3:19])[C:16](Cl)=[O:17]>C(Cl)Cl>[Br:2][CH2:3][CH2:4][CH2:5][NH:6][C:16](=[O:17])[C:15]([CH3:20])([CH3:19])[CH3:14]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCCCBr
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCCCBr
Reaction time: 0.08 h
Yield: 55.4 %

Procedure:
To a suspension of 3-bromopropylamine hydrobromide (290 mg, 1.3 mmol) in CH2Cl2 (10 mL) cooled in ice bath was added triethylamine (470 uL). The resulting mixture was stirred for 5 min and trimethylacetyl chloride (163 uL, 1.3 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 2 hrs, condensed under vacuum, purified by flash chromatography to yield N-(3-bromopropyl)pivalamide as colorless oil (160 mg, 55%). 1H NMR (500 MHz, CDCl3): 8 (5.97 (br s, 1H), 3.40 (m, 4H), 2.07 (m, 2H), 1.17 (s, 9H); 13C NMR (125 MHz, CDCl3): δ 178.7, 37.2, 32.1, 31.1, 27.6.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[CH:5][S:6][C:7]=1[CH2:8][S:9][C:10]1[N:15]=[C:14]([OH:16])[CH:13]=[C:12]([C:17]([F:20])([F:19])[F:18])[N:11]=1)[CH3:2].[CH3:21][O-].[Na+].IC>CO.C(Cl)Cl>[CH2:1]([C:3]1[N:4]=[CH:5][S:6][C:7]=1[CH2:8][S:9][C:10]1[N:15]=[C:14]([O:16][CH3:21])[CH:13]=[C:12]([C:17]([F:20])([F:19])[F:18])[N:11]=1)[CH3:2]
Reactant: CCc1ncsc1CSc1nc(O)cc(C(F)(F)F)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: CO
Solvent: ClCCl
Product: CCc1ncsc1CSc1nc(OC)cc(C(F)(F)F)n1
Temperature: 65 °C
Yield: 60 %

Procedure:
To a solution of 2-{[(4-ethyl-1,3-thiazol-5-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol (500 mg, 1.56 mmol) in anhydrous methanol (10 mL) was added dropwise a solution of 30% sodium methoxide in methanol (310 μL, 1.71 mmol) at 0° C. The mixture was heated to 65° C. for 1 hour. Iodomethane (220 μL, 3.43 mmol) was added at room temperature, and the reaction was heated overnight at 65° C. The solvent was evaporated, and the residue was extracted three times with dichloromethane/water. The combined organic phases were washed with brine, dried over magnesium sulfate, and evaporated to afford a crude oil. The residue was dissolved in DCM and purified on silica gel using DCM/MeOH (0 to 10%) to afford 4-ethyl-5-({[4-methoxy-6-(trifluoromethyl)pyrimidin-2-yl]sulfanyl}methyl)-1,3-thiazole (315 mg, 60% yield). 1H NMR (500 MHz, MeOH-d4): δ 1.21 (t, J=7.5 Hz, 3H), 2.79 (q, J=7.5 Hz, 2H), 3.40 (s, 3H), 4.74 (s, 2H), 6.76 (s, 1H), 8.89 (s, 1H). LRMS (ES+) m/z 336 (100%, M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH3:14])[C:12]=1[CH3:13])[N:9]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:8][C:7]1([CH2:21][CH2:20][CH2:19]1)[CH2:6]2.[C:22](O)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH3:14])[C:12]=1[CH3:13])[N:9]([CH2:15][CH2:16][CH2:17][NH:18][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:8][C:7]1([CH2:19][CH2:20][CH2:21]1)[CH2:6]2
Reactant: O=C(O)c1ccccc1
Reactant: COc1cc2c(c(C)c1C)N(CCCN)CC1(CCC1)C2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc2c(c(C)c1C)N(CCCNC(=O)c1ccccc1)CC1(CCC1)C2
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a solution of 3-(6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline]-1′-yl)propan-1-amine (80 mg) prepared as described herein, dissolved in 2 mL dichloromethane, was added benzoic acid (67.6 g), 1,3-dicyclohexylcarbodiimide (68.4 mg), 4-dimethylaminopyridine (18 mg) at room temperature. After 2 hours, more dichloromethane was added and the mixture was filtered. The filtrate was concentrated onto silica gel and purified through a column (Hexane/EtOAc, 10:6-10:7), to give N-(3-(6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline]-1′-yl)propyl)benzamide (95 mg). Demethylation as described herein gave N-(3-(6′-hydroxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline]-1′-yl)propyl)benzamide (62.4 mg, Hexane/EtOAc, 10:12 as a light yellow oil.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]=[C:10]1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](Br)(=[O:19])[CH3:18].C(N(CC)CC)C>CC(C)=O>[C:17]([N:11]1[CH:12]=[CH:13][C:14](=[O:15])[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]1[CH3:16])(=[O:19])[CH3:18]
Reactant: CC1=NC=CC(=O)C1OCc1ccccc1
Reactant: CC(=O)Br
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)n1ccc(=O)c(OCc2ccccc2)c1C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
1 3-Benzyloxy-2-methylpyrid-4-one (4 g) is dissolved in dry acetone (100 ml). Acetylbromide (3 g) and triethylamine (2.7 g) are added and the resulting mixture is mechanically stirred overnight. The mixture is then filtered and the filtrate is rotary evaporated to dryness. The residue is dissolved in methylene chloride and washed with dilute hydrochloric acid (pH 3.0), then twice with water, and is dried over Na2SO4 and rotary evaporated to yield a solid residue. Recrystallisation of this residue from an ethylacetate/hexane mixture gives 1-acetyl-3-benzyloxy-2-methylpyrid-4-one as an oil (3.1 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CCN(CC)CC.[C:22](Cl)(=[O:24])[CH3:23]>C(Cl)Cl>[C:22]([NH:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1cc(N)c(OC)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(NC(C)=O)c(OC)cc1Cl
Reaction time: 12 h
Yield: 62.7 %

Procedure:
To a mixture of methyl 5-amino-2-chloro-4-methoxybenzoate (3.6 g, 16.7 mmol), Et3N (6.7 g, 66.8 mmol) and DCM (100 mL) at RT, acetyl chloride (1.57 g, 20.1 mmol) was added dropwise and the resulting mixture was stirred for 12 h. The reaction mixture was partitioned between dichloromethane and water. The organic layer was washed with saturated NaHCO3 solution and brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether=1:1) to afford the desired product (2.7 g, 63% yield).
Reaction SMILES: [CH3:1][N:2]([S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23])[C:3]1[CH:4]=[C:5]([O:17][C:18]([F:21])([F:20])[F:19])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([O:14]CC)=[O:13])=[CH:8]2.[OH-].[Na+].O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[CH3:1][N:2]([S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:23])=[O:24])[C:3]1[CH:4]=[C:5]([O:17][C:18]([F:20])([F:21])[F:19])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]2
Reactant: CCOC(=O)c1cc2cc(OC(F)(F)F)cc(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(c1cc(OC(F)(F)F)cc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.9 %

Procedure:
A mixture of ethyl 7-[methyl(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indole-2-carboxylate (2.19 g), 1N aqueous sodium hydroxide solution (10 mL), tetrahydrofuran (10 mL) and ethanol (10 mL) was stirred at room temperature for 15 hr. The reaction mixture was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was washed with hexane to give the title compound (2.05 g, yield 100%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C@@H:8]([OH:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:13]=[C:14](O)[CH:15]=[CH:16][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[F:11][C:12]1[CH:17]=[C:16]([CH:15]=[CH:14][CH:13]=1)[O:10][C@@H:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=1)[CH3:9]
Reactant: C[C@H](O)c1ccnc(N)n1
Reactant: Oc1cccc(F)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](Oc1cccc(F)c1)c1ccnc(N)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 47.7 %

Procedure:
(S)-1-(2-aminopyrimidin-4-yl)ethanol (6b) (7.75 g), 3-fluorophenol (6.87 g) and triphenylphosphine (16.07 g) were added to tetrahydrofuran (150 mL) under nitrogen and cooled to 0° C. (brine/ice bath). The resulting brown mixture was stirred at 0° C. for 20 min then diisopropyl azodicarboxylate (12.06 mL, 12.39 g) was added dropwise as a solution in tetrahydrofuran (40 mL). The reaction was maintained at 0-2° C. throughout the addition and was then allowed to warm to room temperature overnight. The solvent was removed under reduced pressure before the crude product was loaded onto a silica plug and purified by flash chromatography on silica eluting with heptane/ethyl acetate 7:3 followed by crystallisation from ethanol to give the title compound (6.2 g) as a white crystalline solid, MS (ES): m/z 234.0 [M+H]+; [α]D−153.0 (methanol, c=1.8 mg/ml).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.ClCCl.Cl[C:16]([CH3:24])([CH2:18][CH2:19][C:20](Cl)([CH3:22])[CH3:21])[CH3:17]>O>[OH:11][C:5]1[CH:10]=[CH:9][C:8]2[C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][C:16]([CH3:24])([CH3:17])[C:7]=2[CH:6]=1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: Oc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(O)ccc21
Temperature: 25 °C
Reaction time: 19 h

Procedure:
The synthesis process is as set forth in the chemical reaction formula below. The AlCl3 in the reaction path stands for aluminum chloride. Into phenol (1.02 g, 10.8 mmol) were added anhydrous dichloromethane (5 mL), aluminum chloride (144 mg, 1.08 mmol), and 2,5-dichloro-2,5-dimethylhexane (2.18 g, 11.9 mmol) followed by stirring at room temperature for 19 hours. The reaction solution was poured into cold water and extracted by ethyl acetate. The organic layer was washed by water, a saturated sodium hydrogen carbonate aq. solution, and a saturated saline solution, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by recrystallization in a solvent of hexane. The yield was 1.83 g (83%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[NH:7][C:8]([NH2:17])=[C:9]2[C:13]([N:14]=1)=[N:12][C:11]([O:15][CH3:16])=[N:10]2)[CH2:2][CH2:3][CH3:4].[CH2:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26]O)[CH2:22][CH2:21]1)[CH3:19].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:15][CH3:16])[N:12]2[CH2:26][CH:23]2[CH2:24][CH2:25][N:20]([CH2:18][CH3:19])[CH2:21][CH2:22]2)=[C:8]([NH2:17])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: CCN1CCC(CO)CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCCOc1nc(N)c2nc(OC)n(CC3CCN(CC)CC3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.1 %

Procedure:
2-(Butyloxy)-8-(methyloxy)-1H-purin-6-amine (300 mg, 1.264 mmol), (1-ethyl-4-piperidinyl)methanol (362 mg, 2.53 mmol) and tributylphosphine (0.624 ml, 2.53 mmol) were dissolved in THF (12 ml). 1,1′-(Azodicarbonyl)dipiperidine (638 mg, 2.53 mmol) was added and the reaction mixture stirred at rt overnight. The solvent was removed in vacuo and the residue purified by column chromatography, loading in dichloromethane and purified on Flashmaster II silica (Si) 20 g using a 0-100% ethyl acetate in cyclohexane+0-20% methanol (+1% Et3N) gradient over 30 mins. The appropriate fractions were combined and evaporated in vacuo. The material (300 mg) was dissolved in 1:1 MeOH:DMSO 3 ml and re-purified by Mass Directed AutoPrep (Method A). The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus to give the title compound as a clear gum (60 mg).
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[F:7][C:8]([F:13])([F:12])[C:9](O)=O>>[CH3:1][N:2]1[C:9]([C:8]([F:13])([F:12])[F:7])=[N:5][NH:4][C:3]1=[S:6]
Reactant: O=C(O)C(F)(F)F
Reactant: CNC(=S)NN
Product: Cn1c(C(F)(F)F)n[nH]c1=S
Yield: 95.5 %

Procedure:
257 g (2.44 mol) of 4-methyl-thiosemicarbazide are added to 1.2 liters of trifluoroacetic acid, and the mixture is refluxed for 16 hours. It is then concentrated under a water pump vacuum, the residue is triturated with diethyl ether/petroleum ether (5:100 by volume), and the product, which is obtained as crystals, is isolated by filtration. 444.5 g (95.5% of theory) of 4-methyl-5-trifluoromethyl-2,4-dihydro-3H-1,2,4-triazole-3-thione of melting point 115° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH2:7][C:8]2[N:9]([CH3:22])[C:10]3[C:15]([C:16]=2[CH2:17][CH2:18][C:19](O)=[O:20])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[C:25]([N:32]1[CH:36]=[CH:35]N=[CH:33]1)(N1C=CN=C1)=O.CN([N:40]1[CH2:45]CC[CH2:42][CH2:41]1)C>O1CCCC1>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH2:7][C:8]2[N:9]([CH3:22])[C:10]3[C:15]([C:16]=2[CH2:17][CH2:18][C:19]([N:40]2[CH2:45][CH2:35][CH:36]([N:32]([CH3:25])[CH3:33])[CH2:42][CH2:41]2)=[O:20])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C)N1CCCCC1
Reactant: Cn1c(COc2ccc(Cl)cc2)c(CCC(=O)O)c2ccccc21
Solvent: C1CCOC1
Product: CN(C)C1CCN(C(=O)CCc2c(COc3ccc(Cl)cc3)n(C)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere 3-{2-[(4-chlorophenoxy)methyl]-1-methyl-1H-indol-3-yl}propanoic acid (0.286 g, 0.832 mmol) was dissolved in 6 ml of dry tetrahydrofuran. To this solution 1,1′-carbonyldiimidazole (0.141 g, 0.874 mmol) was added and the resulting mixture was stirred at room temperature for about two hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was then heated to 65° C. and maintained at this temperature for about 35 minutes. To this reaction mixture dimethylaminopiperidine (0.112 g, 0.874 mmol), dissolved in about 3.6 ml of tetrahydrofuran. This mixture was stirred at room temperature overnight.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][C:8]2[C:9](=[O:15])[NH:10][C:11](=[S:14])[NH:12][CH:13]=2)[CH:4]=[N:3][CH:2]=1.[CH3:16]CN(C(C)C)C(C)C.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:38]=[CH:37][C:36]([CH2:39]Cl)=[CH:35][CH:34]=2)=[CH:28][C:27]=1[C:41]([F:44])([F:43])[F:42].CI>C(Cl)Cl.[Zn+2].[Br-].[Br-].CN1C(=O)CCC1>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:38]=[CH:37][C:36]([CH2:39][S:14][C:11]3[N:12]([CH3:16])[CH:13]=[C:8]([CH2:7][C:5]4[CH:6]=[N:1][CH:2]=[N:3][CH:4]=4)[C:9](=[O:15])[N:10]=3)=[CH:35][CH:34]=2)=[CH:28][C:27]=1[C:41]([F:44])([F:43])[F:42]
Reactant: CCN(C(C)C)C(C)C
Reactant: FC(F)(F)c1cc(Oc2ccc(CCl)cc2)ccc1Cl
Reactant: O=c1[nH]c(=S)[nH]cc1Cc1cncnc1
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: CI
Product: Cn1cc(Cc2cncnc2)c(=O)nc1SCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 7.3 %

Procedure:
To a solution of 5-(5-pyrimidinylmethyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (70 mg, 0.318 mmol) and DIPEA (0.083 ml, 0.477 mmol) in DCM (2 ml) was added 1-chloro-4-{[4-(chloromethyl)phenyl]oxy}-2-(trifluoromethyl)benzene (110 mg, 0.343 mmol). The reaction mixture was heated at 60° C. overnight. After removing the solvent by nitrogen, the residue was dissolved in MeCN (4 ml), and NMP (1.5 ml), and ZnBr2 (107 mg, 0.477 mmol) and DIPEA (0.083 ml, 0.477 mmol) were added. The mixture was then stirred at 60° C. for 10 min and MeI (0.020 ml, 0.318 mmol) was added dropwise, then stirred at 60° C. for 1.5 h. Purification via MDAP then afforded the title compound (12 mg, 5.97% yield). LCMS: rt=3.38 min, [M+H+]=519
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N+:5]([O-])[CH:6]=[CH:7][CH:8]=1.[CH2:10]([N:12](CC)CC)C>C(#N)C>[C:10]([C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][N:5]=1)#[N:12]
Reactant: COc1ccc[n+]([O-])c1
Reactant: CCN(CC)CC
Solvent: CC#N
Product: COc1cccnc1C#N

Procedure:
3-Methoxypyridine-1-oxide (25.2 g, 209 mmol) was dissolved in acetonitrile (260 mL). Trimethylsilycyanide (66.35 g, 669 mmol) and triethylamine (45.13 g, 446 mmol) were added and the reaction mixture heated at reflux for overnight. The cooled solution was concentrated in vacuo to give a brown solid which was partitioned between CH2Cl2 and 3M Na2CO3. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using 1:1 EtOAc/hexanes as eluent. Compound 762B was isolated (17.63 g, 63%) as a light yellow solid. HPLC: 96.2% at 1.37 min(YMC S5 ODS column) eluting with 10-90% aqueous methanol containing 0.2% phosphoric acid over a 4 min gradient monitoring at 220 nm. MS (ES): m/z 134.88 [M+H]+.