Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1[N:3]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14]4[N:15]3[CH:18]([CH3:23])[C:19](=[O:22])[NH:20][N:21]=4)=[CH:10][CH:9]=2)C(C)=CC=1.C(N(CC)CC)C.Cl.NO>CCO.O>[NH2:3][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][C:14]3[N:15]2[CH:18]([CH3:23])[C:19](=[O:22])[NH:20][N:21]=3)=[CH:10][CH:9]=1
Reactant: Cc1ccc(C)n1-c1ccc2c(c1)N1C(=NNC(=O)C1C)CC2
Agent: Cl
Agent: NO
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CC1C(=O)NN=C2CCc3ccc(N)cc3N21
Temperature: 25 °C
Yield: 67.6 %

Procedure:
To a solution of 9-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-5,6-dihydro-1H-[1,2,4]triazino[4,3-a]quinolin-2(3H)-one (0.140 g, 0.45 mmol) and triethylamine (0.138 g, 1.362 mmol) in EtOH (9 mL) was added a solution of hydroxylamine hydrochloride (0.095 g, 1.362 mmol) in water (3 mL) and the reaction mixture was heated to reflux for 3 h. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (eluting with 50-100% EtOAc in petroleum ether) to give 9-amino-1-methyl-5,6-dihydro-1H-[1,2,4]-triazino[4,3-a]quinolin-2(3H)-one (0.070 g, 67%). 1H NMR (CDCl3, 400 MHz): δ 8.06 (brs, 1H), 6.91 (d, J=8.0 Hz, 1H), 6.31 (d, J=8.0 HZ, 1H), 6.26 (s, 1H), 4.60 (q, J=6.8 HZ, 1H), 3.63 (brs, 2H), 2.67 (m, 2H), 2.53 (m, 2H), 1.42 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[C:19]([F:20])=[CH:18][C:17]([N:21]3[CH2:25][C@H:24](CO)[O:23][C:22]3=[O:28])=[CH:16][C:15]=2[F:29])=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([O:33]C(=O)C)(=[O:32])[CH3:31].[C:37](=O)(O)[O-].[Na+].C(=O)=O>ClCCl.CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[C:15]([F:29])=[CH:16][C:17]([N:21]3[CH:25]([CH3:37])[C@H:24]([O:33][C:30](=[O:32])[CH3:31])[O:23][C:22]3=[O:28])=[CH:18][C:19]=2[F:20])=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C1O[C@@H](CO)CN1c1cc(F)c(C2=CCN(Cc3ccccc3)CC2)c(F)c1
Reactant: O=C([O-])O
Agent: CN(C)c1ccncc1
Agent: O=C=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@@H]1OC(=O)N(c2cc(F)c(C3=CCN(Cc4ccccc4)CC3)c(F)c2)C1C
Reaction time: 1 h

Procedure:
3-(4-(1-Benzyl-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-5(R)-hydroxymethyloxazolidin-2-one (20 g, 50 mM, see WO 97-30995) was suspended by stirring in dry dichloromethane (400 ml) under nitrogen at 0°, and treated with triethylamine (5.5 g, 54.4 mM) and 4-dimethylaminopyridine (0.3 g, 2.7 mM). Acetic anhydride (5.3 g, 52 mM) was added dropwise to give a solution, which was stirred for 1 hour, allowing the temperature to rise to ambient. The mixture was shaken with 5% aqueous sodium bicarbonate (200 ml) until carbon dioxide evolution ceased. The organic phase was separated, dried (magnesium sulfate) and evaporated, then azeotroped with toluene (2×50 ml) to give semi-crystalline product of sufficient purity for the next stage (24 g). NMR (DMSO-d6) δ: 2.03 (s, 3H); 2.30 (br, 2H); 2.61 (t, 2H); 3.04 (m, 2H); 3.58 (s, 2H); 3.82 (dd, 1H); 4.14 (t, 1H); 4.23 (dd, 1H); 4.30 (dd, 1H); 4.95 (m, 1H); 5.78 (s, 1H); 7.30(s overlapping m, 7H). MS (ESP): 443 (MH+) for C24H24F2N2O4
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([CH:11]([CH3:13])[CH3:12])[C:3]=12.C(=O)([O-])[O-].[Cs+].[Cs+].F[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][C:22]=1[CH:29]=[O:30].C(Cl)(Cl)Cl>C(#N)C.O>[CH:29]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:21]=1[N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([I:1])=[C:3]2[C:10]([CH:11]([CH3:13])[CH3:12])=[N:9]1)[C:25]#[N:26])=[O:30]
Reactant: CC(C)c1n[nH]c2nccc(I)c12
Reactant: N#Cc1ccc(F)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)c1nn(-c2ccc(C#N)cc2C=O)c2nccc(I)c12
Yield: 69 %

Procedure:
Compound (100a) (2.0 g), cesium carbonate (3.41 g), and 4-fluoro-3-formylbenzonitrile (1.25 g) were suspended in acetonitrile (23 mL), followed by reflux for 3 hr. The reaction solution was distributed between chloroform and water, and the organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and then the solvent was distilled away. The residue was purified by neutral silica gel column chromatography (hexane/ethyl acetate) to obtain compound (125a) (2.00 g, 67%) as a white solid.
Reaction SMILES: [C:1]1([S:7]([CH:10]([NH2:30])[C:11]2[N:16]([CH3:17])[C:15]([C:18](O)=[O:19])=[C:14]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13](=[O:29])[CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:31][N:32](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:31][NH:32][C:18]([C:15]1[N:16]([CH3:17])[C:11]([CH:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[NH2:30])=[CH:12][C:13](=[O:29])[C:14]=1[O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:19]
Reactant: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(OCc2ccccc2)c1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(C(N)S(=O)(=O)c2ccccc2)n1C
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
To a stirred solution of 6-(benzene sulfonyl amino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-01) (400.0 mg, 0.935 mmol) in dimethylformamide (10 mL) were added HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (426.17 mg, 1.12 mmol) and diisopropylethylamine (1.08 mL, 6.54 mmol). The mixture was stirred for 30 min., thenmethylamine hydrochloride salt (189.31 mg, 2.80 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, it was quenched with ice cold water and the reaction mixture was extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. It was then purified using normal column chromatography to get 6-(benzene sulfonyl amino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methyl amide (15-01) (180.0 mg, 43.62%) as a white solid.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([O:17][C@H:18]([CH3:23])[C:19](OC)=[O:20])[CH:11]=3)=[O:5])[CH2:3][CH2:2]1.[AlH4-].[Li+]>O1CCCC1>[OH:20][CH2:19][C@H:18]([O:17][C:12]1[CH:11]=[C:10]2[C:15]([CH:16]=[C:7]([NH:6][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[N:8]=[CH:9]2)=[CH:14][CH:13]=1)[CH3:23]
Reactant: COC(=O)[C@@H](C)Oc1ccc2cc(NC(=O)C3CC3)ncc2c1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](CO)Oc1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: -78 °C
Yield: 43.2 %

Procedure:
To a solution of (R)-methyl 2-(3-(cyclopropanecarboxamido)isoquinolin-7-yloxy)propanoate (0.301 mmol, 0.301 mmol) in tetrahydrofuran (5.0 mL, 62 mmol) at −78° C. was added 1.0 M of lithium tetrahydroaluminate in tetrahydrofuran (0.40 mL). The reaction mixture was cooled at −78° C. for one hour, and then stirred at room temperature for an additional hour. The reaction mixture was quenched by sequential addition of 20 μL water, then 20 μL 15% aq NaOH, then 60 μL water. The resulting mixture was stirred at room temperature for 15 minutes, then diluted with dichloromethane, dried over MgSO4, filtered through celite, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 37.2 mg (43%) of (R)-N-(7-(1-hydroxypropan-2-yloxy)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (Min)=3.213, M+H=287.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.98 (s, 1H), 8.36 (s, 1H), 7.77 (d, J=9.0 Hz, 1H), 7.47 (d, J=2.0 Hz, 1H), 7.34 (dd, J=9.0, 2.4 Hz, 1H), 4.89 (s, 1H), 4.58 (dd, J=11.2, 5.7 Hz, 1H), 3.56 (t, J=15.1 Hz, 2H), 2.04 (td, J=7.7, 3.9 Hz, 1H), 1.28 (d, J=6.1 Hz, 3H), 0.89-0.71 (m, 4H).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=3[CH3:21])[C:15]([OH:17])=O)=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.P(Cl)(Cl)([Cl:24])=O.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>C([O-])(O)=O.[Na+].O>[Cl:24][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=3[CH3:21])[C:15]([NH:30][CH:27]3[CH2:29][CH2:28]3)=[O:17])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc2c(O)nncc2c1
Reactant: O=P(Cl)(Cl)Cl
Reactant: NC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(Cl)nncc2c1
Temperature: 105 °C

Procedure:
A mixture of 3-(1-hydroxyphthalazin-6-yl)-4-methylbenzoic acid (1.08 g, 3.85 mmol) and phosphorus oxychloride (25.0 mL, 268 mmol) was heated to 105° C. for 3 h. After cooling to RT, the solvents were removed in vacuo. The residue was re-dissolved in CH2Cl2 and treated carefully with cyclopropylamine (1.36 mL, 19.3 mmol) at RT. The mixture was diluted with sat aq. NaHCO3 and H2O and extracted with CH2Cl2 (4×). The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified using column chromatography (MeOH/CH2Cl2=0→3%). Found MS (ESI, pos. ion) m/z: 338 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[CH2:16]1[CH2:20]OC[CH2:17]1.C([Li])(C)C>O>[CH:16]([C:2]1([OH:1])[CH2:3][CH2:4][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:6][CH2:7]1)([CH3:20])[CH3:17]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: [Li]C(C)C
Solvent: O
Product: CC(C)C1(O)CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of tert-butyl (4-oxocyclohexyl)carbamate (3.04 g) and THF (100 mL), isopropyllithium (0.7 M pentane solution) (40.3 mL) was added at −78° C. and stirred over 4 hours until it reached −50° C. After addition of water (150 mL), the reaction liquid was heated to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=3:1) and further purified (eluent; chloroform:methanol=30:1) to give tert-butyl (4-isopropyl-4-hydroxycyclohexyl)carbamate (Preparation Example 250) (0.854 g), which was a low-polarity product, as a white solid and tert-butyl (4-isopropyl-4-hydroxycyclohexyl)carbamate (Preparation Example 252) (0.179 g), which was a high-polarity product, as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([F:24])[CH:18]=1.Cl>CC(O)C.CC(C)=O>[ClH:1].[Cl:15][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:21][C:20]3[CH:22]=[CH:23][C:17]([Cl:16])=[CH:18][C:19]=3[F:24])=[N:3][CH:4]=[N:5]2)=[CH:10][C:9]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1Cl
Reactant: Nc1ccc(Cl)cc1F
Agent: Cl
Solvent: CC(C)=O
Solvent: CC(C)O
Product: O=[N+]([O-])c1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1Cl
Yield: 90 %

Procedure:
A mixture of 4,7-dichloro-6-nitroquinazoline (24.4 g, 0.1 mol), 4-chloro-2-fluoroaniline and ethereal hydrogen chloride (100 ml of a 1M solution) in 2-propanol (600 ml) was heated at reflux for 1.5 hours. The mixture was allowed to cool and diluted with acetone. The solid product was collected by filtration, washed with acetone and dried to give 7-chloro-4-(4-chloro-2-fluoroanilino)-6nitroquinazoline hydrochloride (35.0 g, 90%) as a yellow powder.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[CH2:6]([O:8][C:9]([C:11]1[C:12]([CH3:25])=[C:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[NH:14][C:15]=1[CH:16]=[O:17])=[O:10])[CH3:7]>O1CCCC1>[CH2:6]([O:8][C:9]([C:11]1[C:12]([CH3:25])=[C:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[NH:14][C:15]=1[CH:16]([CH:1]1[CH2:3][CH2:2]1)[OH:17])=[O:10])[CH3:7]
Reactant: CCOC(=O)c1c(C=O)[nH]c(C(=O)OC(C)(C)C)c1C
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(O)C2CC2)[nH]c(C(=O)OC(C)(C)C)c1C
Temperature: -10 °C
Yield: 39.6 %

Procedure:
Cyclopropylmagnesium bromide (15 m, 0.5 mol/L) was cooled down to −10° C. in an ice-salt bath under an argon atmosphere. 5-Formyl-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1b (1.26 g, 4.5 mmol) was dissolved in 10 ml of tetrahydrofuran under stirring, the resulting solution was added dropwise to the above solution while maintaining the temperature at −10° C. Upon completion of the addition, the ice-salt bath was removed, and the reaction mixture was stirred for 1 hour at room temperature. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was quenched with water, added with sulfuric acid solution (20 ml, 10%) and stirred for 30 minutes, and extracted with ethyl acetate (50 ml×3). The combined organic extracts were washed with saturated brine (50 ml), dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 5-(cyclopropyl-hydroxy-methyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 60a (576 mg, yield 39.6%) as a white solid.
Reaction SMILES: [Mg].[NH2:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2Cl)[NH:5][N:4]=1.C(Br)(C)C.O=O.C(=O)=[O:20].S(=O)(=O)(O)O>O.C(OCC)C>[NH2:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[OH:20])[NH:5][N:4]=1
Reactant: O=C=O
Reactant: Nc1n[nH]c2cccc(Cl)c12
Agent: O=O
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CC(C)Br
Solvent: CCOCC
Solvent: O
Product: Nc1n[nH]c2cccc(O)c12
Reaction time: 12 h
Yield: 42 %

Procedure:
To 20 ml of diethyl ether solution containing 600 mg of magnesium powder was added dropwise a mixed solution consisting of 1.68 g of 3-amino-4-chloroindazole prepared by the method as described in Beck. Gunkther et al., Justus Liebigs Ann. Chem., 716, 47(1968), 2.06 g of isopropyl bromide and 20 ml of diethyl ether. Into the solution were introduced dried oxygen gas and dried carbon dioxide gas for 10 hours so as to reflux the solution, and the solution was left to stand for 12 hours. The pH of the solution was adjusted to 4.0 by adding dropwise sulfuric acid to the solution at 0° C. The solution was added with 50 ml of water and filtered. To the aqueous layer of the filtrate was added an aqueous potassium carbonate solution to separate crystals. The crystals were obtained by filtration and dried to give 0.626 g of 3-amino-4-hydroxyindazole having the following analytical values in a yield of 42%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH2:8][NH2:9])[CH:7]=1.C([C:18]1[NH:19][CH:20]=CN=1)(C1NC=CN=1)=O.CN.C1C[O:28]CC1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH2:8][NH:9][C:20]([NH:19][CH3:18])=[O:28])[CH:7]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: C1CCOC1
Reactant: NCc1cc(Br)ccc1Cl
Agent: CN
Solvent: ClCCl
Product: CNC(=O)NCc1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-2-chlorobenzenemethanamine (i.e. the product of Synthesis Example 2, Step A) (1.3 g, 5.5 mmol) in dichloromethane (25 mL) at 0° C. was added carbonyl diimidazole (1.4 g, 8.6 mmol). The reaction mixture was stirred at room temperature for 1 h. Then the reaction mixture was cooled to 0° C., a solution of methylamine in THF (2 M, 3.0 mL, 6.0 mmol) was added, and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was filtered, and the solid residue was washed with pentane to provide the title product (1.0 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([OH:20])=[O:19])[C:3]=1Br.[F:22][C:23]([F:27])([F:26])[CH2:24][OH:25].[C:28](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:28][O:20][C:18]([C:4]1[C:3]([O:25][CH2:24][C:23]([F:27])([F:26])[F:22])=[C:2]([NH2:1])[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=1)=[O:19]
Reactant: O=C([O-])[O-]
Reactant: OCC(F)(F)F
Reactant: COc1c(Cl)ccc(-c2nc(N)c(Br)c(C(=O)O)n2)c1F
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1OCC(F)(F)F
Temperature: 80 °C
Yield: 12.2 %

Procedure:
6-Amino-5-bromo-2-(4-chloro-2-fluoro-3-methoxyphenyl)-pyrimidine-4-carboxylic acid (240 mg, 0.64 mmol), 2,2,2-trifluoroethanol (1.4 mL, 1.9 g, 1.9 mmol), cesium carbonate (1.0 g, 3.2 mmol) and cuprous bromide (92 mg, 0.64 mmol) were combined in 7 mL dry DMF and heated to 80° C. for 3 h. After cooling, the mixture was diluted with water and extracted twice with ethyl acetate. The combined extracts were washed twice with water, dried and evaporated. The residue was purified by flash chromatography on silica gel (5 to 20% ethyl acetate in hexane) and then repurified by preparative HPLC (55% acetonitrile buffered with 0.1% v/v acetic acid). The purified acid was taken up in 5 mL methanol, treated with a 2 M solution of (trimethylsilyl)diazomethane in hexanes (1 mL) and stirred for 30 m at 25° C. The excess reagent was destroyed by addition of 0.5 mL acetic acid and the volatiles were removed by evaporation. The residue was taken up in ethyl acetate, washed with saturated sodium bicarbonate, washed with brine, dried and evaporated. The residue was taken up in a small amount of dichloromethane and the product was precipitated as a solid by slow addition of hexane to give 32 mg of the title compound as a white solid: mp 123-125° C.: 1H NMR (CDCl3) δ 7.61 (dd, 1H), 7.20 (dd, 1H), 5.51 (br s, 2H), 4.51 (q, 1H), 4.01 (s, 3H), 3.99 (s, 3H).
Reaction SMILES: [O:1]=[C:2]([CH3:29])[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[CH:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[N:14]=2)=[CH:9][CH:8]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[N:45]=[C:46]=[S:47])([CH3:38])[CH3:37].O>CN(C)C=O>[OH:1]/[C:2](/[CH3:29])=[C:3](/[C:46](=[S:47])[NH:45][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[CH:36]([CH3:37])[CH3:38])\[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:17]=[CH:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:27])([F:26])[F:28])=[CH:20][CH:19]=3)[N:14]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: CC(C)c1ccccc1N=C=S
Reactant: CC(=O)CC(=O)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C/C(O)=C(/C(=O)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)C(=S)Nc1ccccc1C(C)C
Reaction time: 18 h
Yield: 48.5 %

Procedure:
A portion of the solid from Step 1 (0.50 g, 1.24 mmol) was dissolved in 5 mL of dry N,N-dimethylformamide (DMF) and stirred at ambient temperature while potassium carbonate (0.25 g, 1.81 mmol) and 2-isopropylphenyl isothiocyanate (0.25 g, 1.41 mmol) were added. The solution was stirred for 18 h, then it was poured into 15 mL of water, extracted with ether, and the solvent evaporated. Chromatography of the crude product (0-70% EtOAc-hexanes) gave 350 mg of the title compound as an off-white solid. mp 141-144° C. 1H NMR (400 MHz, CDCl3) δ 15.35-14.58 (m, 1H), 10.93 (s, 1H), 8.57 (m, 3H), 8.31-8.11 (m, 6H), 7.71 (m, 12H), 7.56-7.30 (m, 15H), 5.35 (s, 1H), 3.02 (heptet, J=6.9 Hz, 1H), 2.52 (s, 3H), 1.35-1.11 (m, 6H); ESIMS m/z 582 ([M+H]+).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])=[CH:5][CH:4]=1.CN(C=O)C.Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>O>[O:14]=[C:10]1[N:9]([C:6]2[CH:5]=[CH:4][N:3]=[CH:8][CH:7]=2)[CH2:13][CH2:12][N:11]1[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: O=C1NCCN1c1ccncc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CN1CCN(c2ccncc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
Sodium hydride (60% in oil, 0.40 g, 10.1 mmol) was added to a mixture of 1-(4-pyridyl)-2-imidazolidinone (1.5 g, 9.2 mmol) and DMF (20 ml) at 0° C., and the mixture was stirred at room temperature for 30 minutes. Successively, tert-butyl bromoacetate (2.2 g, 11.2 mmol) was added to the mixture, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was combined with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-methanol (5:1, v/v) were collected, concentrated and recrystallized from tetrahydrofuran-hexane to give the titled compound (1.7 g, 68%) as white crystals.
Reaction SMILES: Cl[C:2]1[N:7]2[C:8]([CH3:11])=[N:9][CH:10]=[C:6]2[CH:5]=[C:4]([Cl:12])[N:3]=1.[CH3:13][S-:14].[Na+]>>[Cl:12][C:4]1[N:3]=[C:2]([S:14][CH3:13])[N:7]2[C:8]([CH3:11])=[N:9][CH:10]=[C:6]2[CH:5]=1
Reactant: C[S-]
Reactant: Cc1ncc2cc(Cl)nc(Cl)n12
Agent: [Na+]
Product: CSc1nc(Cl)cc2cnc(C)n12

Procedure:
Using the method of Example 53, 5,7-dichloro-3-methylimidazo[1,5-c]pyrimidine (from Example 35) was reacted with sodium methanethiolate to provide yellow solid 7-chloro-3-methyl-5-methylthioimidazo[1,5-c]pyrimidine, m.p. 153°-155° C. Analysis: Calculated for C8H8ClN3S: %C, 45.0; %H, 3.8; %N, 19.7; Found: %C, 44.8; %H, 3.5; %N, 19.7.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@H:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:22][C:23]1[CH:31]=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=1>CN(C=O)C.C(OCC)(=O)C.N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>[NH2:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:22][C:23]3[CH:31]=[CH:30][C:26]4[O:27][CH2:28][O:29][C:25]=4[CH:24]=3)[CH2:8]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(O[C@H]2CCCNC2)cc1
Reactant: ClCc1ccc2c(c1)OCO2
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc(O[C@H]2CCCN(Cc3ccc4c(c3)OCO4)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To an ice water-cooled solution of (3S)-3-(4-aminophenoxy)piperidine (3.5 g) in DMF (20 mL) was added K2CO3 (7.5 g) and Nal (0.2 g), followed by the addition of 5-chloromethyl-1,3-benzodioxole (4.7 mL). The resulting reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water (100 mL×3) and brine (100 mL), and dried (Na2SO4). The crude product was further purified by column chromatography (methanol:ethyl acetate1:10), to afford (3S)-3-(4-aminophenoxy)-1-[(1,3-benzodioxol-5-yl)methyl]piperidine (4.4 g, 74% yield) as an oil.