Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:24]([C:25](=[O:32])[NH:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:5]2[N:6]=[CH:7][C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[C:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[N:4]2[N:3]=1.N1C=CC=CC=1.[C:39](OC(=O)C)(=[O:41])[CH3:40].Cl>C(OCC)(=O)C>[C:39]([NH:1][C:2]1[C:24]([C:25](=[O:32])[NH:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:5]2[N:6]=[CH:7][C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[C:9]([C:10]3[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=3)[N:4]2[N:3]=1)(=[O:41])[CH3:40]
Reactant: Nc1nn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc2c1C(=O)NC1CCCC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1nn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc2c1C(=O)NC1CCCC1
Temperature: 100 °C
Reaction time: 72 h
Yield: 58 %

Procedure:
A mixture of the compound obtained in Example 40 (60 mg), pyridine (600 μL) and acetic anhydride (200 μL) was stirred at 100° C. for 3 days. After cooling to room temperature, to the reaction mixture was added an aqueous 1N HCl and ethyl acetate and the mixture was stirred. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resultant crude product was purified by a column chromatography on NH-silica gel (Chromatorex NH-silica gel/Fuji Silicia Chem., solvent; hexane/ethyl acetate=90/10 to 50/50) to give 2-acetylamino-6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(N-cyclopentylcarbamoyl)pyrazolo[1,5-a]pyrimidine (38.2 mg; yield: 58%) as a pale yellow solid.
Reaction SMILES: [Li+].CCC[CH2-].Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([OH:17])[CH:11]=[CH:10]2.C([Li])(C)(C)C.CN(C)P(N(C)C)(N(C)C)=O.CN(C)[CH:36]=[O:37]>C1COCC1>[OH:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:36]=[O:37])[CH:16]=[CH:15]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: CN(C)C=O
Agent: [CH2-]CCC
Agent: [Li+]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=Cc1ccc2cc(O)ccc2c1
Reaction time: 0.17 h
Yield: 80.9 %

Procedure:
Step a) N-Butyllithium (35.9 mL, 89.7 mmol) was added dropwise to a cold (-78° C.) solution of 6-bromo-2-naphthol (20.0 g, 89.7 mmol) in THF (200 mL). After stirring for 10 minutes, tert-butyllithium (52.76 mL, 89.7 mmol) was added dropwise. The mixture was stirred for 30 min at -78° C., and two hours at -20° C. Then, hexamethylphosphoramide (15.6 mL, 89.7 mmol) was added to the reaction mixture. After stirring for 20 minutes. N,N-dimethylformamide (6.94 mL, 89.7 mmol) was added dropwise. The mixture was allowed to come to room temperature, stirred for 1 hour, and quenched with aqueous ammonium chloride. The mixture was poured into water, acidified with 2N HCL and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexane/EtOAc 3/1 ), gave a yellow solid (12.5 g, 81% yield, m.p. 173°-174° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9]Br.[S:11]([O-:14])([O-:13])=[O:12].[Na+:15].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][S:11]([O-:14])(=[O:13])=[O:12].[Na+:15]
Reactant: O=S([O-])[O-]
Reactant: BrCCc1ccccc1Br
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])CCc1ccccc1Br
Temperature: 100 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
A solution of 1-bromo-2-(2-bromoethyl)benzene (6.23 g, 23.6 mmol) in ethanol (20.5 mL) was added to a solution of sodium sulfite (3.12 g, 24.7 mmol) in water (25.0 mL). The mixture was heated at 100° C. for 24 hours. The reaction mixture was filtered, and the filtrate was then left to stand at 3° C. overnight. The resulting white crystals were collected by filtration and dried to give sodium 2-(2-bromo-phenyl)ethanesulfonate (4.00 g, 59%).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([C:9]#[N:10])=[CH:7][N:6]=[CH:5][N:4]=1)[CH3:2].[OH-].[NH4+]>CO.[Ni]>[CH2:1]([C:3]1[C:8]([CH2:9][NH2:10])=[CH:7][N:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1ncncc1C#N
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CCc1ncncc1CN
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To the solution of 4-ethylpyrimidine-5-carbonitrile (1.0 equiv.) in MeOH (0.4 M) was added ammonium hydroxide and Raney nickel. The mixture was stirred at room temperature under hydrogen atmosphere overnight and then the reaction mixture was filtered through celite. The filtrate was concentrated in vacuum to give the crude title compound (59%), which was used for the next step without further purification. MS (ESI) m/z 138.1/[M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][C:14]([OH:16])=O)[CH2:7][CH2:6]2.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C(#N)C.C(OCC)(=O)C.O.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][C:14]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])[CH2:7][CH2:6]2
Reactant: C1CCNCC1
Reactant: COc1ccc2c(c1)CCC(CC(=O)O)C2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CCC(CC(=O)N1CCCCC1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.7 %

Procedure:
2-(6-Methoxy-2-tetralinyl)acetic acid (8.8 g) was dissolved in a mixed solution of THF (150 ml) and acetonitrile (50 ml), then piperidine (5.2 g), WSC (12 g), HOBt (6.0 g) and triethylamine (17 ml) were added to the solution, which was stirred at room temperature for 12 hours. Water was added to the reaction mixture, and extraction was conducted using ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water, saturated sodium bicarbonate solution, water, and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was purified using silica gel chromatography (development solvent; ethyl acetate) to give the titled compound (10.3 g). Recrystallization from hexane gave crystals of the following melting points.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]([CH:30]=[CH:31][N:32]=1)[C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=[O:17].[C:33]([O:37][C:38]([C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=1)[C:43](O)=[O:44])=[O:39])([CH3:36])([CH3:35])[CH3:34].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH2:9]([N:8]([CH2:11][CH3:12])[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:43]([C:42]2[CH:41]=[C:40]([CH:48]=[CH:47][CH:46]=2)[C:38]([O:37][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:39])=[O:44])=[C:3]([C:13]2[CH:14]=[C:15]([C:16](=[O:17])[NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)[CH:30]=[CH:31][N:32]=2)[CH:4]=1)[CH3:10]
Reactant: CC(C)(C)OC(=O)c1cccc(C(=O)O)c1
Reactant: CCN(CC)c1ccc(N)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To a mixture of 2-(2-amino-5-(diethylamino)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide (25a, 6.33 mmol, 2.8 g), 3-(tert-butoxycarbonyl)benzoic acid (7.60 mmol, 1.69 g) and DIEA (31.65 mmol, 4.09 g) in DMF (15 mL) was added HATU (7.6 mmol, 2.89 g). The mixture was stirred at 60° C. for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water (2×), sat. aqueous NaHCO3 (1×), brine (1×), dried and concentrated. The residue was purified by column to give a yellow solid (3.9 g, 95%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3].[CH2:11](O)[CH2:12][CH2:13][OH:14].CO>C(Cl)Cl.C1C(=O)N(Br)C(=O)C1>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]2([CH3:1])[O:14][CH2:13][CH2:12][CH2:11][O:3]2)=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: OCCCO
Agent: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: ClCCl
Product: CC1(c2ccc(Cl)cc2)OCCCO1
Temperature: 25 °C
Reaction time: 70 h
Yield: 51.7 %

Procedure:
To a stirred mixture of 4-chloroacetophenone (1.3 mL, 10 mmol), triethylformate (2.0 mL, 12 mmol), 1,3-propanediol (2.2 mL, 30 mmol) and dry methanol (1.2 mL) in dry CH2Cl2 (50 mL) was added NBS (53 mg, 0.30 mmol). The mixture was protected from light and stirred at room temperature under an inert atmosphere of nitrogen for 70 h. After the mixture was washed with saturated aqueous sodium bicarbonate solution (20 mL), the aqueous phase was extracted with dichloromethane (3×30 mL). The combined organic solution was washed with water (2×20 mL), brine (1×20 mL), then dried (Na2SO4) and concentrated under reduced pressure. Flash column chromatography of the residue, eluting with 37% aqueous ammonia:ether:hexane (0.02:1:6) afforded 2-(4-chlorophenyl)-2-methyl-1,3-dioxane (20) as a colourless oil (1.1 g, 52%). 1H nmr (200 MHz, CDCl3) 1.49 (s, 3H, CH3), 1.98-2.25 (m, 2H, OCH2CH2CH2O), 3.65-4.10 (m, 4H, OCH2CH2CH2O), 7.30-7.50 (m, 4H, 4×ArH).
Reaction SMILES: [OH:1][C:2]([C:27]1[NH:31][C:30]2[CH:32]=[CH:33][C:34]([C:36]#[N:37])=[CH:35][C:29]=2[N:28]=1)([C:4]1[C:12]([CH:13]([CH3:15])[CH3:14])=[CH:11][C:10]([CH3:16])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2S(C1C=CC(C)=CC=1)(=O)=O)[CH3:3].OC(C1NC2C=CC(C#N)=CC=2N=1)(C1C(CCC)=CC(C)=C2C=1C=CN2S(C1C=CC(C)=CC=1)(=O)=O)C.C(N)CC(C)C.[OH-].[K+]>C(Cl)Cl>[OH:1][C:2]([C:27]1[NH:31][C:30]2[CH:32]=[CH:33][C:34]([C:36]#[N:37])=[CH:35][C:29]=2[N:28]=1)([C:4]1[C:12]([CH:13]([CH3:15])[CH3:14])=[CH:11][C:10]([CH3:16])=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)(O)c4nc5cc(C#N)ccc5[nH]4)c(C(C)C)cc(C)c32)cc1
Agent: CC(C)CCN
Agent: CCCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(C)(O)c1nc2cc(C#N)ccc2[nH]1
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(C(C)C)c(C(C)(O)c2nc3cc(C#N)ccc3[nH]2)c2cc[nH]c12
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
A mixture of (±)-2-(1-hydroxy-1-(5-isopropyl-7-methyl-1-tosyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(1-hydroxy-1-(7-methyl-5-propyl-1-tosyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (110 mg, 0.215 mmol), isoamylamine (94 mg, 1.073 mmol), and KOH (60.2 mg, 1.073 mmol) was stirred at 100° C. for 0.75 h under the microwave irradiation. The reaction mixture was diluted with CH2Cl2. The mixture was filtered through SiO2. The SiO2 cake was washed with a mixture of CH2Cl2/MeOH (c.a. 6/1). Combined organic solution was concentrated and purified by silica gel flash column chromatography (CH2Cl2/EtOAc=82/18, isocratic) to give (±)-2-(1-hydroxy-1-(5-isopropyl-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile as a pure isomeric form. 1H NMR (400 MHz, ACETONITRILE-d3 with about 5 μL TFA) δ ppm 9.28 (br. s., 1H), 8.05 (s, 1H), 7.73 (d, J=8.60 Hz, 1H), 7.69 (dd, J=1.30, 8.60 Hz, 1H), 7.19 (dd, J=2.80, 2.90 Hz, 1H), 7.00 (s, 1H), 6.66 (dd, J=2.30, 3.00 Hz, 1H), 2.90-3.06 (m, 1H), 2.47 (s, 3H), 2.28 (s, 3H), 0.95 (d, J=6.82 Hz, 3H), 0.92 (d, J=6.57 Hz, 3H). HRMS calcd. for C22H22N4O (M+H)+ 359.1867. found 359.1865.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:6])[CH3:2].O=[C:17]([CH2:22][CH3:23])[C:18]([O:20][CH3:21])=[O:19]>ClCCCl>[CH3:21][O:20][C:18](=[O:19])[CH2:17][CH2:22][CH2:23][N:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH3:6]
Reactant: CCOC(=O)C(C)NCc1ccccc1
Reactant: CCC(=O)C(=O)OC
Solvent: ClCCCl
Product: CCOC(=O)C(C)N(CCCC(=O)OC)Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-Benzylamino-propionic acid ethyl ester (1.4 g, 6.7 mmol), methyl oxo-butanoate (1.7 g, 13.5 mmol), LEA (1.9 mL, 13.5 mmol) and NaBH(Oac)3 (2.9 g, 13.5 mmol) are taken up in 1,2-DCE (35 mL) and stirred at rt for 4 h. The reaction is partitioned between DCM and saturated aqueous NaHCO3. The organic layer is removed, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude residue is used without further purification. MS (ESI) m/z 308.3 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][CH2:15]Br)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][CH2:15][CH:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH3:2])=[CH:12][CH:11]=1
Reactant: Clc1ccc(CCBr)cc1
Reactant: CCc1ccncc1
Product: CC(CCc1ccc(Cl)cc1)c1ccncc1
Yield: 59.6 %

Procedure:
1.0 g (9.35 mmol) of 4-ethylpyridine and 2.05 g (9.35 mmol) of 4-chlorophenethyl bromide were reacted in the same manner as in Example 1. The reaction product was purified to obtain 1.37 g of the desired compound (yield: 59.8%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([OH:13])([CH3:12])[CH3:11])=[N:4][CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[N:4][C:3]=1[C:10]([OH:13])([CH3:12])[CH3:11]
Reactant: CC(C)(O)c1ncc(CO)cc1Cl
Solvent: ClCCl
Product: CC(C)(O)c1ncc(C=O)cc1Cl
Temperature: 40 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
CrO2 (Magtrieve) (1749 mg, 20.83 mmol) was added to a solution of 2-[3-chloro-5-(hydroxymethyl)-2-pyridinyl]-2-propanol (210 mg, 1.041 mmol) in DCM (10 mL) and the mixture was stirred at 40° C. overnight. The suspension was filtered over nylon membrane and it was rinsed with DCM. The process was repeated several times. The combined filtrates were concentrated to afford 5-chloro-6-(1-hydroxy-1-methylethyl)-3-pyridinecarbaldehyde (179 mg, 82%) as yellow solid. It was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N(CC)C(C)C)(C)C.[C:20]1([S:26]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])(=[NH:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([N:28]=[S@:26]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:27])=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CCOC(=O)CS(=N)(=O)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 33.7 %

Procedure:
To a solution of 5-bromonicotinic acid (343 mg, 1.66 mmol) in anhydrous DMF (5.5 μL) was added N,N-diisopropylethylamine (0.58 mL, 3.32 mmol) and ethyl (S-phenylsulfonimidoyl)acetate (415 mg, 1.83 mmol) followed by the final addition of (benzotriazol-1-yloxy)-tris(dimethylamino)-phosphonium hexafluorophophate (0.81 g, 1.83 mmol). The reaction mixture was stirred at room temperature for 20 min, and then partitioned between saturated aqueous NaHCO3 and EtOAc. The organic layer was separated and washed once with brine and dried over anhydrous Na2SO4. The organic layer was concentrated and the residue purified by chromatography (silica gel, gradient elution (5:1 Hexane/EtOAc to 3:1 Hexane/EtOAc). The product containing fractions were concentrated to give the title compound as a white solid (230 mg, 34%).
Reaction SMILES: [OH-].[Na+].CO.[CH3:5][O:6][C:7]([C:9]1[S:10][C:11]([CH2:14][CH2:15][CH2:16][C@H:17]2[CH2:21][CH2:20][C:19]([Cl:22])=[C:18]2[C:23]2[CH:28]=[CH:27][C:26]([C@H:29]([O:35]C(=O)C3C=CC([N+]([O-])=O)=CC=3)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:25][CH:24]=2)=[CH:12][CH:13]=1)=[O:8].Cl>C1COCC1>[CH3:5][O:6][C:7]([C:9]1[S:10][C:11]([CH2:14][CH2:15][CH2:16][C@H:17]2[CH2:21][CH2:20][C:19]([Cl:22])=[C:18]2[C:23]2[CH:24]=[CH:25][C:26]([C@H:29]([OH:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:27][CH:28]=2)=[CH:12][CH:13]=1)=[O:8]
Reactant: CCCCC[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc(C2=C(Cl)CC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCC[C@@H](O)c1ccc(C2=C(Cl)CC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
A solution of 5% NaOH/MeOH (0.25 mL, 0.31 mmol), ester 14 (18 mg, 0.029 mmol) and THF (0.05 mL) was allowed to stir at room temperature. After 30 min., 10 mL 1 M HCl solution was added and the resulting mixture was extracted with ethyl acetate (2×20 mL). The combined ethyl acetate solution was dried (MgSO4), filtered and evaporated. Purification by flash chromatography on silica gel (0%→50% ethyl acetate/hexanes) gave the title compound (11 mg, 0.024 mmol, 82%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li][C:9]([CH3:12])([CH3:11])[CH3:10].C(O)(=O)C.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[OH-].[Na+]>C1COCC1.O.CCOC(C)=O.CCOCC>[C:9]([C:4]1[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[N:3]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: Clc1ncccn1
Reactant: [Li]C(C)(C)C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1ccnc(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
To a dry flask containing 2-chloropyrimidine (1.0 g, 8.7 mmol) was added anhydrous Et2O (8.7 mL) and the solution was cooled to −30° C. tBuLi (1.7 M solution in n-pentane, 5.7 mL, 9.6 mmol) was added dropwise and the reaction was held at −30° C. for 30 min. The reaction was warmed to 0° C. and stirred at that temperature for 30 min, at which time the reaction was quenched by dropwise addition of a solution of acetic acid (0.60 mL, 10.5 mmol) in THF (3 mL) and water (1 mL). The reaction was maintained at 0° C. and a solution of DDQ (2.38 g, 10.5 mmol) in THF (8.7 mL) was added. After 15 minutes, NaOH (1 M, 1 mL) and water (10 mL) were added, and the dark reaction mixture was transferred to a separatory funnel containing EtOAc (50 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted once with EtOAc (50 mL). The combined organic phases were washed with saturated aqueous sodium chloride (50 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Adsorption of the oily black residue on silica, followed by chromatography on silica using a gradient solvent system of 5→30% EtOAc/hexanes furnished 4-tert-butyl-2-chloropyrimidine (1.00 g, 67%) as a pale yellow oil. 1H NMR (500 MHz, CDCl3) δ 8.49 (d, J=5.2, 1H), 7.24 (d, J=5.2, 1H), 1.33 (s, 9H).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[CH2:2][CH2:3][CH3:4].[Li+].CC([N-]C(C)C)C.[CH3:16][C:17]([S:20]([N:22]=[C:23]1[CH2:26][O:25][CH2:24]1)=[O:21])([CH3:19])[CH3:18]>C1COCC1>[C:17]([S:20]([NH:22][C:23]1([CH:2]([CH2:3][CH3:4])[C:1]([O:6][CH3:7])=[O:5])[CH2:26][O:25][CH2:24]1)=[O:21])([CH3:16])([CH3:18])[CH3:19]
Reactant: CC(C)(C)S(=O)N=C1COC1
Reactant: CCCC(=O)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(C(=O)OC)C1(NS(=O)C(C)(C)C)COC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
Methyl butyrate (5.67 g, 55.5 mmol) was dissolved in anhydrous THF (100 mL) and cooled to −78° C. under nitrogen. LDA (2M solution in THF 27.1 mL, 54.2 mmol) was added drop-wise. After 1 hour at −78° C., a solution of 2-methyl-N-oxetan-3-ylidene-propane-2-sulfinamide (Preparation 39, 2.43 g, 13.88 mmol) in anhydrous THF (10 mL) was added. The reaction was gradually warmed to room temperature and stirred for 18 hours. The reaction was quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the title compound as an oil (2.89 g, 75% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.I.O>O1CCOCC1>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:25][C:24]3[CH:26]=[CH:27][C:21]([C:20]([F:19])([F:28])[F:29])=[CH:22][CH:23]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Agent: I
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CN(Cc2ccccc2)CC3)cc1
Temperature: 130 °C
Yield: 91 %

Procedure:
6-Benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (0.6 g, 2.3 mmol) was dissolved in anhydrous dioxane (2 mL) and 4-(trifluoromethyl)aniline was added (0.43 mL, 3.45 mmol), followed by HI/H2O (0.2 ml, 47%). The mixture was heated at 130° C. in a sealed tube for 10 min in a microwave (Smith creator model, Personal Chemistry). The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give the desired compound as a yellow solid (800 mg, 91%) which was used as such for the next step.
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.Cl[C:26]1[N:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][N:27]=1>CN1CCCC1=O>[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][N:22]([C:26]3[N:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:11][CH:12]=2)[CH2:4][CH2:3]1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: CC(C)Oc1cnc(Cl)nc1
Agent: Cl
Solvent: CN1CCCC1=O
Product: CC(C)Oc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrochloride and 2-chloro-5-isopropoxy-pyrimidine following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 16): tR=0.48 min; Mass spectrum (ESI+): m/z=448 [M+H]+.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([F:37])=[C:17]([C:19]23[CH2:26][N:25]([C:27]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:28])[CH2:24][CH:23]2[CH2:22][O:21][NH:20]3)[CH:18]=1>O1CCCC1>[C:1]([NH:9][C:10]([N:20]1[C:19]2([C:17]3[CH:18]=[C:13]([Br:12])[CH:14]=[CH:15][C:16]=3[F:37])[CH2:26][N:25]([C:27]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:28])[CH2:24][CH:23]2[CH2:22][O:21]1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CC2CONC2(c2cc(Br)ccc2F)C1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: O=C(NC(=S)N1OCC2CN(C(=O)OCc3ccccc3)CC21c1cc(Br)ccc1F)c1ccccc1
Reaction time: 8 h
Yield: 72.9 %

Procedure:
Benzoyl isothiocyanate (2.87 mL, 21.28 mmol) is added drop wise to a solution of benzyl 6a-(5-bromo-2-fluoro-phenyl)-3,3a,4,6-tetrahydro-1H-pyrrolo[3,4-c]isoxazole-5-carboxylate (5.977 g, 14.2 mmol) in tetrahydrofuran (95 mL) and stirred overnight under nitrogen. The solvent is removed in vacuo. The crude product is purified over silica gel with a 30 minute 5% to 100% EtOAc in hexanes gradient to give the title compound (6.05 g, 73%). ES/MS (m/e): (79Br/81Br) 584/586 (M+H).