Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.[H-].[Na+].I[CH3:15]>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH3:15]
Reactant: COc1cccc2[nH]ccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc2c1ccn2C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-methoxy-1H-indole (CAS#4837-90-5, 4.0 g, 27.2 mmol) in THF (100 ml) at 0° C. was added sodium hydride (60% dispersion in oil, 1.63 g, 40.08 mmol). The reaction was stirred for 15 minutes at 0° C. and then put at room temperature for 1 h. The reaction was then re-cooled to 0° C. and iodomethane (2.209 ml, 35.3 mmol) was added. The reaction was then put at room temperature and permitted to stir for 45 minutes. The reaction was then quenched with saturated aqueous ammonium chloride and concentrated to approximately half of its original volume. Next, the reaction mixture was diluted with water and dichloromethane and the layers were separated. The aqueous layer was then extracted two additional times with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-heptane 0 to 30%) to afford 4-methoxy-1-methyl-1H-indole; MS: (ES+) m/z 162.0 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([N:16]2[CH:20]=[CH:19][CH:18]=[C:17]2[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][C:9]=1[NH:25][C:26](=[O:38])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:21]([C:17]1[N:16]([C:11]2[C:12]([O:14][CH3:15])=[CH:13][C:8]3[N:7]=[C:28]([C:30]4[CH:31]=[C:32]([CH:33]=[CH:34][CH:35]=4)[C:36]#[N:37])[CH2:27][C:26](=[O:38])[NH:25][C:9]=3[CH:10]=2)[CH:20]=[CH:19][CH:18]=1)([CH3:23])([CH3:24])[CH3:22]
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(C#N)c2)cc1-n1cccc1C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(cc1-n1cccc1C(C)(C)C)NC(=O)CC(c1cccc(C#N)c1)=N2

Procedure:
The title compound was prepared from {4-(2-tert.-butyl-pyrrol-1-yl)-2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-5-methoxy-phenyl}-carbamic acid tert.-butyl ester (Example M19) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (22 mg).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][O:14][CH:13]([N:16]2[CH:26]=[CH:25][C:20]([NH:21]C(=O)C)=[N:19][C:17]2=[O:18])[CH2:12][S:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].C(O)(=O)C>CO>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][O:14][CH:13]([N:16]2[CH:26]=[CH:25][C:20]([NH2:21])=[N:19][C:17]2=[O:18])[CH2:12][S:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccn(C2CSC(COCc3ccccc3)CO2)c(=O)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccn(C2CSC(COCc3ccccc3)CO2)c(=O)n1

Procedure:
1-(5-Benzyloxymethyl-1,4-oxathian-2-yl)-N4 -acetylcytosine (0.31 g) was dissolved in methanol (10 ml), and 0.43M sodium methoxide solution (1 ml) was added to the solution. The resultant mixture was stirred at room temperature for one hour to complete the reaction. The reaction mixture was neutralized with acetic acid, and the solvent was removed by evaporation under reduced pressure to obtain pale yellow solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH2:30][C:31]([OH:33])=O)=[CH:26][CH:27]=5)[C:22]([C:34]5[NH:38][N:37]=[N:36][N:35]=5)=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:39](N1C=CN=C1)([N:41]1C=CN=[CH:42]1)=O.Cl.CNC.C(N(CC)CC)C>ClCCl>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH2:30][C:31](=[O:33])[N:41]([CH3:42])[CH3:39])=[CH:26][CH:27]=5)[C:22]([C:34]5[NH:38][N:37]=[N:36][N:35]=5)=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)c1csc(-c2cc3cc(Cn4cc(-c5nnn[nH]5)c5cc(OCC(=O)O)ccc54)ccc3o2)n1
Agent: CNC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)COc1ccc2c(c1)c(-c1nnn[nH]1)cn2Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 47.7 %

Procedure:
A mixture of 5-{1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(carboxymethoxy)indol-3-yl}-1H-tetrazole (60 mg) and 1,1'-carbonyldiimidazole (60 mg) in dichloromethane (2 ml) was stirred at room temperature for 5 hours. And then, dimethylamine hydrochloride (16.5 mg) and triethylamine (0.5 ml) were added to the mixture successively. After being stirred for 18 hours, the mixture was concentrated under reduced pressure. The resulting residue was acidified with diluted hydrochloric acid and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixture of chloroform, ethyl acetate and methanol. The fractions containing the objective compound were combined and concentrated under reduced pressure to give 5-{1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(N,N-dimethylcarbamoylmethoxy)indol-3-yl}-1H-tetrazole (30.1 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH3:18][C:19]1[N:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1>CN1CCCC1=O.O>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[N:24][CH:23]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1cnc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCc2cnc(C)nc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15.6 %

Procedure:
To a solution of 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.0005 mol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.14 g, 0.0025 mol) and allowed to stir r for 10 min at RT. 2-methyl-5-vinyl pyrimidine (0.151 g, 0.0012 mol) was added and stirred for further 3 h at 80 deg C. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) then purified through preparative TLC. to get the desired compound as yellow oil (0.025 g, 16% yield). 2,8-Dimethyl-5-[2-(2-methyl-pyrimidin-5-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrid[4,3-b]indole (0.025 g, 0.000078 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.0098 g, 0.000078 mol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.015 g, 47% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)[CH3:2].[CH:12]([NH:15][OH:16])([CH3:14])[CH3:13]>>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[N+:15]([CH:12]([CH3:14])[CH3:13])[O-:16])[CH3:2]
Reactant: CC(C)NO
Reactant: CCOc1ccccc1C=O
Product: CCOc1ccccc1C=[N+]([O-])C(C)C

Procedure:
The title compound was prepared according to the procedure described in Example 11 using 2-ethoxybenzaldehyde and N-isopropylhydroxylamine. The title compound was isolated in 48.8% yield as a solid, m.p. 59.4° C. (Rf=0.48 on a silica gel plate using ethyl acetate as the eluant).
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[F:8][C:9]([F:20])([F:19])[C:10]1[CH:11]=[C:12]([N:16]=[C:17]=[O:18])[CH:13]=[CH:14][CH:15]=1>>[CH3:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[N:1][C:17]([NH:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:9]([F:8])([F:19])[F:20])[CH:11]=1)=[O:18]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CN1CCCC1=N
Product: CN1CCCC1=NC(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
Conversion of the hydrochloride salt of 2-imino-1-methylpyrrolidine (6.73 g.; 0.05 mole) to the free base (4.9 g. assuming 100% conversion) is carried out in the usual manner. After drying over K2CO3 the benzene layer is stirred at room temperature and 9.36 g. (0.05 mole) of m-trifluoromethylphenylisocyanate is added (some solid precipitates). The reaction mixture is stirred overnight. The resulting solid is collected, m.p. = 155°-156° C. The benzene filtrate, upon removal of the solvent, affords an additional crop of solid material, m.p. 131°-137° C. Recrystallizations of the combined solids from acetone-pet. ether gives the pure product, 1-(1-methyl-2-pyrrolidylidene)-3-(m-trifluoromethylphenyl)urea, m.p. = 155°-156.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[CH:21]1([CH2:24][NH:25][CH2:26][C:27]2[NH:28][C:29](=[O:38])[C:30]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][C:31]=3[N:32]=2)[CH2:23][CH2:22]1>>[CH:21]1([CH2:24][N:25]([CH2:26][C:27]2[NH:28][C:29](=[O:38])[C:30]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][C:31]=3[N:32]=2)[C:16](=[O:18])[CH2:15][N:12]2[CH2:11][CH2:10][CH:9]([C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[CH2:23][CH2:22]1
Reactant: O=c1[nH]c(CNCC2CC2)nc2c1CCCCC2
Reactant: COc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Product: COc1ccc(C(=O)C2CCN(CC(=O)N(Cc3nc4c(c(=O)[nH]3)CCCCC4)CC3CC3)CC2)cc1
Yield: 7.9 %

Procedure:
The title compound (18 mg, 8% yield) was prepared following the general procedures of Example 1 from 2-(4-(4-methoxybenzoyl)piperidin-1-yl)acetic acid (124 mg, 0.45 mmol) and 2-((cyclopropylmethylamino)methyl)-6,7,8,9-tetrahydro-3H-cyclohepta[d]pyrimidin-4(5H)-one (104 mg, 0.45 mmol). 1H NMR (400 MHz, CDC3) δ 7.85 (d, J=8.5 Hz, 2H), 6.70-6.97 (m, 2H), 4.41 (s, 1H), 4.34 (s, 1H), 3.68-3.91 (m, 3H), 3.41 (s, 3H), 3.33 (d, J=7.0 Hz, 1H), 3.07-3.29 (m, 4H), 2.91 (d, J=10.5 Hz, 2H), 2.57-2.79 (m, 4H), 2.50 (br. s., 1H), 2.12-2.37 (m, 1H), 2.04 (d, J=14.1 Hz, 2H), 1.76 (d, J=5.0 Hz, 4H), 1.36-1.65 (m, 1H), 0.75-1.04 (m, 1H), 0.46 (d, J=7.5 Hz, 1H), 0.26-0.41 (m, 1H), 0.15-0.26 (m, 1H), 0.12 (d, J=4.5 Hz, 1H). HRMS calculated for C23H38N4O4 507.2971. found (ESI, [M+H]+), 507.2975. Retention time=3.54.
Reaction SMILES: [OH-].[Na+].O.C([O:6][C:7]([CH2:9][N:10]1[C:15]2[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=2[O:13][CH2:12][C:11]1=[O:21])=[O:8])C>C(O)C>[C:7]([CH2:9][N:10]1[C:15]2[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=2[O:13][CH2:12][C:11]1=[O:21])([OH:8])=[O:6]
Reactant: CCOC(=O)CN1C(=O)COc2cc(F)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CN1C(=O)COc2cc(F)ccc21
Yield: 97.3 %

Procedure:
Sodium hydroxide (0.7 g) and water (10 ml) were added to a mixture of 4-ethoxycarbonylmethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-one (3.7 g) and ethanol (20 ml), and the mixture was refluxed under heating for 5 hours. After the reaction, the solvent was concentrated, and dissolved in water (50 ml), and washed with methylisobutyl ketone, the aqueous layer was acidified with hydrochloric acid, and extracted with methyl isobutyl ketone, then dried with anhydrous sodium sulfate. After the solvent was distilled off, the residue was mixed with a mixed solvent of toluene-hexane (1:5), the mixture was filtered off to give the desired 4-carboxymethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-one (3.2 g). mp. 183°-184° C.
Reaction SMILES: C[O:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([NH:15][CH:16]1[CH2:21][CH2:20][N:19](CC2C=CC=CC=2)[CH2:18][CH2:17]1)=O)=O.[H][H]>CO.[Pd]>[NH:19]1[CH2:20][CH2:21][CH:16]([N:15]2[CH2:13][CH2:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[NH:5][C:3]2=[O:2])[CH2:17][CH2:18]1
Reactant: [H][H]
Reactant: COC(=O)Nc1ccccc1CC(=O)NC1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=C1Nc2ccccc2CCN1C1CCNCC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
10.00 kg (29.81 mol, 1.0 eq) 3-[1-(phenylmethyl)-4-piperidinyl]-2,3,4,5-tetrahydro-1,3-benzodiazepin-2(1H)-one from Example 3 are dissolved in 100 L methanol, combined with 1.00 kg 10% Pd/C and hydrogenated in the pressurised reactor at 70° C. and 3 bar. After the hydrogen uptake has ended the catalyst is filtered off and washed with 30 L methanol. The filtrate is concentrated in vacuo and the residue is suspended in 100 L acetone. Then the mixture is refluxed, the suspension is stirred for 15 minutes at reflux temperature and half the acetone is distilled off at normal pressure. After the distillation has ended the mixture is cooled to 0° C. and stirred for a further hour. The product is suction filtered, washed with 20 L acetone and dried at 50° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2c(-c3ccncc3)cccc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2cccc(-c3ccncc3)c2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-pyridin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH:1]1([N:7]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[N:31]3)=[CH:26][C:25]=2[CH3:39])[C:8]2[CH:22]=[CH:21][C:11]([C:12]([NH:14][CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[O:13])=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)=O.CC(O)C>>[CH:1]1([N:7]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[N:31]3)=[CH:26][C:25]=2[CH3:39])[C:8]2[CH:22]=[CH:21][C:11]([C:12]([NH:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:13])=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CCNC(=O)c1ccc(N(Cc2ccc(-n3cc(C(F)(F)F)cn3)cc2C)C2CCCCC2)nc1
Agent: O=C=O
Solvent: CC(C)O
Product: Cc1cc(-n2cc(C(F)(F)F)cn2)ccc1CN(c1ccc(C(=O)NCCC(=O)O)cn1)C1CCCCC1

Procedure:
The title compound was prepared by a method analogous to that described in Step D of Example 82, using Isomer 1 of methyl 3-(6-(cyclohexyl(2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methylamino)nicotinamido)propanoate. 1H NMR (400 MHz, CD3OD, δ): 8.68 (s, 1H), 8.41 (d, 1H), 7.95 (s, 1H), 7.72-7.75 (m, 1H), 7.54-7.57 (m, 2H), 7.45 (d, 1H), 6.49 (d, 1H), 5.08 (d, 1H), 3.55 (t, 2H), 2.56-2.60 (m, 5H), 2.08 (m, 1H), 1.68-1.79 (m, 4H), 1.40-1.50 (m, 1H), 1.00-1.35 (m, 5H). MS (M+1) 530.1. Chiral SFC: Chiralpak AD-3, 4.6×50 mm, 3 μm. Modifier: 0.05% DEA. Mobile Phase: 60/40 CO2/2-propanol. Flow: 4 mL/min. Retention time: 0.78 minutes, 99.7% ee (Isomer 1).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([CH2:20][CH:21]([CH3:23])[CH3:22])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:33][O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][C:44]=1[O:45][CH3:46])[N:41]=[CH:40][N:39]=[C:38]2[S:47][C:48]1[CH:49]=[C:50]([CH:52]=[CH:53][CH:54]=1)[NH2:51]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:51][C:50]2[CH:52]=[CH:53][CH:54]=[C:48]([S:47][C:38]3[C:37]4[C:42](=[CH:43][C:44]([O:45][CH3:46])=[C:35]([O:34][CH3:33])[CH:36]=4)[N:41]=[CH:40][N:39]=3)[CH:49]=2)=[O:19])[N:7]([CH2:20][CH:21]([CH3:22])[CH3:23])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)Cn1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4CC(C)C)c3)c2cc1OC
Temperature: 60 °C
Yield: 32 %

Procedure:
A stirred solution of phenyl 3-tert-butyl-1-isobutyl-1H-pyrazol-5-ylcarbamate described in Example 332A (150 mg, 0.47 mmol), N,N-diisopropylethylamine (80 mg, 0.62 mmol) and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (prepared as described in Example 115B) (100 mg, 0.31 mmol) in THF (1.0 mL) was heated at 60° C. for 15 h. After cooling to rt, the reaction solution was partitioned between dichloromethane and a saturated aqueous solution of sodium carbonate. The organic phase was separated and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography (eluting with a gradient of 40:1 to 20:1 dichloromethane:methanol) then reverse-phase preparative HPLC to afford 1-(3-tert-butyl-1-isobutyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (52 mg, 32%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.70 (s, 1H), 8.48 (s, 1H), 7.85 (s, 1H), 7.24-7.53 (m, 5H), 6.07 (s, 1H), 4.00 (s, 6H), 3.72 (d, J=7.2 Hz, 2H), 2.07 (m, 1H), 1.20 (s, 9H), 0.83 (d, J=6.8 Hz, 6H); LC-MS (ESI) m/z 535 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:2].[C:11]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]([CH2:27][C:28]([OH:30])=O)=[O:26])=[CH:21][CH:22]=2)[C:17]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([CH3:31])[CH2:16][C:15]1([CH3:39])[CH3:38])(=[O:13])[CH3:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:11]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]([CH2:27][C:28]([N:3]([CH2:1][CH3:2])[CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:30])=[O:26])=[CH:21][CH:22]=2)[C:17]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([CH3:31])[CH2:16][C:15]1([CH3:38])[CH3:39])(=[O:13])[CH3:12]
Reactant: CC(=O)N1c2ccc(NC(=O)CC(=O)O)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: CCNCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(Cc1ccccc1)C(=O)CC(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O

Procedure:
Condensation of N-ethylbenzylamine (5.2 mg) with 1-acetyl-6-(hydroxycarbonylmethylcarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg), under the agency of HATU (19 mg) and N,N-diisopropylethylamine (16 l) in tetrahydrofuran (2 ml) was performed according to the method described in example 11.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(N(C(C)C)CC)(C)C.[N:18]1([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)CCC>[N:18]1([CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][N:28]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=3)[CH2:29][CH2:30]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: C1CCN(CCN2CCNCC2)C1
Reactant: Nc1cc(Cl)ncn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCN(CCN3CCCC3)CC2)ncn1
Temperature: 125 °C
Reaction time: 18 h

Procedure:
6-Chloropyrimidin-4-amine 7-2 (0.317 g, 2.44 mmol) and diisopropylethylamine (0.0.316 g, 2.44 mmol) were suspended in n-butanol and 1-(2-pyrrolidin-1-ylethyl)piperazine 11-1 (0.448 g, 2.44 mmol) was added. The reaction was stirred at 125° C. for 18 hours. Upon cooling the reaction was purified on a silica column (DCM:MeOH:NH4OH) to afford 11-2. 1NMR (CD3OD): 7.96 ppm (s, 1H); 5.71 ppm (s, 1H); 3.53 ppm (t, 4H); 2.69 ppm (m, 2H); 2.58 ppm (m, 10H); 1.82 ppm (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[CH:12][C:13]([OH:16])=[N:14][CH:15]=1.CS(O[C@@H:22]([CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[O:34][N:33]=[C:32]([CH:35]([CH3:37])[CH3:36])[N:31]=2)[CH2:26][CH2:25]1)[CH3:23])(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[N:14][C:13]([O:16][CH:22]([CH:24]2[CH2:25][CH2:26][N:27]([C:30]3[O:34][N:33]=[C:32]([CH:35]([CH3:36])[CH3:37])[N:31]=3)[CH2:28][CH2:29]2)[CH3:23])=[CH:12][N:11]=1
Reactant: CC(C)c1noc(N2CCC([C@@H](C)OS(C)(=O)=O)CC2)n1
Reactant: CSc1ccc(-c2cnc(O)cn2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(-c2cnc(OC(C)C3CCN(c4nc(C(C)C)no4)CC3)cn2)c(F)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
A mixture of 5-[2-fluoro-4-(methylthio)phenyl]-2-pyrazinol (and tautomers thereof) (prepared as in Example 161, Alternative synthesis, Step 4, 0.40 g, 1.69 mmol), crude (1R)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl methanesulfonate (0.75 g, 2.29 mmol) and K2CO3 (0.48 g, 3.39 mmol) in DMF (16 mL) was stirred at 100° C. in a preheated oil bath overnight. The mixture was cooled to ambient temperature, treated with water, and the mixture was extracted with EtOAc (60 mL×2). The combined organic extract was washed with water, brine and dried over Na2SO4, filtered, and the filtrate was concentrated to a brown oil, which was purified by chromatography on an ISCO silica gel column using 0 to 30% EtOAc/hexanes to give 0.335 g (43%) of 2-[2-fluoro-4-(methylthio)phenyl]-5-[(1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]pyrazine as a yellow viscous oil. 1H NMR (400 MHz, CDCl3): δ 8.52 (s, 1H), 8.23 (d, 1H, J=1.0 Hz), 7.85 (t, 1H, J=8.2 Hz), 7.10 (dd, 1H, Ja=8.3 Hz, Jb=1.7 Hz), 7.00 (dd, 1H, Ja=12.1 Hz, Jb=1.6 Hz), 5.20-5.05 (m, 1H), 4.25-4.15 (m, 2H), 3.10-2.95 (m, 2H), 2.87 (septet, 1H, J=6.9 Hz), 2.50 (s, 3H), 2.00-1.75 (m, 3H), 1.55-1.40 (m, 2H), 1.33 (d, 3H, J=6.4 Hz), 1.26 (d, 6H, J=6.9 Hz); LRMS (ESI), m/z 458 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[N:7]=1.[F-:12].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C.O>[CH3:11][O:10][C:8]([C:6]1[N:7]=[C:3]([CH2:2][F:12])[O:4][CH:5]=1)=[O:9]
Reactant: [F-]
Reactant: COC(=O)c1coc(CCl)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Solvent: O
Product: COC(=O)c1coc(CF)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl 2-(chloromethyl)oxazole-4-carboxylate (CAS208465-72-9) (150 mg, 0.85 mmol) in acetonitrile (4.27 ml) was treated with tetra-n-butylammonium fluoride (2.56 ml, 2.56 mmol). The blue solution turned to orange and was left under stirring at room temperature overnight. For the workup, the reaction mixture was poured in water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate, and concentrated at reduced pressure. The crude material was purified by chromatography on a flash NH2 column using a gradient of heptane/ethyl acetate=100/0 to 50/50 as the eluent. The 2-fluoromethyl-oxazole-4-carboxylic acid methyl ester was obtained as a white solid (64 mg, 47% of theory). MS (ISP): m/z=160.1 [M+H]+. b) 2-Fluoromethyl-oxazole-4-carboxylic acid
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([C@:27]1([CH3:33])[CH2:31][O:30][C:29](=[O:32])[NH:28]1)[CH:21]=[CH:20]2.N1C=CC=CC=1.C(Cl)Cl>>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C@:27]3([CH3:33])[CH2:31][O:30][C:29](=[O:32])[NH:28]3)[CH:23]=2)[CH:18]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@]1(c2ccc3cc(OS(=O)(=O)C(F)(F)F)ccc3c2)COC(=O)N1
Reaction time: 8 h
Yield: 88.5 %

Procedure:
Trifluoromethanesulfonic anhydride (0.144 mL, 0.000859 mol) was slowly added to a solution containing (R)-4-(6-hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one (190 mg, 0.00078 mol), pyridine (2 mL, 0.02 mol), and methylene chloride (2 mL, 0.03 mol) at 0° C. After stirring overnight TLC showed complete reaction. After concentration, the crude was purified by chromatography using a 0-100% EtOAc/hexane gradient to give (R)-6-(4-methyl-2-oxooxazolidin-4-yl)naphthalen-2-yl trifluoromethanesulfonate as a yellow gel (259 mg, 88%). 1H NMR (400 MHz, CDCl3-d) δ=7.95 (s, 1 H), 7.94-7.89 (m, 2 H), 7.77 (d, J=1.9 Hz, 1 H), 7.59 (dd, J=1.6, 8.6 Hz, 1 H), 7.42 (d, J=9.0 Hz, 1 H), 4.48 (d, J=8.4 Hz, 1 H), 4.43 (d, J=8.4 Hz, 1 H), 1.88 (s, 3 H).