Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][C@@H:8]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)(=[O:13])=[O:12])[CH2:9][C@@H:2]12.C(N(CC)CC)C.[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1>ClCCl>[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([N:6]2[CH2:5][CH2:4][N:3]3[CH2:7][C@@H:8]([NH:10][S:11]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=4)(=[O:13])=[O:12])[CH2:9][C@H:2]3[CH2:1]2)=[O:37])=[CH:34][CH:33]=1
Reactant: O=S(=O)(N[C@H]1C[C@H]2CNCCN2C1)c1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)N1CCN2C[C@@H](NS(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 42 (42 mg, 0.12 mmol) in dichloromethane (5 mL) was added triethylamine (17 mg, 0.168 mmol) followed by 4-fluorobenzoyl chloride (27 mg, 0.168 mmol) in dichloromethane (1 mL). The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by chromatography on silica gel (ethyl acetate, then ethyl acetate/methanol=20:1) to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.20 (m, 1H), 1.80-2.10 (m, 3H), 2.20 (m, 1H), 2.70-2.95 (m, 3H), 3.12 (m, 1H), 3.40-3.70 (m, 2H), 4.45 (m, 1H), 7.22 (m, 2H), 7.42 (m, 2H), 7.82 (m, 1H), 8.05-8.20 (m, 4H); MS (ESI) m/z 472 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][N:17]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.ClCCl>[CH2:8]([NH:7][C:5](=[O:6])[C:4]1[CH:15]=[CH:16][N:17]=[C:2]([NH:1][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=2[F:18])[CH:3]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1F
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NCc1ccccc1)c1ccnc(NC(=O)c2ccccc2F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.5 %

Procedure:
To a solution of 2-amino-N-benzylisonicotinamide (0.10 g, 0.44 mmol) and 4-dimethylaminopyridine (0.01 g, 0.08 mmol) in pyridine (3.0 mL) was added 2-fluorobenzoyl chloride (0.07 g, 0.44 mmol). The resulting solution was stirred at ambient temperature for 16 hours, diluted with dichloromethane (25 mL), washed with water (2×25 mL) and brine (10 mL). The organic solution was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with 45% ethyl acetate in hexanes to give N-benzyl-2-(2-fluorobenzamido)isonicotinamide as a colorless solid (0.07 g, 44%): mp 175-176° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 9.21 (d, J=13.7 Hz, 1H), 8.64 (s, 1H), 8.46-8.42 (m, 1H), 8.12-8.06 (m, 1H), 7.64-7.48 (m, 2H), 7.35-7.16 (m, 7H), 6.68 (s, 1H), 4.65 (d, J=5.7 Hz, 2H); 13C NMR (CDCl3, 75 MHz) δ 165.2, 162.1, 161.9, 158.8, 151.7, 148.8, 144.1, 137.5, 134.5, 134.4, 131.9, 128.8, 127.7, 125.1, 120.7, 118.8, 116.6, 116.3, 111.0, 44.2; MS (ES+) m/z 350.6 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:12][C:13]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16]>>[CH3:12][C:13]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][C:14]=1[C:15]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)=[O:16]
Reactant: Nc1ccc2cccnc2c1
Reactant: Cc1nc(-c2ccccc2)ccc1C(=O)O
Product: Cc1nc(-c2ccccc2)ccc1C(=O)Nc1ccc2cccnc2c1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (28 mg, 0.9 mmol) and 2-methyl-6-phenylnicotinic acid (D23) (50 mg, 0.24 mmol) as a yellow solid. MS(ES): MH+ 340, M-H+ 338
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11]1[N:16]=[C:15](Cl)[C:14]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:13]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[N:12]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].O.[NH2:32][NH2:33]>C(O)(C)C>[CH3:1][C:2]([NH:10][C:11]1[N:16]=[C:15]([NH:32][NH2:33])[C:14]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:13]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[N:12]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3]
Reactant: NN
Reactant: CC(C)(Nc1nc(Cl)c(-c2ccc(F)cc2)c(-c2ccncc2)n1)c1ccccc1
Solvent: O
Solvent: CC(C)O
Product: CC(C)(Nc1nc(NN)c(-c2ccc(F)cc2)c(-c2ccncc2)n1)c1ccccc1
Temperature: 70 °C

Procedure:
2-((1-methyl-1-phenylethyl)amino)-4-chloro-5-(4-fluorophenyl)-6-(4-pyridyl)pyrimidine (218 mg, 0.52 mmol) was combined with a solution of hydrazine hydrate (130 mg 2.60 mmol) and isopropylalcohol (ca. 10 mL). The mixture was heated at 70° C. for 4 h. The reaction was cooled to RT, the solvent was evaporated in vacuo and the residue was purified by flash chromatography (2% MeOH:CHCl3) to provide the product as an off-white solid; MS m/z (M+H)+ 415; C24H23FN6 requir. 414.5.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([CH2:12][C:13]1([CH2:20][CH3:21])[C:18](=[O:19])[CH:17]=[CH:16][CH2:15][CH2:14]1)([O:10][CH3:11])=[O:9]>C1COCC1.S(C)C>[C:8]([CH2:12][C:13]1([CH2:20][CH3:21])[CH2:14][CH2:15][CH:16]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:17][C:18]1=[O:19])([O:10][CH3:11])=[O:9]
Reactant: Br[Mg]C1CCCC1
Reactant: CCC1(CC(=O)OC)CCC=CC1=O
Solvent: CSC
Solvent: C1CCOC1
Product: CCC1(CC(=O)OC)CCC(C2CCCC2)CC1=O
Reaction time: 1.5 h
Yield: 73.9 %

Procedure:
Following the procedure of Paquette et al., J. Am. Chem. Soc., 103, 1831 (1981) a solution of cyclopentylmagnesium bromide (222.5 mmol, 111.2 ml of 2M in Et2O), in 481 ml of dry THF under nitrogen was cooled to -78° C. and treated dropwise with a solution of 120.4 mmol (24.75 g) of CuBr.Me2S in 170 ml of Me2S. After 1.5 hours at -78° C., a solution of the enone, 6-carbomethoxymethyl-6-ethyl-2-cyclohexene-1-one prepared in Example 1, Step (c), (40.77 mmol, 8 g) in 80 ml of THF was added dropwise. After 1.5 hours, TLC indicated the consumption of enone and the reaction was quenched with 250 ml of 1M HCl (aq.) and extracted with 2×100 ml of CH2Cl2 and 2×100 ml of petroleum ether. Drying (Na2SO4) and flash chromatography afforded 8.027 g (30.13 mmol, 74%) of pale yellow oil containing a mixture of diastereomers. This material was combined with another batch to give 11.04 g and this was separated by preparative HPLC to afford 2.96 g of a less polar isomer and 4.3 g of a more polar isomer.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH3:21][C:22]1([CH3:29])[O:26][CH:25]([CH2:27][NH2:28])[CH2:24][O:23]1>CO.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:28][CH2:27][CH:25]2[CH2:24][O:23][C:22]([CH3:29])([CH3:21])[O:26]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1
Reactant: Cc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: CC1(C)OCC(CN)O1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(Cl)nc(NCC3COC(C)(C)O3)c2c1
Yield: 100 %

Procedure:
A solution of 2,4-dichloro-6-methylquinazoline (300.0 mg, 1.4 mmol), triethylamine (0.5 mL) and 2,2-dimethyl-1,3-dioxolane-4-methanamine (0.2 mL, 1.5 mmol) in methanol (2.0 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with brine (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 431 mg of the crude product as a white solid. MS obsd. (ESI+) [(M+H)+] 308.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.[F:13][C:14]([F:26])([F:25])[O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:14]([F:25])([F:26])[O:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][N:8]3[CH2:11][CH3:12])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CCn1ccc2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCn1ccc2ccc(-c3ccc(OC(F)(F)F)cc3)cc21
Yield: 55.8 %

Procedure:
Following the procedure described in Step 2 of Example 2, 6-bromo-1-ethyl-1H-indole (0.410 g , 1.83 mmol) was reacted with 4-trifluoromethoxybenzene boronic acid (0.422 g, 2.05 mmol), using tetrakis(triphenylphosphine)palladium (0.0651 g, 0.0563 mmol), and sodium carbonate (0.792 g, 7.47 mmol) in water (3.7 mL), ethanol (1.4 mL), and toluene (8 mL). Purification by flash chromatography using hexane as an eluant yielded the title compound as a yellow oil (0.312 g, 56%). 1HNMR (300 MHz, DMSO-d6): δ 7.85 (d, 2H, J=6.3 Hz), 7.8 (s, 1H), 7.65 (d, 1H, J=7.8 Hz), 7.4-7.5 (m, 3H), 7.35 (d, 1H, J=6.2 Hz), 6.45 (d, 1H, J=2.3 Hz), 4.3 (q, 2H, J=7.0 Hz), and 1.4 ppm (t, 3H, J=7.0 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]2[NH:13][C:14]([C:19]3[C:20](=[O:34])[N:21]([N:30]=[CH:31][CH2:32][CH3:33])[C:22]4[C:27]([C:28]=3[OH:29])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[BH4-].[Li+]>O1CCCC1.Cl>[CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]2[NH:13][C:14]([C:19]3[C:20](=[O:34])[N:21]([NH:30][CH2:31][CH2:32][CH3:33])[C:22]4[C:27]([C:28]=3[OH:29])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC=Nn1c(=O)c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCNn1c(=O)c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
The product of Example 358A (0.045 g, 0.09 mmol) in tetrahydrofuran (2 mL) at 0° C. was treated with methanol (0.005 mL, 0.35 mmol), followed by dropwise addition of a 2.0 M solution of lithium borohydride in tetrahydrofuran (0.07 mL, 0.13 mmol), stirred at 25° C. for one hour, and diluted with 1 N hydrochloric acid. The resulting precipitate was filtered and dried. The solid was dissolved in tetrahydrofuran and absorbed onto silica gel by evaporating to dryness. The resulting silica was loaded onto a 2 g Alltech sep pack and eluted with dichloromethane to give the title compound (0.020 g, 44%). MS (ESI−) m/z 503 (M−H)−.
Reaction SMILES: C[C:2]1[C:12](=[O:13])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:4](=[O:5])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](O)=O)=[CH:17][CH:16]=1>>[CH3:2][C:3]1[C:4](=[O:5])[CH:6]2[CH:11]([C:12](=[O:13])[C:22]=1[CH2:21][C:18]1[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=1)[CH:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CC1=CC(=O)c2ccccc2C1=O
Product: CC1=C(Cc2ccc(Cl)cc2)C(=O)C2C=CC=CC2C1=O
Yield: 75 %

Procedure:
As starting materials for the coupling reaction menadione and 4-chlorophenylacetic acid were used. Synthesis is realized according to the general procedure described in general procedure of example 1. After chromatography on silica gel (cyclohexane:ethyl acetate=3:1, UV), 6.46 g (21.8 mmol, 75% yield) of P_TM30 were isolated as yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][C@H:13]3[CH2:18][CH2:17][C@H:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)C=2)[CH:3]=1.BrC1C=C2C(=CC=1)[N:30]=C(O)C=C2>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:30]=[C:7]([O:12][CH:13]1[CH2:18][CH2:17][CH:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]1)[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(Br)ccc2n1
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(Br)ccc3c2)CC1
Product: CC(C)(C)C1CCC(Oc2ccc3cc(Br)ccc3n2)CC1

Procedure:
Synthesized as per 2-bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalene using 6-Bromo-quinolin-2-ol as starting material. ESI-MS (M+H+): 362.1/364.10).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:22]=[C:21]([NH2:23])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:6]=[C:7]([O:11]C)[C:8]=1[O:9]C.B(Br)(Br)Br>C(Cl)Cl>[C:5]1([CH3:13])[CH:6]=[CH:7][C:8]([NH:23][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([C:5]3[CH:6]=[C:7]([OH:11])[C:8]([OH:9])=[C:3]([OH:2])[CH:4]=3)[N:22]=2)=[CH:3][CH:4]=1
Reactant: COc1cc(-c2nc(N)c3ccccc3n2)cc(OC)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc(Nc2nc(-c3cc(O)c(O)c(O)c3)nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
An aryl methoxy derivative p-tolyl-[2-(3,4,5-trimethoxy-phenyl)-quinazolin-4-yl]-amine (2, 30 mg, 7.5e-5 mol) was dissolved in anhydrous DCM (minimal volume, not fully dissolved); the round flask was then sealed. BBr3 (76 μl, 0.111 gr, 205 gr/mol, d=1.45, 2 equiv/per methoxy group, here 6 eq. were used 5.5e-4 mol) was added drop wise (from a syringe) and the reaction mixture was stirred at room temperature for 1 h. The degree of conversion was monitored by HPLC until full conversion was achieved, and the reaction was then quenched with methanol and evaporated to low volume. Another wash was performed using methanol, followed by a wash with acetonitrile and evaporation, to obtain 5-(4-(p-tolylamino)quinazolin-2-yl)benzene-1,2,3-triol, 21 (24 mg, 6.6e-5 mol, 90%). m.p>250° C.; 1H NMR (300 MHz, DMSO-d6) δ 2.35 (s, 3H), 6.75 (s, 2H), 7.22 (d, J=8.0 Hz, 2H), 7.35 (d, J=7.5 Hz, 2H), 7.56 (t, J=8.0 Hz, H), 7.82 (t, J=8.2 Hz, 2H), 8.24 (d, J=7.5 Hz, 1H). Anal. (C21H17N3O3) C, H, N.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:26]#[N:27])[C:10]([CH3:25])=[C:11]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:12]=3[C@H:13]3[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]3)[N:8]=2)[CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>ClCCl>[CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:26]#[N:27])[C:10]([CH3:25])=[C:11]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:12]=3[CH:13]3[CH2:17][CH2:16][C:15](=[O:18])[CH2:14]3)[N:8]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(-c2ccccc2)c([C@H]2CC[C@@H](O)C2)c2oc(C3CC3)nc2c1C#N
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(C2CCC(=O)C2)c2oc(C3CC3)nc2c1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
2-Cyclopropyl-7-[(1S*,3R*)-3-hydroxycyclopentyl]-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-302) (50 mg, 0.14 mmol) was dissolved in dichloromethane (1 ml), and at 0° C., Dess-Martin reagent (118 mg, 0.28 mmol) was added. The solution was stirred at room temperature for 3 hours, then again cooled at 0° C., and aqueous saturated sodium thiosulfate solution and an aqueous saturated sodium hydrogencarbonate solution were added, followed by further stirring for 10 minutes. The solution was extracted three times with dichloromethane. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away and the resulting residue was purified by middle-pressure liquid chromatography (eluent, n-hexane:ethyl acetate=3:1, v/v) to obtain the entitled compound (44 mg, 89%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH3:13])[CH3:12].[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH3:13])[CH3:12].[CH3:14][O:15][C:16]1[CH:21]=[C:20]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[C:5]3([CH3:13])[CH3:12])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)C(=O)Nc2ccc(Br)cc21
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COc1cccc(-c2ccc3c(c2)C(C)(C)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31.4 %

Procedure:
5-bromo-1,3-dihydro-3,3-dimethyl-2H-indol-2-one (0.33 g, 1.38 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.094 g) were stirred under an atmosphere of nitrogen in dimethoxyethane (12 cm3). After 15 minutes, 3-methoxyphenylboronic acid (0.42 g, 2.76 mmol) was added, followed by potassium carbonate (1.15 g, 8.34 mmol) in water (5 cm3). The reaction was heated to reflux for 5 hours, and then cooled to room temperature. Saturated aqueous ammonium chloride and EtOAc were added and the mixture was filtered. The aqueous layer was extracted with EtOAc (×2), and the combined organic layers were dried (MgSO4), filtered, and evaporated. The residue was purified by column chromatography (SiO2, EtOAc:hexane 1:3) to afford the title compound (0.11 g, 31%), mp=157-158° C.; 1H NMR (DMSO-d6) δ 3.34 (s, 6H), 3.82 (s, 3H), 6.87-6.93 (m, 2H), 7.20-7.15 (m, 2H), 7.37-7.32 (m, 1H), 7.49-7.46 (m, 1H), 7.63 (d, 1H, J=1.14 Hz), 10.4 (s, 1H); MS (EI) m/z 266 (M−H)−; Anal. Calc. for C17H17NO2: C, 76.38; H, 6.41; N, 5.24; Found: C, 76.02; H, 6.49; N, 5.02.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:22])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[CH3:21])=O.S(O)(O)(=O)=O.[NH2:28][OH:29]>CO>[CH3:1][NH:2][C:3](=[O:22])/[C:4](/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[CH3:21])=[N:28]/[OH:29]
Reactant: CNC(=O)C(=O)c1ccccc1COc1cc(C)ccc1C
Reactant: NO
Agent: O=S(=O)(O)O
Solvent: CO
Product: CNC(=O)/C(=N/O)c1ccccc1COc1cc(C)ccc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.6 %

Procedure:
N-methyl-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-oxoacetamide (11.89 g, 0.04 mol) was suspended in methanol (40 ml). Hydroxylamine sulfate (4.92 g, 0.06 mol) was added, and the mixture was refluxed for 8 hours. After completion of the reaction, methanol was evaporated under reduced pressure. The resulting residue (E/Z=46/54) was dissolved in methylene chloride (80 ml), conc. hydrochloric acid (20 ml) was added, and the mixture was stirred at room temperature for 15 hours. Water (50 ml) and toluene (80 ml) were added, and the mixture was stirred at room temperature for 5 minutes. Then the resulting crystals were separated by filtration, washed with water (50 ml) and toluene (50 ml) and dried to give (E)-N-methyl-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-hydroxyiminoacetamide (11.32 g, Yield: 90.6%, E/Z=99/1).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=2[OH:15])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:16]([O-])([O-])=O.[K+].[K+].COS(OC)(=O)=O.CCO>CC(C)=O.CCOCC.O>[CH3:1][C:2]1([C:8]2[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C([O-])[O-]
Reactant: CC1(c2cc(Br)ccc2O)CCCCC1
Agent: [K+]
Solvent: CCO
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1ccc(Br)cc1C1(C)CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
To a suspension of 2-(1-methylcyclohexyl)-4-bromophenol (29.68 g, 0.110 mol) and K2CO3 (30.48 g, 0.221 mol) in 200 mL of anhydrous acetone was added a neat solution of dimethylsulfate (13.91 g, 0.110 mol) dropwise through a syringe over 5 minute at RT under argon. The resulting thick suspension was stirred over night at RT and 100 mL of EtOH was added. After 1 hour, the mixture was diluted with ether and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, brine and dried with MgSO4. After filtration, the solvents were removed and the residue distilled under reduced vacuum, 130–132° C. (0.7 mm/Hg). The impure fractions were combined and further purified on silica gel (hexane) to give a total amount of 2-(1-methylcyclohexyl)-4-bromoanisole as an oil (13.66 g, 44%). 1H NMR (300 MHz, CDCl3): δ 1.26 (s, 3H), 1.30–1.70 (m, 8H), 1.90–2.10 (m, 2H), 3.79 (s, 3H), 6.74 (d, J=8.4 Hz, 1H), 7.26 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H), 7.36 (d, J=2.4 Hz, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH3:11])=O.[CH3:12][N:13]1[CH2:21][C:20]2[C:19]([C:22](=[S:24])[NH2:23])=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]1=[O:25]>>[CH3:12][N:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[C:22]2[S:24][CH:2]=[C:3]([C:5]3[CH:6]=[N:7][CH:8]=[CH:9][C:10]=3[CH3:11])[N:23]=2)[C:14]1=[O:25]
Reactant: Cc1ccncc1C(=O)CBr
Reactant: CN1Cc2c(cccc2C(N)=S)C1=O
Product: Cc1ccncc1-c1csc(-c2cccc3c2CN(C)C3=O)n1
Yield: 24.9 %

Procedure:
By the reaction in the same manner as in Example 25-ii) using 2-methyl-1-oxo-4-isoindolincarbonitrile (364 mg), crude 2-methyl-1-oxoisoindolin-4-carbothioamide (603 mg) was obtained as a brown powder. Then, by the reaction in the same manner as in Example 25-iii), 2-bromo-1-(4-methylpyridin-3-yl)ethanone hydrobromate (500 mg) and 2-methyl-1-oxoisoindolin-4-carbothioamide (520 mg), the title compound (187 mg) was obtained as colorless powder crystals.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]([C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=O)=O)C1C=CC=CC=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].O>O1CCCC1.C(OCC)(=O)C>[CH3:15][N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[CH2:22][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1
Reactant: O=C(c1c[nH]c2ccccc12)C1CCCN1C(=O)OCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CN1CCCC1Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred mixture of lithium aluminum hydride (1.71 g, 45.1 mmol, 4.5 eq) in anhydrous tetrahydrofuran (40 mL) at 0° C. was added dropwise a solution of the 3-(N-benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-1H-indole (10.0 mmol) in anhydrous tetrahydrofuran (20 mL). The resulting reaction mixture was heated at reflux under nitrogen for 6 hours. The reaction mixture was cooled, and sodium sulfate decahydrate (50 g) was added very carefully portionwise, followed by water (1mL), and ethyl acetate (100 mL). The resulting mixture was stirred at room temperature under nitrogen for 24 hours. The reaction mixture was then filtered through Celite®, and the filtrate was evaporated under reduced pressure. The residue was then column chromatographed using silica gel (approximately 100 g) eluting with an appropriate solvent system to afford the desired 3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole.
Reaction SMILES: C(O[C:4](=[O:23])[CH2:5][N:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:8]=[N:7]1)C.[CH2:24]([N:26]([CH2:31][CH3:32])[CH2:27][CH2:28][CH2:29][NH2:30])[CH3:25].O>CCOCC>[CH2:24]([N:26]([CH2:31][CH3:32])[CH2:27][CH2:28][CH2:29][NH:30][C:4](=[O:23])[CH2:5][N:6]1[C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:8]=[N:7]1)[CH3:25]
Reactant: CCN(CC)CCCN
Reactant: CCOC(=O)Cn1ncc(-c2ccccn2)c1-c1ccccc1
Solvent: O
Solvent: CCOCC
Product: CCN(CC)CCCNC(=O)Cn1ncc(-c2ccccn2)c1-c1ccccc1
Yield: 43.1 %

Procedure:
A solution of 10 g (0.032 mol) of ethyl 5-phenyl-4-(2-pyridinyl)pyrazole-1-acetate of example 1 in 15 mL (0.095 mol) of 3-(diethylamino)propanamine was heated at 100° for 3 hr. The excess amine was stripped in vacuo and the residue distributed between water and ether. The ether solution was dried over MgSO4, stripped and applied to 350 g of silica gel in a small amount of methylene chloride. The column was eluted with 20:1 acetone-triethylamine and a light yellow oil was obtained that crystallized upon triturating with cyclohexane to yield 5.4 g of product, mp 82°-83° C.