Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[C:17]([CH3:23])[N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:24]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:33]B1OB(C)OB(C)O1>C1COCC1.CCOC(C)=O>[CH:20]([N:19]1[C:15]([C:13]2[N:14]=[C:7]3[C:6]4[CH:24]=[C:2]([CH3:33])[CH:3]=[CH:4][C:5]=4[O:11][CH2:10][CH2:9][N:8]3[CH:12]=2)=[N:16][C:17]([CH3:23])=[N:18]1)([CH3:22])[CH3:21]
Reactant: CB1OB(C)OB(C)O1
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(Br)ccc2OCC3)n(C(C)C)n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)-c1nc(-c3nc(C)nn3C(C)C)cn1CCO2
Temperature: 140 °C

Procedure:
A microwave vial was charged with a suspension of 10-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.200 mg, 0.515 mmol) in 2.0 ml THF/0.400 mL water. To this suspension was added potassium phosphate (330 mg, 0.0015 mol) and trimethylboroxine (0.14 ml, 1.00 mmol). The reaction suspension was degassed by bubbling nitrogen through the stirred mixture via a syringe. After several minutes the syringe was removed and Bis(ditertbutyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (18 mg, 0.02 mmol) was added and the reaction vial was quickly sealed. The sealed vial was flash heated in a microwave at 140° C. for 40 minutes. The cooled reaction was diluted with EtOAc and the organic solution was washed with water ×1, saline ×1 and dried (Na2SO4) before concentration in vacuo. The crude residue was purified by preparative RP-HPLC to give 481. MS: (ESI+)=324.1
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[C:19](Cl)(=[O:24])[CH2:20][CH2:21][CH2:22][CH3:23]>C(Cl)Cl>[C:19]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:24])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: COC(=O)c1cccc(N)c1
Reactant: CCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)Nc1cccc(C(=O)OC)c1
Yield: 86.7 %

Procedure:
To a solution of methyl 3-aminobenzoate (6.0 g) and triethylamine (4.5 g) in methylene chloride (90 ml) was added dropwise, while stirring under ice-cooling, valeryl chloride (4.8 g). The mixture was stirred for one hour. The reaction mixture was washed with an aqueous solution of sodium bicarbonate, dilute hydrochloric acid and water, followed by drying and concentration to dryness. The concentrate was crystallized from ethyl acetate - hexane to afford colorless prisms (8.1 g, 87%), m.p. 101°-102° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][NH:6]1.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[S:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:20])=[O:19]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](O)CN1S(=O)(=O)c1ccccc1
Yield: 73.3 %

Procedure:
In a 250 mL round bottom flask was dissolved 10.0 g (55 mmol) of trans-4-hydroxyproline methyl ester hydrochloride 14 (Bachem) in 100 mL anhydrous pyridine at 0° C. with stirring to give a cloudy white mixture. To this was added 7.9 mL (62 mmol, 1.1 equiv.) of benzenesulfonyl chloride in four portions over 15 minutes to give a bright yellow mixture. This reaction mixture was stirred under a CaCl2 drying tube at 4° C. (cold room) overnight, then concentrated in vacuo, and the residue dissolved in ethyl acetate (˜200 mL.) The solution was washed with 1 N HCl (three times), with H2O, 1 N NaOH (three times), then brine, and the organic solution was dried (MgSO4), filtered, and concentrated to give a yellow oil. This was dissolved in ethyl acetate, loaded onto silica, and eluted with 3:2 ethyl acetate/hexanes to give 11.5 g (40.3 mmol, 73%) of compound 15 as a white crystalline solid. 1H-NMR (400 MHz, CDCl3, δ ppm) 7.85 (dt, J=2 Hz, 7 Hz, 2H), 7.57 (tt, J=1 Hz, 8 Hz, 1H), 7.49 (td, J=2 Hz, 7 Hz, 2H), 4.41 (br s, 1H), 4.37 (t, J=8 Hz, 1H), 3.70 (s, 3H), 3.57 (dd, J=4 Hz, 11 Hz, 1H), 3.37 (dt, J=2 Hz, 11 Hz, 1H), 2.17 (m, 2H), 2.06 (m, 1H); 13C-NMR (400 MHz, CDCl3, δ ppm) 173.01, 138.05, 133.43, 129.42, 128.05, 70.37, 59.85, 56.83, 52.99, 39.81; m/z: 286 (M+1)+. See, for example, DiCesare, P., et al.; J. Med. Chem.; 35(22), pp. 4205–4213 (1992), which is incorporated by reference in its entirety.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[N+:11]([O-:13])=[O:12].[OH-:14].[Na+].Cl>CS(C)=O.O>[F:8][C:6]1[CH:5]=[C:4]([O:9][CH3:10])[C:3]([N+:11]([O-:13])=[O:12])=[C:2]([OH:14])[CH:7]=1
Reactant: [OH-]
Reactant: COc1cc(F)cc(F)c1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(F)cc(O)c1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To a solution of 1,5-difluoro-3-methoxy-2-nitro-benzene (20 g, 105 mmol) in dimethylsulfoxide (50 ml) is added a 10N aqueous solution of sodium hydroxide (31.5 ml) and the mixture is stirred at room temperature for 18 h and at 60° C. for 3 h. After completion of reaction (monitored by TLC), the mixture is diluted with water (50 ml), acidified with 2N hydrochloric acid to pH 3 and extracted with ethyl acetate (3×100 ml). The combined organic layers are washed with water (50 ml), brine (50 ml), dried over sodium sulfate and concentrated in vacuo. The crude product is purified by flash column chromatography (15% ethyl acetate/hexane) to yield 5-fluoro-3-methoxy-2-nitro-phenol (12.0 g, 63.5 mmol, 60%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[C:13]([Cl:18])[N:14]=[CH:15][C:16](I)=[C:11]2[C:10]([CH3:19])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.[C:25](=[O:27])=[O:26]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:12]2[C:13]([Cl:18])=[N:14][CH:15]=[C:16]([C:25]([OH:27])=[O:26])[C:11]=2[C:10]([CH3:19])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C=O
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(I)c12
Agent: CC(C)[Mg]Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)O)c12

Procedure:
To a solution of 7-chloro-4-iodo-3-methyl-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (200 mg) in dry tetrahydrofuran (4 ml) at −40° C. under an atmosphere of nitrogen, was added dropwise, a solution of isopropylmagnesium chloride (2M in tetrahydrofuran, 600 ul) and the solution stirred at −40° C. for 15 minutes. The solution was saturated with a stream of carbon dioxide gas and then diluted with ethyl acetate. The organic was extracted with saturated ammonium chloride followed by 1N sodium hydroxide solution. The combined aqueous was then acidified to pH1 with concentrated hydrochloric acid to afford a precipitate. The precipitate was filtered and washed with water until neutral. The solid was then sucked dry and dried over sodium hydroxide at 50° C. to afford the title compound (86 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[N:17]=[C:16]([C:26]([OH:29])([CH3:28])[CH3:27])[CH:15]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>C(#N)C>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:18]1[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:37](=[O:39])[CH3:38])[CH:3]=3)=[CH:9][CH:10]=2)=[CH:15][C:16]([C:26]([OH:29])([CH3:27])[CH3:28])=[N:17]1
Reactant: CC(=O)Cl
Reactant: CC(C)(O)c1cc(-c2ccc(-c3cccc(N)c3)cc2)n(-c2ccccc2Cl)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(-c2ccc(-c3cc(C(C)(C)O)nn3-c3ccccc3Cl)cc2)c1
Temperature: 75 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
To a solution of 2-(5-(3′-aminobiphenyl-4-yl)-1-(2-chlorophenyl)-1H-pyrazol-3-yl)propan-2-ol (370 mg, 037 mmol) in acetonitrile (1.6 mL) was added triethylamine (0.12 mL, 0.86 mmol) followed by acetyl chloride (27 μL, 380 μmol). The reaction vial was then shaken at 75° C. overnight. After cooling the reaction solution was concentrated under reduced pressure and the crude product was purified by flash column chromatography eluting with a gradient from 0% to 100% EtOAc/hexane to afford N-(4′-(1-(2-chlorophenyl)-3-(2-hydroxypropan-2-yl)-1H-pyrazol-5-yl)biphenyl-3-yl)acetamide (82 mg, 49% yield) as an oil. 1H NMR (400 MHz CDCl3): δ 7.79 (1H, s), 7.49-7.42 (4H, m), 7.41-732 (4H, m), 7.31-7.21 (3H, m), 6.54 (1H, s), 2.68 (1H, s), 2.19 (3H, s), 1.69 (6H, s). MS(ES): 445[M+H]+. The following compounds are prepared essentially according to the previous examples:
Reaction SMILES: F[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([NH:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)=[N:11][C:10]=2[C:25]([NH2:27])=[O:26])=[O:7])=[CH:4][CH:3]=1.[NH2:30][CH2:31][CH2:32][OH:33]>CN1C(=O)CCC1.O>[OH:33][CH2:32][CH2:31][NH:30][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([NH:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)=[N:11][C:10]=2[C:25]([NH2:27])=[O:26])=[O:7])=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)c1ccc(F)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)c1ccc(NCCO)cc1
Yield: 31.3 %

Procedure:
A solution of 5-(4-fluorobenzamido)-2-(naphthalen-2-ylamino)thiazole-4-carboxamide (0.10 g, 0.25 mmol) and 2-aminoethanol (0.15 g, 2.46 mmol) in NMP (1 mL) was treated using a microwave synthesizer for 1 hr (CEM Corp., 180° C.). The, reaction mixture was diluted with water (3 mL), and the resulting solids were collected by filtration. The solids were washed with water, and dried to give 0.035 g (31% yield) of the titled compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:9]([C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=2)[NH:10][C:11](=[O:25])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:13]=1[CH3:14])=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>CN(C)C=O.CO>[C:30]([C:29]1[CH:28]=[CH:27][C:26]([CH:9]2[N:10]([CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:11](=[O:25])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=3)[C:13]([CH3:14])=[C:8]2[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])=[CH:33][CH:32]=1)#[N:31]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC1=C(C(=O)c2ccco2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC1=C(C(=O)c2ccco2)C(c2ccc(C#N)cc2)N(CC(=O)OC(C)(C)C)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred suspension of 4-{5-(2-furoyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetr-a-hydropyrimidin-4-yl}benzonitrile (Example 20A) (150 mg, 0.33 mmol) and potassium carbonate (83 mg, 0.60 mmol) in dimethylformamide (5 ml) is treated with tert.-butyl bromoacetate (71 mg, 0.36 mmol), then stirred at room temperature overnight (16 h). The reaction solution is then diluted with methanol (7 ml) and purified directly by preparative HPLC(RP18 column; eluent: acetonitrile/water 10:90→90:10).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.OC1CCNC1.[NH:33]1[CH2:41][CH2:40][CH:36]([C:37]([NH2:39])=[O:38])[CH2:35][CH2:34]1>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:33]3[CH2:41][CH2:40][CH:36]([C:37]([NH2:39])=[O:38])[CH2:35][CH2:34]3)[CH:7]=2)=[CH:9][C:10]=1[C:23]([F:26])([F:25])[F:24]
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Reactant: NC(=O)C1CCNCC1
Agent: OC1CCNC1
Product: COc1ccccc1Sc1ccc(-c2ccnc(N3CCC(C(N)=O)CC3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with isonipecotamide. A yellow solid 105 was obtained (0.0272 g, 57%). 1H-NMR (CDCl3, 400 MHz) δ 1.90–1.99 (m, 2H), 2.08–2.14 (m, 2H), 2.59–2.66 (m, 1H), 3.39–3.47 (m, 2H), 3.83 (s, 3H), 4.29–4.34 (m, 2H), 5.57 (br s, 1H), 5.99 (br s, 1H), 6.97 (d, J=6.6 Hz, 1H), 6.99 (s, 1H), 7.00–7.05 (m, 2H), 7.06 (d, J=8.4 Hz, 1H), 7.46–7.52 (m, 3H), 7.85 (s, 1H), 8.20 (d, J=6.6 Hz, 1H); MS (APCI) m/z 488 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(O)(=O)C.[Br:14]Br>>[Br:14][C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:2]([CH3:1])[C:3]=1[NH2:4]
Reactant: BrBr
Reactant: Cc1ccc(N)c(C)c1
Solvent: CC(=O)O
Product: Cc1cc(C)c(N)c(Br)c1
Reaction time: 0.33 h

Procedure:
To a solution of 50.0 g (0.413 mol) of 2,4-dimethylaniline in 1500 cm3 of glacial acetic acid 21.2 ml (65.6 g, 0.410 mol) of bromine was added dropwise while vigorously stirring for ca. 20 min. This mixture was stirred for 2 h at 40° C. The precipitate formed was filtered off, washed with 50 ml of acetic acid, and dried in air. Then, this white solid was added to a solution of 100 g of potassium hydroxide in 400 ml of water. This mixture was stirred for 30 min. The crude product was extracted with 3×100 ml of dichloromethane. The combined extract was dried over Na2SO4 and evaporated to dryness. Fractional distillation gave a yellowish liquid, bp 83-85° C./1 mm Hg. Yield 46.9 g (57%).
Reaction SMILES: C([O:8][C:9]1[CH:40]=[CH:39][C:12]([O:13][CH2:14][C@@H:15]([OH:38])[CH2:16][NH:17][C@H:18]([CH2:36][OH:37])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:28])=[CH:22][CH:21]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.O1CCOCC1.[Pd]>[OH:37][CH2:36][C@@H:18]([NH:17][CH2:16][C@H:15]([OH:38])[CH2:14][O:13][C:12]1[CH:39]=[CH:40][C:9]([OH:8])=[CH:10][CH:11]=1)[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:28])=[CH:24][CH:25]=1
Reactant: O=C(Nc1ccccc1)Nc1ccc(C[C@@H](CO)NC[C@H](O)COc2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(Nc1ccccc1)Nc1ccc(C[C@@H](CO)NC[C@H](O)COc2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.3 %

Procedure:
N-[4-[(2S)-2-[[(2S)-3-[4-(Benzyloxy)phenoxy]-2-hydroxypropyl]amino]-3-hydroxypropyl]phenyl]-N′-phenylurea (159 mg) was dissolved in a mixed solvent of methanol (2.5 ml) and 1,4-dioxane (2.5 ml) under heating. After cooling to room temperature, 10% palladium on activated carbon (50% wet, 159 mg) was added and the mixture was hydrogenated at 1 atm for 4 hours. The catalyst was removed by filtration and washed with methanol. The filtrate was concentrated in vacuo to give N-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino]propyl]phenyl]-N′-phenylurea (129 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([CH3:60])[C:17](=[O:59])[C:18]2[CH:58]=[CH:57][CH:56]=[C:20]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:26][C:25]=3[C:36]3[CH:41]=[C:40]([C:42](=[O:55])[NH:43][CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=4)[CH:39]=[CH:38][N:37]=3)=[O:22])[CH:19]=2)[CH2:10][CH2:9]1)=[O:7].[CH3:61]OC(NC)C>>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:61])[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([CH3:60])[C:17](=[O:59])[C:18]2[CH:58]=[CH:57][CH:56]=[C:20]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]4)=[CH:26][C:25]=3[C:36]3[CH:41]=[C:40]([C:42](=[O:55])[NH:43][CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:52])([F:53])[F:54])[CH:46]=4)[CH:39]=[CH:38][N:37]=3)=[O:22])[CH:19]=2)[CH2:10][CH2:9]1)=[O:7]
Reactant: CNC(C)OC
Reactant: COCCNC(=O)N1CCN(CCN(C)C(=O)c2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1
Product: COCCN(C)C(=O)N1CCN(CCN(C)C(=O)c2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1

Procedure:
This compound was prepared according to the procedure described for the synthesis of N1-(2-(4-((2-methoxyethyl)carbamoyl)piperazin-1-yl)ethyl)-N3-(2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)-N1-methylisophthalamide Example 207 substituting methoxy-N-methylethanamine in place of 2-methoxyethanamine LC-MS (ES, m/z): 843 [M+H]+ H-NMR (300 MHz, CD3OD, ppm): 8.99 (d, J=5.1 Hz, 1H), 8.77 (d, J=9.0 Hz, 1H), 8.46 (s, 1H), 8.19 (m, 3H), 7.90 (m, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.74˜7.67 (m, 4H), 7.62˜7.53 (m, 2H), 4.72 (s, 2H), 4.00 (s, 2H), 3.90˜3.65 (m, 9H), 3.57 (d, J=5.1 Hz, 1H), 3.47 (d, J=4.8 Hz, 1H), 3.34 (s, 3H), 3.12 (s, 3H), 2.97 (s, 3H), 2.04 (d, J=4.8 Hz, 4H), 1.83 (d, J=4.2 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][S-:10].[Na+].O>C(OCC)(=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([S:10][CH3:9])=[N:3][CH:4]=1
Reactant: C[S-]
Reactant: Brc1ccc(Br)nc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CSc1ccc(Br)cn1
Temperature: 160 °C
Yield: 89 %

Procedure:
2,5-Dibromo-pyridine (3.0 g, 12.7 mmol) and sodium thiomethoxide (0.84 g, 12 mmol) were dissolved in 18 ml anhydrous N N-dimethylformamide. The mixture was heated at 160° C. under nitrogen for 6 hrs. After cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The aqueous layer was extracted with ethyl acetate several times. The combined extract was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (0→6% EtOAC/Hexane) to give 5-Bromo-2-methylsulfanyl-pyridine as a white solid (2.18 g, 84% yield). 1H-NMR (400 MHz, CDCl3): δ 2.55 (s, 3H), 7.09 (dd, 1H, J=0.7, J=8.6), 7.59 (dd, 1H, J=2.4, J=8.6), 8.50 (m, 1H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][CH:3]=1.[CH2:26](I)[CH3:27]>C1COCC1.C([Li])(C)(C)C>[CH2:26]([C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][CH:3]=1)[CH3:27]
Reactant: CCI
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)ccc(OC)c21
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCc1ccc(OC)c2c1nc(-c1ccc(C(C)C)cc1)n2CCOC
Temperature: -78 °C
Reaction time: 1 h
Yield: 31.8 %

Procedure:
To a solution of 150 mg (0.223 mmol) 4-bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole in 8 ml THF, 0.289 ml tert-butyllithium (1.7M in pentane) is slowly added at −78° C. This mixture is stirred for 1 h at −78° C. then 54 μl (0.669 mmol) ethyl iodide is added. The reaction mixture is warmed to room temperature and stirring is continued for 12 h. The reaction mixture is cooled to room temperature, poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=2:1) to afford 25 mg of the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:15][O:14][C:13]([C:16]3[CH:20]=[C:19]([CH3:21])[N:18]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)[N:17]=3)=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[O-2].[O-2].[Mn+4]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]=[C:13]([C:16]3[CH:20]=[C:19]([CH3:21])[N:18]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)[N:17]=3)[O:14][CH:15]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(Cn2nc(C3=NC(c4ccc(C(C)(C)C)cc4)CO3)cc2C)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(C(C)(C)C)cc4)co3)cc2C)cc1
Temperature: 25 °C
Yield: 48.9 %

Procedure:
A solution of 4-(4-tert-butylphenyl)-2-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-4,5-dihydro-1,3-oxazole (Example 70, 100 mg, 0.26 mmol) in THF (2 mL) was treated with manganese dioxide (45 mg, 0.52 mmol), and the resultant mixture was stirred to reflux. Further portions of manganese dioxide (45 mg and 90 mg) were added after 2.5 and 4.5 h. After a total of 6.5 h, the mixture was cooled to rt, diluted with 2 ml THF and filtered over a pad of celite. The filtrate was concentrated in vacuo, re-disolved in dichloromethane and successively washed with aqueous HCl (1.0 N) and water, dried (MgSO4), filtered, and concentrated to dryness. The crude material was purified by flash chromatography (silica) eluting with cyclohexane/ethyl acetate 2:1. The combined product fractions were then further purified by preparative HPLC to afford the title compound as a white solid (49 mg, 50%): 1H NMR (400 MHz, DMSO-d5) δ 8.58 (s, 1H), 7.75 (d, 2H), 7.47 (d, 2H), 7.18 (d, 2H), 7.08 (d, 2H), 6.67 (s, 1H), 5.37 (s, 2H), 2.29 (s, 3H), 2.28 (s, 3H), 1.31 (s, 9H); ES-MS m/z 386, HPLC RT (Method E) 2.81 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=O.[NH2:19][C:20]1[C:21]([CH3:29])=[N:22][N:23]([CH2:26][CH:27]=[CH2:28])[C:24]=1Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[C:3]2[CH:4]=[C:5]([CH3:9])[C:6]([CH3:8])=[CH:7][C:2]=2[N:1]=[C:24]2[N:23]([CH2:26][CH:27]=[CH2:28])[NH:22][C:21]([CH3:29])=[C:20]2[N:19]=1
Reactant: C=CCn1nc(C)c(N)c1Cl
Reactant: Cc1cc(N)c(C(=O)c2ccccc2Cl)cc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: C=CCN1NC(C)=C2N=C(c3ccccc3Cl)c3cc(C)c(C)cc3N=C21
Temperature: 170 °C

Procedure:
A mixture of 3.0 g (0.0116 mole) of (2-amino-4,5-dimethylphenyl)-(2-chlorophenyl)-methanone (Xw), 2.0 g (0.0116 mole) of 4-amino-5-chloro-3-methyl-1-(2-propenyl)-1H-pyrazole (XIII), 2.21 g (0.0116 mole) of p-toluenesulfonic acid monohydrate and 40 mL of isopropanol was heated in a sealed tube at 170° C. for 90 minutes. The mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and then washed twice with saturated sodium bicarbonate solution. The aqueous washes were reextracted with ethyl acetate, and the combined ethyl acetate layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Trituration of the residue with hexane gave the intermediate 5-(2-chlorophenyl)-1,2-dihydro-3,7,8-trimethyl-1-(2-propenyl)-pyrazolo[3,4-b][1,4]benzodiazepine (XIVw), as a yellow solid. Purification of the filtrates by silica gel chromatography, eluting with ethyl acetate-dichloromethane (1:1) provided additional XIVw and was combined with the material obtained above for a total yield of 2.7 g of XIVw as a yellow solid, which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH2:11].[N:12]([C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[CH:18][NH:19]2)=[C:13]=[O:14]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:13]([NH:12][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[CH:18][NH:19]2)=[O:14]
Reactant: NCCc1ccc(Cl)cc1Cl
Reactant: O=C=Nc1cccc2[nH]ccc12
Product: O=C(NCCc1ccc(Cl)cc1Cl)Nc1cccc2[nH]ccc12

Procedure:
2-(2,4-Dichlorophenyl)ethylamine (0.21 g, 1.1 mmol) and the product of Example 80A (0.16 g, 1. mmol) were treated as described in Example 80B to provide the title compound. mp 170° C.; 1H NMR (300 MHz, DMSO-d6) δ 2.90 (m, 2H), 3.31 (m, 2H), 6.47 (m, 2H), 6.93 (m, 2H), 7.23 (m, 1H), 7.40 (m, 2H), 7.60 (m, 2H), 8.15 (s, 1H), 11.02 (s, 1H). MS (DCI+) m/z 347 (M+H). Anal. Calcd. for C17H15N3Cl2O: C, 58.63; H, 4.34; N, 12.07. Found: C, 58.49; H, 4.49; N, 12.38.