Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[CH3:7][N:8]1[C:21]2[CH:20]=[CH:19][C:18]([CH:22]=O)=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([CH:24]=O)[CH:13]=2.[CH:26](P(=O)(OCC)OCC)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CO>CS(C)=O>[C:2]1([C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:24][C:12]2[CH:11]=[CH:10][C:9]3[N:8]([CH3:7])[C:21]4[C:16]([S:15][C:14]=3[CH:13]=2)=[CH:17][C:18]([CH:22]=[C:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:19][CH:20]=4)[CH:3]=[CH:17][CH:16]=[CH:21][CH:1]=1
Reactant: CN1c2ccc(C=O)cc2Sc2cc(C=O)ccc21
Reactant: CCOP(=O)(OCC)C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Product: CN1c2ccc(C=C(c3ccccc3)c3ccccc3)cc2Sc2cc(C=C(c3ccccc3)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3.46 g (30.4 mmol) of potassium tert-butoxide and then 3.60 g (13.4 mmol) of 10-methylphenothiazine-3,7-dicarbaldehyde were added with stirring and at room temperature to a solution of 8.20 g (26.8 mmol) of diethyl benzhydrylphosphonate (prepared analogously to Example 13 in U.S. Pat. No. 5,130,603) in 60 ml of anhydrous dimethyl sulfoxide, in the course of which the temperature rose from 25 to 43° C. After stirring at room temperature for 5 hours, the reaction solution was admixed with 150 ml of methanol, stirred for 15 min and filtered through a black band filter. The residue was washed with 300 ml of methanol and dried at 80° C. under reduced pressure. The crude product (4.7 g) was dissolved in 150 ml of methylene chloride, purified on silica gel and recrystallized from 83 ml of butylglycol. 3.56 g (23% of theory) of greenish microcrystals having a melting point of 233-241° C. were obtained.
Reaction SMILES: CO[C:3](=[O:27])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[C:12]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])=[N:17][NH:16][C:13]3=[N:14][CH:15]=2)[CH:5]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]1[C:12]2[C:13](=[N:14][CH:15]=[C:10]([C:6]3[CH:5]=[C:4]([C:3]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])[CH:9]=[CH:8][CH:7]=3)[CH:11]=2)[NH:16][N:17]=1
Reactant: COC(=O)c1cccc(-c2cnc3[nH]nc(-c4ccccc4OC)c3c2)c1
Reactant: C1CCNC1
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(C(=O)N4CCCC4)c3)cc12
Temperature: 90 °C
Reaction time: 16 h
Yield: 66.3 %

Procedure:
3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid methyl ester (30 mg, 83 μmol) was dissolved in pyrrolidine (0.35 ml, 4.15 mmol) and the mixture was stirred at 90° C. for 16 h. The mixture was then concentrated and the crude product purified by flash silica gel chromatography using a gradient of 10% v/v of methanol in ethyl acetate to afford {3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-pyrrolidin-1-yl-methanone as a yellow solid (22 mg, 55 μmol, 67% yield). 1H-NMR (500 MHz, d6-MeOH) δ8.82 (d, 1H), 8.39 (d, 1H), 7.83 (t, 1H), 7.79 (td, 1H), 7.66 (dd, 1H), 7.55-7.59 (m, 2H), 7.48 (ddd, 1H), 7.20 (d, 1H), 7.11 (dt, 1H), 3.88 (s, 3H), 3.63 (t, 2H), 3.52 (t, 2H), 2.02 (m, 2H), 1.92 (m, 2H). MS: m/z 399 [MH+].
Reaction SMILES: N[C:2]1[C:13]([C:14]([O:16]N2C3C=CC=CC=3N=N2)=O)=C2N=CC(CC#N)=CN2N=1.[Cl:26][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([F:39])[C:32]=1[C:33]1[CH2:34][CH2:35][NH:36][CH2:37][CH:38]=1.O1CC(=O)C1.CO>C1COCC1>[Cl:26][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([F:39])[C:32]=1[C:33]1[CH2:34][CH2:35][N:36]([CH:13]2[CH2:14][O:16][CH2:2]2)[CH2:37][CH:38]=1
Reactant: Fc1cncc(Cl)c1C1=CCNCC1
Reactant: N#CCc1cnc2c(C(=O)On3nnc4ccccc43)c(N)nn2c1
Agent: O=C1COC1
Solvent: C1CCOC1
Solvent: CO
Product: Fc1cncc(Cl)c1C1=CCN(C2COC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
Sodium triacetoxyborohydride (Sodium Ion (1)) (1.026 g, 4.842 mmol) was added in portions to a stirred solution of 3-chloro-5-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)pyridine (468 mg, 2.201 mmol) and 3-oxetanone (269.7 mg, 239.9 μL, 3.742 mmol) in THF (10 mL) at 0° C. under an atmosphere of nitrogen. The reaction was allowed to warm to ambient temperature over 16 hours. MeOH (2 mL) was added dropwise and the mixture stirred at ambient temperature for 30 minutes. The mixture was concentrated in vacuo and partitioned between water and EtAOc. The pH of the aqueous layer was adjusted to pH 7-8 by the addition of NH4OH and the layers separated. The aqueous layer was extracted with EtOAc (×3) and the combined organic extracts washed with brine (×1), dried (MgSO4), filtered and concentrated in vacuo to give 3′-chloro-5′-fluoro-1-(oxetan-3-yl)-1,2,3,6-tetrahydro-4,4′-bipyridine as a white solid (573 mg, 97% Yield). MS (ES+) 269.1.
Reaction SMILES: N([O-])=O.[Na+].O.[CH2:6]([C:8]1[CH:14]=[CH:13][C:11](N)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])[CH3:7].[ClH:18]>[Cu]Cl>[Cl:18][C:11]1[CH:13]=[CH:14][C:8]([CH2:6][CH3:7])=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=1
Reactant: CCc1ccc(N)cc1[N+](=O)[O-]
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCc1ccc(Cl)cc1[N+](=O)[O-]
Reaction time: 1.5 h
Yield: 56 %

Procedure:
A solution of sodium nitrite in water (4.2 g, 60 mmol, 5 M, 12 mL) was added dropwise to a cooled (0° C.) solution of 4-ethyl-3-nitroaniline (10 g, 60 mmol) in HCl (conc., 200 mL) and the reaction mixture was stirred at the same temperature for 1.5 h. Copper(I) chloride (9.5 g, 96 mmol) was then added and the solution was stirred at r.t. for 1 h and then at 80° C. for an additional hour. After cooling down the reaction mixture was extracted with DCM (3×100 mL) and the combined organic layers were dried over sodium sulfate. The crude was then purified by flash chromatography (hexane:AcOEt 9:1) to obtain the title compound as a yellow oil (6.28 g, 56%).
Reaction SMILES: [Br:1][C:2]1[C:6]([C:7]#[N:8])=[C:5](Br)[S:4][C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:21][CH2:22][CH:23]1[O:28][CH2:27][CH2:26][NH:25][CH2:24]1.O1CCCC1>O>[Br:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([N:25]2[CH2:26][CH2:27][O:28][CH:23]([CH2:22][OH:21])[CH2:24]2)[S:4][C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: OCC1CNCCO1
Reactant: CCOC(=O)c1sc(Br)c(C#N)c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1sc(N2CCOC(CO)C2)c(C#N)c1Br
Temperature: 90 °C
Reaction time: 4 h
Yield: 41 %

Procedure:
Ethyl 3,5-dibromo-4-cyanothiophene-2-carboxylate (0.360 g, 1.06 mmol), cesium carbonate (1.05 g, 3.21 mmol), 2-hydroxymethylmorpholine (137 mg, 1.17 mmol), and tetrahydrofuran (4.5 mL, 36 mmol) were combined in a 15 mL pressure vessel equipped with a stir bar. The vessel was sealed, and the r×n was heated @ 90° C. with stirring for 4 hours. The reaction was cooled to rt. The r×n was poured into water/saline. The reaction vessel was washed out with additional water, then ethyl acetate, and these were added to the quench which was then transferred to a separatory funnel. The aqueous layer was extracted 3× with EtOAc. The extracts were combined, washed with saline, dried over Na2SO4, filtered, added Celite, concentrated in vacuo, and dried on high vac 30 min. Purified dry load via silica gel chromatography (gradient elution: 0-60% EtOAc/hexanes) to give 163 mg solid (41% yield). 1H NMR (400 MHz, DMSO) δ 4.91 (t, J=5.7 Hz, 1H), 4.25 (q, J=7.1 Hz, 2H), 3.99-3.92 (m, 3H), 3.69-3.58 (m, 2H), 3.50 (dt, J=10.5, 5.2 Hz, 1H), 3.41 (dt, J=11.5, 5.8 Hz, 1H), 3.37-3.27 (m, 1H, under H2O peak), 3.15-3.08 (m, 1H), 1.26 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])/[C:4](/[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=[C:5](/[CH:10]([CH3:12])[CH3:11])\[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32][CH3:33])=[O:31].C1(C)C=CC=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1.O>[CH3:9][O:8][C:6](=[O:7])/[C:5](/[CH:10]([CH3:11])[CH3:12])=[C:4](/[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:18][CH:19]=1)\[C:3]([O:2][CH3:1])=[O:21]
Reactant: COC(=O)/C(Cc1ccc(O)cc1)=C(\C(=O)OC)C(C)C
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)COc1ccc(C/C(C(=O)OC)=C(/C(=O)OC)C(C)C)cc1
Temperature: 25 °C
Yield: 82.1 %

Procedure:
To a solution of 2-(4-hydroxybenzyl)-3-isopropylmaleic acid dimethyl ester (44.1 mg, 0.151 mmol) in (880 μL) were added potassium carbonate (34.7 mg, 0.251 mmol) and methyl bromoacetate (138.4 mg, 0.904 mmol) with stirring at room temperature. After stirring at room temperature for 20 h, the reaction mixture was diluted with toluene and water to separate the phases. The aqueous layer was extracted again with toluene, and the combined organic layer was concentrated under reduced pressure and the residue thus obtained was subjected to silica gel column chromatography (toluene-ethyl acetate 10:1) to give 45.2 mg of the title compound as oil (yield: 82%).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].O.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=1>O1CCCC1>[F:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[N:22][CH:23]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1ccc(F)cn1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
The product is prepared according to the procedure described in Example 19, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of Example 1 and using a mixture of 7 ml of water and 1.5 ml of tetrahydrofuran in place of the methanol, and 134 mg of 2-amino-5-fluoropyridine in place of the 3-(tert-butyl)aniline. After stirring for 1 h 30 at ambient temperature, a precipitate forms. The reaction mixture is filtered through sintered glass. The solid obtained is washed with water, ethyl acetate and ethyl ether. 130 mg of N-(5-fluoropyridin-2-yl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of an off-white solid, the characteristics of which are the following:
Reaction SMILES: [S:1](=[N:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])=[O:2].[CH2:13]([C:15]1[CH:20]=[C:19]([C:21]([F:30])([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])[CH:18]=[C:17]([CH3:31])[C:16]=1[NH2:32])[CH3:14]>[2H]C(Cl)(Cl)Cl>[S:1](=[N:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:32][C:16]1[C:17]([CH3:31])=[CH:18][C:19]([C:21]([F:30])([C:22]([F:23])([F:24])[F:25])[C:26]([F:27])([F:28])[F:29])=[CH:20][C:15]=1[CH2:13][CH3:14])=[O:8])=[O:2]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Reactant: O=S=Nc1cccc(C(=O)Cl)c1
Agent: [2H]C(Cl)(Cl)Cl
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc(N=S=O)c1
Temperature: 25 °C

Procedure:
To a solution of 3-sulfinylamino-benzoyl chloride (0.033 g, 0.165 mmol) (Example 1.1) in dry deuterochloroform (0.5 ml) was added under stirring at 25° C., a solution of 2-ethyl-6-methyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenylamine (0.050 g, 0.165 mmol) (prepared according to EP 1,006,102) in deuterochloroform (0.5 ml). After stirring for 60 hours at 25° C., a sample of the reaction mixture was submitted to 1H-NMR spectroscopy. The desired compound was detected in the reaction mixture together with unreacted starting materials. Integration of the signals showed a conversion of 40%. 1H-NMR (CDCl3, 400 MHz): 8.35 (s, 1H), 8.07 (d, 1H), 7.95 (d, 1H) 7.58 (t, 1H), 7.49 (s, 1H), 7.37 (s, 2H), 2.70 (q, 2H), 2.31 (s, 3H), 1.22 (t, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[C:29]([Cl:36])[CH:28]=1.CCN(CC)CC>ClCCCl>[CH3:24][O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([N:17]([C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:35])=[C:29]([Cl:36])[CH:28]=1
Reactant: COC(=O)c1ccc(N=C=O)c(Cl)c1
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)c1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(Cl)c1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-amine (example 11.1) was reacted with 3-chloro-4-isocyanato-benzoic acid methyl ester (example 9.1) in 1,2-dichloroethane in the presence of Et3N (1.4 eq.) for 2 days under reflux conditions to give the title compound as brown solid. MS: m/e=537.1 [M+H+].
Reaction SMILES: [C:1](O)(=O)[C:2](O)=O.[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[NH:17][CH:16]([CH2:18][NH2:19])[CH2:15][N+:14]([O-:20])=[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:12]=2[CH:28]=1.C(C(CC)(CC)C([O-])([O-])[O-])C>C(#N)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]3[C:1]([CH3:2])=[N:19][CH2:18][CH:16]3[CH2:15][N+:14]([O-:20])=[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:12]=2[CH:28]=1
Reactant: NCC1C[N+]([O-])=C(c2ccccc2F)c2cc(Cl)ccc2N1
Reactant: O=C(O)C(=O)O
Agent: CCC(CC)(CC)C([O-])([O-])[O-]
Solvent: CC#N
Product: CC1=NCC2C[N+]([O-])=C(c3ccccc3F)c3cc(Cl)ccc3N12
Reaction time: 1 h

Procedure:
A slurry of 7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine-2-methanamine-4-oxide oxalate salt (VIII, EXAMPLE 6, 35 g, 85 mmol) and triethylorthoacetate (23.5 ml, 128 mmol) in acetonitrile (175 ml) is stirred at reflux for 2 hr during which time the 7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine-2-methanamine-4-oxide (VIII) dissolves and ethanol/acetonitrile (about 75 ml) is removed by distillation under ordinary pressure. TLC and HPLC analysis shows the reaction is complete. The temperature is adjusted to 40° and methyl t-butyl ether (175 ml) is added dropwise over about 1 hr. The resulting slurry is cooled to 5°, stirred 1 hr, the solids are collected and are washed with t-butyl ether. The product is dried in the vacuum oven at 35° to give the title compound as the oxalate salt, mp=178-180°; TLC (methylene chloride/methanol/ammonium hydroxide, 90/10/1) Rf =0.28.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][C:13]#[N:14].[C:15](=O)([O-])[O-].[K+].[K+].O>CC(=O)CC.[I-].[K+]>[C:13]([CH2:12][CH2:11][CH2:15][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)#[N:14]
Reactant: N#CCCBr
Reactant: OCc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: N#CCCCOc1ccc(CO)cc1
Yield: 105.9 %

Procedure:
The 4-hydroxybenzyl alcohol (24.8 g, 0.2 mol) and 3-bromopropionitrile (29.6 g, 0.2 mol) were dissolved in 250 ml of 2-butanone. Potassium carbonate (30 g) and catalytic potassium iodide (0.2 g) were added and the reaction was refluxed for 48 hrs. After cooling, water was added and the layers were separated. The organic layer was washed with water, 1N sodium hydroxide and water again, dried over MgSO4, filtered, and concentrated to dryness. The resultant oil was slurried in hexane and the precipitate was filtered to afford 40.5 g of the subtitle compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])[CH2:24][CH2:23]2)[C:9]2[CH:21]=[CH:20][C:12]([C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(=O)C1C=CC([C@@H](N2CCN(CC=C)CC2)C2C=CC=C(N[CH2:51][C:52]3[S:53][CH:54]=[CH:55][CH:56]=3)C=2)=CC=1)C.C(O)(C(F)(F)F)=O>CO>[CH2:16]([N:15]([CH2:18][CH3:19])[C:13](=[O:14])[C:12]1[CH:20]=[CH:21][C:9]([C@@H:8]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])[CH2:24][CH2:23]2)[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:51][C:52]3[S:53][CH:54]=[CH:55][CH:56]=3)[CH:3]=2)=[CH:10][CH:11]=1)[CH3:17]
Reactant: C=CCN1CCN([C@H](c2ccc(C(=O)N(CC)CC)cc2)c2cccc(NCc3cccs3)c2)CC1
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2cccc(N)c2)N2CCN(CC=C(C)C)CC2)cc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=O)c1ccc([C@H](c2cccc(NCc3cccs3)c2)N2CCN(CC=C(C)C)CC2)cc1

Procedure:
Synthesized using COMPOUND 67 and the method described for COMPOUND 69. Purity (HPLC): >99%; Optical purity (Chiral HPLC): >99%; (400 MHz, CD3OD) 1.06 (t, J=6.61 Hz, 3H), 1.19 (t, J=6.61 Hz, 3H), 1.76 (s, 3H), 1.82 (s, 3H), 2.11-2.27 (m, 2H), 2.89-3.14 (m, 4H), 3.14-3.26 (m, 2H), 3.32-3.42 (m, 2H), 3.45-3.54 (m, 2H), 3.71 (d, J=7.93 Hz, 2H), 4.27 (s, 1H), 4.47 (s, 2H), 5.22-5.29 (m, 1H), 6.56 (ddd, J=7.94 Hz, 2.37 Hz, 1.02Hz, 1H), 6.68-6.71 (m, 1H), 6.77 (t, J=2.20Hz, 1H), 6.91 (dd, J=5.07 Hz, 3.38 Hz, 1H), 6.95-6.97 (m, 1H), 7.02 (t, J=7.77 Hz, 1H), 7.21 (dd, J=5.07 Hz, 1.19 Hz, 1H), 7.26 (d, J=8.05 Hz, 1H), 7.47 (d, J=8.12 Hz, 2H). Found: C, 59.49; H, 6.40; N, 7.85. C32H42N4O×0.7H2O 1.4 CF3COOH has C, 59.46; H, 6.42; N, 7.97%. [a]D20=−20.30 deg [c 0.650, MeOH]
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[C:5]([NH2:14])[NH:4][N:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=O)[CH2:23][C:24](OCC)=[O:25])=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[C:2]([CH3:1])=[N:3][N:4]3[C:22]([C:19]4[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=4)=[CH:23][C:24](=[O:25])[NH:14][C:5]=23)=[CH:8][CH:9]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: Cc1ccc(-c2c(C)n[nH]c2N)cc1
Solvent: c1ccncc1
Product: Cc1ccc(-c2c(C)nn3c(-c4ccc(F)cc4)cc(=O)[nH]c23)cc1
Temperature: 25 °C

Procedure:
3-Methyl-4-(4-methylphenyl)-1H-pyrazol-5-amine and ethyl 3-(4-fluorophenyl)-3-oxopropanoate are stirred overnight in a pyridine (10 mL) solvent at 95° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and purified by column chromatography to yield the target compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(Cl)Cl.O>CCOCC>[C:10]([C:5]1[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1cc[nH]c1
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)c1c[nH]c(C(=O)c2ccccc2)c1
Reaction time: 0.25 h
Yield: 69.8 %

Procedure:
Under nitrogen, methyl pyrrole-3-carboxylate (5 g., 40 mmoles) was combined with benzoyl chloride (4.8 ml., 40 mmoles) and stannic chloride (9.2 ml. 80 mmoles) in 75 ml. of methylene chloride and stirred for 3 hours at room temperature. Ice and water (50 ml.) was added slowly and stirring continued for an additional 15 minutes. Ether (150 ml.) was then added and, after equilibration, the phases separated. The upper, organic phase was washed sequentially with 50 ml. of water, 50 ml. of 1N sodium hydroxide and 50 ml. of water, and evaporated to dryness to yield crude product (6.4 g. of solid). Recrystallization from acetonehexane gave purified methyl 5-benzoylpyrrole-3-carboxylate (4.1 g., Rf 0.4 on silica gel thin layer chromatography eluted with ethyl acetate-1/hexane-5/5% acetic acid).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9](Br)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:14](=[O:17])([O-])[O-].[Na+].[Na+].[CH2:20]1[CH2:24]O[CH2:22][CH2:21]1>C(Cl)(Cl)Cl>[CH3:5][N:4]1[C@H:1]2[C@@:20]([CH3:24])([C:20]3[CH:24]=[CH:8][C:7]([C:9]4[CH:8]=[C:7]5[C:12](=[CH:11][CH:10]=4)[N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]5)=[CH:6][C:21]=3[CH2:22][CH2:2]2)[CH2:21][CH2:22][C:14]1=[O:17]
Reactant: CC(=O)N1CCc2cc(Br)ccc21
Reactant: O=C([O-])[O-]
Reactant: C1CCOC1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCc2cc(-c3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)ccc21
Yield: 26 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo [f]quinolin-3-one-8-boronic acid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 1-acetyl-5-bromoindoline (156 mg, 0.65 mmol), 0.65 mL of 2M sodium carbonate and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (5% methanol/ethyl acetate eluent) to give 67 mg (26%) of the title compound as a yellow solid. mp 197°-200°. FDMS: m/e=388. α[D]589 =+77.92 (c=0.36, chloroform).
Reaction SMILES: [CH2:1]([N:8]([C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([C:25]([N:27]([CH:41]([CH3:43])[CH3:42])[C@@H:28]3[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]3)=[O:26])[C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:15]=2[O:14][C:13]([CH2:45][OH:46])([CH3:44])[C:12]1=[O:47])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:65][S:66](Cl)(=[O:68])=[O:67].O>O1CCCC1>[CH2:1]([N:8]([C:48]([O:50][CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)=[O:49])[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([C:25]([N:27]([CH:41]([CH3:42])[CH3:43])[C@@H:28]3[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:38])[CH3:39])=[O:35])[CH2:29]3)=[O:26])[C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:15]=2[O:14][C:13]([CH3:44])([CH2:45][O:46][S:66]([CH3:65])(=[O:68])=[O:67])[C:12]1=[O:47])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(CO)C(=O)N2CCN(Cc1ccccc1)C(=O)OCc1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(COS(C)(=O)=O)C(=O)N2CCN(Cc1ccccc1)C(=O)OCc1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (3R)-3-[{[4-(2-{benzyl[(benzyloxy)carbonyl]amino}ethyl)-2-(hydroxymethyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}-(isopropyl)amino]piperidine-1-carboxylate (700 mg) and triethylamine (0.25 ml) in tetrahydrofuran (8 ml) was added dropwise methanesulfonyl chloride (0.11 ml), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (793 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[C:17]([F:20])([F:19])[F:18])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:32][S:33]([N:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)(=[O:35])=[O:34]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[C:17]([F:19])([F:18])[F:20])=[O:9])=[CH:6][N:5]=[C:4]([NH:42][CH:39]2[CH2:40][CH2:41][N:36]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:37][CH2:38]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: CCS(=O)c1ncc(C(=O)c2cc(F)ccc2C(F)(F)F)c(N)n1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3cc(F)ccc3C(F)(F)F)c(N)n2)CC1

Procedure:
The compound was prepared from (4-amino-2-ethylsulfinyl-pyrimidin-5-yl)-(5-fluoro-2-trifluoromethyl-phenyl)-methanone (Example 199) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) in an analogous manner as described in Example 172. HR-MS (ES, m/z) calculated for C18H20N5O3SF4 [(M+H)+] 462.1218, observed 462.1222.