Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:5][C:6]([OH:8])=O)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:52][CH2:53][C:54]1[O:58][C:57]([C:59]2[CH:64]=[CH:63][C:62]([C:65]3[C:70]([CH3:71])=[CH:69][CH:68]=[C:67]([C:72]([NH:74][CH:75]4[CH2:77][CH2:76]4)=[O:73])[CH:66]=3)=[CH:61][CH:60]=2)=[N:56][N:55]=1>CN(C=O)C>[CH:75]1([NH:74][C:72]([C:67]2[CH:66]=[C:65]([C:62]3[CH:63]=[CH:64][C:59]([C:57]4[O:58][C:54]([CH2:53][NH:52][C:6](=[O:8])[CH2:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N:55][N:56]=4)=[CH:60][CH:61]=3)[C:70]([CH3:71])=[CH:69][CH:68]=2)=[O:73])[CH2:77][CH2:76]1
Reactant: CC(C)(C)CC(=O)O
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN)o2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CNC(=O)CC(C)(C)C)o2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
t-Butylacetic acid (10 mg) and HATU (33 mg) in DMF (1 ml) were stirred for 10 minutes at room temperature. To this solution was added HOBt (11.6 mg), DIPEA (0.45 ml) and 4′-[5-(aminomethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Example 53) (30 mg) in DMF (3 ml) and the reaction stirred at room temperature for 72 hours. The solvent was evaporated under vacuum and the residue dissolved in DCM and washed with water (2×5 ml). The organic phase was reduced to dryness and the residue purified by bond-elut (silica, 5 g) eluting with an ethyl acetate/cyclohexane gradient and then by preparative HPLC to give, after evaporation of the solvents, N-cyclopropyl-4′-(5-{[(3,3-dimethylbutanoyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C@H:10]2[CH2:15][CH2:14][NH:13][CH2:12][C@H:11]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:7][C:8]=1[Cl:9].C(N(CC)CC)C.[F:29][C:30]([F:45])([F:44])[C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[C:34](Cl)=[O:35]>ClCCl.O>[F:29][C:30]([F:44])([F:45])[C:31]1[CH:32]=[C:33]([C:34]([N:13]2[CH2:14][CH2:15][C@H:10]([C:5]3[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=3)[C@H:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12]2)=[O:35])[CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=1
Reactant: Clc1ccc([C@H]2CCNC[C@H]2c2ccccc2)cc1Cl
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2ccc(Cl)c(Cl)c2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a suspension of rac-cis-4-(3,4-dichlorophenyl)-3-phenyl-piperidine hydrochloride (200 mg, 0.58 mmol) in 20 mL dichloromethane was added triethylamine (0.35 mL, 2.5 mmol) and 3,5-bistrifluoromethyl-benzoyl chloride (0.11 mL, 0.60 mmol). The reaction mixture was stirred at room temperature overnight and then diluted with 20 mL water. The organic phase was separated and the aqueous layer was extracted twice with 20 mL dichloromethane. Organic phases were pooled, dried with magnesium sulfate and evaporated. Recrystallization of the crude product from diisopropylether and hexanes gave the desired product (268 mg, 84%) as white crystalls, MS: m/e=546.1 (M+).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1(S)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Br.BrCCN.C(CC(=O)C)C(C)=O>C(O)(=O)C.C(N(CC)CC)C>[C:1]1([S:7][CH2:8][CH2:9][N:10]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:16]2[CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: NCCSc1ccccc1
Agent: Br
Agent: CC(=O)CCC(C)=O
Agent: NCCBr
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: Cc1ccc(C)n1CCSc1ccccc1
Yield: 70 %

Procedure:
Phenylthioethylamine (5.00 g, 32.68 mmoles) prepared by reacting thiophenol and β-bromoethylamine hydrobromide in the presence of triethylamine and 3.74 g (32.68 mmoles) of acetonylacetone were heated under reflux for 4 hours in 80 ml of acetic acid. The acetic acid was distilled off under reduced pressure, and toluene was added to the residue. The mixture was distilled under reduced pressure. The resulting crude product was chromatographed on a column of silica gel using hexane/benzene as an eluent to afford 2,5-dimethylpyrrol-1-yl-ethyl phenyl sulfide (5.32 g, 22.88 mmoles, 70%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].ClC1C2C(=CC=C([CH:25]([C:27]3[N:31]([CH3:32])[C:30](C)=[N:29][CH:28]=3)O)C=2)N=C(OC)C=1CC1C=NC(C(F)(F)F)=CC=1.N1C=C(C=O)C=NC=1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>N1C=CC=CC=1.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([CH2:25][C:27]1[CH:28]=[N:29][CH:30]=[N:31][CH:32]=1)=[C:5]2[OH:13]
Reactant: O=c1cc(O)c2cc(Br)ccc2[nH]1
Reactant: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: O=Cc1cncnc1
Solvent: c1ccncc1
Solvent: CCO
Product: O=c1[nH]c2ccc(Br)cc2c(O)c1Cc1cncnc1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a dark solution of 6-bromo-4-hydroxyquinolin-2(1H)-one (3.92 g, 16.31 mmol, Intermediate 45: step a) and pyrimidine-5-carbaldehyde (1.94 g, 17.95 mmol) in pyridine (29 mL) was added diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (4.13 g, 16.31 mol). The resulting mixture was warmed with stirring in a 100° C. oil bath for a period of 5 hours. After cooling to room temperature, the mixture was diluted with ethanol. The tan precipitate was isolated by filtration, rinsing further with EtOH then acetonitrile and dried to provide the title compound that was carried to the next step without further purification.
Reaction SMILES: [CH:1](=O)[CH2:2][CH3:3].O=O.C(O[CH2:11][CH3:12])(=O)C>>[CH:2]12[C:3]([CH3:12])([CH3:11])[CH:3]1[CH2:2][CH:1]=[C:11]([CH3:12])[CH2:1]2
Reactant: CCC=O
Reactant: CCOC(C)=O
Agent: O=O
Product: CC1=CCC2C(C1)C2(C)C
Reaction time: 4 h

Procedure:
Δ-3-carene was epoxidized by the above-described procedure, using Di(acetate)3 as catalyst (1% based on the weight of Δ-3-carene) and ethyl acetate as solvent (volume ratio solvent to Δ-3-carene 3:1). The final mol ratio propionaldehyde to Δ-3-carene was 1.5:1, oxygen was bubbled through at a rate of 8 liters/hour, and reaction time was 4 hours.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[C:43]([CH2:44][CH2:45][CH3:46])=[C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[C:26]([S:28]([N:31]4[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[CH2:33][CH2:32]4)(=[O:30])=[O:29])[CH:25]=[CH:24][C:23]=3[O:39][CH2:40][CH2:41][CH3:42])[NH:19][C:20](=[O:21])[C:15]2=[N:14]1>N1C=CC=CC=1>[CH2:37]([N:34]1[CH2:35][CH2:36][N:31]([S:28]([C:26]2[CH:25]=[CH:24][C:23]([O:39][CH2:40][CH2:41][CH3:42])=[C:22]([C:18]3[NH:19][C:20](=[O:21])[C:15]4[C:16](=[C:43]([CH2:44][CH2:45][CH3:46])[N:13]([C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=5[NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[N:14]=4)[N:17]=3)[CH:27]=2)(=[O:30])=[O:29])[CH2:32][CH2:33]1)[CH3:38]
Reactant: CCCOc1ccc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CCC)n(-c3ccccc3N)nc2c(=O)[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCCOc1ccc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CCC)n(-c3ccccc3NS(C)(=O)=O)nc2c(=O)[nH]1
Temperature: 50 °C
Reaction time: 18 h
Yield: 32 %

Procedure:
Methanesulphonyl chloride (0.156 ml, 2.0 mmol) was added to a stirred solution of the title compound of Example 116 (583 mg, 1.0 mmol) in pyridine (8 ml), under nitrogen, and the resulting solution stirred at 50° C. for 18 hours, then evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water, then the separated organic phase washed with brine, dried (MgSO4) and evaporated under reduced pressure. The resulting brown foam was purified by column chromatography on silica gel, using an elution gradient of dichloromethane:methanol (100:0 to 99:1 to 98:2 to 97:3), to yield the title compound (32%) as a cream foam. Found: C, 53.96; H, 6.01; N, 14.38. C30H39N7O6S2; 0.60 H2O requires C, 53.89; H, 6.06; N, 14.67%. δ (CDCl3): 0.91 (3H, t), 1.01 (3H, t), 1.19 (3H, t), 1.75 (2H, m), 2.07 (2H, m), 2.40 (2H, q), 2.53 (4H, m), 2.93 (2H, t), 3.07 (3H, s), 3.09 (4H, m), 4.29 (2H, t), 7.16 (2H, m), 7.35 (2H, m), 7.57 (1H, t), 7.82 (2H, d), 8.80 (1H, s), 10.74 (1H, s). LRMS: m/z 658 (M+1)+.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:19])[NH:6][C:7]2[C:12]([C:13]=1O)=[CH:11][C:10]1[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=1[CH:8]=2)(=O)[CH3:2].[NH2:20][NH2:21]>Cl.CC(N(C)C)=O>[CH3:2][C:1]1[NH:20][N:21]=[C:13]2[C:12]3[CH:11]=[C:10]4[CH:15]=[CH:16][CH:17]=[CH:18][C:9]4=[CH:8][C:7]=3[NH:6][C:5](=[O:19])[C:4]=12
Reactant: NN
Reactant: CC(=O)c1c(O)c2cc3ccccc3cc2[nH]c1=O
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1[nH]nc2c1c(=O)[nH]c1cc3ccccc3cc12
Temperature: 140 °C

Procedure:
A mixture of 3-acetyl-4-hydroxybenzo[g]quinolin-2(1H)-one (1-4) (3.95 g, 15.6 mmol, 1.0 equiv), hydrazine (0.74 ml, 0.75 g, 23.4 mmol, 1.5 equiv), and catalytic conc. HCl (2 drops) in DMA (30 ml) were heated to 140° C. under nitrogen for 55 hours. The solution was cooled and the solid precipitate was filtered, washed with methanol (100 ml×3), and dried to yield 3-methyl-2,5-dihydro-4H-benzo[g]pyrazolo[4,3-c]quinolin-4-one (1-5) as a tan solid. 1H NMR (500 MHz, DMSO-d6)) δ 11.14 (s, 1H), 8.61 (s, 1H), 7.97 (d, 1H, J=8.0 Hz) 7.85 (d, 1H, J=8.5 Hz), 7.70 (s, 1H), 7.50 (m, 1H), 7.41 (m, 1H), 2.59 (s, 3H). LRMS m/z/z (M+H) 250.2 found, 250.1 required.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][NH:14][CH2:13][CH2:12][NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH:10]1[NH:11][CH2:12][CH2:13][N:14]([S:28]([C:24]2[S:23][CH:27]=[CH:26][CH:25]=2)(=[O:30])=[O:29])[CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: c1ccc(COCC2CNCCN2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cccs1)N1CCNC(COCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
A 250 mL round-bottomed flask was charged with 2-(benzyloxymethyl)piperazine (2.10 g, 10.1 mmol), triethylamine (1.42 mL, 10.2 mmol) and CH2Cl2 (50 mL). After cooling to 0° C., 2-thiophenesulfonyl chloride (1.84 g, 10.1 mmol, Sigma-Aldrich, St. Louis, Mo.) was added slowly via syringe. After 2 h, the mixture was concentrated and diluted with EtOAc (200 mL). The organic solution was washed with 1 N HCl (2×50 mL) and the combined acidic layers made basic with Na2CO3. The resulting basic solution was extracted with EtOAc (3×100 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated to give 3-(benzyloxymethyl)-1-(thiophen-2-ylsulfonyl)piperazine (1.79 g) as a yellow tar.
Reaction SMILES: [CH:1]([NH:4][C:5]1[O:9][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15](S(C2C=CC(C)=CC=2)(=O)=O)[CH:14]=[C:13]3[C:29]2[CH:30]=[N:31][CH:32]=[C:33]([CH:38]=2)[C:34]([NH:36][CH3:37])=[O:35])=[N:7][N:6]=1)([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[CH:1]([NH:4][C:5]1[O:9][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[C:13]3[C:29]2[CH:30]=[N:31][CH:32]=[C:33]([CH:38]=2)[C:34]([NH:36][CH3:37])=[O:35])=[N:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: CNC(=O)c1cncc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccc(-c4nnc(NC(C)C)o4)cc23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CNC(=O)c1cncc(-c2c[nH]c3ccc(-c4nnc(NC(C)C)o4)cc23)c1
Yield: 28.2 %

Procedure:
To a solution of 5-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)-N-methylnicotinamide (150 mg, 0.283 mmol) in 1,4-dioxane (3 mL) was added aq.NaOH (7 M, 3 mL) and the reaction was heated at 90° C. for 1 h. The reaction was then quenched with water to get a precipitate. The precipitate was filtered and washed with water (2×100 mL) and dried. The crude product was purified with preparative HPLC (eluting with 30-70% MeCN in water with 0.1% TFA in each solvent) to give 5-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1H-indol-3-yl)-N-methylnicotinamide (30 mg, 28%). MS (ESI, pos. ion) m/z: 377.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 9.04 (d, 1H, J=2.0 Hz), 8.89 (d, 1H, J=2.0 Hz), 8.74-8.76 (m, 1H), 8.44-8.45 (m, 1H), 8.24 (s, 1H), 8.02 (d, 1H, J=2.0 Hz), 7.73 (dd, 1H, J=8.8, 2.0 Hz), 7.62-7.66 (m, 2H), 3.71-3.76 (m, 1H), 2.85 (d, 3H, J=4.4 Hz), 1.22 (d, 6H, J=6.4 Hz).
Reaction SMILES: C([O:3][C:4](=[O:37])[CH:5]([C:10]1[CH:11]=[C:12]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][N:17]2[CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[K+]>CCO>[CH3:8][CH:7]([CH3:9])[CH2:6][CH:5]([C:10]1[CH:11]=[C:12]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][N:17]2[CH2:22][CH2:23][CH:24]([CH3:25])[CH3:26])[CH:15]=1)[C:4]([OH:37])=[O:3]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCCN2CCC(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CCN1CCCCC1c1cc(-c2ccc(C(F)(F)F)cc2)cc(C(CC(C)C)C(=O)O)c1
Temperature: 78 °C

Procedure:
To a solution of 4-Methyl-2-{5-[1-(3-methyl-butyl)-piperidin-2-yl]-4′-trifluoromethyl-biphenyl-3-yl}-pentanoic acid ethyl ester, compound 10c (32.0 mg, 0.06 mmol)in EtOH (3 mL) was added 2M KOH (130 μl, 0.25 mmol). The reaction was heated to 78° C. for 2 hours, cooled to room temperature, and concentrated in vacuo. Purification via Gilson HPLC, followed by salt exchange with aqueous 1N HCl, followed by lyophilization gave the title compound as a white solid. (12.0 mg, 40%) 1H NMR (300 MHz, MeOD) δ ppm 0.70-0.77 (m, 6 H) 0.90-0.98 (m, 6 H) 1.32 (dt, J=11.59, 5.70 Hz, 1 H) 1.46-1.55 (m, 1 H) 1.63 (td, J=11.59, 6.22 Hz, 1 H) 1.71-1.87 (m, 2 H) 1.98-2.11 (m, 4 H) 2.13-2.18 (m, 1 H) 2.81-2.97 (m, 2 H) 3.22 (td, J=12.15, 3.96 Hz, 1 H) 3.71-3.87 (m, 2 H) 4.32-4.42 (m, 1 H) 7.54-7.60 (m, 1 H) 7.75-7.89 (m, 6 H) Calcd for C29H38F3NO2 (M+H) 489.61, Found 490.0.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([P:19](=[O:26])([O:23]CC)[O:20]CC)=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[N:3]=1.C[Si](Br)(C)C>C(Cl)Cl>[OH:1][C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([P:19](=[O:20])([OH:26])[OH:23])=[CH:17][CH:18]=2)[CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[N:3]=1
Reactant: CCOP(=O)(OCC)c1ccc([C@H](C)NC(=O)c2cnc(-c3ccccn3)nc2O)cc1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: C[C@H](NC(=O)c1cnc(-c2ccccn2)nc1O)c1ccc(P(=O)(O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of diethyl (S)-4-(1-(4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxamido)ethyl)phenylphosphonate, 3-6, (400 mg, 0.88 mmol) in DCM (10 ml) was added dropwisely TMSBr (2.0 g, 13.15 mmol) at 0° C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness and the residue was treated with MeCN and water at room temperature. The resulting solid was collected via filtration to give the product, 3-7, (200 mg). 1H NMR (DMSO-d6, 300 MHz,): δ 10.71 (s, 4H), 9.93-9.96 (m, 1H), 8.80-8.81 (m, 1H), 8.56 (s, 1H), 8.37-8.39 (m, 1H), 8.08-8.13 (m, 1H), 7.61-7.74 (m, 3H), 7.42-7.46 (m, 2H), 5.12-5.17 (t, 1H), 2.07 (s, 1H), 1.49-1.51 (d, 3H).
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[Br:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=3)=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(-c3ccc(Br)cc3)nc2c1
Yield: 11.9 %

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, using methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv) and 4-bromophenylboronic acid (67.9 mg, 0.34 mmol, 1.50 equiv) as reactants. Purification via silica gel column (dichloromethane/methanol (5:1)) yielded 14 mg (10%) of 3-(4-bromophenyl)-2-phenylquinoxaline-6-carboxylic acid as a light yellow solid.
Reaction SMILES: [CH3:1][NH2:2].C(O)(=O)C.[Br:7][C:8]1[CH:38]=[CH:37][C:11]([CH2:12][CH:13]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:14]([NH:16][CH2:17][C:18](=O)[CH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][CH3:22])=O)=[CH:10][CH:9]=1>C1(C)C(C)=CC=CC=1>[Br:7][C:8]1[CH:38]=[CH:37][C:11]([CH2:12][CH:13]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:14]2[N:2]([CH3:1])[C:18]([CH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][CH3:22])=[CH:17][N:16]=2)=[CH:10][CH:9]=1
Reactant: CN
Reactant: CCC(C)(C)CC(=O)CNC(=O)C(Cc1ccc(Br)cc1)NC(=O)OCc1ccccc1
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: CCC(C)(C)Cc1cnc(C(Cc2ccc(Br)cc2)NC(=O)OCc2ccccc2)n1C
Temperature: 150 °C
Reaction time: 2 h

Procedure:
Methylamine (2 M in tetrahydrofuran) (1.2 mL, 24 mmol) followed by acetic acid (1.2 mL) were added to an ambient temperature solution of benzyl {1-(4-bromobenzyl)-2-[(4,4-dimethyl-2-oxohexyl)amino]-2-oxoethyl}carbamate (for synthesis see Example 37) (600 mg, 1.2 mmol) in xylene (10 mL). After stirring at 150° C. for 2 h, the reaction mixture was concentrated in vacuo. High pressure liquid chromatography (KR100-5C18 100×21.2 mm column) eluting with 10-100% acetonitrile/water containing 0.05% trifluoroacetic acid afforded benzyl {2-(4-bromophenyl)-1-[5-(2,2-dimethylbutyl)-1-methyl-1H-imidazol-2-yl]ethyl}carbamate.
Reaction SMILES: I[CH2:2][CH2:3][CH3:4].[OH:5][C:6]1[C:7]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:18][O:17][CH2:16][CH2:15][O:14][C:7]1[C:6]([O:5][CH2:2][CH2:3][CH3:4])=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[O:10]
Reactant: COCCOc1c(O)cccc1C=O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1cccc(C=O)c1OCCOC
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1-Iodopropane (3.09 mL, 31.60 mmol) was added to a solution of 3-hydroxy-2-(2-methoxyethoxy)benzaldehyde (3.1 g, 15.8 mmol) and potassium carbonate (4.37 g, 31.60 mmol) in DMF (80 mL) and the mixture was stirred at 100° C. overnight under a nitrogen atmosphere. The reaction mixture was partitioned between saturated ammonium chloride (aq.) and CH2Cl2. The organic phase was washed with brine, dried (Na2SO4) and concentrated to give the title compound in quantitative yield (3.8 g) as an oil. This material was used in the next step without further purification.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:18]=[CH:17][C:9]([CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][N:12]2[CH3:16])=[CH:8][CH:7]=1.C(N(CC)CC)C.O>C1C=CC=CC=1.C(OCC)C>[C:1]([NH:5][C:6]1[CH:18]=[CH:17][C:9]([CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][N:12]2[CH3:16])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CN1CCCC1Cc1ccc(N)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O
Product: CC(=O)Nc1ccc(CC2CCCN2C)cc1
Reaction time: 1 h

Procedure:
Add a solution of 0.78 g of acetyl chloride in 5 ml of benzene dropwise to a solution of 1.9 g of 2-(4-aminobenzyl)-1-methylpyrrolidine and 1 g of triethylamine in 10 ml of benzene. After one hour, concentrate the resulting reaction mixture. Then take it up with water and diethyl ether. Collect the organic phase and concentrate it to obtain the title compound as a yellowish oil.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].I[C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH2:26][CH2:27][CH3:28])[CH:20]=1.C(OCC)(=O)C>C(Cl)Cl>[OH:25][C:22]1[CH:23]=[CH:24][C:19]([C:2]#[C:1][C:3]2([CH3:17])[CH2:8][CH2:7][C:6]3[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=3[O:4]2)=[CH:20][C:21]=1[CH2:26][CH2:27][CH3:28]
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: CCCc1cc(I)ccc1O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1cc(C#CC2(C)CCc3c(C)c(O)c(C)c(C)c3O2)ccc1O

Procedure:
This compound was obtained by reacting rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 4-iodo-2-propylphenol under the conditions described in Example 1. The product was isolated by chromatography over the 40 fold amount of silica gel using 10% (V/V) of ethyl acetate in methylene chloride. It was crystallized from ether/hexane to give off-white crystals with m.p. 154°-156°.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:19][CH2:20][CH2:21]O)=[O:18])[CH:15]=2)[C:10]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=2)=[O:24])=[C:9]1[CH:35]([CH3:37])[CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.CS(Cl)(=O)=O>C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[O:18][CH2:21][CH2:20][N:19]=3)[CH:15]=2)[C:10]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=2)=[O:24])=[C:9]1[CH:35]([CH3:37])[CH3:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)NCCO)cc2n1Cc1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C3=NCCO3)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
General Procedure H. To a solution of 1-benzyl-N3-(3,4-difluorobenzyl)-N6-(2-hydroxyethyl)-2-isopropyl-1H-indole-3,6-dicarboxamide (Compound 63, 17 mg, 0.033 mmol) in CH2Cl2 (2 ml) at 0° C under argon was added Et3N (0.03 ml, 0.2 mmol), and then added MsCl (7 mg, 0.066 mmol). The reaction was stirred at 25° C. for 3 h, quenched with H2O diluted with EtOAc, washed with brine, dried over Na2SO4, concentrated in vacuo. The residue was purified by chromatography on silica gel (100% EtOAc) to yield the title compound as a yellow solid.
Reaction SMILES: [H-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:11]1[N:16]2[N:17]=[C:18]([NH:20][C:21]([CH:23]3[CH2:25][CH2:24]3)=[O:22])[N:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1>>[C:3]1([S:9][C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:21]([CH:23]4[CH2:24][CH2:25]4)=[O:22])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Nc1nc2cccc(Br)n2n1)C1CC1
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: O=C(Nc1nc2cccc(Sc3ccccc3)n2n1)C1CC1
Temperature: 160 °C
Reaction time: 0.08 h

Procedure:
A microwave tube was charged with sodium hydride (0.036 g, 0.889 mmol) in anhydrous well-degassed dioxane (1 mL). Thiophenol (0.091 mL, 0.889 mmol) was added dropwise and the mixture allowed to stir for 5 min. Cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide (0.05 g, 0.178 mmol) was added and the mixture was heated to 160° C. for 20 min in a microwave. The crude product was purified by preparatory HPLC. LCMS method: 2, RT: 4.32 min, MI: 311 [M+1]. NMR (1H, DMSO, 300 MHz): 11.17 (s, 1H), 7.70 (m, 2H), 7.57 (m, 3H), 7.49 (d, 2H), 6.28 (t, 1H), 2.03 (brs, 1H), 0.83 (d, 4H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][C:15]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)([OH:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([C:15]2([OH:18])[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][CH2:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:26])[CH2:17][CH2:16]2)=[CH:24][CH:23]=1
Reactant: OC(CCCN1CCC(O)(c2ccc(Cl)cc2)CC1)c1ccc(F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=C(CCCN1CCC(O)(c2ccc(Cl)cc2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of 4.0 g of 1-(p-fluorophenyl)-4-[4-(p-chlorophenyl)-4-hydroxypiperidino]-1-butanol in 100 ml of chloroform was added 10 g of manganese dioxide (fine powder). And then the mixture was stirred at room temperature for 7 hours. The reaction product was filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was recrystallized from aqueous acetone to obtain γ-[4-(p-chlorophenyl)-4-hydroxypiperidino]-p-fluorobutyrophenone, melting at 150° - 151°C.