Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1.[ClH:24]>CO.CCOCC>[ClH:24].[ClH:24].[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: O=c1[nH]c2ncccc2n1C1CCNCC1
Reaction time: 2 h

Procedure:
2-Oxo-1-(1-tert-butoxycarbonylpiperidin-4-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine (1.03 g, 3.23 mmol) was dissolved in methanol (25 mL) and a solution of 2 N hydrochloric acid in ether (8 mL) was added at room temperature. After 2 h, the volatiles were removed in vacuo, to give the title compound (0.92 g). MS 219 (M+1). 1H NMR (500 MHz, CD3OD) δ 8.01 (dd, J=6, 1 Hz, 1H), 7.83 (d, J=8 Hz, 1H), 7.28 (dd, J=8, 6 Hz, 1H), 4.60 (m, 1H), 3.59 (d, J=12 Hz, 2H), 3.21 (t, J=12 Hz, 2H), 2.70 (dq, J=13, 4 Hz, 2H), 2.12 (d, J=13 Hz, 2H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11](=[O:17])[NH:12][C@@H:13]([CH3:16])[CH2:14][OH:15])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[CH3:1][S:2]([O:15][CH2:14][C@@H:13]([NH:12][C:11]([O:10][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:17])[CH3:16])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Methanesulfonyl chloride (13.2 mL, 170 mmol) was added to a 0° C. solution of tert-butyl[(2S)-1-hydroxypropan-2-yl]carbamate (28.4 g, 162 mmol) and triethylamine (27 mL, 190 mmol) in dichloromethane (350 mL), and the reaction mixture was allowed to stir for 30 minutes. After aqueous ammonium chloride solution was added to the reaction mixture, the aqueous layer was extracted with dichloromethane, and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting sticky white solid was slurried with diethyl ether (100 mL), stirred for 10 minutes, and filtered to afford the product as a white solid. Yield: 28.8 g, 114 mmol, 70%. The filtrate was concentrated under reduced pressure and recrystallized from diethyl ether (the hot mixture was filtered through Celite before crystallization) to provide additional product as a white solid. Yield: 11.66 g, 45.63 mmol, combined yield 98%. 1H NMR (400 MHz, CDCl3) δ 1.24 (d, J=7.0 Hz, 3H), 1.45 (s, 9H), 3.04 (s, 3H), 3.91-4.04 (br m, 1H), 4.16 (dd, half of ABX pattern, J=10.1, 4.2 Hz, 1H), 4.19-4.28 (br m, 1H), 4.62 (br s, 1H).
Reaction SMILES: [N+:1]([CH2:4][C:5](=O)[CH3:6])([O-:3])=[O:2].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][NH2:19])=[CH:11][N:10]=1.O>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][NH:19][C:5]([CH3:6])=[CH:4][N+:1]([O-:3])=[O:2])=[CH:11][N:10]=1
Reactant: CC(=O)C[N+](=O)[O-]
Reactant: CN(CCN)Cc1ccc(Cl)nc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=C[N+](=O)[O-])NCCN(C)Cc1ccc(Cl)nc1
Yield: 70.1 %

Procedure:
Nitroacetone (1.1 g) and N-(2-chloro-5-pyridylmethyl)-N-methylethylenediamine (2.0 g) were dissolved in toluene (60 ml), and the solution was refluxed for 3 hours in a flask equipped with a water separating device while removing water formed by the reaction. Toluene was concentrated under reduced pressure, and the remaining solid was recrystallized from ethanol to give the desired N-(2-chloro-5-pyridylmethyl)-N-methyl-N'-(1-methyl-2-nitrovinyl)ethylenediamine (2.0 g) having a melting point of 78° to 80° C.
Reaction SMILES: [CH3:1][C:2]([NH:22]C(=O)OCC1C=CC=CC=1)([CH2:4][CH2:5][S:6]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])(=[O:8])=[O:7])[CH3:3]>CO>[CH3:3][C:2]([NH2:22])([CH2:4][CH2:5][S:6]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])(=[O:8])=[O:7])[CH3:1]
Reactant: COCCOCCOCCOCCS(=O)(=O)CCC(C)(C)NC(=O)OCc1ccccc1
Solvent: CO
Product: COCCOCCOCCOCCS(=O)(=O)CCC(C)(C)N
Reaction time: 5 h

Procedure:
A solution of benzyl 2-methyl-4-(2-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)ethylsulfonyl)butan-2-ylcarbamate (6.07 g, 12.8 mmol) was dissolved in methanol (150 ml) was purged with N2. 10% palladium on carbon (890 mg) was added, and the suspension was put under a H2 (1.3 atmospheres) atmosphere. The suspension was stirred for 5 hours, filtered through Celite, and the solution concentrated in vacuo. The material was used without further purification. LRMS (ESI/APCI): 342 [M+H]+.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2](OCC)=O.[Cl:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[C:15]([C:23]([NH2:25])=[O:24])[C:16]([NH2:22])=[N:17]2>CCCCCC>[Cl:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[C:15]1[C:23](=[O:24])[NH:25][C:2]([C:1]([O:8][CH2:9][CH3:10])=[O:7])=[N:22][C:16]1=[N:17]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: NC(=O)c1cc2c(Cl)cccc2nc1N
Solvent: CCCCCC
Product: CCOC(=O)c1nc2nc3cccc(Cl)c3cc2c(=O)[nH]1

Procedure:
Diethyl oxalate (350 ml.) and 5-chloro-2-aminoquinoline-3-carboxamide (5.9 g., 0.0267 mole) are heated together at 170° C. for 4 hours. By-product water and ethanol are distilled from the reaction mixture. The dark reaction mixture is cooled, treated with hexane (300 ml.) and filtered. The brown solid is dissolved in methylene chloride:ethanol (1:1), decolorized with charcoal and concentrated to give a tan solid. The solid recrystallized from methylene chloride-hexane. It is purified further by chromatography on silica gel using methylene chloride:ethanol (9:1) as eluant. The product, recovered by evaporation of the eluate, is recrystallized from methylene chloride-ethanol. Yield = 0.756 g. (9.3%). M.P. 278°-279° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[CH:8][CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[CH:25]([S:27]([CH:30]=[CH2:31])(=[O:29])=[O:28])=[CH2:26]>CC(O)C>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:7]1[C:6]2[C:5]3[C:13](=[CH:14][C:2]([N:1]4[CH2:31][CH2:30][S:27](=[O:29])(=[O:28])[CH2:25][CH2:26]4)=[CH:3][CH:4]=3)[NH:12][C:11]=2[C:10]([C:15]([NH2:17])=[O:16])=[CH:9][CH:8]=1
Reactant: C=CS(=O)(=O)C=C
Reactant: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(N)ccc12
Solvent: CC(C)O
Product: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(N3CCS(=O)(=O)CC3)ccc12
Temperature: 100 °C
Yield: 28.3 %

Procedure:
A suspension of 7-amino-4-(2-fluorophenyl)-9H-carbazole-1-carboxamide (Example 54-1, 36 mg, 0.113 mmol) in 2-propanol (1.0 mL) was treated with vinylsulfonylethene (20 μL, 0.199 mmol) at rt. The reaction mixture was heated at 100° C. for 26 h. The mixture was cooled to rt, concentrated and the residue was purified by preparative HPLC to provide 4-(2-fluorophenyl)-7-(1,1-dioxothiomorpholino)-9H-carbazole-1-carboxamide as a yellow solid (14 mg, 28%). 1H NMR (400 MHz, DMSO-d6) δ 11.26 (1H, s), 8.17 (1H, br. s.), 7.90 (1H, d, J=7.9 Hz), 7.47-7.62 (3H, m), 7.37-7.46 (2H, m), 7.35 (1H, d, J=1.8 Hz), 7.01 (1H, d, J=7.9 Hz), 6.93 (1H, d, J=8.3 Hz), 6.74 (1H, dd, J=9.0, 2.4 Hz), 3.77-3.81 (4H, m), 3.08-3.19 (4H, m). Mass spectrum m/z 438.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][C@@H:25]([CH2:28][CH3:29])[CH2:26][OH:27]>>[OH:27][CH2:26][C@@H:25]([NH:24][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)[CH2:28][CH3:29]
Reactant: CC[C@H](N)CO
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: CC[C@@H](CO)NC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Yield: 85 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using (S)-(+)-2-amino-1-butanol instead of 2-aminoethyl isopropylether, to the title compound (210 mg, 85%) which was obtained as a white solid. MS: m/e=380.2 [M−H]−.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[C:9]([C:13]1[CH:14]=[CH:15][C:16]([OH:21])=[C:17]([CH:20]=1)[CH:18]=[O:19])([CH3:12])([CH3:11])[CH3:10].C(OCC)(=O)C.C([O-])(O)=O.[Na+]>C(#N)C>[C:9]([C:13]1[CH:14]=[C:15]([N+:7]([O-:8])=[O:6])[C:16]([OH:21])=[C:17]([CH:20]=1)[CH:18]=[O:19])([CH3:12])([CH3:10])[CH3:11]
Reactant: O=[N+]=O
Reactant: CC(C)(C)c1ccc(O)c(C=O)c1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(C=O)c(O)c([N+](=O)[O-])c1
Temperature: -15 °C

Procedure:
At −30° C. 4.84 g nitroniumtetrafluoroborate are added to a solution of 5.00 g 5-tert-butyl-2-hydroxy-benzaldehyde in 200 ml acetonitrile. The solution is heated to −15° C. within 1 h and then combined with ethyl acetate and saturated aqueous NaHCO3 solution. The resulting mixture is extracted with ethyl acetate, and the combined extracts are washed with saturated aqueous saline solution, dried (MgSO4) and evaporated down. The residue is taken up in 2 ml of water and 40 ml concentrated acetic acid, and the resulting mixture is refluxed for 2 h. The cooled solution is poured into ice-cold water, and the precipitate formed is filtered off and dissolved in ethyl acetate. The organic solution is dried (MgSO4) and evaporated down. The oil remaining rapidly solidifies.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:9]([NH2:14])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH2:27][CH3:28])[C:24](O)=O)=[O:21])([CH3:18])([CH3:17])[CH3:16].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>C(Cl)Cl>[C:15]([O:19][C:20](=[O:21])[NH:22][C@H:23]([C:24]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1)[CH2:27][CH3:28])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccccc1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)c1nc2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
A mixture of N-phenylbenzene-1,2-diamine (1.0 g, 5.43 mmol), (S)-2-tertbutoxycarbonylaminobutyric acid (1.21 g, 5.97 mmol), HOAt (813 mg, 5.97 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.15 g, 5.97 mmol) and 4-methylmorpholine (1.31 mL, 11.95 mmol) in DCM (20 mL) was stirred at RT for 2 h. The crude reaction mixture was diluted with DCM (100 mL), then washed with a saturated solution of NaHCO3, followed by brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was dissolved in AcOH (20 mL) and heated to 70° C. for 18 h. After cooling to RT, volatiles were evaporated under reduced pressure and the residue was dissolved in EtOAc (150 mL) and washed with a saturated solution of NaHCO3. The organic layer was then washed with brine, dried (Na2SO4) and then concentrated in vacuo. The resulting residue was absorbed onto HM-N and purified twice by column chromatography (Si—PCC, gradient 0-50% EtOAc in cyclohexane) affording [(S)-1-(1-Phenyl-1H-benzoimidazol-2-yl)propyl]carbamic acid tertbutyl ester (1.76 g). LCMS: RT 3.23 min [M+H-tBu]+ 352.2
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[CH3:14][C@@H:15]1[CH2:19][O:18][C:17](=[O:20])[NH:16]1>>[CH3:13][O:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[N:16]1[C@H:15]([CH3:14])[CH2:19][O:18][C:17]1=[O:20])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(Br)c(OC)c1
Reactant: C[C@@H]1COC(=O)N1
Product: COc1cc(C(=O)O)ccc1N1C(=O)OC[C@H]1C
Yield: 97.5 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 45 and using methyl 4-bromo-3-methoxybenzoate (1 g) and (R)-4-methyloxazolidin-2-one (607 mg) described in Preparation Example 25, the title compound (1 g) was obtained.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][C@H:22]([C:25]([OH:27])=O)[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].Cl.[CH3:29][NH:30][O:31][CH3:32]>ClCCl>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][C@H:22]([C:25](=[O:27])[N:30]([O:31][CH3:32])[CH3:29])[CH2:21]1)=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)O)C1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
Add 1,1′-carbonyldiimidazole (414.33 g, 2.56 mol) portion wise to a stirred solution of (S)-N-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (500 g, 2.32 mol) in dichloromethane (5.81 L) and stir at room temperature under nitrogen for 1 hour. Add N,O-di-methylhydroxylamine hydrochloride (253.04 g, 2.56 mol) and stir at room temperature for 48 hours. Quench the reaction with 1N HCl, and extract with ethyl acetate (2×). Wash the combined organics with saturated NaHCO3 and brine. Dry (MgSO4), filter and concentrate under reduced pressure to provide 535 g (89%) of the title compound. MS (m/z)=203 (M−55).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([NH2:10])=[O:9].[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=O.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.CN(C)C=O>[Br:7][C:5]1[S:4][C:3]2[C:8](=[O:9])[NH:10][C:14]([C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[Cl:11])=[N:1][C:2]=2[CH:6]=1
Reactant: NC(=O)c1sc(Br)cc1N
Reactant: O=C(Cl)c1ccccc1Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=c1[nH]c(-c2ccccc2Cl)nc2cc(Br)sc12
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3-amino-5-bromothiophene-2-carboxamide (100 mg), 2-chlorobenzoylchloride (57 μL), N,N-dimethylpyridin-4-amine (55 mg), pyridine (1.0 mL) and N,N-dimethylformamide (2.0 mL) was stirred at 70° C. for 1.5 hr. The reaction system was concentrated under reduced pressure, 2M aqueous sodium hydroxide solution was added to the residue, and the mixture was heated to 120° C. After 1 hr, insoluble material was removed by filtration, and the filtrate was neutralized with 1M hydrochloric acid. The precipitate was collected by filtration and washed with water to give the title compound (120 mg) as a dark orange solid.
Reaction SMILES: [Br-].[Li+].C[O:4][C:5](=[O:19])[CH:6]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>CC(C)=O>[C:11]([O:10][C:8](=[O:9])[CH2:7][CH:6]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:5]([OH:19])=[O:4])([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)C(CC(=O)OC(C)(C)C)CC(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: CC(C)=O
Product: CC(C)CC(CC(=O)OC(C)(C)C)C(=O)O
Yield: 95.4 %

Procedure:
Anhydrous lithium bromide (10.6 g, 121.8 mmol) was added to a stirring mixture of 2 (5.95 g, 24.4 mmol) in acetone (50 mL) under argon, and the mixture was refluxed for 2 hours. After cooling, the acetone was evaporated under reduced pressure, and the residue was taken up in ether (50 mL), washed with water (50 mL), brine, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane/ethyl acetate, 95:5) to give the dibromide 3 (5.36 g, 86%) as an orange liquid; Rf (heptane-ethyl acetate, 8:2), 0.82. δH (400 MHz; CDCl3): 3.6 (2H, m), 3.45 (2H, m), 2.85 (2H, m), 2.1 (2H, m), 1.7 (2H, m; δc(400 MHz; CDCl3): 39.70, 33.79, 23.95.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][N:19]([CH3:35])[C@@H:20]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][C:28]=2[CH:33]=O)=[O:26])[CH2:21]1>C(O)C.N1CCCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:33][C:28]2[NH:29][C:30]([CH3:32])=[CH:31][C:27]=2[C:25]([N:22]2[CH2:23][CH2:24][C@@H:20]([N:19]([CH3:18])[CH3:35])[CH2:21]2)=[O:26])[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)N2CC[C@@H](N(C)C)C2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)N2CC[C@@H](N(C)C)C2)c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.8 %

Procedure:
To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 3-[(3R)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(3-chloro-phenyl)-3-[3-[(3R)-3-dimethylamino-pyrrolidine-1-carbonyl)5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (71 mg, 60%).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3Br)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:31][C:32]1[C:37]([CH:38]([CH3:40])[CH3:39])=[CH:36][C:35](B(O)O)=[C:34]([O:44][CH3:45])[CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[C:35]3[CH:36]=[C:37]([CH:38]([CH3:40])[CH3:39])[C:32]([F:31])=[CH:33][C:34]=3[O:44][CH3:45])[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1cc(F)c(C(C)C)cc1B(O)O
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(Cl)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(Cl)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-chlorobenzyl)-4-methyl-1,3-oxazolidin-2-one (44 mg, 0.085 mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (Example 78, 23 mg, 0.11 mmol), potassium carbonate (25 mg, 0.18 mmol) and catalytic amount of PdOAc in a 4:1 mixture of acetone/water was heated to reflux for 1 h. Acetone was removed and water was added. The organic was extracted with methylene chloride (3×15 ml). The combined methylene chloride layers were washed with brine and dried over sodium sulfate. The title compound was obtained as a solid after preparative reverse phase HPLC. 1H NMR (CDCl3, 500 MHz) δ 1:1 mixture of rotamer δ 7.90 (s, 1H), 7.73 (s, 2H), 7.49 (m, 1H), 7.40 (m, 1H), 7.20 (m, 1H), 7.00 (m, 1H), 6.68 (dd, J=12.0, 3.0 Hz, 1H), 5.63 (d, J=8.0 Hz, ½ H), 5.44 (d, J=8.0 Hz, ½ H), 4.85 (d, J=10.0 Hz, ½ H), 4.82 (d, J=10.0 Hz, ½ H), 4.03 (d, J=16.0 Hz, ½ H), 3.84 (m, 1½ H), 3.80 (s, 3H), 3.20 (m, 1H), 1.20 (m, 6H), 0.56 (d, J=6.5 Hz, 3/2 H), 0.38 (d, J=6.5H, 3/2 H). LC-MS (M+1): 604.3, 4.61 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:12])[C:9]([OH:11])=[O:10].[OH-].[K+].CO.[N+:17]([C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26]Br)=[CH:22][CH:21]=1)([O-:19])=[O:18]>CN(C)C=O>[N+:17]([C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: CC(C(=O)O)c1ccccc1O
Reactant: O=[N+]([O-])c1ccc(OCCBr)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C(=O)O)c1ccccc1OCCOc1ccc([N+](=O)[O-])cc1
Reaction time: 0.17 h

Procedure:
25 g (0.15 M) of 2-hydroxyphenylpropanoic acid and 16.9 g (0.12 M) of potassium hydroxide are added to a mixture of 150 ml of methanol and 20 ml of dimethylformamide in a 1000 ml reactor. After stirring for 10 minutes, 30 g (0.15 M) of 2-(4-nitrophenoxy)ethyl bromide are added and the reaction medium is then refluxed for 24 hours with stirring. The methanol is evaporated off and the residue is taken up in water. The aqueous phase obtained is first washed with ethyl acetate and then acidified with dilute aqueous hydrochloric acid and extracted with ethyl acetate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5](Cl)[C:6]([CH3:8])=O)[CH3:2].[CH:11]([NH2:13])=[O:12].C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:3][C:4]([C:5]1[O:12][CH:11]=[N:13][C:6]=1[CH3:8])=[O:10])[CH3:2]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1ocnc1C
Temperature: 120 °C
Reaction time: 12 h
Yield: 39.8 %

Procedure:
To ethyl-2-chloroacetoacetate(5.6 g) was added formamide(4.6 g). The reaction mixture was stirred at 120° C. for 12 hours, cooled to 0° C. and aqueous potassium carbonate was added thereto. The mixture was extracted with benzene, dried with anhydrous magnesium sulfate, and concentrated in vacuo to obtain the target product(2.1 g).
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10](Cl)(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[NH2:24]>>[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[NH:24][S:10]([C:6]1[C:3]2=[N:4][S:5][N:1]=[C:2]2[CH:9]=[CH:8][CH:7]=1)(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)c1cccc2nsnc12
Reactant: COC(=O)c1ccc(C)cc1N
Product: COC(=O)c1ccc(C)cc1NS(=O)(=O)c1cccc2nsnc12
Yield: 53 %

Procedure:
The title compound (1.22 g, 53%) was prepared from benzo[1,2,5]thiadiazole-4-sulfonyl chloride and 2-amino-4-methyl-benzoic acid methyl ester as in Example 10, Part A. 1H NMR (500 MHz, CDCl3): 11.28 (s, 1H), 8.36 (dd, J=7.1, 1.0, 1H), 8.19 (dd, J=8.8, 1.0, 1H), 7.73 (d, J=8.1, 1H), 7.68 (dd, J=8.8, 7.1, 1H), 7.51 (br s, 1H), 6.77 (dd, J=8.1, 0.9, 1H), 3.89 (s, 3H), 2.28 (s, 3H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCCCC.[H-].[Na+].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1>CS(C)=O>[CH:4]1[CH:5]=[CH:6][C:1]([O:7][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[CH:2][CH:3]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCC
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
Phenol (1.89 g, 20 mmol) was added to a slurry of hexane-washed NaH (60% oil suspension, 820 mg, 20.5 mmol) in DMSO (20 mL), stirred under nitrogen at 20° C., producing strong gas evolution. After 30 minutes, 1-fluoro-4-nitrobenzene (2.82 g, 20 mmol) was added dropwise to the light grey slurry. After about 10 minutes, the reaction mixture became orange and quite strongly exothermic, and a lot of gas was evolved. After 2 hours, the reaction mixture was poured onto ice-water (200 mL), and the solid was collected by Buchner filtration, rinsed with water (2×50 mL), and air dried to give 4-nitrodiphenyl ether (3.945 g, 91.6%) as dull yellow crystals.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].[CH3:23]I.O>O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH3:23])=[O:8])=[CH:19][CH:20]=1)#[N:2]
Reactant: COc1ccc(CNC(=O)c2ccc(C#N)cc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN(C)C(=O)c2ccc(C#N)cc2)cc1
Reaction time: 0.25 h

Procedure:
79 mg of 4-cyano-N-(4-methoxybenzyl)benzamide was dissolved in 2.5 ml of tetrahydrofuran, and 24 mg of 60% sodium hydride was added thereto, followed by heating under reflux for 5 minutes in an atmosphere of nitrogen. After cooling, 0.1 ml of methyl iodide was added thereto, followed by stirring for 15 minutes. Thereafter, the reaction was stopped by the addition of 1 ml of distilled water. After the product was extracted with ethyl acetate, the extract was successively washed with 2 N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the resulting crude product was purified by TLC (using a 1:1 mixture of ethyl acetate and hexane as the developing solvent) to obtain 72 mg of 4-cyano-N-(4-methoxybenzyl)-N-methylbenzamide.