Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:3]=1[C:20]([CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1)=[O:21].[OH-].[Na+].OO.C(OCC)(=[O:40])C>CO.O>[OH:40][C:22]1[C:20](=[O:21])[C:3]2[CH:4]=[C:5]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:7][C:2]=2[O:1][C:23]=1[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1
Reactant: COc1ccc(C=CC(=O)c2cc(Oc3ccccc3)c(NS(C)(=O)=O)cc2O)cc1OC
Reactant: CCOC(C)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2oc3cc(NS(C)(=O)=O)c(Oc4ccccc4)cc3c(=O)c2O)cc1OC
Reaction time: 10 h
Yield: 10.7 %

Procedure:
2.0 g of 2-(3,4-dimethoxyphenyl)vinyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone was suspended in 20 ml of methanol. Thereto was added 3.7 ml of a 15% aqueous sodium hydroxide solution to obtain a solution. Thereto was dropwise added 2.5 ml of a 15% aqueous hydrogen peroxide solution in 10 minutes at 0°-5° C. The mixture was stirred for 10 hours at the same temperature. The reaction mixture was introduced into a mixture of 50 ml of ethyl acetate and 50 ml of water. The organic layer was separated, washed with water, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: a 200 : 1 mixture of chloroform and methanol) to obtain 220 mg (yield: 10.7%) of 3-hydroxy-7-methylsulfonylamino-2-(3,4-dimethoxyphenyl)-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([O-:8])=O)[CH3:2].[K+].C(N(CC)CC)C.[Cl-].[Mg+2].[Cl-].[F:21][C:22]1[C:27](C(Cl)=O)=[CH:26][CH:25]=[CH:24][N:23]=1>C(#N)C>[F:21][C:22]1[C:27]([C:6](=[O:8])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9])=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(Cl)c1cccnc1F
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CC(=O)c1cccnc1F
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Potassium 3-(ethoxy)-3-oxopropanoate (6.06 g, 35.6 mmol) was suspended in acetonitrile (100 mL), cooled to 0° C. and treated successively with triethylamine (4.96 mL, 35.6 mmol, 1 equiv) and anhydrous magnesium(II) chloride (3.39 g, 35.6 mmol, 1 equiv). The ice bath was removed and the mixture was warmed to ambient temperature and stirred for 2.5 hours. An acetonitrile (5 mL) solution of 2-fluoropyridine-3-carbonyl choride (5.68 g, 35.6 mmol) was added and the mixture was stirred for 72 hours at ambient temperature. The mixture was concentrated in vacuo and the residue was concentrated from toluene (1×75 mL). The residue was suspended in toluene (50 mL), cooled to 0° C. and treated with hydrochloric acid (20 mL, 12 N aqueous). After 15 minutes, the mixture was warmed to ambient temperature and stirred for an additional 45 minutes. The mixture was poured into water (50 mL) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 1:1; hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[O:29])=[CH:26][CH:25]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)OC2CCN(Cc3ccccc3)CC2)cc1
Yield: 34.9 %

Procedure:
1.41 g (0.00733 mol) of 1-benzyl-4-hydroxypiperidine and 1.8 ml (0.0129 mol) of triethylamine were dissolved in 50 ml of toluene and treated with 0.79 ml (0.00586 mol) of 4-methoxy-benzoyl chloride. The mixture was boiled at reflux for 2 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:3→1:2). 0.666 g (35%) of 1-benzyl-piperidin-4-yl 4-methoxy-benzoate was obtained as yellowish crystals; m.p. 55°-56°.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:15]2[C:10](=[C:11]3[CH:23]=[CH:22][CH:21]=[CH:20][C:12]3=[C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]3=2)[C:9]2[C:4]1=[C:5]1[CH:31]=[CH:30][CH:29]=[CH:28][C:6]1=[C:7]1[CH:27]=[CH:26][CH:25]=[CH:24][C:8]1=2.[C:32](OC(=O)C)(=[O:34])[CH3:33]>OS(O)(=O)=O>[C:32]([O:1][CH2:2][CH:3]1[C:15]2[C:10](=[C:11]3[CH:23]=[CH:22][CH:21]=[CH:20][C:12]3=[C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]3=2)[C:9]2[C:4]1=[C:5]1[CH:31]=[CH:30][CH:29]=[CH:28][C:6]1=[C:7]1[CH:27]=[CH:26][CH:25]=[CH:24][C:8]1=2)(=[O:34])[CH3:33]
Reactant: OCC1c2c(c3ccccc3c3ccccc23)-c2c1c1ccccc1c1ccccc21
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)OCC1c2c(c3ccccc3c3ccccc23)-c2c1c1ccccc1c1ccccc21
Reaction time: 1 h

Procedure:
17-Hydroxymethyltetrabenzo(a,c,g,i)fluorene (0.207 g, 0.522 mmol) was dissolved in acetic anhydride (4 ml). To this solution was added 2 drops of H2SO4 (2M). The reaction mixture was stirred for 1 h. Compound (35) was obtained as a yellow solid which was washed with water (80 ml) and dried to constant weight over P2O5 in a vacuum desiccator (183.8 mg, 80%); m.p. 209-210°, (Found: C, 87.0; H, 5.08; C32H22O2 requires: C, 87.7; H, 5.02%); t.l.c. Rf (A) 0.32, Rf (F) 0.22; νmax (CH2Cl2) 3060 (CH stretching, aromatic), 1740 (CO, ester), 1610, 1500 (aromatic rings), 1230, 1045 (CO, stretching) cm−1; λmax 380 (17885), 368 (19345), 302 (45260), 290 (36865), 254 (72271) nm; δH (CDCl3, 80 MHz), 8.83-8.57 (6H, m, aromatic), 8.29-8.17 (2H, m, aromatic), 7.78-7.54 (8H, m, aromatic), 5.12 (1H, t, 3J=5.5 Hz, CH), 4.60 (2H, d, 3J=5.5 Hz, CH2), 1.84 (3H, s, CH3); δC (CDCl3, 50 MHz) 170.7 (CO, ester), 141.8, 137.0, 131.5, 130.4, 128.6, 128.0 (quaternary aromatic C's), 127.4, 126.8, 126.1, 126.0, 125.0, 124.9, 123.5, 123.3 (aromatic CH's), 67.9 (CH2), 47.1 (CH), 20.7 (CH3); m/z (EI) 438 (M+), 378, 364.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:21]([NH:23][C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@H:27]([O:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:41]([N:44]([CH:48]([CH3:50])[CH3:49])[CH:45]([CH3:47])[CH3:46])=[N:42][N:43]=4)[CH:40]=3)[CH2:26][CH2:25]2)=[O:22])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][OH:19])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:60][S:61](Cl)(=[O:63])=[O:62]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:21]([NH:23][C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@H:27]([O:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:41]([N:44]([CH:45]([CH3:46])[CH3:47])[CH:48]([CH3:50])[CH3:49])=[N:42][N:43]=4)[CH:40]=3)[CH2:26][CH2:25]2)=[O:22])[N:8]([C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[O:16][CH2:17][CH2:18][O:19][S:61]([CH3:60])(=[O:63])=[O:62])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)N(c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12)C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N(c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12)C(C)C
Reaction time: 2 h
Yield: 131.8 %

Procedure:
To an ice-bath cooled solution of Intermediate 103e (97 mg, 0.13 mmol) in DCM (2 mL) was added DIPEA (58 μL, 0.32 mmol) followed by methanesulfonyl chloride (22 μL, 0.27 mmol). The reaction mixture was stirred for 2 h then partitioned between DCM and water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (130 mg, quantitative). LCMS (Method 1): Rt 3.69 min, m/z 759 [MH+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[S:24]1(=[O:31])(=[O:30])[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:25]4[CH2:26][CH2:27][CH2:28][CH2:29][S:24]4(=[O:31])=[O:30])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: O=S1(=O)CCCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 55.1 %

Procedure:
Using (4-bromophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (187 mg) described in Preparation Example 165 and [1,2]thiazinane 1,1-dioxide (68 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (118 mg) was obtained.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[C:7]([C:10]1[CH:11]=[CH:12][C:13]2[NH:19][C:18](=O)[CH:17]([CH3:21])[N:16]=[C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:14]=2[CH:29]=1)(=[O:9])[CH3:8].CI>CC(C)=O>[C:7]([C:10]1[CH:11]=[CH:12][C:13]2[N:19]([CH3:18])[C:1](=[O:4])[CH:17]([CH3:21])[N:16]=[C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:14]=2[CH:29]=1)(=[O:9])[CH3:8]
Reactant: CC(=O)c1ccc2c(c1)C(c1ccccc1F)=NC(C)C(=O)N2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CC(=O)c1ccc2c(c1)C(c1ccccc1F)=NC(C)C(=O)N2C
Temperature: 25 °C
Reaction time: 21 h

Procedure:
7.15 g of potassium carbonate are added to a solution of 7.15 g (23.04 mmol) of 7-acetyl-5-(o-fluorophenyl)-1,3-dihydro-3-methyl-2H-1,4-benzodiazepin-2-one and 15 ml of methyl iodide in 300 ml of acetone and the mixture is stirred at room temperature for 21 hours. The insoluble material is filtered off and the solution is evaporated in vacuo. The residue is taken up in methylene chloride, washed with water, dried and evaporated. From cyclohexane there is obtained 7-acetyl-5-(o-fluorophenyl)-1,3-dihydro-1,3-dimethyl-2H-1,4-benzodiazepin-2-one of melting point 65°.
Reaction SMILES: [Br:1]Br.[N:3]1([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[N:3]1([C:9]2[C:14]([Br:1])=[CH:13][N:12]=[C:11]([CH3:15])[CH:10]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: Cc1cc(N2CCCCC2)ccn1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N2CCCCC2)c(Br)cn1
Reaction time: 3.5 h

Procedure:
A solution of bromine (9.3 ml) in dimethylformamide (50 ml) was added dropwise-to a stirred mixture of 4 -piperidino-2 -picoline (15 g), potassium carbonate (23.5. g) in dimethylformamide (50 ml) at 25°-30°. After 3.5 hours, the mixture was stripped and the residue taken up in water, adjusted to pH 13 with 40 % aqueous NAOH, and extracted with ether. After drying (K2CO3 ) and stripping, the residue was chromatographed (silica gel, n-hexane:ether) to give 4 -piperidino-5 -bromo-2 -picoline, 11.18 g, as an oil and 4 -piperidino-3 -bromo-2 -picoline, 3.5 g, as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=O)[NH:10][N:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.O=P(Cl)(Cl)[Cl:30]>C1(C)C=CC=CC=1>[Cl:30][C:9]1[N:10]=[N:11][CH:12]=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ncc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2cnnc(Cl)c2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.3 %

Procedure:
4,5-Bis(4-chlorophenyl)pyridazin-3(2H)-one (16.5 g, 52.2 mmol) was suspended in toluene (50 mL). To the resultant solution was added pyridine (8.3 mL, 104.4 mmol), followed by the addition of POCl3 (14.3 mL, 156.6 mmol). The reaction mixture was placed in an oil bath preheated at 110° C. After 4 h, the reaction mixture was cooled to RT, then poured over 500 g ice to quench the excess POCl3. The dark mixture was extracted with EtOAc (2×300 mL). The combined organic layers were washed with water (500 mL), and filtered through a silica gel pad (˜50 g). The filtrate was concentrated under reduced pressure to give the title compound, 3-chloro-4,5-bis(4-chlorophenyl)pyridazine as a pale colored solid (16.0 g, 92%). MS: M+H=335. 1H NMR (CDCl3, 500 MHz): δ 9.24(1H, s), 7.35 (2H, d, J=10 Hz), 7.26 (2H, d, J=10.0 Hz), 7.08–7.16 (4H, m).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[CH:13][S:12][C:4]=2[N:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[N:7]=1>C(O)C>[CH3:11][S:8]([C:6]1[N:7]=[CH:2][C:3]2[CH:14]=[CH:13][S:12][C:4]=2[N:5]=1)(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1nc(Cl)c2ccsc2n1
Solvent: CCO
Product: CS(=O)(=O)c1ncc2ccsc2n1
Yield: 85.6 %

Procedure:
To 500 mL round-bottom flask was added 4-chloro-2-(methylsulfonyl)thieno[2,3-d]pyrimidine (15 g, 60 mmol), ethyl alcohol (300 mL), nitrogen gas was bubbled for 5 minutes. To this solution was added 10% palladium on activated charcoal (15 g). To the resulting mixture was bubbled hydrogen gas over night. The reaction mixture was filtered through Celite. The filtrate was concentrated to give the title compound (11.0 g). MS (ES+): 215 (M+H)+.
Reaction SMILES: C[Al](C)C.[C:5]([C:9]1[CH:13]=[C:12]([NH2:14])[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=1)([CH3:8])([CH3:7])[CH3:6].[O:21]=[C:22]1[NH:27][C:26]2[N:28]=[CH:29][CH:30]=[C:31]([O:32][C:33]3[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=3)[C:36](OC)=[O:37])[C:25]=2[N:24]=[CH:23]1>C1COCC1>[C:5]([C:9]1[CH:13]=[C:12]([NH:14][C:36](=[O:37])[C:35]2[CH:40]=[CH:41][CH:42]=[C:33]([O:32][C:31]3[C:25]4[N:24]=[CH:23][C:22](=[O:21])[NH:27][C:26]=4[N:28]=[CH:29][CH:30]=3)[CH:34]=2)[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: COC(=O)c1cccc(Oc2ccnc3[nH]c(=O)cnc23)c1
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2)n1
Agent: C[Al](C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)c2cccc(Oc3ccnc4[nH]c(=O)cnc34)c2)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Method H1: A solution of AlMe3 (solution in toluene 2M, 0.85 mL, 1.68 mmol) was added dropwise to a cooled (0 C) solution of 3-tert-butyl-1-phenyl-1H-pyrazol-5-amine (362 mg, 1.68 mmol) in THF (5.0 mL). When the addition was complete, the mixture was allowed to warm to room temperature and stirring was continued for 30 minutes. Then methyl 3-(3-oxo-3,4-dihydropyrido[2,3-b]pyrazin-8-yloxy)benzoate (100 mg, 0.336 mmol) was added and the mixture was heated under reflux for 19 h. The mixture was cooled to room temperature and carefully quenched with 5% aq HCl (3.0 mL). After evaporation of solvent, the residue was retaken in CH2Cl2, washed with saturated solution of NaHCO3 and dried over MgSO4 and evaporated under vacuum. The obtained residue was chromatographed (eluent: CH2Cl2/EtOAc: 2/1 towards 1/3) and the title compound was obtained as a slightly yellow solid (29 mg, 18%).
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:21]2[C:16](=[C:17](C)[CH:18]=[C:19]([CH3:22])[CH:20]=2)[N:15]=[CH:14][C:13]=1[NH:24][C:25](=[O:38])[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34]C)=[C:30]([O:36]C)[CH:29]=1.[C:39](=O)([O-])O.[Na+]>ClCCl>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:21]2[C:16](=[CH:17][C:18]([CH3:39])=[C:19]([CH3:22])[CH:20]=2)[N:15]=[CH:14][C:13]=1[NH:24][C:25](=[O:38])[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([OH:36])[CH:29]=1
Reactant: COc1ccc(C=CC(=O)Nc2cnc3c(C)cc(C)cc3c2-c2ccccc2Cl)cc1OC
Reactant: O=C([O-])O
Agent: BrB(Br)Br
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc2ncc(NC(=O)C=Cc3ccc(O)c(O)c3)c(-c3ccccc3Cl)c2cc1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 44.8 %

Procedure:
A solution of boron tribromide in dichloromethane (1:2, 1 ml) was added to a solution of 4-(2-chlorophenyl)-3-(3,4-dimethoxycinnamoylamino)-6,8-dimethylquinoline (473 mg) in dichloromethane (5 ml) under ice-cooling. After being stirred for 20 minutes under ice-cooling, and further for 30 minutes at room temperature, the mixture was poured into ice water. The solution was made neutral with a sodium hydrogen carbonate saturated solution and was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4). The solvent was removed, and the residue was crystallized to give crystals of 4-(2-chlorophenyl)-3-(3,4-dihydroxycinnamoylamino)-6,7-dimethylquinoline (212 mg, 44.8%). The crystals were recrystallized from acetone to obtain yellowish prisms (1/2 acetone solvate).
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([C:10]([OH:12])=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C([O:20][C:21]1[C:30]([CH3:31])=[CH:29][C:24]([C:25]([NH:27][NH2:28])=O)=[CH:23][C:22]=1[CH2:32][CH3:33])C1C=CC=CC=1>>[CH2:32]([C:22]1[CH:23]=[C:24]([C:25]2[O:12][C:10]([C:8]3[S:9][C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])=[CH:6][CH:7]=3)=[N:28][N:27]=2)[CH:29]=[C:30]([CH3:31])[C:21]=1[OH:20])[CH3:33]
Reactant: CC(C)Cc1ccc(C(=O)O)s1
Reactant: CCc1cc(C(=O)NN)cc(C)c1OCc1ccccc1
Product: CCc1cc(-c2nnc(-c3ccc(CC(C)C)s3)o2)cc(C)c1O

Procedure:
2-Ethyl-4-[5-(5-isobutyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-6-methyl-phenol is prepared in analogy to Example 29 from 5-isobutyl-thiophene-2-carboxylic acid and 4-benzyloxy-3-ethyl-5-methyl-benzoic acid hydrazide; LC-MS: tR=1.03 min, [M+1]+=343.22.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([CH:36]=[O:37])=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)=[O:23])=[CH:14][CH:13]=1)[C:8]([OH:10])=[O:9])[CH2:4][CH2:5][CH3:6].C(O)(=O)C>C(O)C>[CH2:3]([CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:31]=[CH:32][C:33]([CH2:36][OH:37])=[CH:34][CH:35]=3)=[CH:28][CH:29]=2)=[O:23])=[CH:14][CH:13]=1)[C:8]([OH:10])=[O:9])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccc(C=O)cc3)cc2)cc1)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccc(CO)cc3)cc2)cc1)C(=O)O
Reaction time: 1.5 h
Yield: 90.1 %

Procedure:
Sodium borohydride (95%, 34 mg) was added to a solution of 2-butyl-3-[4-[2-(4′-formylbiphenyl-4-carbonylamino)ethoxy]phenyl]propionic acid (366 mg) in ethanol (10 ml) at ambient temperature. The mixture was stirred for 1.5 hours. At the end of this time 50% acetic acid was added to the reaction mixture. The mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Diisopropyl ether was added to the residue to give the title compound (331 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH2:7])=[CH:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+].[Cl:25][CH2:26][CH2:27][C:28](Cl)=[O:29]>O>[Cl:25][CH2:26][CH2:27][C:28]([NH:7][C:6]1[C:2]([Cl:1])=[N:3][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=1)=[O:29]
Reactant: Nc1cn(-c2cccnc2)nc1Cl
Reactant: O=C(Cl)CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCCl)Nc1cn(-c2cccnc2)nc1Cl
Temperature: 5 °C
Yield: 95.5 %

Procedure:
A 100 mL, three-neck round bottom flask was charged with 3-chloro-1-(pyridine-3-yl)-1H-pyrazol-4-amine (1.00 g, 5.14 mmol) and ethyl acetate (10 mL). Sodium bicarbonate (1.08 g, 6.17 mmol) was added and the reaction mixture was cooled to 5° C. 3-Chloropropanoyl chloride (0.783 g, 6.17 mmol) was added dropwise at <20° C. The reaction was allowed to warm up to 20° C. and stirred for 2 hours, at which point thin layer chromatography analysis (Eluent: ethyl acetate) indicated that the reaction was complete. The reaction was diluted with water (50 mL) and the layers separated. The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers were concentrated to dryness to afford a white solid (1.40 g, 96%): mp 152-154° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 9.07 (d, J=2.7 Hz, 1H), 8.89 (s, 1H), 8.54 (dd, J=4.7, 1.4 Hz, 1H), 8.23 (ddd, J=8.4, 2.7, 1.4 Hz, 1H), 7.54 (dd, J=8.4, 4.7, Hz, 1H), 3.90 (t, J=6.2 Hz, 2H), 2.94 (t, J=6.2 Hz, 2H); 13C NMR (101 MHz, DMSO-d6) δ 167.90, 147.50, 139.47, 135.46, 133.47, 125.51, 124.20, 122.47, 119.87, 40.63, 37.91; ESIMS m/z 285 ([M+H]+).
Reaction SMILES: [Cl-].[OH:2][NH3+:3].C(=O)([O-])O.[Na+].[CH3:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH2:26][C:27]3[N:32]=[C:31]([C:33](OC)=[O:34])[CH:30]=[CH:29][CH:28]=3)=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:17]2)=[CH:13][CH:12]=1>CS(C)=O.O>[OH:2][NH:3][C:33]([C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:26][C:15]2[C:14]3[C:18](=[CH:19][C:11]([O:10][CH3:9])=[CH:12][CH:13]=3)[NH:17][C:16]=2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:32]=1)=[O:34]
Reactant: COC(=O)c1cccc(Cc2c(-c3ccccc3)[nH]c3cc(OC)ccc23)n1
Reactant: [NH3+]O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2c(Cc3cccc(C(=O)NO)n3)c(-c3ccccc3)[nH]c2c1
Temperature: 50 °C
Reaction time: 1.17 h
Yield: 92.8 %

Procedure:
To a solution of hydroxylammonium chloride (373 mg) in dimethylsulfoxide (2.7 mL) was added sodium hydrogen carbonate (541 mg), and this mixture was stirred at 50° C. for 70 minutes. Then, methyl 6-(6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxylate (200 mg) was added thereto, followed by stirring at 50° C. for 3 days. The reaction mixture was left to be cooled and diluted with water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: methanol-dichloromethane) to obtain the title compound (186 mg). 1H-NMR (DMSO-d6) δ ppm: 3.77 (3H, s), 4.38 (2H, s), 6.63 (1H, dd, J=2.3, 8.5 Hz), 6.87 (1H, d, J=2.3 Hz), 7.15 (1H, dd, J=1.5, 7.3 Hz), 7.29-7.39 (2H, m), 7.42-7.53 (2H, m), 7.59-7.70 (2H, m), 7.70-7.81 (2H, m), 9.13 (1H, s), 11.10 (1H, s), 11.18 (1H, s). ESI-MS (m/z): 374 (M+H)+
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12]([C:14]1[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][CH:15]=1)=[O:13])[CH3:10]>C(O)(=O)C>[CH2:9]([O:11][C:12]([C:14]1[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:15]=1[Cl:1])=[O:13])[CH3:10]
Reactant: CCOC(=O)c1csc(CC)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CC)sc1Cl
Reaction time: 8 h
Yield: 69.9 %

Procedure:
N-Chlorosuccinimide (0.8 g, 5.9 mmol) was added to a solution of 5-ethyl-thiophene-3-carboxylic acid ethyl ester (1 g, 5.43 mmol) in acetic acid (10 mL) and stirred overnight. The reaction was filtered and the solvent removed under vacuum. The product was purified by flash chromatography on silica, eluting with 0%-100% t-butylmethyl ether in cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.83 g). 1H NMR (400 MHz, CHCl3-d): δ 7.05 (s, 1H), 4.3 (q, 2H), 2.75 (q, 2H), 1.4 (t, 3H), 1.3 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][OH:12])[C:9]#[N:10])=[C:4]([CH3:13])[CH:3]=1.ClC1C=C[C:18]([O:21]C(F)F)=[CH:17]C=1C(CO)C#N>>[C:18]([O:12][CH2:11][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[CH3:13])[C:9]#[N:10])(=[O:21])[CH3:17]
Reactant: N#CC(CO)c1cc(OC(F)F)ccc1Cl
Reactant: Cc1cc(Cl)ccc1C(C#N)CO
Product: CC(=O)OCC(C#N)c1ccc(Cl)cc1C
Yield: 74 %

Procedure:
This ester was prepared using the procedure described in Example 5, except 2(-2-(4-chloro-2-methylphenyl)-3-hydroxypropanenitrile was used in place of 2-(2-chloro-5-(difluoromethoxy)phenyl-3-hydroxypropanenitrile. The preparation of 2(2-(4-chloro-2-methylphenyl)-3-hydroxypropanenitrile is described in Example 11. The recovered ester product was a white solid (74% yield in two crops), m. p. 61-63° C.