Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:13][CH3:14])=[CH:8][CH:9]=2)[CH:4]=1)#[N:2].[CH3:15][O:16]C(Cl)Cl.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]2[C:10]([CH:9]=[CH:8][C:7]([O:13][CH3:14])=[C:6]2[CH:15]=[O:16])=[CH:11][CH:12]=1)#[N:2]
Reactant: COC(Cl)Cl
Reactant: COc1ccc2ccc(C#N)cc2c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc2ccc(C#N)cc2c1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 3.7 g of 2-cyano-7-methoxynaphthalene was dissolved in 40 ml of dichloro- methane, and 6.6 ml of titanium tetrachloride and 4.6 ml of dichloromethyl methyl ether were added dropwise into the resulting solution at 0° in this order. The resulting mixture was stirred at room temperature for 30 minutes and cooled to 0° C. again. Water was added to the resulting mixture to cease the reaction, and the resulting mixture was extracted with dichloromethane (100 ml×2) The organic layers were combined, washed with water, a saturated aqueous solution of sodium bicarbonate and brine successively, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and the resulting crude crystal was washed with ether and dried to give 3.3 g of the title compound as colorless crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=3[O:18][CH3:19])[CH:13]=[O:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH3:22]I.O>CN(C=O)C>[CH3:22][N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=3[O:18][CH3:19])[CH:13]=[O:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CI
Reactant: COc1ccc(C=O)cc1-c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1-c1ccc2c(ccn2C)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 90.5 %

Procedure:
A solution of 3-(indol-5-yl)-4-methoxybenzaldehyde (0.50 g, 2.0 mmol) in DMF (10 mL) was cooled to 0° C. and NaH (60% dispersion in mineral oil, 0.14 g, 3.0 mmol) was added. The mixture was stirred at 0° C. for 45 minutes, then methyl iodide (0.34 g, 4.4 mmol) was added and the reaction was stirred for 16 hours at room temperature. The mixture was then poured into water and extracted with ethyl acetate, washed with water and dried over sodium sulphate. The solvent was removed in vacuo and the crude was purified by column chromatography (hexane/ethyl acetate 7/3) to give 0.48 g of title compound.
Reaction SMILES: [CH:1]1([C:4](Cl)=O)[CH2:3][CH2:2]1.[K].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:16]2([CH2:22][CH2:23][NH2:24])[CH2:21][CH2:20][CH2:19][CH:18]=[CH:17]2)[CH:13]=[CH:14][CH:15]=1>C(Cl)Cl.CCOCC>[CH:1]1([CH2:4][NH:24][CH2:23][CH2:22][C:16]2([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH3:8])[CH:11]=3)[CH2:21][CH2:20][CH2:19][CH:18]=[CH:17]2)[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: COc1cccc(C2(CCN)C=CCCC2)c1
Agent: [K]
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cccc(C2(CCNCC3CC3)C=CCCC2)c1

Procedure:
3.45 g of cyclopropanecarboxylic acid chloride are placed in 50 ml of methylene chloride, whereafter 5.0 g of potassium carbnate are added, and then a solution of 7.0 g of 1-(m-methoxyphenyl)-2-cyclohexene-1-ethylamine in 10 ml of methylene chloride is added dropwise while stirring. The mixture is stirred at room temperature overnight and subsequently at reflux for 30 minutes and cooled. Then, the precipitate is removed by filtration under suction, the filtrate is evaporated, and the oil obtained is taken up in ether. The ethereal solution is washed with 1 N hydrochloric acid and subsequently with water, dried over magnesium sulfate and evaporated, and N-[2-[1-(m-methoxyphenyl)-2-cyclohexen-1-yl]ethyl]-cyclopropanecarboxamide remains as the residue. 6.5 g of this compound, dissolved in 30 ml of absolute tetrahydrofuran, are added dropwise to a dispersion of 6 g of lithium aluminum hydride in 100 ml of absolute tetrahydrofuran. The mixture is boiled at reflux for 3 hours, cooled and worked-up in the usual manner, and there is obtained N-(cyclopropylmethyl)-1-(m-methoxyphenyl)-2-cyclohexene-1-ethylamine, the hydrochloride of which melts at 141°-142° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=O)=[CH:7][CH:6]=1.[CH3:20][C:21]1([CH3:30])[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23](=O)[CH2:22]1>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[C:23]2[CH2:24][C:25]([CH3:28])([CH3:27])[CH2:26][C:21]([CH3:30])([CH3:20])[CH2:22]2)[C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCO)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(OCCO)cc2)CC(C)(C)C1
Temperature: 25 °C
Yield: 41.5 %

Procedure:
To a stirred suspension of Zn (0.50 g, 7.59 mmol) in THF (10 mL) was added TiCl4 (0.42 mL, 3.79 mmol) dropwise. The mixture was refluxed under nitrogen for 2.5 h. Cooled to room temperature, a solution of 96 (0.245 g, 0.95 mmol) and 3,3,5,5-tetramethylcyclohexanone (0.45 g, 2.85 mmol) in THF (15 mL) was added at once. The reaction mixture was refluxed for another 2.5 h. Cooled to room temperature, the reaction was quenched with 10% K2CO3 (20 mL). The quenched reaction mixture was filtered through a pad of Celite and the pad was washed with EtOAc (100 mL). The filtrate was transferred to a separatory funnel, the layers were separated and the aqueous phase was extracted with EtOAc (50 mL). The organic extracts were combined, washed with brine and dried (Na2SO4). Concentration yielded a pale brown oil which was further purified by chromatography on a silica gel column eluted with a gradient from hexanes to 45% EtOAc:hexanes to give a light yellow solid, Crystallization from 7:1 hexanes:EtOAc yielded 97 as colorless needles (0.15 g, 42%). mp 154-155° C. 1H NMR (400 MHz, CD3OD): δ 0.91 (s, 6H), 0.92 (s, 6H), 1.28 (s, 2H), 1.96 (s, 2H), 1.98 (s, 2H), 3.80-3.90 (m, 2H), 4.00-4.10 (m, 2H), 6.67 (d, J=8.5 Hz, 2H), 6.84 (d, J=8.6 Hz, 2H), 6.94 (d, J=8.6 Hz, 2H), 7.03 (d, J=8.6 Hz, 2H). LRMS (ESI): m/z 381 (M+H)+, 379 (M−H)−. The sample was silated prior to EI analysis. HRMS (EI) Calcd for C31H48O3Si2: 524.3142 (M+−). Found: 524.3128.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[C:19]3[C:14]([C@H:15]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[C:31][Si](C)(C)C)[CH:25]=4)[CH2:16][N:17]4[CH2:23][CH2:22][CH2:21][C@H:18]43)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+]>CO>[C:30]([C:26]1[CH:25]=[C:24]([C@H:15]2[C:14]3[C:19](=[CH:20][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:12][CH:13]=3)[C@@H:18]3[CH2:21][CH2:22][CH2:23][N:17]3[CH2:16]2)[CH:29]=[CH:28][CH:27]=1)#[CH:31]
Reactant: C[Si](C)(C)C#Cc1cccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)c1
Yield: 55.9 %

Procedure:
A solution of cis-9-(3-piperidin-1-yl-propoxy)-6-(3-trimethylsilanylethynyl-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline (Example 33, 40.0 mg, 0.082 mmol) and K2CO3 (2.0 mg, 0.008 mmol) in MeOH (4.1 mL, 0.2 M) was stirred for 2 h at rt. The crude reaction mixture was purified directly after filtration by reverse-phase HPLC to give 19.0 mg (36%) of the desired product as a TFA salt. MS: exact mass calcd for C28H34N2O, 414.3; m/z found, 415.5 [M+H]+. 1H NMR (acetone-d6): 7.45 (m, 4H), 6.96 (m, 1H), 6.79 (dd, J=3.2,10.9, 1H), 6.64 (d, J=10.9, 1H), 4.92 (m, 1H), 4.62 (m, 1H), 4.12 (t, J=7.5, 2H), 3.93 (m, 1H), 3.66 (m, 4H), 3.51 (m, 1H), 3.39 (m, 1H), 3.31 (m, 2H), 2.93 (m, 3H), 2.32 (m, 5H), 1.89 (m, 5H), 1.51 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([C:19](=[N:21][OH:22])[NH2:20])=[CH:14][CH:15]=3)[N:10]=[C:9]2[S:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:4][CH:3]=1.[C:32](OC(=O)C)(=O)[CH3:33]>N#N>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([C:19]4[N:20]=[C:32]([CH3:33])[O:22][N:21]=4)=[CH:14][CH:15]=3)[N:10]=[C:9]2[S:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)CSc1nc2cc(C(N)=NO)ccc2c(=O)n1-c1ccc(F)cc1
Agent: N#N
Product: Cc1nc(-c2ccc3c(=O)n(-c4ccc(F)cc4)c(SCC(=O)OC(C)(C)C)nc3c2)no1

Procedure:
A solution of tert-butyl 2-(3-(4-fluorophenyl)-7-(N′-hydroxycarbamimidoyl)-4-oxo-3,4-dihydroquinazolin-2-ylthio)acetate (10B, 30 mg, 0.0676 mmol) in 3 mL of acetic anhydride was heated in N2 atmosphere 110° C. for 4 hours. The reaction was concentrated to yield tert-butyl 2-(3-(4-fluorophenyl)-7-(5-methyl-1,2,4-oxadiazol-3-yl)-4-oxo-3,4-dihydroquinazolin-2-ylthio)acetate (10C). MS (M+H)=469.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[OH:16][C:17]1[C:22]2[O:23][C:24]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:25][C:21]=2[CH:20]=[C:19]([C:38](Cl)=[O:39])[CH:18]=1>C(Cl)Cl>[OH:16][C:17]1[C:22]2[O:23][C:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:25][C:21]=2[CH:20]=[C:19]([C:38]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:39])[CH:18]=1
Reactant: C1CCNCC1
Reactant: O=C(Cl)c1cc(O)c2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(O)c2c(c1)OC(c1ccccc1)(c1ccccc1)O2)N1CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.8 %

Procedure:
Piperidine (0.3 ml, 2 mmol) and ethyl diisopropylamine (0.5 ml, 3 mmol) were dissolved in methylene chloride (10 ml). 7-Hydroxy-2,2-diphenyl-benzo[1,3]dioxole-5-carbonyl chloride (353 mg, 1 mmol) dissolved in methylene chloride (3 ml) was added dropwise at room temperature. The reaction was stirred at room temperature for 24 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was extracted with IN aqueous HCl solution, brine, dried over sodium sulfate and filtered. The solvent was evaporated and the residue purified by column chromatography on silica gel (20 g, 5% methanol in dichloromethane eluant) to yield the phenol as a white solid (180 mg, 45%).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)=[C:9]([CH:37]=1)[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:22]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:21]3[CH:29]=[CH:30][C:31]([C:33]([O:35][CH3:36])=[O:34])=[CH:32][C:20]=3[N:19]=2)=[CH:14][CH:13]=1)(O)=[O:3].C(Cl)(=O)C(Cl)=O.[CH3:51][N:52](C)C=O>ClCCl>[Cl:44][C:41]1[CH:42]=[CH:43][C:38]([C:8]2[CH:7]=[CH:6][C:5]([C:2](=[O:3])[NH:52][CH3:51])=[CH:37][C:9]=2[CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[N:22]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[C:21]4[CH:29]=[CH:30][C:31]([C:33]([O:35][CH3:36])=[O:34])=[CH:32][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)=[CH:39][CH:40]=1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc(C(=O)O)ccc3-c3ccc(Cl)cc3)cc1)n2C1CCCCC1
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CNC(=O)c1ccc(-c2ccc(Cl)cc2)c(COc2ccc(-c3nc4cc(C(=O)OC)ccc4n3C3CCCCC3)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
Methyl 2-{4-[5-carboxy-2-(4-chlorophenyl)benzyloxy]phenyl}-1-cyclohexylbenzimidazole-5-carboxylate hydrochloride (400 mg) obtained in Example 246 was suspended in dichloromethane (5 ml), and oxalyl chloride (0.08 ml) and dimethylformamide (catalytic amount) were added. The mixture was stirred for 2 hr at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (5 ml). The resulting solution was added dropwise to a mixed solution of 40% aqueous methylamine solution (5 ml) and tetrahydrofuran (5 ml) under ice-cooling. The reaction mixture was stirred for 1 hr and concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogencarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was crystallized from ethyl acetate and diisopropyl ether. The crystals were collected by filtration and dried under reduced pressure to give the title compound (335 mg, yield 86%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(OC(=O)C)(=O)C.S(=O)(=O)(O)O.[C:17]([NH:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)(=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]>>[N+:1]([C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:24]=1[NH:23][C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])[C:28]([O:30][CH3:31])=[O:29])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCCCC(=O)Nc1ccc(C(=O)OC)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CCCCC(=O)Nc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Fuming nitric acid (1.4 ml) was added dropwise to acetic anhydride (12 ml) under ice-cooling and then was added conc. sulfuric acid (0.1 ml). To the stirred mixture was added methyl 4-valerylaminobenzoate (2.3 g) under ice-cooling, followed by stirring for one hour. To the resultant mixture was added ice water, and the crystals separated out were recrystallized from ethyl acetate-hexane to give yellow prisms (2.14 g, 76%), m.p. 106-107° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[C:9](SC)[N:10]=[CH:11][C:6]=2[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:3]1=[O:23]>CCO.[Ni]>[CH3:1][N:2]1[C:7]2[N:8]=[CH:9][N:10]=[CH:11][C:6]=2[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:3]1=[O:23]
Reactant: CSc1ncc2cc(-c3cccc([N+](=O)[O-])c3)c(=O)n(C)c2n1
Agent: [Ni]
Solvent: CCO
Product: Cn1c(=O)c(-c2cccc([N+](=O)[O-])c2)cc2cncnc21
Yield: 41.3 %

Procedure:
To a solution of 8-methyl-2-(methylsulfanyl)-6-(3-nitrophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 3 mmol) in EtOH (10 mL) was added Raney® nickel (5 g) and the mixture refluxed for 3 h. After cooling, the reaction was filtered and the filtrate concentrated to give 8-methyl-6-(3-nitrophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one (0.35 g, 41% yield), which was used in the next reaction without further purification.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[C:13]1([CH2:19][C:20]([OH:22])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OC(=O)C)(=O)C.Cl>C(N(CC)CC)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[C:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:20]([OH:22])=[O:21]
Reactant: O=C(O)Cc1ccccc1
Reactant: O=Cc1ccc2ccccc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: O=C(O)C(=Cc1ccc2ccccc2c1)c1ccccc1
Yield: 89 %

Procedure:
A mixture of 2-naphthaldehyde (5 g, 32 mmole), phenylacetic acid (4.4 g, 32 mmole), triethylamine (5 mL) and acetic anhydride (10 mL) were refluxed for 5 hours. The solution was poured into 2N HCl (150 mL) and a precipitate formed immediately. This was recrystallized from 50% aqueous ethanol to yield 7.8 g (89% yield) of a white power.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[CH3:19][C:20]1[C:24]([C:25]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[O:26])=[CH:23][NH:22][C:21]=1[CH:34]=O>C(O)C.N1CCCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[C:11](=[CH:34][C:21]2[NH:22][CH:23]=[C:24]([C:25]([N:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)=[O:26])[C:20]=2[CH3:19])[C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Reactant: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]cc(C(=O)N4CCN(C)CC4)c2C)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.4 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (61.2 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-(4-methoxy-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (94 mg, 82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1/[C:11](=[CH:15]\[N:16](C)C)/[C:12](=[O:14])[CH3:13].NO.Cl>CCO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:15]=[N:16][O:14][C:12]=1[CH3:13]
Reactant: COc1ccc(/C(=C\N(C)C)C(C)=O)c(OC)c1
Agent: Cl
Agent: NO
Solvent: CCO
Product: COc1ccc(-c2cnoc2C)c(OC)c1

Procedure:
Dissolve (3E)-3-(2,4-dimethoxyphenyl)-4-(dimethylamino)but-3-en-2-one (5.1 g, 20.6 mmol) in EtOH (50 mL) and add NH2OH.HCl (3.05 g, 44.0 mmol). Heat to reflux under N2 for 20 min. Cool and evaporate to red-brown oil. Dissolve in CH2Cl2, dry over Na2SO4, filter and concentrate to red-brown oil (4.4 g). Use without further purification. LCMS=220.2 (MH+); 218.2 (M−).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[C:7]1([Li])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)C>[OH:1][CH2:5][CH2:4][CH2:3][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6]
Reactant: O=C1CCCO1
Reactant: [Li]c1ccccc1
Solvent: CCOCC
Product: O=C(CCCO)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a solution of dihydrofuran-2-one (5.71 g, 66 mmol) in diethyl ether (70 mL) at −78° C. was slowly added phenyl lithium (24 mL, 40 mmol, 1.67 M solution in cyclohexane/diethyl ether). After stirring at −78° C. for 2 hours, the reaction mixture was quenched by the addition of 10% NH4Cl (35 mL). The mixture was warmed to room temperature and the layers separated. The aqueous layer was extracted with diethyl ether (2×40 mL). The combined organics were washed with water (2×40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (2:3 hexanes/ethyl acetate) to provide the product (6.4 g, 97%) as pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][NH2:6].N1C=CC=CC=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][NH:6][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([C:18]([F:17])([F:28])[F:29])=[CH:20][CH:21]=1
Reactant: NCCc1ccccc1Br
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(NCCc1ccccc1Br)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 100 mL round-bottomed flask was added 2-bromophenethylamine (1800 mg, 9 mmol, Aldrich), pyridine (5 mL), 4-(trifluoromethyl)benzoyl chloride (2 mL, 9 mmol, Fluka). The reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2×50 mL). The organic extract was washed with water (30 mL), saturated NaCl (30 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 30% EtOAc/hexanes to give N-(2-bromophenethyl)-4-(trifluoromethyl)benzamide. MS (ESI pos. ion) m/z: 372 (M+1).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:18]=[CH:17][C:9]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=1.[OH-:19].[Na+]>O.S(=O)(=O)(O)O>[OH:19][C:6]1[CH:18]=[CH:17][C:9]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=1
Reactant: Nc1ccc(Cc2cccnc2)cc1
Reactant: [OH-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Oc1ccc(Cc2cccnc2)cc1
Temperature: 160 °C
Reaction time: 0.17 h

Procedure:
A solution of sodium nitrite (0.350 g) in water (1.5 ml) is cooled in ice, and added, with stirring, to a cold (ice-bath) solution of 3-(4'-aminobenzyl)pyridine (Preparation 8, 0.920 g, 0.0050 mole) in water (3.75 ml), concentrated sulfuric acid (2.5 ml), and ice (7 g). This solution in turn is added dropwise to a third solution of water (5 ml) and sulfuric acid (6.25 ml) that is maintained at 160° C. in an oil bath. The resulting solution is kept at 160° C. for 10 min and then cooled to room temperature. The pH of the solution is adjusted to 7.0 by addition of aqueous 50% sodium hydroxide. The resulting mixture is extracted 4 times with 25 ml of ether. The aqueous portion is further extracted continuously with ether for 40 hr. The ether extracts are washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crystalline residue is decolorized with activated charcoal and is recrystallized from acetone-hexane, giving a first crop (0.426 g) of the titled crystals, with a melting point of 182°-185° C. A second crop (0.034 g) and third crop (0.050 g, total 0.510 g, 0.00276 mole, 55%) of titled crystals are also obtained. Recrystallization of the first crop from acetone-hexane gives the titled product as colorless crystals with a melting point of 184°-186° C. IR (nujol) peaks are observed at 2900, 2800, 2720, 2680, 2600, 1615, 1590, 1580, 1515, 1485, 1280, 1250, 845, 800, 710, and 640 cm-1.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:15][CH:14]=1.[C:27](Cl)(=[O:31])[C:28](Cl)=[O:29]>>[C:23]([O:22][C:20]([NH:19][C:16]1[CH:17]=[CH:18][C:13]([N:12]2[C:3]3[CH:4]=[CH:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:1][C:28](=[O:29])[C:27]2=[O:31])=[CH:14][CH:15]=1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Nc2ccc3ccccc3c2N)cc1
Reactant: O=C(Cl)C(=O)Cl
Product: CC(C)(C)OC(=O)Nc1ccc(-n2c(=O)c(=O)[nH]c3c4ccccc4ccc32)cc1
Yield: 37.7 %

Procedure:
1-Amino-2-(4-tertbutoxycarbonylaminophenyl)aminonaphthalene (700 mg, 2.0 mmol) and oxalyl chloride (330 mg, 2.6 mmol) were used in a process similar to Example 1(3) to give the titled compound (304 mg, yield 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH:20]4[O:22][CH2:21]4)=[CH:15][CH:16]=3)[C:11](=[O:23])[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:26][NH2:27]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH:20]([OH:22])[CH2:21][NH:27][CH3:26])=[CH:15][CH:16]=3)[C:11](=[O:23])[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: CC1(C)CC(c2ccc(Cl)cc2)c2ccc(OCC3CO3)cc2C1=O
Solvent: CCO
Product: CNCC(O)COc1ccc2c(c1)C(=O)C(C)(C)CC2c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-(4-chlorophenyl)-7-(2,3-epoxypropoxy)-2,2-dimethyl-1-tetralone (3.7 g) in ethanol (25 ml) was added methylamine (8 ml) in ethanol (8 ml). The mixture was allowed to stand overnight. The solvent was removed and the residue shaken with ether-dilute hydrochloric acid. The aqueous layer was separated basified, extracted with ether and the extract dried (MgSO4). Evaporation gave 4(4-chlorophenyl)-7-(2-hydroxy-3-methylaminopropoxy)-2,2-dimethyl-1-tetralone as a semi-solid foam.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])C=C.[C:19]1(C)[CH:24]=C(C)C=C(C)[CH:20]=1>>[CH2:24]([C:10]1[CH:9]=[CH:8][C:7]([F:11])=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:5]=1[OH:4])[CH:19]=[CH2:20]
Reactant: C=CCOc1cccc(F)c1-c1ccccc1Cl
Reactant: Cc1cc(C)cc(C)c1
Product: C=CCc1ccc(F)c(-c2ccccc2Cl)c1O
Yield: 81 %

Procedure:
A solution of 2-allyloxy-2′-chloro-6-fluorobiphenyl (9.0 g, 33.7 mmol) in mesitylene (100 mL) was refluxed for 24 h. The solvent was removed under reduced pressure. Purification by ISCO using a solvent gradient of 0 to 20% ethyl acetate in hexanes provided 7.0 g (81%) of 3-allyl-2′-chloro-6-fluorobiphenyl-2-ol as a colorless oil.