Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[C:9]1(=O)[O:14][C:12](=[O:13])[CH:11]=[CH:10]1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CN(C)C=O>O>[OH:8][C:3]1[CH:4]=[CH:5][C:6]([N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]2=[O:14])=[CH:1][CH:2]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccc(O)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CN(C)C=O
Solvent: O
Product: O=C1C=CC(=O)N1c1ccc(O)cc1
Temperature: 15 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
In a reactor, 30.0 g (0.275 moles) of p-aminophenol, 29.7 g (0.303 moles) of maleic anhydride, 39.0 g (0.275 moles) of phosphorus pentoxide and 100 g of dimethylformamide were charged and stirred at 15° C. for 2 hours. The reaction mixture was then gradually heated to 60° C., at which temperature the reaction was further continued for 2.5 hours. After cooling to room temperature, the resulting reaction mixture was admixed with water to precipitate N-(p-hydroxyphenyl) maleimide in the form of crystals. The crystals were separated by filtration, washed with water and then dried to obtain 25.1 g (0.133 moles) of N-(p-hydroxyphenyl) maleimide (yield 48.2%).
Reaction SMILES: [C:1]([O:13]C)(=O)[C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=1.[CH3:15][C:16]([CH3:18])=[O:17].[H-].[Na+].Cl>C1(C)C=CC=CC=1.O>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([C:1](=[O:13])[CH2:15][C:16](=[O:17])[CH3:18])[CH:3]=1
Reactant: CC(C)=O
Reactant: COC(=O)c1cccc(C(=O)OC)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cccc(C(=O)CC(C)=O)c1
Temperature: 100 °C
Yield: 13.1 %

Procedure:
A solution of dimethyl isophthalate (12 g, 61.85 mmole) and acetone (5 mL, 68 mmole) in a mixture of toluene/dimethoyethane (90 mL/30 mL) was added to a suspension of NaH 60% (2.97 g, 74.23 mmole) in dry toluene (30 mL) under argon. The mixture was heated at 100° C. for 4 hours. The reaction mixture was cooled to rt and 25 mL of water were added. The mixture was poured into water (250 mL) and the pH was adjusted to 3-4 with HCl 2N. The aqueous mixture was extracted with ethyl acetate (2×250 mL), washed with brine, dried over sodium sulphate and evaporated to afford a yellow solid which was purified by column cromatography (n-Hex/EtOAc 9:1 to 8:2) to afford the title compound (1.78 g, 11% yield) as a yellow solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].[CH3:16]I>O1CCCC1.O>[CH3:16][O:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CO[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C

Procedure:
tert-Butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (12.5 g, 66.70 mmol) was dissolved in tetrahydrofuran (334 mL) and the reaction mixture cooled to 0° C. in an ice bath. The reaction mixture was treated with 80% sodium hydride in mineral oil (2.20 g, 73.3 mmol) and stirred until back at room temperature. The reaction mixture was then treated with methyl iodide (14.5 g, 100.0 mmol) and stirred at room temperature for 18 hours. The reaction mixture was diluted with water (100 mL) and concentrated in vacuo until just the aqueous remained. The aqueous solution was treated with ethyl acetate (750 mL), the organic layer separated, dried over magnesium sulphate and concentrated in vacuo to yield the title product as a brown oil, 12.48 g. 1H NMR (CDCl3, 400 MHz) δ: 1:41 (s, 9H), 1.95 (m, 2H), 3.30 (s, 3H), 3.40 (m, 4H), 3.86 (m, 1H)
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[O:6]CCO1.[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1/[CH:25]=[CH:26]/[C:27]([NH:16][C:13]1[CH:14]=[CH:15][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:2](=[O:6])[CH3:1])[N:12]=1)=[O:28]
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1Cl
Reactant: CC1(CCCCn2ccc(N)n2)OCCO1
Product: CC(=O)CCCCn1ccc(NC(=O)/C=C/c2ccc(Cl)cc2Cl)n1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-3-ylamine and (E)-3-(2,4-dichloro-phenyl)-acrylic acid.
Reaction SMILES: [C:1]1([C:7]2([NH2:12])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[N:21]=[C:22]=[O:23]>C(OC(=O)C)C>[CH3:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH3:13])[C:15]=1[NH:21][C:22]([NH:12][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:23]
Reactant: NC1(c2ccccc2)CCCC1
Reactant: Cc1cccc(C)c1N=C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1NC(=O)NC1(c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 1-phenylcyclopentyl amine (1.0 gm, 0.006 mole) in 30 ml of ethylacetate, 2,6-dimethylphenyl isocyanate (0.91 g; 0.006 mole) is added and the reaction mixture is stirred at room temperature for 20 hours. Volatiles are removed under reduced pressure and the residue is crystallized from ethylacetate-hexane yielding 1.65 g of N-(2,6-dimethylphenyl-N'-(1-phenylcyclopentyl) urea having a melting point of 227°-229° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N:14]3[CH2:19][CH2:18][NH:17][C@H:16]([CH3:20])[CH2:15]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:21]([O:25][CH3:26])(=[O:24])[CH:22]=O.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N:14]3[CH2:19][CH2:18][N:17]([CH2:22][C:21]([O:25][CH3:26])=[O:24])[C@H:16]([CH3:20])[CH2:15]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C=O
Reactant: C[C@@H]1CN(C2(c3ccc(Cl)cc3)CCCCC2)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: COC(=O)CN1CCN(C2(c3ccc(Cl)cc3)CCCCC2)C[C@H]1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.5 %

Procedure:
To a solution of (R)-1-(1-(4-chlorophenyl)cyclohexyl)-3-methylpiperazine (0.6 g, 2.05 mmol) in dichloromethane at room temperature were added methyl glyoxalate (0.23 g, 2.61 mmol), acetic acid (0.18 g, 3 mmol) and Na(OAc)3BH (1.08 g, 5.1 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude product. It was purified by silica gel (100-200 mesh) column chromatography eluting with ethyl acetate in n-hexanes to afford 0.49 g of (R)-methyl 2-(4-(1-(4-chlorophenyl)cyclohexyl)-2-methyl-piperazin-1-yl)acetate.
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][C@H:6]2[C:9]3[C:14]([CH2:15][CH2:16][C@H:5]2[CH2:4][CH2:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.CC(C)([O-])C.[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>C1COCC1>[CH2:23]([N:8]1[C:2](=[O:1])[CH2:3][CH2:4][C@@H:5]2[CH2:16][CH2:15][C:14]3[C:9]([C@@H:6]2[CH2:7]1)=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CC[C@@H]2CCc3ccccc3[C@@H]2CN1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CC[C@@H]2CCc3ccccc3[C@@H]2CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
To a suspension of cis-1,3,4,5,5a,6,7,11b-octahydro-3-oxo-2H-naphth[1,2-c]azepine (1.0 g, 4.65 mmol), from Step 3 of Example 75, in 20 mL of dry THF, was added potassium t-butoxide (0.78 g, 6.9 mmol). The reaction mixture was stirred at ambient temperature for 0.5 h and then cooled to 0° C. and benzyl bromide (0.8 mL, 6.7 mmol) was added. The reaction mixture was allowed to warm to ambient temperature, stirred for 3 h and then poured into water and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was crystalized from ether/hexane to afford 1.1 g (79% yield) of the title compound, m.p. 114°-115° C.; MS DCI-NH3M/Z: 306 (M+H)+ ; 1H NMR (CDCl3) δ1.5-2.2 (5H, m), 2.42-2.54 (1H, m), 2.58-3.03 (5H, m), 3.79 (1H, dd, J=9.5, 13.6 Hz), 4.44 (1H, d, J=13.6 Hz), 4.95 (1H, d, J=13.6 Hz), 6.47-6.5 (1H, m), 6.97-7.45 (8H, m).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@H:2]([C@@H:4]([C:6]([OH:8])=O)[OH:5])[OH:3].[C:11](Cl)(=[O:15])[CH:12]([CH3:14])[CH3:13]>C1(C)C=CC=CC=1.CCOCC.CCCCCC>[O:10]=[C:1]1[C@@H:2]([O:3][C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])[C@H:4]([O:5][C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])[C:6](=[O:8])[O:9]1
Reactant: CC(C)C(=O)Cl
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)C(=O)O[C@@H]1C(=O)OC(=O)[C@H]1OC(=O)C(C)C
Reaction time: 22 h
Yield: 70.6 %

Procedure:
To a suspension of D-tartaric acid (5.0 g, 33.3 mmol) in toluene (60 mL) was added isobutyryl chloride (11.3 mL, 107 mmol). The resulting suspension was heated to reflux and stirred for 22 h at reflux temperature. The reaction mixture was then concentrated in vacuo to afford a crystalline solid, which was suspended in a mixture of ether and hexane (1:3), filtered, washed with hexane and dried to afford the desired compound (30) as a white crystalline solid (6.4 g, 71%). 1H-NMR (400 MHz, CDCl3): δ 1.25 (d, J=6.8 Hz, 12H), 2.72 (hept, J=6.8 Hz, 2H), 5.63 (s, 2H).
Reaction SMILES: CCCCCC[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].CO[C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH2:22][CH2:21][CH2:20][CH2:19]2.C1(C)C(C2C(C)=CC=CC=2)=CC=CC=1>>[CH3:13][C:12]1[CH:7]=[CH:8][C:9]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][CH:11]=1
Reactant: COc1ccc2c(c1)CCCC2
Reactant: CCCCCCCCCCCCC
Agent: Cc1ccccc1-c1ccccc1C
Product: Cc1ccc(-c2ccc3c(c2)CCCC3)cc1
Temperature: 25 °C
Yield: 35 %

Procedure:
In a reaction flask was placed NiCl2(dcpb) (38.0 mg, 0.0655 mmol), dcpb (34.6 mg, 0.0768 mmol), tridecane (164.5 mg, 0.892 mmol, as an internal standard), and 6-methoxy-1,2,3,4-tetrahydronaphthalene (169.3 mg, 1.044 mmol). The solvent in the Grignard reagent (1 M in ether, 3.0 mmol) was exchanged with t-AmOMe (5.0 mL) and this solution added to the above catalyst mixture under a nitrogen atmosphere at room temperature. The resulting solution was stirred for several minutes at room temperature and then warmed to 80° C. for 15 hours. A sample was withdrawn and quenched into saturated aqueous ammonium chloride and was extracted with ethyl acetate. GC analysis of the organic phase showed the presence of 6-(4-methylphenyl)-1,2,3,4-tetrahydronaphthalene (0.363 mmol, 35% yield), bitoluene (0.216 mmol), and 6-methoxy-1,2,3,4-tetrahydronaphthalene (0.429 mmol) in the reaction mixture.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[O:27][CH2:26][CH2:25][OH:24])[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCCC(=O)C1
Reactant: OCCOc1ccccc1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#Cc3ccccc3OCCO)CCCC(=O)C2)cc1OC1CCCC1
Temperature: 80 °C
Yield: 13.9 %

Procedure:
To a solution of the compound from Example 3 (E1) (0.25 g, 0.8 mmol) and 2-hydroxyethoxy-1-iodobenzene (0.21 g, 0.8 mmol) in triethylamine (5 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palladium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C. for 1 h, was cooled to room temperature and was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, was dried (MgSO4) and was evaporated. Purification by flash chromatography, eluting with 1:1 hexanes/ethyl acetate, provided the title compound as a white solid (0.05 g, 14%), m.p. 93-94° C.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:26]([C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[CH:33]=2)=[O:30])=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([NH:18][CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[O:17])[CH:12]=2)[CH:6]=1.[OH-].[Na+].O.Cl>C1COCC1.CO>[F:1][C:2]1[CH:28]=[CH:27][C:26]([C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[CH:33]=2)=[O:30])=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([NH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:17])[CH:12]=2)[CH:6]=1
Reactant: COC(=O)CCNC(=O)c1c[nH]c(-c2cc(Oc3cc(C(=O)Nc4cccc(C)c4)ccc3F)ccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cccc(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)NCCC(=O)O)c[nH]4)c3)c2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of methyl 3-[({5-[4-(2-fluoro-5-{[(3-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]propanoate (80 mg, 0.16 mmol) in a mixture of THF/MeOH (5 ml/5 ml) was added 1M NaOH solution (1 ml, 1 mmol). The mixture was stirred at room temperature for 3 hours and poured into 50 ml of water. 1M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give 3-[({5-[4-(2-fluoro-5-{[(3-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]propanoic acid as white solid. Yield: 70 mg, 90%.
Reaction SMILES: C(O[CH2:5][C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH2:14][CH2:15][CH3:16])[CH:9]=[CH:8][N:7]=1)(=O)C.S(Cl)(Cl)=O.[SH:21][C:22]1[NH:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1.C[O-].[Na+]>C(Cl)(Cl)Cl.CO>[CH2:14]([O:13][C:10]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:5][S:21][C:22]2[NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]=2)[C:11]=1[CH3:12])[CH2:15][CH3:16]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CCCOc1ccnc(COC(C)=O)c1C
Agent: C[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: CO
Product: CCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Yield: 100.4 %

Procedure:
11.0 g of 2-acetoxymethyl-3-methyl-4-propoxy-pyridine was dissolved in chloroform, and 30 g (4 eq.) of thionyl chloride was added. The mixture was heated to reflux for one hour and then concentrated, and a residue resulting therefrom was dissolved in methanol. The solution was added in advance to 8.7 g (1 eq.) of 2-mercaptobenzimidazole, 73 mL of a 28% sodium methoxide solution, and 300 mL of methanol, and the mixture was heated to reflux for one hour. Methanol was distilled off, ice was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate. Subsequently, the ethyl acetate solution was concentrated to dryness, and the resulting residue was purified by silica gel column chromatography, and then was concentrated to dryness, to obtain 15.5 g of yellow crystals. The yellow crystals were recrystallized from ethyl acetate, to obtain 6.3 g of colorless crystals. Total yield 17% (purity by HPLC: 98.1%).
Reaction SMILES: [C:1]([C:4]([C:13]1[CH:24]=[CH:23][C:16]2[N:17]([CH3:22])[C:18](=[O:21])[N:19]([CH3:20])[C:15]=2[CH:14]=1)=[CH:5][C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1)(=O)[CH3:2].C1(C)C=CC(S([NH:34][NH2:35])(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH3:22][N:17]1[C:16]2[CH:23]=[CH:24][C:13]([C:4]3[C:1]([CH3:2])=[N:34][NH:35][C:5]=3[C:6]3[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=3)=[CH:14][C:15]=2[N:19]([CH3:20])[C:18]1=[O:21]
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: CC(=O)C(=Cc1cccc(C)c1)c1ccc2c(c1)n(C)c(=O)n2C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cccc(-c2[nH]nc(C)c2-c2ccc3c(c2)n(C)c(=O)n3C)c1
Temperature: 115 °C
Yield: 23.7 %

Procedure:
5-(1-Acetyl-2-m-tolyl-vinyl)-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (1.07 g) in acetic acid (5 mL) was treated with p-toluenesulfonhydrazide (0.685 g). The reaction mixture was heated to 115° C. for 5 hours. Additional p-toluenesulfonhydrazide (0.601 g) was added and the reaction was heated for an additional 4 hours. The mixture was then allowed to cool, was poured onto saturated sodium bicarbonate and extracted into ethyl acetate. Chromatography on silica gel afforded 1,3-Dimethyl-5-(3-methyl-5-m-tolyl-1H-pyrazol-4-yl)-1,3-dihydro-benzoimidazol-2-one (0.263 g).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1Cl)=[CH:16][CH:15]=[CH:14][C:13]=2[O:20][CH3:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[C:24]([CH3:29])=[CH:25][CH:26]=[CH:27][CH:28]=1>O1CCOCC1>[C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])=[CH:16][CH:15]=[CH:14][C:13]=2[O:20][CH3:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc2c(Cl)c(C(=O)c3ccccc3)cnc12
Reactant: Cc1ccccc1N
Solvent: C1COCCO1
Product: COc1cccc2c(Nc3ccccc3C)c(C(=O)c3ccccc3)cnc12

Procedure:
3-Benzoyl-4-chloro-8-methoxyquinoline (3.0 g, 0.01 mol) was heated under reflux in 1,4-dioxan (100 ml) with o-toluidine (5.0 ml) for 1 hour. The solvent was evaporated and the residue was dissolved in dichloromethane, and washed with dilute hydrochloric acid, sodium hydrogen carbonate solution, water and brine. The organic solution was dried and evaporated to an oil which was chromatographed (silic gel, 1% methanolic ammonia in dichloromethane). 3-Benzoyl-4-(2-methylphenylamino)-8-methoxyquinoline was isolated as crystals (0.95 g, 25.8%) from ether/hexane, m.p. 128-130.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[C:8]2[C:9]3[N:10]([N:13]=[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:15]=3C(OC)=O)[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5]1>S(=O)(=O)(O)O.O.C(=O)([O-])O.[Na+]>[C:20]1([C:14]2[CH:15]=[C:9]3[C:8]4[CH:4]([CH2:3][CH2:2][NH2:1])[CH2:5][CH2:6][C:7]=4[CH:12]=[CH:11][N:10]3[N:13]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1c(-c2ccccc2)nn2ccc3c(c12)C(CCN)CC3
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NCCC1CCc2ccn3nc(-c4ccccc4)cc3c21
Temperature: 100 °C
Reaction time: 72 h

Procedure:
Methyl 9-(2-aminoethyl)-2-phenyl-8,9-dihydro-7H-cyclopenta[c]pyrazolo[1,5-a]pyridine-1-carboxylate (295 mg, 0.881 mmol) was dissolved in 40% (v/v) sulfuric acid (6 mL), and the mixture was stirred at 100° C. for 3 days. The reaction solution was diluted with water and neutralized with sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound. The obtained title compound was used for the reaction of Example 34 without purification.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=O)[CH2:5]1)(=[O:3])[CH3:2].[CH3:14][C:15]1([CH3:23])[CH2:20][C:19](=[O:21])[CH2:18][C:17](=[O:22])[CH2:16]1.C(N(CC)CC)C>C(O)(=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:18]2[C:19](=[O:21])[CH2:20][C:15]([CH3:23])([CH3:14])[CH2:16][C:17]2=[O:22])=[CH:5]1)(=[O:3])[CH3:2]
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: CC(=O)N1CC(=O)c2ccccc21
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(=O)n1cc(C2C(=O)CC(C)(C)CC2=O)c2ccccc21
Yield: 76 %

Procedure:
1-Acetyl-1,2-dihydroindol-3-one of Example 1d (131.3 g, 0.75 mol) and 5,5-dimethyl-cyclohexane-1,3-dione (105 g, 0.75 mol) were added to a mixture of acetic acid (700 mL) and triethylamine (105 mL, 0.75 mol) at room temperature under stirring. The reaction mixture was refluxed for 6 h. About ⅓ volume of solvents was removed in vacuum, and the mixture was cooled and diluted with water (50 mL). The precipitate was filtered off, washed with ethanol-water, 1:1 and dried to afford 169.4 g (76%) of colorless crystals; m.p. 225-227° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[CH:26])[CH2:20][CH2:19][C:18]4([O:24][CH2:23][CH2:22][O:21]4)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][O:28][C:29](=[O:39])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35](I)=[CH:34][CH:33]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:29]([CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:26]#[C:25][C:15]2([C:9]3[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:8]=3)[CH2:20][CH2:19][C:18]3([O:21][CH2:22][CH2:23][O:24]3)[CH2:17][CH2:16]2)=[CH:34][CH:33]=1)([O:28][CH3:27])=[O:39]
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC2(CC1)OCCO2
Reactant: COC(=O)COc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(C#CC2(c3ccc(OC)c(OC4CCCC4)c3)CCC3(CC2)OCCO3)cc1
Yield: 73.2 %

Procedure:
A stirred mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-ethynylcyclohexane (0.075 g, 0.21 mmol) and 4-iodophenoxyacetic acid methyl ester (0.060 g, 0.21 mmol, prepared as described in Example 35a) in dry triethylamine (2 mL) was treated at 80° C. for 1.5 hr by the procedure of Example 11 with a mixture of tetrakis(triphenylphosphine)palladium (0.018 g, 0.016 mmol), cuprous iodide (0.004 g, 0.021 mmol), and triphenylphosphine (crystal). The crude product was chromatographed (silica 40 to 50% ethyl acetate in hexanes) and stripped in vacuo to afford the tided intermediate as a dark red oil (0.080 g, 73%). 1H-NMR (400 MHz, CDCl3) δ 7.98 (d, 9.4 Hz, 2H), 7.50 (d, J=9.4 Hz, 2H), 7.20 (d, J=1.9 Hz, 1H), 7.12 (d-d, J=1.9 Hz, J=8.6 Hz, 1H), 6.84 (d, J=8.6, 1H), 4.80 (p, J=3.8 Hz, 1H), 4.00 (s, br, 4H), 3.92 (s, 3H), 3.85 (s, 3H), 2.3 to 1.5 (m, 17H with H2O).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12](CC2C=CC=CC=2)[CH2:11][CH2:10][N:9]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCO.[Pd]>[CH2:1]([C@H:8]1[CH2:13][NH:12][CH2:11][CH2:10][N:9]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)(c1ccc(N2CCN(Cc3ccccc3)C[C@@H]2Cc2ccccc2)cc1)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: CC(O)(c1ccc(N2CCNC[C@@H]2Cc2ccccc2)cc1)C(F)(F)F
Yield: 73.8 %

Procedure:
In a 100 mL round bottomed flask a mixture of 2-(4-((2S)-2,4-dibenzyl-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (355 mg, 0.781 mmol) and 10% Pd/C (83 mg) in EtOH (20 mL) was placed under a hydrogen atmosphere (1 atm) 16 h. The mixture was filtered through a pad of Celite® (diatomaceous earth) and then concentrated onto silica gel and purified via column chromatography (40 g, 0 to 10% MeOH in CH2Cl2) to give 2-(4-((2S)-2-benzyl-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (0.210 g).