Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH3:10])[N:7]([C:11]3[N:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=3)[C:6]=2[CH:18]=1.[C:19]([Si:21]([CH3:24])([CH3:23])[CH3:22])#[CH:20]>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.C(N(CC)CC)C>[CH3:10][C:8]1[N:7]([C:11]2[N:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)[C:6]2[CH:18]=[C:2]([C:20]#[C:19][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=[CH:4][C:5]=2[N:9]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1nc2ccc(Br)cc2n1-c1ncnc(N)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Cc1nc2ccc(C#C[Si](C)(C)C)cc2n1-c1ncnc(N)n1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 4-(6-bromo-2-methyl-1,3-benzodiazol-1-yl)-1,3,5-triazin-2-amine (250 mg, 0.74 mmol), tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.06 mmol), copper(I) iodide (11 mg, 0.06 mmol) and ethynyl(trimethyl)silane 0.230 ml, 1.51 mmol) was added triethylamine (2.6 mL). The mixture was purged with nitrogen for 2 minutes and was stirred at 80° C. for 15 min in the microwave. LC-MS shows 50% conversion. The mixture was retreated with another equivalent of tetrakis(triphenylphosphine)palladium (70 mg) copper(I) iodide (11 mg) and ethynyl(trimethyl)silane (0.230 ml). Heating in the microwave at 90° C. was continued for another
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][C:8]([CH2:18][N:19]([CH3:31])[C:20]([NH:22][C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)=[O:21])([C:11]3[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[C:32]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)#[N:33].C([O-])([O-])=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1.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.O>[C:32]([C:34]1[CH:39]=[C:38]([C:14]2[CH:15]=[CH:16][C:11]([C:8]3([CH2:18][N:19]([CH3:31])[C:20]([NH:22][C:23]4[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=4)=[O:21])[CH2:9][CH2:10][N:5]([CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[CH:12][CH:13]=2)[CH:37]=[CH:36][CH:35]=1)#[N:33]
Reactant: CN(CC1(c2ccc(I)cc2)CCN(CC2CC2)CC1)C(=O)Nc1cc(Cl)cc(Cl)c1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CN(CC1(c2ccc(-c3cccc(C#N)c3)cc2)CCN(CC2CC2)CC1)C(=O)Nc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Yield: 59 %

Procedure:
To a flask containing 1-[1-cyclopropylmethyl-4-(4-iodo-phenyl)-piperidin-4-ylmethyl]-3-(3,5-dichloro-phenyl)-1-methyl-urea (0.094 g, 0.164 mmol) was added Pd(PPh3)4 (0.02 g, 0.017 mmol, 10 mol %), 3-cyanophenylboronic acid (0.037 g, 0.25 mmol, 1.5 eq.) and Na2CO3 (0.212 g, 2 mmol). The mixture was suspended in toluene (3 mL), EtOH (1.5 mL) and H2O (1 mL) and heated to 80° C. for 18 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc (5 mL) and saturated Na2CO3 (5 mL). The organic layer was washed with saturated Na2CO3 (3×5 mL), saturated brine (3×5 mL), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to give a brown solid which was purified by HPLC to give the title compound 1-[4-(3′-cyano-biphenyl-4-yl)-1-cyclopropylmethyl-piperidin-4-yl methyl]-3-(3,5-dichloro-phenyl)-1-methyl-urea (0.053 g, 60%). 1H NMR (300 MHz, CDCl3): δ 7.95 (s, 1H), 7.92 (d, 1H), 7.79-7.66 (m, 4H), 7.57 (d, 2H), 7.41 (s, 2H), 7.33 (br.s, 1H), 7.06 (s, 1H), 3.76 (m, 2H), 3.63 (s, 1H), 3.60 (s, 2H), 3.08 (s, 3H), 2.87 (br.m, 2H), 2.69 (m, 5H), 1.14 (br.m, 1H), 0.84 (d, 2H), 0.44 (d, 2H)
Reaction SMILES: O[CH:2]=[C:3]1[C:15]2[N:14]3[CH:16]=[CH:17][N:18]=[C:13]3[C:12](=[O:19])[NH:11][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2.CN(C)C=O>[Pd].CO>[CH3:2][CH:3]1[C:15]2[N:14]3[CH:16]=[CH:17][N:18]=[C:13]3[C:12](=[O:19])[NH:11][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2
Reactant: O=c1[nH]c2c3ccccc3c(=CO)c2n2ccnc12
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: CC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Yield: 37.1 %

Procedure:
A mixture of 1 g of 10-hydroxymethylene-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 80 ml of dimethylformamide and 20 ml of methanol is hydrogenated at a temperature in the region of 20° C. and at normal pressure for 4 hours in the presence of 10% palladium on charcoal. After filtration of the catalyst under inert atmosphere, the solvents are evaporated off and the beige solid obtained (1.25 g) is purified by chromatography on a column of silica (100 g) with a mixture of dichloromethane and methanol (95/5 by volume). After drying at 90° C., 0.35 g of 10-methyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is obtained, in the form of a cream-coloured solid melting above 260° C. (Analysis % calculated C: 70.87, H: 4.67, N: 17.71, O: 6.74, % found C: 70.5, H: 4.4, N: 17.4).
Reaction SMILES: [Cl:1][C:2]([CH2:4]Cl)=[CH2:3].[C:6]1(=[O:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C1(C)C=CC=CC=1>[Zn].O>[Cl:1][C:2](=[CH2:3])[CH2:4][C:6]1([OH:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C1CCCCC1
Reactant: C=C(Cl)CCl
Agent: [Zn]
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(Cl)CC1(O)CCCCC1

Procedure:
45.23 Grams of 2,3-dichloro-1-propene were added dropwise to a mixture of 20.00 g of cyclohexanone, 60 g of toluene, 60 g of water and 26.65 g of zinc powder at 35° C., and after the addition, the resultant mixture was maintained at the same temperature for 5 hours. After the reaction was completed, zinc-derived insolubles were filtered off, and the resultant filtrate was separated. The organic phase thereof was washed with a 7% sodium carbonate aqueous solution, and dried over magnesium sulfate. The desiccant was filtered off, and the resultant toluene solution was concentrated under reduced pressure to give 32.75 g of 1-(2'-chloroallyl)-1-cyclohexanol; nD20 =1.495, EI-MS m/e 156 (M-H2O+), 158 (M-H2O+2+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH:8](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:9].[CH3:23][N:24]1[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][C:27](=[O:34])[N:26]([C:35]2[CH:40]=[C:39]([NH2:41])[C:38]([Cl:42])=[CH:37][C:36]=2[F:43])[C:25]1=[O:44].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH:8]([NH:41][C:39]1[CH:40]=[C:35]([N:26]2[C:27](=[O:34])[CH:28]=[C:29]([C:30]([F:32])([F:33])[F:31])[N:24]([CH3:23])[C:25]2=[O:44])[C:36]([F:43])=[CH:37][C:38]=1[Cl:42])[CH3:9]
Reactant: COC(=O)CCNC(=O)C(C)OS(=O)(=O)c1ccc(C)cc1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)CCNC(=O)C(C)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 38.7 %

Procedure:
3-[2-(Toluene-4-sulfonyloxy)-propionylamino]propionic acid methyl ester (307 mg) was dissolved in acetonitrile (5 mL). After addition of 1-methyl-3-(5-amino-4-chloro-2-fluorophenyl)-6-trifluoromethyl-1H-pyrimidin-2,4-dione (300 mg) and potassium carbonate (135 mg), the reaction mixture was heated for 6 hours under reflux without cooling. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). Thus obtained organic layer was dried with magnesium sulfate and concentrated. The concentrate was purified by silica gel column chromatography to give the target compound (170 mg).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[O:16][C:15]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])=[N:14][C:13]=2[CH2:23][CH2:24][CH2:25][CH2:26][OH:27])=[CH:4][CH:3]=1.[CH3:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[O:16][C:15]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])=[N:14][C:13]=2[CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[CH3:28])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1O
Reactant: Cc1nccn1-c1nc(CCCCO)c(-c2ccc(F)c3ccccc23)o1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccccc1OCCCCc1nc(-n2ccnc2C)oc1-c1ccc(F)c2ccccc12
Reaction time: 1 h

Procedure:
To a mixture of 5-(4-fluoro-1-naphthyl)-2-(2-methyl-1-imidazolyl)-4-oxazolebutanol (180 mg), 2-methylphenol (108 mg), tributylphosphine (202 mg) and tetrahydrofuran (5 ml) was added 1,1′-(azodicarbonyl)dipiperidine (252 mg) at room temperature, and the resulting mixture was stirred for 1 hour. After the reaction mixture was concentrated, the residue was subjected to silica gel column chromatography, and 5-(4-fluoro-1-naphthyl)-2-(2-methyl-1-imidazolyl)-4-[4-(2-methylphenoxy)butyl]oxazole was obtained as an oil (180 mg, 80%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][N:15]=2)[N:10]=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18]>>[Cl:3][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][N:15]=2)[N:10]=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cnc2cccnc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnc2cccnc2c1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.9 %

Procedure:
Phosphorus oxychloride (38 mL, 408 mmol) was added dropwise over a period of 70 minutes to a stirred suspension of 4-hydroxy-3-nitro[1,5]naphthyridine (60 g, 313.9 mmol). The orange suspension was stirred at ambient temperature for 5 hours and then poured into ice water (1.9 L) and stirred for 30 minutes. The solid was isolated by filtration, washed with water (3×200 mL), and then dissolved in dichloromethane (1.2 L). The solution was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 61.1 g of 4-chloro-3-nitro[1,5]naphthyridine as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Cl:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+](=[CH2:17])=[N-]>CO>[CH3:17][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Cl:14])[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[NH2:1]
Reactant: C=[N+]=[N-]
Reactant: Nc1c(C(=O)O)cc(Cl)cc1[N+](=O)[O-]
Solvent: CO
Product: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1N

Procedure:
To a solution of 2-amino-5-chloro-3-nitro-benzoic acid (2 g, 1.0 mmol) in methanol (100 mL) was added a saturated ethereal solution of diazomethane gas (50 mL) till all the starting material was consumed. The reaction mixture was concentrated to dryness and the residue obtained was purified by column chromatography using 5% ethyl acetate in hexane as an eluent to obtain the title compound as yellow solid which was directly used for the next step (1.8 g, 84.11%).
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:18]([NH:19][CH:20]=O)=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C(Cl)(Cl)Cl>[CH2:1]([S:8][C:9]1[C:18]([NH:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(NC=O)c1SCc1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CNc1cccc(C(=O)OC)c1SCc1ccccc1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 93.1 %

Procedure:
20 ml of borane/dimethyl sulfide complex (BMS) are added dropwise to a solution of 61.5 g of methyl 2-benzylmercapto-3-formylaminobenzoate (cf. Example d)) in 100 ml of CHCl3 at 0° C. The mixture is subsequently heated at 60° C. for 2 h, a further 20 ml of BMS are added, and the mixture is stirred at this temperature for a further 2.5 h. Then 30 ml of MeOH are added dropwise at 0° C. The mixture is transferred to a separating funnel, washed with water and brine and then dried over MgSO4. Volatile components are removed by distillation to give 54.60 g of methyl 2-benzylmercapto-3-methylaminobenzoate in the form of a yellowish oil. 1H NMR (CDCl3, 80 MHz): δ:2.6 (d, 3H, NH-CH3), 3.8 (s, 3H, OCH3), 3.9 (s, 2H, SCH2Ph), 5.2 (s, broad, 1H, NH-Me), 6.5 (d, 1H, Harom.), 6.8 (d, 1H, Harom.), 7.0-7.4 (m, 6H, Harom.).
Reaction SMILES: [CH:1]12[O:10][CH:7]([CH2:8][CH2:9]1)[CH:6]1[CH:2]2[C:3](=[O:12])[CH2:4][C:5]1=[O:11].[CH3:13]O>[Na+].Cl[Au-](Cl)(Cl)Cl>[CH3:13][O:12][C:3]1[CH:2]2[CH:6]([CH:7]3[O:10][CH:1]2[CH2:9][CH2:8]3)[C:5](=[O:11])[CH:4]=1
Reactant: CO
Reactant: O=C1CC(=O)C2C3CCC(O3)C12
Agent: Cl[Au-](Cl)(Cl)Cl
Agent: [Na+]
Product: COC1=CC(=O)C2C3CCC(O3)C12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a suspension of 10-oxa-tricyclo[5.2.1.0*2,6*]decane-3,5-dione (9.97 g, 60 mmol) in methanol (200 ml) is added sodium tetrachloroaurate (597 mg, 1.5 mmol) and the reaction mixture is heated to 60° C. for 7 hours. The reaction mixture is allowed to cool down to room temperature and left to stand overnight. The reaction mixture is concentrated under reduced pressure, dissolved in ethyl acetate (200 ml) and washed with aqueous 2N sodium carbonate (100 ml), followed by saturated brine (100 ml). The organic layer is then dried over magnesium sulphate and concentrated under reduced pressure to give 5-methoxy-10-oxa-tricyclo[5.2.1.0*2,6*]dec-4-en-3-one (8.62 g)
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:30])[C:8]4[CH:20]=[C:19]([O:21][CH2:22][C@H:23]5[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24]5)[CH:18]=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:33]C(N(C)C)=O.CI>O>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:30])[C:8]4[CH:20]=[C:19]([O:21][CH2:22][C@H:23]5[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24]5)[CH:18]=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[N:12]2[CH3:33])=[CH:4][CH:3]=1
Reactant: CC1(C)OC[C@H](COc2ccc3c(c2)C(=O)c2c([nH]c4cc(Br)ccc24)C3(C)C)O1
Reactant: CC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cn1c2c(c3ccc(Br)cc31)C(=O)c1cc(OC[C@H]3COC(C)(C)O3)ccc1C2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To the mixture of 3-bromo-9-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound JJ3-1, 33.2 mg, 0.0706 mmol) and sodium hydride (60% in oil, 6.4 mg, 2.3 eq.), DMA (0.55 mL) and methyl iodide (0.015 mL, 3.4 eq.) were added under nitrogen atmosphere at 0° C., and the mixture was stirred at room temperature overnight. The reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After filtration and the concentration under reduced pressure, the resulting solid was washed with MTBE to obtain the title compound (white solid, 31.2 mg, 91%).
Reaction SMILES: [CH3:1][N:2]([CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[NH:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[C:21]1([C:27]2[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][CH2:35]Br)[CH2:31][CH:32]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39]>CN(C)C=O.C(Cl)Cl.C(C(C)=O)C>[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39].[CH3:1][N:2]([CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]1[CH2:35][CH2:34][CH2:33][N:30]1[CH2:29][CH:28]=[C:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:32][CH2:31]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: BrCCCN1CC=C(c2ccccc2)CC1
Reactant: CN(c1ccccc1)C1NC(=O)c2ccccc21
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Solvent: ClCCl
Product: CN(c1ccccc1)C1c2ccccc2C(=O)N1CCCN1CC=C(c2ccccc2)CC1
Reaction time: 1 h
Yield: 83.8 %

Procedure:
A solution of 3-(N-methyl-N-phenylamino)-1-isoindolinone (10 g) in anhydrous dimethylformamide (200 cc) is added to a suspension of sodium hydride (as a 50% suspension in oil) (2.2 g) in anhydrous dimethylformamide (200 cc) at a temperature close to 20° C. in the course of 30 minutes and agitation is continued for 1 hour. Then, a solution of 3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)-1-bromopropane (13 g) in dimethylformamide (100 cc) is added in the course of 15 minutes, and agitation is continued for a further 20 hours. The solution obtained is evaporated to dryness under reduced pressure (1 mm Hg; 0.1 kPa). The residue obtained is dissolved in methylene chloride (200 cc) and washed with distilled water (3×50 cc). The organic extracts are dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7.kPa) at 40° C. The residue obtained is dissolved in methylene chloride (40 cc) then poured onto silica (800 g) contained in a column of 8 cm diameter. Elution is carried out with a mixture of methylene chloride and methanol (95-5 by volume). The first 2300 cc are eliminated and the next 1100 cc are concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa). The residue obtained is dissolved in methyl ethyl ketone (50 cc). A solution of oxalic acid (1.1 g) in methyl ethyl ketone (15 cc) is added, and agitation continued for 1 hour at a temperature close to 20° C. The precipitate formed is separated by filtration. 5.4 g of 3-(N-methyl-N-phenylamino)-2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone oxalate are obtained, melting at 159° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[Cl:20])[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.Br[C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[C:24]([O:31][CH3:32])[CH:23]=1.[CH3:33][PH:34](=[O:36])[CH3:35]>>[Cl:20][C:13]1[C:14]([F:19])=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[CH:10]([O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:25]2[CH:26]=[CH:27][C:22]([P:34]([CH3:35])([CH3:33])=[O:36])=[CH:23][C:24]=2[O:31][CH3:32])[CH:3]=1)[CH3:11]
Reactant: COc1cc(Br)ccc1B(O)O
Reactant: C[PH](C)=O
Reactant: CC(Oc1cc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Product: COc1cc(P(C)(C)=O)ccc1-c1cnc(N)c(OC(C)c2c(Cl)ccc(F)c2Cl)c1

Procedure:
The title compound was prepared from 5-bromo-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine, 4-bromo-2-methoxyphenylboronic acid, and dimethylphosphine oxide following the same procedures as Example 1 Step 1 and Step 3; ESMS: m/z 483 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH2:17])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].B1C2CCCC1CCC2.[OH-:27].[Na+].OO>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:27])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: [OH-]
Reactant: C=Cc1ccc(Oc2ccc(C)c(F)c2)cc1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccc(CCO)cc2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.1 %

Procedure:
To the solution of 4-ethenylphenyl 3-fluoro-4-methylphenyl ether (900 mg, 3.94 mmol) in dry THF (30 mL), was added 9-BBN (9.46 mL, 4.73 mmol) at 0° C. The mixture was stirred at room temperature overnight, and quenched with water (1.2 mL), followed by aq. NaOH (5.26 mL, 15.77 mmol), and 30% H2O2 (4.03 mL, 39.4 mmol). The reaction mixture was heated at 50° C. for 2 h. Then THF was removed under reduced pressure, and the residue was diluted with DCM. The organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated and purified by flash chromatography to afford the title compound (1.02 g, 4.14 mmol, 105% yield) as a yellow oil. LCMS: rt=3.29 min, [M+H+]=229
Reaction SMILES: CI.[Br:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[CH:12]1[C:21]2[C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:16]=2[N:15]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:14](=[O:33])[NH:13]1)[C:7]#[N:8].[C:34](=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[CH:12]1[C:21]2[C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:16]=2[N:15]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:32])[F:30])[CH:24]=2)[C:14](=[O:33])[N:13]1[CH3:34])[C:7]#[N:8]
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CCC3)c(Br)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1Br
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methyliodide (3.55 mL, 57.1 mmol) is added to a mixture of 3-bromo-4-[2,5-dioxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4,5,6,7,8-octahydro-quinazolin-4-yl]-benzonitrile (INTERMEDIATE 22, 14.0 g, 28.6 mmol) and cesium carbonate (18.6 g, 57.1 mmol) in DMF (140 mL). The mixture is stirred at room temperature for 90 min. Ethyl acetate is added and the organic phase is washed with water three times, dried over MgSO4 and concentrated. The crude product is purified by flash chromatography on silica (cyclohexane/ethyl acetate 30:70). Yield: 13.4 g. ESI mass spectrum: [M+H]+=504 (bromine isotope pattern); Retention time HPLC: 0.70 min (X012_S02).
Reaction SMILES: [CH3:1][C:2]([CH:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]=[CH:6][CH:5]1[CH3:12])=[O:3].CC(C)([O-])C.[Na+].C1CCCCCCCCCCC1.[CH3:31][C:32]([C@@H:34]1[C:39]([CH3:41])([CH3:40])[CH2:38][CH:37]=[CH:36][C@H:35]1[CH3:42])=[O:33]>CS(C)=O>[CH3:1][C:2]([CH:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH2:7][CH:6]=[C:5]1[CH3:12])=[O:3].[CH3:31][C:32]([C:34]1[C:39]([CH3:41])([CH3:40])[CH2:38][CH2:37][CH2:36][C:35]=1[CH3:42])=[O:33]
Reactant: CC(=O)[C@H]1[C@H](C)C=CCC1(C)C
Reactant: CC(=O)C1C(C)C=CCC1(C)C
Agent: C1CCCCCCCCCCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)C1=C(C)CCCC1(C)C
Product: CC(=O)C1C(C)=CCCC1(C)C

Procedure:
In a 100-ml four-necked flask equipped with a thermometer, a condenser and a stirrer, placed were 2,6,6-trimethyl-3-cyclohexenyl methyl ketone (10 g) synthesized in Referential Example 1, sodium t-butoxide (2.5 g), dimethyl sulfoxide (30 ml) and, as an internal standard substance for the analysis by gas chromatography, cyclododecane (3 g). They were reacted at 120° C. for 4 hours. The reaction mixture was treated in an usual manner. Analysis by gas chromatography showed that the content of trans-2,6,6-trimethyl-3-cyclohexenyl methyl ketone was 52.3%, while those of 2,6,6-trimethyl-2-cyclohexenyl methyl ketone and 2,6,6-trimethyl-1-cyclohexenyl methyl ketone produced by the above reaction were 32.9% and 14.8%, respectively. As a result of calculation, the yield of a mixture of these three methyl ketones was found to be 9.1 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][N:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][C:15]4[O:16][C:17]([C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=5)=[N:18][N:19]=4)=[CH:6][CH:7]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1Cc1nnc(-c2ccccc2)o1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Cc4nnc(-c5ccccc5)o4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 4, using 2-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-5-phenyl-[1,3,4]oxadiazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.