Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:10][C@@H:9]1[CH2:28][N:29]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:30])=O)(C)(C)C.[ClH:38]>O1CCOCC1>[ClH:38].[ClH:38].[CH2:31]([N:29]([CH3:30])[CH2:28][C@H:9]1[CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:12][CH2:13][NH:8]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COc1ccc(N2CCN(C(=O)OC(C)(C)C)[C@@H](CN(C)Cc3ccccc3)C2)cc1OC1CCCC1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(N2CCN[C@@H](CN(C)Cc3ccccc3)C2)cc1OC1CCCC1
Reaction time: 6 h

Procedure:
The intermediate (S)-2-[(Benzyl-methyl-amino)-methyl]-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (300 mg, 0.65 mmol) was then dissolved in 1,4-dioxane (2 mL) and treated with a 4 N solution of hydrogen chloride in 1,4-dioxane (4 mL) and stirred for 6 h. The reaction was then evaporated to afford the title compound as a colorless solid. (180 mg, 99%). LC/MS (Method B) 2.32 min, [M+1]+ 410.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][CH:12]=[CH2:13])=[CH:7][C:8]=1[O:9][CH3:10].CO[CH:16]([O:21][CH3:22])[C:17](=[CH2:20])[C:18]#[N:19].C(Cl)Cl>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:17]([C:18]#[N:19])=[CH:16][O:21][CH3:22])[C:6]([CH2:11][CH:12]=[CH2:13])=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C=C(C#N)C(OC)OC
Reactant: C=CCc1ccc(OC)c(OC)c1
Solvent: CCOCC
Solvent: ClCCl
Product: C=CCc1cc(OC)c(OC)cc1CC(C#N)=COC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 10 g. of methyl eugenol and 8.1 g. of 2-dimethoxymethylacrylonitrile in 200 ml. of dry methylene chloride was added 1.97 ml. of stannic chloride. After stirring for 5 hours at room temperature, 300 ml. of ether was added and the mixture washed with a 5% sodium bicarbonate solution (until basic). The organic layer was dried (MgSO4) and the solvent removed under reduced pressure. The residue was triturated with ether to give 1,2-dimethoxy-4-(2-propenyl)-5-(2-cyano-3-methoxy-2-propenyl)benzene, m.p. 77°-79°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:19]=[C:18]([F:20])[C:7]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=2)=[C:6]([F:21])[CH:5]=1.[BH4-].[Na+]>CO>[F:21][C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][CH2:2][CH2:3][CH:4]([CH3:19])[CH3:5])[CH:19]=[C:18]([F:20])[C:7]=1[O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=1
Reactant: NCCc1cc(F)c(Oc2ccc(C(N)=O)cn2)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCNCCc1cc(F)c(Oc2ccc(C(N)=O)cn2)c(F)c1
Yield: 96.3 %

Procedure:
Combine 3-methyl-butylaldehyde (26 μl, 0.24 mmol) amine from step 6 above and 3 A molecular sieves (900 mg) in methanol (3 mL), stir the mixture at room temperature overnight. Add NaBH4 (45 mg, 1.20 mmol) and stir at room temperature for 3 hours. Filtrate the mixture over celite and eliminate the solvent. Submit the crude to a SCX column to obtain a solid which was further purified by HPLC (Column: X-Terra MS C18. A=10 Mm NH4HCO3 pHB8/B=CH3CN. Gradient mode: from 30 to 70% B. Flow rate: 1 mL/min) to obtain the title compound (42 mg). Electrospray MS M+1 ion=364. 1H-NMR (metanol-d4, 300 MHz): 8.60 (d, 1H, J=2.0 Hz), 8.32 (dd, 1H, J=2.2 and 8.5 Hz), 7.19 (d, 1H, J=8.7 Hz), 7.01-6.98 (m, 2H), 2.85 (m, 4H), 2.63 (m, 2H), 1.62 (m, 1H), 1.42 (q, 1H, J=7.3 Hz), 0.92 (d, 6H, J=6.5 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH:7]=O)[NH:4][N:3]=1.S([O-])(O)=O.[Na+].O.[CH3:15][C:16]1([CH3:29])[C:25]2[C:20](=[CH:21][C:22]([NH2:27])=[C:23]([NH2:26])[CH:24]=2)[NH:19][C:18](=[O:28])[CH2:17]1>C(O)C>[CH3:15][C:16]1([CH3:29])[C:25]2[CH:24]=[C:23]3[NH:26][C:7]([C:5]4[NH:4][N:3]=[C:2]([CH3:1])[CH:6]=4)=[N:27][C:22]3=[CH:21][C:20]=2[NH:19][C:18](=[O:28])[CH2:17]1
Reactant: Cc1cc(C=O)[nH]n1
Reactant: CC1(C)CC(=O)Nc2cc(N)c(N)cc21
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(-c2nc3cc4c(cc3[nH]2)C(C)(C)CC(=O)N4)[nH]n1

Procedure:
1.5 g. (13.6 mmole) 3-methyl-1H-pyrazole-5-aldehyde was stirred with 4.5 g. sodium hydrogen sulphite in 9 ml. water for 3 hours at 60° C. The evaporation residue was stirred with 2.79 g. (13.6 mmole) 4,4-dimethyl-6,7-diamino-1,2,3,4-tetrahydroquinolin-2-one and 40 ml. ethanol for 3 hours at 60° C. while passing through air. Half of the ethanol was distilled off, water was added and the residue was filtered off with suction and recrystallized from ethyl acetate/methanol to give 3.3 g. (82.5% of theory) of the title compound; m.p. 242°-245° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][C:18]([N+:28]([O-:30])=[O:29])=[C:19]([O:24][CH:25]([CH3:27])[CH3:26])[CH:20]=3)[C:15]2=[O:31])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:25]([O:24][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[N+:28]([O-:30])=[O:29])[C:15](=[O:31])[N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:22]2=[O:23])([CH3:27])[CH3:26]
Reactant: CC(C)Oc1cc2c(cc1[N+](=O)[O-])C(=O)N(C1CCN(C(=O)OC(C)(C)C)CC1)C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1cc2c(cc1[N+](=O)[O-])C(=O)N(C1CCNCC1)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(5-isopropoxy-6-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester generated in the previous step in 3 mL of DCM is added TFA (3 mL). The reaction mixture is stirred at room temperature for 1 h. After concentration, water (5 mL) is added to the crude reaction mixture, the resulting mixture is neutralized to pH=8 by adding NaHCO3, and the product is extracted with DCM. The organic extracts are dried over Na2SO4, filtered and concentrated in vacuo to give crude 5-isopropoxy-6-nitro-2-piperidin-4-yl-isoindole-1,3-dione, which is directly used in the next step without further purification.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O-:19])=[O:18])=[C:15]([OH:20])[C:14]([C:21]3[CH:25]=[CH:24][O:23][CH:22]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:27][C:28]#[N:29]>>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][C:11]([CH3:16])([CH3:12])[CH3:10])=[O:18])=[C:15]([O:20][CH2:27][C:28]#[N:29])[C:14]([C:21]3[CH:25]=[CH:24][O:23][CH:22]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCBr
Reactant: O=C([O-])c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Product: CC(C)(C)OC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCC#N

Procedure:
6-(benzenesulphonylmethyl)-3-(furan-3-yl)-2-hydroxybenzoate (Intermediate 120) and bromoacetonitrile.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:17])=[C:9]2[C:18](=O)[CH3:19])[CH:5]=[CH:6][CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+]>CO.C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:17])=[C:9]2[CH:18]([NH2:27])[CH3:19])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1c(C)c2ccccc2n1-c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: Cc1c(C(C)N)n(-c2cccc(F)c2)c2ccccc12
Temperature: 65 °C
Yield: 96.6 %

Procedure:
A mixture of 1-[1-(3-fluorophenyl)-3-methyl-1H-indol-2-yl]ethanone (0.165 g, 0.617 mmol) and ammonium acetate (0.476 g, 6.17 mmol) in methanol (2.0 mL) and acetonitrile (2.0 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, sodium cyanoborohydride (0.12 g, 1.9 mmol) was added to the resultant mixture. The reaction was heated at 65° C. over the weekend. The reaction was cooled to room temperature and quenched with saturated NaHCO3 solution and then extracted with dichloromethane, dried over MgSO4 and concentrated to give the crude amine (0.16 g), which was used directly in next step. LCMS calculated for C17H18FN2(M+H)+: m/z=269.1. Found: 252.1.
Reaction SMILES: BrC1C=CC(S(N2CCC2)(=O)=O)=CC=1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.[F:26][C:27]1[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][C:28]=1[NH2:29]>ClCCl.C([O-])([O-])=O.[K+].[K+]>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:29][C:28]2[CH:30]=[CH:31][C:32]([CH3:34])=[CH:33][C:27]=2[F:26])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(N)c(F)c1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(c1ccc(Br)cc1)N1CCC1
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc(NS(=O)(=O)c2ccc(Br)cc2)c(F)c1

Procedure:
The title compound is analogously synthesized as described for 1-(4-bromo-benzenesulfonyl)-azetidine (compound C3) from 767 mg of 4-bromo-benzenesulfonyl chloride, 451 mg of commercially available 2-fluoro-4-methyl-aniline in 12.0 ml of dichloromethane and 6.0 ml of K2CO3 solution to yield 727 mg of the title compound as colorless, amorphous solid of m.p. 111° C. ESI-MS: 361.2/363.3 (MNH4+, 100%:87%). TLC: Rf=0.57 (neat dichloromethane).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+].C(O)C.CN(C)C=O>[Fe].O>[C:15]1([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:22][CH:21]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccncc2-c2ccccc2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1ccc(Oc2ccncc2-c2ccccc2)cc1
Yield: 62.4 %

Procedure:
4-(4-Nitrophenoxy)-3-phenylpyridine (150 mg), iron powder (300 mg), ammonium chloride (600 mg), ethanol (5 ml), dimethylformamide (5 ml) and water (2.5 ml) were stirred at 100° C. for 15 minutes. The mixture was filtered with celite, water was added to the filtrate, and extraction was performed with ethyl acetate. The organic layer was washed 5 times with water, and then the solvent was distilled off under reduced pressure to obtain 4-(3-phenylpyridin-4-yl)oxyaniline (84 mg) as a yellow oil.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[N:9][CH:8]=[CH:7]2.C(OCC)(=O)C>C(Cl)(Cl)Cl>[Br:1][C:5]1[C:4]([OH:3])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][N:9]=[CH:10]2
Reactant: Oc1ccc2cnccc2c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Oc1ccc2cnccc2c1Br
Yield: 88.4 %

Procedure:
7.9 mL (19.18 g, 120 mmol) of bromine were added dropwise to a suspension of 17.42 g (120 mmol) of compound 7 in 250 mL of chloroform at room temperature. After stirring for 2 h ethyl acetate was added. The precipitate was filtered, washed with ethyl acetate and dried. Aqueous NaHCO3 solution was added carefully. The precipitate was filtered and washed with NaHCO3 solution until the filtrate had a pH of 8. Drying gave 23.78 g (88%) of compound 9 as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-])=O)[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl-].[NH4+].C(O)C>[Fe].O>[Br:1][C:2]1[CH:3]=[C:4]([NH2:12])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1cc(Br)c2ncccc2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cc(Br)c2ncccc2c1
Yield: 47.6 %

Procedure:
To a flask containing 8-bromo-6-nitroquinoline (2.05 g, 8.1 mmol), electrolytic iron (2.26 g, 40.5 mmol) and ammonium chloride (2.25 g, 42.1 mmol) was added ethanol (20 ml) and water (10 ml). The flask was fitted with an efficient reflux condenser and then heated to near reflux (oil bath) for 3 hours. The hot material was then filtered through a plug of celite and rinsed well with hot methanol (100 ml). The solvent was removed. The residue was taken up in ethyl acetate (60 ml) and water (60 ml) and transferred to a separatory funnel, agitated and the organic phase collected. The organic phase was washed with an equal volume of brine. The aqueous phases were back extracted with ethyl acetate (2×50 ml). The combined ethyl acetate extracts were dried over MgSO4, and concentrated in vacuo. The resulting residue was crystallized from hot dichloromethane/hexanes to provide the desired product as a brown powder (860 mg).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([S:25][C:26]1[C:34]([N:35]([CH3:37])[CH3:36])=[CH:33][C:29]3[O:30][CH2:31][O:32][C:28]=3[CH:27]=1)[N:6]2[CH2:11][CH2:12][CH2:13][N:14]1C(=O)C2C(=CC=CC=2)C1=O.O.NN.CO>C(Cl)Cl>[NH2:14][CH2:13][CH2:12][CH2:11][N:6]1[C:5]([S:25][C:26]2[C:34]([N:35]([CH3:37])[CH3:36])=[CH:33][C:29]3[O:30][CH2:31][O:32][C:28]=3[CH:27]=2)=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[NH2:1]
Reactant: CN(C)c1cc2c(cc1Sc1nc3c(N)ncnc3n1CCCN1C(=O)c3ccccc3C1=O)OCO2
Agent: NN
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CN(C)c1cc2c(cc1Sc1nc3c(N)ncnc3n1CCCN)OCO2
Yield: 80.4 %

Procedure:
2-(3-(6-Amino-8-(6-(dimethylamino)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-9-yl)propyl)isoindoline-1,3-dione (0.72 g, 1.38 mmol), hydrazine hydrate (2.86 g, 2.78 mL, 20.75 mmol), in CH2Cl2:MeOH (4 mL:28 mL) was stirred for 2 h at rt. The mixture was dried under reduced pressure and the residue purified by column chromatography (CH2Cl2:MeOH—NH3(7N), 20:1) to give 430 mg (80%) of the titled compound. 1H NMR (500 MHz, CDCl3): δ 8.33 (s, 1H), 6.77 (s, 1H), 6.49 (s, 1H), 5.91 (s, 2H), 5.85 (br s, 2H), 4.30 (t, J=6.9 Hz, 2H), 2.69 (s, 6H), 2.65 (t, J=6.5 Hz, 2H), 1.89-1.95 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 154.5, 153.1, 151.7, 148.1, 147.2, 146.4, 144.8, 120.2, 120.1, 109.3, 109.2, 101.7, 45.3, 45.2, 40.9, 38.6, 333; HRMS (ESI) m/z [M+H]+ calcd. for C17H22N7O2S, 388.1556. found 388.1544.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([S:14]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:16])=[O:15])([CH3:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C>CO.[OH-].[Na+]>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][S:14]([C:5]([CH3:13])([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([OH:26])=[O:3])(=[O:15])=[O:16])=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(C)(Cc1ccccc1)S(=O)(=O)Cc1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CS(=O)(=O)C(C)(Cc2ccccc2)C(=O)O)cc1

Procedure:
2-(4-Methoxy-phenylmethanesulfonyl)-2-methyl-3-phenyl-propionic acid was prepared starting from 2-(4-Methoxy-phenylmethanesulfonyl)-2-methyl-3-phenyl-propionic acid ethyl ester (3.5 g, 9.0 mmol) dissolved in methanol (50 ml) and 10 N NaOH. (30 ml). The resulting reaction mixture was worked up as outlined in Example 9. Yield 930 mg, 31%. Colorless solid, mp: 106-108 C;. MS: 347 (M−H)+.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[CH2:29][C:30](O)=[O:31]>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[CH2:29][C:30]([NH:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18])=[O:31]
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: COc1ccc(OC)c(CC(=O)O)c1
Product: COc1ccc(OC)c(CC(=O)Nn2nc(N3CCOCC3)c3ccccc3c2=O)c1

Procedure:
The product of Example 1B and 2-(2,5-dimethoxyphenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ 8.32 (d, J=7.8, 1H), 8.03 (d, J=7.8, 1H), 8.01-7.95 (m, 1H), 7.94-7.88 (m, 1H), 6.99 (d, J=3.1, 1H), 6.93 (d, J=8.9, 1H), 6.82 (dd, J=8.9, 3.1, 1H), 3.85-3.81 (m, 4H), 3.76 (s, 3H), 3.72 (s, 3H), 3.59 (s, 2H), 3.14-3.07 (m, 4H); MS (ESI+) M/Z 425 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH3:12][Si](C=[N+]=[N-])(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:12][O:2][C:1](=[O:3])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 9.6 g (63.6 mmol) of 4-carboxybenzaldehyde (Aldrich Chemical Co.) in 100 mL of CH2Cl2 at 0° C. was added excess trimethylsilyldiazomethane and the resulting mixture was allowed to stir at 0° C. for 1 h. The mixture was poured into saturated aqueous NaHCO3 and extracted three times with ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated to give 4.3 g of the ester 167 as an oil. 1H NMR consistent with the product.
Reaction SMILES: [OH:1][CH:2]([CH3:17])[C:3]([NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15])([CH3:5])[CH3:4].C(N(CC)CC)C.O>CS(C)=O>[O:1]=[C:2]([CH3:17])[C:3]([NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15])([CH3:4])[CH3:5]
Reactant: CC(O)C(C)(C)NC(=O)c1ccc(F)cc1F
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)C(C)(C)NC(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.9 %

Procedure:
To a solution of N-(2-hydroxy-1,1-dimethylpropyl)-2,4-difluorobenzamide obtained in Example 33 (0.30 g, 1.2 mmol) and triethylamine (0.37 g, 3.7 mmol) in DMSO (3 ml) was added pyridine sulfur trioxide complex (0.59 g, 3.7 mmol) portionwise and stirred at room temperature for 3 hours. The reaction mixture was added to a mixture of ice and water and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, saturated aqueous NaHCO3 and brine, successively dried over Na2SO4 and concentrated under a reduced pressure. The residue was crystallized from hexane/ethyl acetate to give the title compound (0.24 g; 81%).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:17])[CH2:4][CH2:5][C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2.O1CCCC1.[C:23]1([Li])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCC)(=O)C>O>[OH:17][C:3]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:4][CH2:5][C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:16]=2[N:15]=[CH:14][CH:13]=[CH:12]3)=[C:2]1[CH3:1]
Reactant: [Li]c1ccccc1
Reactant: CC1=C(c2cccc3cccnc23)CCC1=O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1=C(c2cccc3cccnc23)CCC1(O)c1ccccc1
Temperature: -90 °C
Yield: 57.9 %

Procedure:
A mixture of 2.4 g (10.75 mmol) of 2-methyl-3-(8-quinolyl)cyclopent-2-enone and 100 ml of tetrahydrofuran was cooled to −90° C., and 7.2 ml of phenyllithium (1.8 M in cyclohexane/diethyl ether, 12.9 mmol) were subsequently added while stirring. The mixture was stirred for a further one hour at this temperature and 1 ml of ethyl acetate was then added. The mixture was then allowed to warm to room temperature while stirring, refluxed for 10 minutes, cooled to room temperature and 100 ml of water were then added. The aqueous phase was then separated off from the organic phase and the aqueous phase was extracted twice with diethyl ether. The organic phases were combined, dried over magnesium sulfate, filtered and the solvent was distilled off. The residue was dissolved in 5 ml of toluene and then admixed with 80 ml of hexane. The precipitate formed was filtered off and dried. This gave 1.874 g (6.22 mmol, 57.9% yield) of 3-hydroxy-2-methyl-3-phenyl-1-(8-quinolyl)cyclopentene.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](O[C@@H]3CCC[C@H](N4C(=O)C5C(=CC=CC=5)C4=O)C3)=[CH:7][CH:8]=2)C=N1.O[C@@H]1CCC[C@H](N2C(=O)C3C(=CC=CC=3)C2=O)C1.[CH3:46][C:47]1[C:55]([OH:56])=[CH:54][CH:53]=[C:52]2[C:48]=1[CH:49]=[N:50][NH:51]2>>[CH3:46][C:47]1[C:55]([O:56][C@H:6]2[CH2:5][CH2:4][C@H:9]([NH2:1])[CH2:8][CH2:7]2)=[CH:54][CH:53]=[C:52]2[C:48]=1[CH:49]=[N:50][NH:51]2
Reactant: Cc1c(O)ccc2[nH]ncc12
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CCC[C@@H](Oc2ccc3[nH]ncc3c2)C1
Agent: O=C1c2ccccc2C(=O)N1[C@H]1CCC[C@@H](O)C1
Product: Cc1c(O[C@H]2CC[C@H](N)CC2)ccc2[nH]ncc12

Procedure:
The following compound of Example 409 was synthesized by carrying out reaction according to the method described in Example 385, except for using the cis-2-[3-(1H-indazol-5-yloxy)cyclohexyl]-1H-isoindole-1,3(2H)-dione obtained in Example 326, (d) and the 4-methyl-1H-indazol-5-ol obtained in Example 402, as starting materials.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][OH:17])[CH:11]([CH3:18])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>ClCCl.C(Cl)(Cl)Cl.CO>[CH3:33][S:34]([O:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:10][CH:11]1[CH3:18])(=[O:36])=[O:35]
Reactant: CC1CC(N(Cc2ccccc2)Cc2ccccc2)CCN1CCO
Reactant: CS(=O)(=O)Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC1CC(N(Cc2ccccc2)Cc2ccccc2)CCN1CCOS(C)(=O)=O

Procedure:
A mixture 2-[4-(dibenzylamino)-2-methylpiperidin-1-yl]ethanol (Intermediate 216, 660 mg, 1.9 mmol) in dry dichloromethane (6 mL) and triethyl amine (0.375 mL, 2.7 mmol) was treated at 0° C. with methanesulfonyl chloride (0.175 mL, 8.4 mmol). After 45 minutes the reaction was complete by TLC (chloroform/methanol 6:1, rf 0.54). Potassium phosphate buffer (pH 7, 1M, 25 mL) was added, dichloromethane was removed under reduced pressure and it was extracted with ice cold ethyl acetate (2×100 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure and the crude preparation of the mesylate was used without delay for the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:12][NH:11][C:10](=O)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.OC1[NH:27][C:26](=O)[CH:25]=[C:24]([C:29]2[CH:30]=[C:31](C)[CH:32]=[CH:33][CH:34]=2)C1C1C=CN=CC=1.OS(O)(=O)=O>C(Cl)(Cl)Cl>[C:29]1([CH2:24][CH2:25][CH2:26][NH:27][C:10]2[CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:12][N:11]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1cccc(C2=CC(=O)NC(O)C2c2ccncc2)c1
Reactant: Cc1cccc(-c2cc(=O)[nH]cc2-c2ccncc2)c1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: Cc1cccc(-c2cc(NCCCc3ccccc3)ncc2-c2ccncc2)c1
Temperature: 55 °C

Procedure:
Preparation of 4-(3-methylphenyl)-5-(4-pyridyl)-1H-pyrid-one To a solution of 6-hydroxy-4-m-tolyl-5,6-dihydro-1H-[5,4′]bipyridinyl-2-one (83 mg, 0.29 mmole) in CHCl3 (3 mL) at r.t. was added 2 ml of conc. H2SO4. The resulting mixture was heated to 55° C. for 2 hr. The mixture was cooled down to r.t. and was carefully quenched with aqueous sodium carbonate. Standard work up (extraction of compound with methylene chloride), followed by purification (silica gel, methanol/methylene chloride) gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:36])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:32])([CH3:31])[C:28](=[O:30])[CH3:29])=[CH:23][C:22]=3[O:33][CH2:34][CH3:35])=[N:9]2)=[CH:4][CH:3]=1.[C:37](Cl)([Cl:39])=[O:38]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:36])[C:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:37]([Cl:39])=[O:38])[C:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:32])([CH3:31])[C:28](=[O:30])[CH3:29])=[CH:23][C:22]=3[O:33][CH2:34][CH3:35])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: CCOc1cc(C(C)(C)C(C)=O)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Solvent: CCN(CC)CC
Product: CCOc1cc(C(C)(C)C(C)=O)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In a manner analogous to the method described in example 3, 3-{4-[4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-phenyl}-3-methyl-butan-2-one was reacted with phosgene in the presence of triethylamine to give the title compound.