Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:20][C:19]2[C@H:14]([CH2:15][CH2:16][C:17](=[O:21])[CH:18]=2)[C@@H:13]2[C@@H:4]1[C@H:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C@@H:8]([OH:22])[CH2:7][CH2:6]1)[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24].O>N1C=CC=CC=1>[C:23]([O:22][C@H:8]1[CH2:7][CH2:6][C@H:5]2[C@H:4]3[C@H:13]([CH2:12][CH2:11][C@:9]12[CH3:10])[C@@H:14]1[C:19](=[CH:18][C:17](=[O:21])[CH2:16][CH2:15]1)[CH2:20][C@H:3]3[CH2:1][CH3:2])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Solvent: c1ccncc1
Solvent: O
Product: CC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
i)—A solution of (7α,17β)-7-ethyl-17-hydroxyestr-4-en-3-one (Example 1, 2.0 g) in dry pyridine (15 ml) was treated with acetic anhydride (1.86 ml) and the reaction mixture was stirred at room temperature for 6.5 h; additional acetic anhydride (1.86 ml) was added after 3 h. The mixture was cooled to 0° C.; water was added and stirring was continued for 30 min. The product was extracted into ethyl acetate; the combined organic phases were washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure, to give (7α,17β)-17-(acetyloxy)-7-ethylestr-4-en-3-one (2.15 g). The product was used in the next step without further purification.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O:15]C(=O)C)=[CH:7][C:6]=1[CH3:19])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O.Cl>CO>[C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[CH:7][C:6]=1[CH3:19])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(C)c(OC(C)=O)c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=O)Oc1c(C)cc(O)c2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.3 %

Procedure:
To a solution of 4-(acetyloxy)-2-methyl-1-naphthyl acetate (25 g, 96.8 mmol) in methanol (300 mL) was added potassium carbonate (58.1 g, 420 mmol), and the mixture was stirred under argon atmosphere at room temperature for 15 minutes. Water was poured into the mixture, which was neutralized with hydrochloric acid and then extracted with ethyl acetate. The extract was washed with a saturated brine and dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 21 g (yield: quantitative) of the title compound. Oily matter.
Reaction SMILES: [H-].[Na+].[CH:3]1([N:9]2[C:13]3[CH:14]=[C:15]([O:18][CH2:19][CH2:20][O:21][CH3:22])[CH:16]=[CH:17][C:12]=3[NH:11][C:10]2=[O:23])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CN(C=O)C.[CH3:29][O:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[C:35]([O:43][CH3:44])[CH:34]=1)=[O:32]>O>[CH:3]1([N:9]2[C:13]3[CH:14]=[C:15]([O:18][CH2:19][CH2:20][O:21][CH3:22])[CH:16]=[CH:17][C:12]=3[N:11]([S:39]([C:36]3[CH:37]=[CH:38][C:33]([C:31]([O:30][CH3:29])=[O:32])=[CH:34][C:35]=3[O:43][CH3:44])(=[O:41])=[O:40])[C:10]2=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COCCOc1ccc2[nH]c(=O)n(C3CCCCC3)c2c1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)OC)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
0.095 g of sodium hydride as a 60% dispersion in oil is added in portions to a mixture of 0.7 g of 3-cyclohexyl-1,3-dihydro-5-(2-methoxyethoxy)-2H-benzimidazol-2-one and 50 ml of DMF and the mixture is stirred for 30 minutes at RT. 0.6 g of 4-methoxycarbonyl-2-methoxybenzenesulfonyl chloride is then added and the mixture is stirred for two hours at RT. The reaction mixture is poured into a mixture of water and ice, extracted with AcOEt, washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum to give 0.8 g of the expected product, which is used as such in the next step.
Reaction SMILES: [K].[CH3:2][C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:6](=[O:8])[NH:5][C:4]1=[O:9].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26](Cl)(=[O:28])=[O:27]>O1CCCC1>[CH3:2][C:3]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:7]([S:26]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)(=[O:28])=[O:27])[C:6](=[O:8])[N:5]([S:26]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)(=[O:28])=[O:27])[C:4]1=[O:9]
Reactant: CC1(c2ccccc2)NC(=O)NC1=O
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: [K]
Solvent: C1CCOC1
Product: CC1(c2ccccc2)C(=O)N(S(=O)(=O)c2ccc3ccccc3c2)C(=O)N1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.8 %

Procedure:
5-Methyl-5-phenylimidazolidine-2,4-dione potassium salt (1.00 g) was suspended in tetrahydrofuran (10 mL), 2-naphthalenesulfonyl chloride (1.02 g) was added slowly, and the mixture was stirred at room temperature overnight. After the solvent was distilled off, ethyl acetate (100 mL) was added to the reaction solution, and the mixture was washed with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution and a saturated brine in turn. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. Further purification by silica gel chromatography (hexane:ethyl acetate=2:1) afforded 242 mg of white crystals.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH:15]=2)[C:10]([CH3:24])=[C:9]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:38][C:39]([O:41][CH3:42])=[O:40]>CC(C)=O>[CH3:42][O:41][C:39](=[O:40])[CH2:38][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[CH:15]=[C:16]3[C:11]([C:10]([CH3:24])=[C:9]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:8]3[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:12][CH:13]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)CBr
Reactant: Cc1c(-c2ccccc2)n(Cc2ccccc2)c2cc(-c3ccc(O)cc3)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(-c2ccc3c(C)c(-c4ccccc4)n(Cc4ccccc4)c3c2)cc1

Procedure:
The desired product was prepared using a procedure similar to step 1 of example 4. Thus, 4-(1-benzyl-3-methyl-2-phenyl-1H-indol-6-yl)-phenol (0.291 g, 0.747 mmol) was reacted with K2CO3 (0.134 g, 0.971 mmol) and methyl bromoacetate (0.149 g, 0.971 mmol) in acetone (5 ml) to give the product (0.305 g, 0.661 mmol, 88%) as a white solid, mp 145-148° C. 1H NMR (DMSO-d6) δ 2.24 (s, 3H), 3.70 (s, 3H), 4.81 (s, 2H), 5.39 (s, 2H), 6.86 (d, J=7.2 Hz, 2H), 6.98 (d, J=8.9 Hz, 2H), 7.13 (t, J=7.2 Hz, 1H), 7.18 (t, J=7.0 Hz, 2H), 7.34 (dd, J=1.4, 8.1 Hz, 1H), 7.39-7.44 (m, 3H), 7.49 (t, J=7.0 Hz, 2H,) 7.56-7.62 (m, 4H); [ESI(+)], m/z 462 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH:10]3[S:12][C:7]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)([NH:8][CH2:9]3)[C:6]=2[CH:19]=1.S[CH2:21][C:22](O)=[O:23]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:22](=[O:23])[CH2:21][S:12][CH:10]3[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: O=C(O)CS
Reactant: Clc1ccc2c(c1)C1(c3ccccc3)NCC(N2)S1
Solvent: C1CCOC1
Product: O=C1CSC2CN=C(c3ccccc3)c3cc(Cl)ccc3N12

Procedure:
A solution of 7-chloro-2,3,4,5-tetrahydro-5-phenyl-2,5-epithio-1H-1,4-benzodiazepine (500 mg) in THF was treated slowly with excess mercaptoacetic acid (0.5 ml) and stirred and heated under reflux for 16 hours. The cooled solution was washed with aqueous sodium carbonate, dried, evaporated, and the oily residue taken up in ether. The desired product was re-crystallized from methylene chloride/methanol and was obtained as pale yellow crystals, m.p. 228°-230°.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:12]([NH2:14])=O>>[CH3:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:14][CH:12]=[N:1]2)=[CH:7][CH:8]=1
Reactant: NC=O
Reactant: Cc1ccc(C(=O)O)c(N)c1
Product: Cc1ccc2c(=O)[nH]cnc2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 2-amino-4-methylbenzoic acid (31.6 g, 206 mmol) in formamide (60 mL) is heated to 130° C. for 1 hour, then at 175° C. for 3 hours. The solution is poured into 500 mL of ice water. The resulting solid is collected by filtration and further dried under reduced pressure. The title compound (26.2 g, 170 mmol) is obtained as a white solid. MS (EI): m/z 159 (M+).
Reaction SMILES: [S:1]1[C:8]2[CH:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[NH:5][C:4]=2[CH:3]=[CH:2]1.Br[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=2)[CH:18]=[CH:17][CH:16]=1>>[CH3:12][O:11][C:9]([C:6]1[N:5]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:4]2[CH:3]=[CH:2][S:1][C:8]=2[CH:7]=1)=[O:10]
Reactant: Fc1ccc2cccc(CBr)c2c1
Reactant: COC(=O)c1cc2sccc2[nH]1
Product: COC(=O)c1cc2sccc2n1Cc1cccc2ccc(F)cc12

Procedure:
Using general procedure B, methyl 4H-thieno[3,2-b]pyrrole-5-carboxylate was coupled with 1-bromomethyl-7-fluoro-naphthalene (from Example 49.3.) to give 4-(7-fluoro-naphthalen-1-ylmethyl)-4H-thieno[3,2-b]pyrrole-5-carboxylic acid methyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a white solid. MS: 324.4 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][N:14](C(=O)C4C(Cl)=CC=CC=4Cl)[C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C1COCC1.N>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(=O)c3c(Cl)cccc3Cl)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Yield: 74 %

Procedure:
Crude compound 9 and THF (6 L) were added to a 12 L round-bottom flask and stirred until the clear solution was obtained. A solution of ammonia in methanol (1.24 L; 7M) was added and stirred for 24 h at 28-35° C. The reaction mixture was concentrated to near dryness after with methanol was added and concentrated at 45-50° C. The separated solid was filtered and dried at 45-50° C. under vacuum to obtain crude compound 10 (601.7 g; Purity=≧95%; Yield=85.4%). Recrystallization of the crude in acetone/methanol (2:1) provided compound 10 in 74% yield with a purity of 98.5%. 1H NMR (DMSO-d6): δ (ppm) 9.78 (s, 1H), 8.72-8.73 (d, J=2.2 Hz, 1H), 8.65 (brs, 1H), 8.26 (s, 1H), 7.79-7.82 (d, J=8.5 Hz, 2H), 7.57-7.61 (m, 3H), 7.28-7.32 (t, J=8.3 Hz, 1H), 2.50-2.52 (m, 2H), 1.73-1.78 (m, 2H), and 0.96-0.98 (t, 3H). MS (ESI) [M+H+]+=490.1 and 492.1.
Reaction SMILES: [I:1][C:2](=[C:5]([I:7])[I:6])[CH2:3][OH:4].[CH:8](O)=[O:9]>>[CH:8]([O:4][CH2:3][C:2]([I:1])=[C:5]([I:7])[I:6])=[O:9]
Reactant: O=CO
Reactant: OCC(I)=C(I)I
Product: O=COCC(I)=C(I)I
Reaction time: 3 h

Procedure:
2.0 g of 2,3,3-triiodoallyl alcohol and 30 ml of formic acid were refluxed, with stirring, for 3 hours. After cooling the mixture, the crystals which precipitated were collected by filtration, dissolved in ethyl acetate, adsorbed in a dry silica gel chromatography column and eluted with 3:1 by volume mixture of hexane and ethyl acetate, to give 1.8 g of the desired Compound No. 81 in the form of crystals melting at 84°-85° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH3:6])=[O:4].[C:7]1([N:13]=[C:14]=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCOCC1>[CH3:1][NH:2][C:3]([N:5]([CH3:6])[C:14]([NH:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:15])=[O:4]
Reactant: O=C=Nc1ccccc1
Reactant: CNC(=O)NC
Solvent: C1COCCO1
Product: CNC(=O)N(C)C(=O)Nc1ccccc1
Reaction time: 15 h
Yield: 60.3 %

Procedure:
In 50 ml of anhydrous dioxane, 3.5 g (0.04 mol) of 1,3-dimethyl urea was dissolved, and under stirring 4.8 g (0.04 mol) of phenylisocyanate was added thereinto. The reaction was carried out at a room temperature for 15 hours, then the reaction mixture was treated a procedure same as in Example 1. The residue thus obtained was recrystallized from ethanol-petroleum ether to obtain 5.0 g (yield 60%) of 1,3-dimethyl-5-phenylbiuret having a melting point of 93°-95° C.
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7](OCC)=[O:8])[CH2:3][CH2:2]1.O.[NH2:20][NH2:21]>C(O)C>[NH:20]([C:7]([CH:4]1[CH2:5][CH2:6][N:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:2][CH2:3]1)=[O:8])[NH2:21]
Reactant: NN
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Temperature: 25 °C

Procedure:
10.0 g (38.9 mmol) of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate were initially charged in 35 ml of ethanol, and 3.8 ml (3.90 g, 78 mmol) of hydrazine hydrate were added with stirring. The mixture was stirred at reflux for 9 h. The reaction mixture was cooled to RT, 1.9 ml (39 mmol) of hydrazine hydrate were added and the reaction solution was stirred at reflux for another 24 h. The solvent was concentrated, ethanol (50 ml) was added and the mixture was concentrated again. Diethyl ether (150 ml) was added, and the mixture was stirred in an ultrasonic bath for 5 min. The product was filtered off and dried. This gave 9.20 g (97% of theory) of the product.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3](=[O:16])[C@H:4]([CH2:12][CH:13]([CH3:15])[CH3:14])[NH:5][C:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]=1.[F:18][C:19]([F:40])([F:39])[C:20]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:21]=1[CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([CH:29]=O)[CH2:25][CH2:24]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:40][C:19]([F:18])([F:39])[C:20]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:21]=1[CH2:22][N:23]1[CH2:28][CH2:27][CH:26](/[CH:29]=[C:10]2/[C:6]([NH:5][C@H:4]([C:3]([N:2]([CH3:1])[CH3:17])=[O:16])[CH2:12][CH:13]([CH3:14])[CH3:15])=[N:7][C:8](=[O:11])[S:9]/2)[CH2:25][CH2:24]1
Reactant: CC(C)C[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CC(C)C[C@H](NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)C(=O)N(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 51.2 %

Procedure:
To a solution of N,N-dimethyl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-L-leucinamide (772 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1221 mg) in 2-propanol (10 mL) was added piperidinium acetate (523 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight. After evaporation of the solvent, the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (888 mg).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11]3)[CH2:5][CH2:4][O:3]1.[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=O.N1CCCCC1>C(O)C>[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=[C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][N:6]3[CH2:5][CH2:4][O:3][C:2]3=[O:1])[CH:9]=2)[NH:13][C:12]1=[O:17]
Reactant: O=C1Cc2cc(CN3CCOC3=O)ccc2N1
Reactant: Cc1cc(C)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C)c(C=C2C(=O)Nc3ccc(CN4CCOC4=O)cc32)[nH]1

Procedure:
A solution of 5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-one (4.3 mmoles), 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (5.17 mmoles) and piperidine (3 mmoles) in ethanol (30 ml) is heated at reflux for 24 hours. The solid formed is filtered off, washed with ethanol, with water and then with ethanol and dried in vacuo to yield the title product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:27][C:14]1[C:13]([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:30]4[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=4)[CH:3]=3)[NH:8][CH:9]=2)=[O:12])=[C:18]([F:19])[CH:17]=[CH:16][C:15]=1[NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cccnc4)cc23)c1F
Temperature: 160 °C

Procedure:
To propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-0773, prepared as described in Example 1, 65.0 mg, 0.14 mmol) in acetonitrile (4.0 mL) was added pyridine-3-boronic acid (609, 25.0 mg, 0.20 mmol), tetrakis (triphenylphosphine)palladium(0) (11 mg, 1.0% mmol) and aqueous potassium carbonate (1.0 M, 2.0 mL). The reaction was heated to 160° C. for 10 minutes in a CEM Discover microwave instrument. The reaction was poured into water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtrated and concentrated. The desired compound was isolated by silica gel column chromatography (methylene chloride/methanol 5%) to give a white solid (P-0088, 30 mg, 46.9%). MS (ESI) [M+H+]+=457.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41](O)=[O:42])=[CH:38][CH:39]=3)[C:34]([CH3:44])=[C:33]2[CH3:45])=[CH:27][CH:26]=1)=[O:18])(C)(C)C>>[CH3:45][C:33]1[N:32]([CH2:31][C:28]2[CH:29]=[CH:30][C:25]([C:20]3[C:19]([C:17]([OH:18])=[O:16])=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:26][CH:27]=2)[C:40]2[C:35]([C:34]=1[CH3:44])=[CH:36][C:37]([C:41](=[O:42])[NH:8][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[CH:38][CH:39]=2
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3cccc([N+](=O)[O-])c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 3-nitrobenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[C:24]([C:18]1[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:29])(=[O:28])[CH:25]([CH3:27])[CH3:26]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2C(=O)C(C)C)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c1C(=O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
The mixture of 2-(2-isobutyryl-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (228) (170 mg, 0.43 mmol) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (20 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more precipitate came out of the water. The precipitate is filtered to give a pure product (229) as white solid (140 mg, 89%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[N:11]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:14]=[CH:13][N:12]=[N:11]1
Reactant: c1c[nH]nn1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(-n2ccnn2)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of 100 g (803 mmol) of p-fluorobenzaldehyde in 400 ml of DMF, 95 g (1377 mmol) of 1-H-1,2,3-triazole and 200 g (1449 mmol) of K2CO3 are added successively and the mixture is stirred for 4 h at 100° C. The mixture is cooled to r.t. and filtrated through celite. The filtrate is concetrated under reduced pressure to give crude crystals which are washed with AcOEt several times. The solid which is not well soluble in AcOEt is washed with water and dried in vacuo to give 4-[1,2,3]-triazol-1-yl-benzaldehyde (B). The filtrate is concentrated under reduced pressure, the obtained solid is solved in CH2Cl2 and then absorbed on silica gel for dry CC (n-Hexane:AcOEt=2:1˜1:2 ) to provide 4-[1,2,3]-triazol-2-yl-benzaldehyde (A) and further compound (B) as pale yellow solids: 1H-NMR (400 MHz, CDCl3): compound A, 7.88 (s, 2H), 8.01 (d, 2H, J=8.56 Hz), 8.29 (d, 2H, J=8.56 Hz), 10.06 (s, 1H); compound B: 7.90 (s, 1H), 7.98 (d, 2H, J=8.56 Hz), 8.07 (d, 2H, J=8.56 Hz), 8.13 (s, 1H), 10.09 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH:11]=[C:12](O)[CH3:13])=[CH:5][CH:4]=1)[CH3:2].O.[NH2:17][NH2:18]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:11]=[C:12]([CH3:13])[NH:18][N:17]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: NN
Reactant: CCc1ccc(CC(=O)C=C(C)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1ccc(Cc2cc(C)[nH]n2)cc1
Temperature: 100 °C

Procedure:
A solution of the above 1-(4-ethylphenyl)-4-hydroxy-3-penten-2-one (3.98 g) and hydrazine hydrate (4.0 ml) in toluene (20 ml) was stirred under heating at 100° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and washed successively with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:ethyl acetate=2:1) to give 3-(4-ethylphenylmethyl)-5-methyl-1H-pyrazole (3.12 g) as yellow oil. APCI-Mass m/Z 201 (M+H).
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[CH3:27][O:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH2:31][CH2:32][CH2:33][CH:34]2[CH2:39][CH2:40]Br>CN(C)C=O>[CH3:27][O:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH2:31][CH2:32][CH2:33][CH:34]2[CH2:39][CH2:40][N:12]1[C:11](=[O:14])[CH:10]=[CH:9][C:8]([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[N:13]1
Reactant: COc1cccc2c1CCCC2CCBr
Reactant: O=c1ccc(C(c2ccccc2)c2ccccc2)n[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc2c1CCCC2CCn1nc(C(c2ccccc2)c2ccccc2)ccc1=O
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 6-diphenylmethyl-3(2H)-pyridazinone (0.22 g) and potassium tert-butoxide (0.10 g) in N,N-dimethylformamide (2 ml) was added a solution of 2-(5-methoxy-1,2,3,4-tetrahydro-1-naphthyl)ethyl bromide (0.18 g) in N,N-dimethylformamide (3 ml) at room temperature. The reaction mixture was stirred for 2 hours at the same temperature and partitioned between water and ethyl acetate. The organic layer was washed with water (3 times) and brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed (n-hexane-ethyl acetate) over silica gel to afford 2-[2-(5-methoxy-1,2,3,4-tetrahydro-1-naphthyl)ethyl]-6-diphenylmethyl-3(2H)-pyridazinone (0.25 g) as an oil.