Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([N:23]=[N+:24]=[N-:25])=[CH:11][C:10]=1[CH:26]([CH3:28])[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][OH:38])=[CH:33][CH:32]=1)#[CH:30].CCOC(C)=O.O>CN(C=O)C>[CH2:16]([O:15][C:13]1[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]([CH:26]([CH3:28])[CH3:27])=[CH:11][C:12]=1[N:23]1[C:29]([C:31]2[CH:36]=[CH:35][C:34]([CH2:37][OH:38])=[CH:33][CH:32]=2)=[CH:30][N:25]=[N:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)c1cc(N=[N+]=[N-])c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: C#Cc1ccc(CO)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)c1cc(-n2nncc2-c2ccc(CO)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 72 %

Procedure:
1,5-bis-benzyloxy-2-isopropyl-4-azido-benzene (890 mg, 2.38 mmol) was dissolved in DMF (5 ml) and (4-ethynylphenyl)-methanol (286 mg, 2.16 mmol) was added at RT. The flask was subjected to three vacuum-nitrogen cycles. [Cp*RuCl]4 was then added (116 mg, 0.11 mmol) and three further cycles were done. The reaction was left to RT until completion (monitored by TLC). AcOEt and water were then added. The organic phase was extracted four times with AcOEt, washed with water (three times) and brine (one time) and dried over Na2SO4; the solvent was removed under reduced pressure and the mixture was purified by column chromatography (PE/AcOEt: 60:40). The title compound was obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH:26]=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Cl.[NH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].[OH-].[Na+].C([O-])([O-])=O.[K+].[K+]>C(O)C.CC(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][NH:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C=O)c[nH]c34)no2)cc1Cl
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CCNCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole-3-carbaldehyde (D71) (381 mg) and ethyl β-alaninate hydrochloride (246 mg) were added to a solution of NaOH (27 mg) in ethanol (20 mL), followed by addition of AcOH (3 mL). Under stirring NaBH3CN (50 mg) in ethanol (2 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight and then basified to pH ˜9 by K2CO3 solution. The mixture was concentrated and EtOAc (50 mL) was added. The organic layer was separated and washed with water and brine. After the solvent was evaporated off the residue was purified by Mass Directed AutoPrep to afford ethyl N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}-β-alaninate (D72) (176 mg) as a yellow solid. δH (DMSO-d6, 400 MHz): 1.16 (3H, t), 1.38 (6H, d), 2.47 (2H, t), 2.80 (2H, t), 3.90 (2H, s), 4.04 (2H, q), 4.88-4.94 (1H, m), 7.21 (1H, t), 7.37 (1H, t), 7.46 (1H, d), 7.89 (1H, d), 7.94 (1H, dd), 8.22 (1H, dd), 8.39 (1H, d), 10.89 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:28](=O)[O:29][CH2:30][C:23]=12.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:28]1[C:24]2[C:23](=[N:22][CH:27]=[CH:26][CH:25]=2)[CH2:30][O:29]1
Reactant: O=C1OCc2ncccc21
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2ccc(F)cc2C1=C1OCc2ncccc21
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 37.3 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (453 mg, 3.0 mmol.) in THF (3 mL) is placed under an Argon atmosphere and cooled in an ice bath. A solution of lithium bis(trimethylsilyl)amide (6.0 mL of a 1M in THF, 6.0 mmol, 3 eq.) is added slowly at 0° C. and the resulting solution is stirred for 10 min. The ice-bath is removed and a solution of 7H-furo[3,4-b]pyridin-5-one (270 mg, 2.0 mmol) in THF (6 mL) is added dropwise to the reaction mixture. The resulting solution is stirred at room temperature for 4 h and poured into a 10% aqueous HCl solution (50 mL). After 10 min at room temperature, the reaction is heated to ˜90° C. for 45 min. and then let stir at room temperature for 36 h. The solid which forms is collected by filtration and washed sequentially with MeOH, EtOAc, Et2O (3×5 mL) and dried under vacuum to give the title compound (200 mg, 37%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[N:17]=[C:16]([C@@H:18]4[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]4)[NH:15][N:14]=3)[CH:11]=2)[NH:6][N:5]=1.[C:31](Cl)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[Br:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[N:17]=[C:16]([C@@H:18]4[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]4)[NH:15][N:14]=3)[CH:11]=2)[N:6]([C:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:5]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](c2nc(-c3ccc4[nH]nc(Br)c4c3)n[nH]2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](c2nc(-c3ccc4c(c3)c(Br)nn4C(c3ccccc3)(c3ccccc3)c3ccccc3)n[nH]2)C1
Reaction time: 0.5 h

Procedure:
Added Sodium Hydride (100 mg; 2.5 mmol) to a solution of (R)-tert-butyl 3-(3-(3-bromo-1H-indazol-5-yl)-1H-1,2,4-triazol-5-yl)piperidine-1-carboxylate (530 mg, 0.988 mmol) in DMF (5 ml) at 0° C., then stirred for 30 minutes. Trityl Chloride (570 mg, 2.05 mmol) was added, and stirred at room temperature overnight. Added water (100 ml), filtered precipitated solid, washed with water, dried, then chromatographed on silica gel eluting with 30% v/v EtOAc/Hexanes to yield a mixture of mono and dialkylated products (560 mg, 8:2 mono/dialkylation).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]#[C:6][C:7]([O:9][CH3:10])=[O:8])=[O:4].[NH2:11][NH2:12]>C(OCC)C.C1COCC1>[CH3:1][O:2][C:3](=[O:4])/[C:5](/[NH:11][NH2:12])=[CH:6]\[C:7]([O:9][CH3:10])=[O:8]
Reactant: NN
Reactant: COC(=O)C#CC(=O)OC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)/C=C(/NN)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
To a solution of dimethylacetylene dicarboxylate (1.4 g, 9.9 mmol) in diethylether (40 mL) under argon was added a solution of hydrazine in THF (1 M, 10 mL) and the resulting mixture stirred at room temperature overnight. The precipitate was filtered off and dried to afford the title compound (597 mg, 35%) as a white solid. MS: m/e=175.2 [M+H]+.
Reaction SMILES: [O:1]1[C:6](=[O:7])[CH2:5][C:4]2([C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:14][C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:3][C:2]1=O.[CH3:22][NH2:23].Cl>>[CH3:22][N:23]1[C:2](=[O:1])[CH2:3][C:4]2([C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:14][C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:5][C:6]1=[O:7]
Reactant: CN
Reactant: O=C1CC2(CC(=O)O1)c1ccccc1Oc1ccccc12
Agent: Cl
Product: CN1C(=O)CC2(CC1=O)c1ccccc1Oc1ccccc12

Procedure:
This anhydride is treated with excess aqueous methylamine at room temperature. After ten minutes, the solution is acidified with dilute hydrochloric acid and the monoacid-monoamide is filtered and dried. Without further purification it is treated with excess acetic anhydride at reflux for 0.5 hours, and the reaction mixture then poured into cold aqueous sodium bicarbonate. The product, extracted with ethyl acetate, is chromatographed on silica gel and eluted with 2% ethyl acetate-petroleum ether (b.p. 60°-80° C.), giving 1'-methylxanthene-9-spiro-4'-piperidin-2',6'-dione which is recrystallised from ethyl acetate-petroleum ether (b.p. 60°-80° C.), m.p. 148°-149° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[CH3:13])=[O:4].[C:14](O)(=O)C>>[Cl:12][C:8]1[C:7]([CH3:13])=[C:6]([N:5]2[C:3](=[O:4])[CH2:2][NH:1][CH2:14]2)[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1c(Cl)cccc1NC(=O)CN
Reactant: CC(=O)O
Product: Cc1c(Cl)cccc1N1CNCC1=O
Temperature: 90 °C

Procedure:
A mixture of 2-amino-N-(3-chloro-2-methyl-phenyl)-acetamide (74) (1.18 g, 1 equiv), paraformaldehyde (HCHO)n (0.77 g, 1.5 equiv) and 3 mL of acetic acid was heated at 90° C. for 3 h and evaporated to dryness to afford 3-(3-chloro-2-methyl-phenyl)-imidazolidin-4-one (75) as acetic acid salt.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].Br[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1>>[N+:22]([C:21]1[C:16]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)=[N:17][CH:18]=[CH:19][CH:20]=1)([O-:24])=[O:23]
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Reactant: O=[N+]([O-])c1cccnc1Br
Product: COC(=O)CCc1ccc(C#Cc2ncccc2[N+](=O)[O-])cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (95 mg, 0.51 mmol) and 2-bromo-3-nitropyridine (113 mg, 0.56 mmol) according to the general procedure IF to give 84 mg (53%) of a red solid after purification by flash chromatography (SiO2, EtOAc:PE, 1:8): Rf=0.16 (EtOAc:PE, 1:4); 1H NMR (CDCl3) δ 8.84 (dd, J=4.7, 1.6 Hz, 1H), 8.39 (dd, J=8.3, 1.6 Hz, 1H), 7.64-7.59 (m, 2H), 7.44 (dd, J=8.3, 4.7 Hz, 1H), 7.24 (d, J=8.4 Hz, 2H), 3.68 (s, 3H), 2.99 (t, J=7.7 Hz, 2H), 2.65 (t, J=7.7 Hz, 2H); 13C NMR (CDCl3) δ 173.0, 153.5, 146.8, 143.0, 137.6, 132.8, 132.5, 128.6, 122.5, 119.3, 98.0, 85.0, 51.7, 35.2, 30.9; ESI-MS m/z 333.1 (M+Na+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C)C=O.[CH2:17]([NH:24][CH2:25][CH2:26][OH:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>S(Cl)(Cl)=O.O1CCCC1.O>[CH2:17]([N:24]([CH2:25][CH2:26][OH:27])[C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:11])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCCNCc1ccccc1
Reactant: O=C(O)c1cc(Br)ccc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cc(Br)ccc1F)N(CCO)Cc1ccccc1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
A solution of 5-bromo-2-fluorobenzoic acid (3.00 g, 13.7 mmol) and N,N-dimethylformamide (0.100 ml) in thionylchloride (20 ml) was stirred at 85° C. for 2 hr, and the solvent was evaporated under reduced pressure. The residue was added under ice-cooling to a solution of N-benzylethanolamine (2.07 g, 13.7 mmol) and triethylamine (2.87 ml, 20.6 mmol) in tetrahydrofuran (30 ml), and the mixture was stirred under ice-cooling for 1 hr and at room temperature for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the desired product (4.75 g, 98.3%) as an oil.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:12].[C:13]1([C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][O:15]1)=O.Cl>CN(C=O)C.O>[C:13]1(=[C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:3][C:4]2=[O:12])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][O:15]1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=C1OCc2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2ccccc2C1=C1OCc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.7 %

Procedure:
To a suspension of sodium hydride (6.0 g, 150 mmol, 60% in mineral oil) in 300 mL DMF was added oxindole (10.0 g, 75.1 mmol) in 50 mL DMF over 8 min. After stirring for 15 min at room temperature, a solution of phthalide (13.1 g, 97.6 mmol) in 50 mL DMF was added over 1 min. The mixture was stirred for 1.25 h, then poured into 1100 mL H2O. Addition of 4% aqueous HCl solution gave a yellow solid which was filtered and rinsed with H2O to give the title compound (8.75 g, 47%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:11][C:10](=[O:12])[C:9]([CH2:13][CH:14]([CH3:16])[CH3:15])=[N+:8]([O-:17])[C:7]=1[OH:18])=[O:5])[CH3:2].[CH2:19](OCC)C.[N+](=C)=[N-].C(O)(=O)C>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[NH:11][C:10](=[O:12])[C:9]([CH2:13][CH:14]([CH3:15])[CH3:16])=[N+:8]([O-:17])[C:7]=1[O:18][CH3:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(=O)c(CC(C)C)[n+]([O-])c1O
Reactant: CCOCC
Agent: C=[N+]=[N-]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c(=O)c(CC(C)C)[n+]([O-])c1OC
Reaction time: 0.5 h

Procedure:
To a suspension of 5.45 g of 6-ethoxycarbonyl-5-hydroxy-3-isobutyl-1,2-dihydropyrazin-2-one 4-oxide in chloroform was added dropwise gradually about equivalent quantity of diethyl ether solution of diazomethane at -15° C. 30 Minutes after the addition, 0.5 ml of acetic acid was added to the reaction mixture, and this mixture was allowed to stand for 30 minutes. Then the whole mixture was washed with water, and the solvent was removed by distillation, to the thus obtained residue was added 30 ml of chloroform and dissolved by heating, then 200 ml of diisopropyl ether was added gradually thereto so as to form crystals. The precipitated crystals were collected by filtration, and said operation were repeated twice to obtain 3.10 g of 6-ethoxycarbonyl-3-isobutyl-5-methoxy-l,2-dihydropyrazin-2-one 4-oxide.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:31]=[C:30]([CH3:32])[C:17]3[N:18]=[C:19]([C:21]4[C:22]([O:28]C)=[N:23][CH:24]=[CH:25][C:26]=4[I:27])[NH:20][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[I:27][C:26]1[CH:25]=[CH:24][NH:23][C:22](=[O:28])[C:21]=1[C:19]1[NH:20][C:16]2[CH:15]=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:31]=[C:30]([CH3:32])[C:17]=2[N:18]=1
Reactant: COc1nccc(I)c1-c1nc2c(C)cc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2[nH]1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(N2CCNCC2)cc2[nH]c(-c3c(I)cc[nH]c3=O)nc12
Temperature: 75 °C
Yield: 93.1 %

Procedure:
To a stirred solution of 4-[2-(4-Iodo-2-methoxy-pyridin-3-yl)-7-methyl-3H-benzoimidazol-5-yl]-piperazine-1-carboxylic acid tert-butyl ester (24 g, 43.7 mmol) was added 1,4-dioxane (750 mL) and 6 N aqueous HCl (30 mL) and the mixture was heated to 75° C. overnight. The solution was cooled to room temperature, the supernatent was poured off, and the resulting dark gummy solid was washed with anhydrous diethyl ether (3×500 mL) and dried in vacuo to give 17.7 g (93%) of the title compound as a dark solid that was used as described to prepare 4-[2-(4-Chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-7-methyl-3H-benzoimidazol-5-yl]-piperazine-1-carboxylic acid tert-butyl ester and 4-[2-(4-Iodo-2-oxo-1,2-dihydro-pyridin-3-yl)-7-methyl-3H-benzoimidazol-5-yl]-piperazine-1-carboxylic acid tert-butyl ester; LCMS (M+H)+ m/z 436. (Note: A small peak (4-chloro-pyridin-2-one) in the LC/MS shows m/z 344, 346).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:2]1.[Cl-].[Al+3].[Cl-].[Cl-].Br[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(=S)=S>[CH:16]1([C:5]2[NH:1][CH:2]=[C:3]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:4]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: BrC1CCCCC1
Reactant: CCOC(=O)c1cc[nH]c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCOC(=O)c1c[nH]c(C2CCCCC2)c1
Temperature: 50 °C
Yield: 16 %

Procedure:
Under an argon atmosphere, to a solution of ethyl 1H-pyrrole-3-carboxylate (2.09 g) and aluminum(III) chloride (4.0 g) in carbon disulfide (30 mL) was added bromocyclohexane (1.84 mL) under ice-cooling with stirring, and the mixture was stirred at room temperature for 30 min. The mixture was heated to 50° C., and stirred for 2 hr. The reaction product was cooled to room temperature, poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→8:2), and recrystallized from hexane to give the title compound as a colorless solid (yield 530 mg, 16%).
Reaction SMILES: ClCl.[OH-:3].[Na+:4].[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16](=[O:18])C)[CH:10]=[CH:9]2.[Cl:19][O-].[Na+]>>[Cl:19][O-:3].[Na+:4].[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16]([OH:18])=[O:3])[CH:10]=[CH:9]2
Reactant: [OH-]
Reactant: CC(=O)c1ccc2cc(Br)ccc2c1
Agent: ClCl
Agent: [Na+]
Agent: [O-]Cl
Product: O=C(O)c1ccc2cc(Br)ccc2c1
Temperature: 0 °C

Procedure:
The title compound can be prepared by two procedures designated as procedure A and procedure B below. The starting material of formula II used in each of these procedures is prepared as follows: A sodium hypochlorite solution was prepared by introducing chlorine gas (11.2 g) into a solution of NaOH (15.3 g) in 200 ml of ice water. Solid (6-bromo-2-naphthalenyl)ethanone [9.5 g, 38.1 mmoles, prepared according to the procedure of R. B. Girdler et al., J. Chem. Soc. (C), 518 (1966)] was added to the stirred sodium hypochlorite solution at 0° C. and then the mixture was heated on a steam bath for 1 hr. The precipitate was removed by filtration. Sodium metabisulfite (5 g) was added to the cooled (0° C.) filtrate. The mixture was adjusted to pH 5 with concentrated HCl. The precipitate was collected and dried. The collected precipitate was crystallized from boiling ethanol by the addition of water to afford 5.5 g (two crops) of 6-bromo-2-naphthalenecarboxylic acid; mp 288°-290° C.; NMR (CDCl3) δ 7.68 (2d, J=8 Hz, J2 =2 Hz, 1H), 7.97 (m, 2H), 8.05 (d, J=8 Hz, 1H), 8.25 (d, H), 8.58 (d, 1H), IR (CHCl3), 2800, 1680, 1625, 1567 cm-1 ; UVλmax (EtOH) 333 nm (ε1080), 323 (880), 317 (1020), 286 (9040), 237 (54,350).
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.CO[CH:38]1[CH2:42][CH2:41][CH:40](OC)O1>C(O)(=O)C>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]4[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=4)[CH2:21][CH2:20]3)[C:9]3[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=3)=[O:7])=[CH:34][CH:35]=2)[CH:38]=[CH:42][CH:41]=[CH:40]1
Reactant: COC1CCC(OC)O1
Reactant: COc1ccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(N)cc2)cc1
Solvent: CC(=O)O
Product: COc1ccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(-n3cccc3)cc2)cc1
Yield: 82.6 %

Procedure:
4-Amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(4-methoxyphenyl)benzamide (237.0 mg, 0.50 mmol) was dissolved in acetic acid (5.0 ml), and the solution was mixed with 2,5-dimethoxytetrahydrofuran (0.065 ml, 0.50 mmol) and heated for 1 hour under reflux. After cooling, acetic acid was distilled off under a reduced pressure, the residue was dissolved in ethyl acetate, and the organic layer was washed with water and saturated brine, and dried on anhydrous sodium sulfate. Thereafter, the solvent was distilled off under a reduced pressure, and the resulting residue was purified by a silica gel column chromatography (hexane:ethyl acetate=1:4) to obtain 217.0 mg (82,7%) of the title compound in a colorless amorphous form.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[Br:11]Br.[OH-].[Na+]>C(O)(=O)C>[Br:11][C:6]1[C:7]([NH2:10])=[N:8][CH:9]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[CH:5]=1
Reactant: BrBr
Reactant: Nc1ccc(C2CC2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1ncc(C2CC2)cc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-cyclopropylpyridin-2-amine (1.33 g) in acetic acid (15 mL) was added bromine (762 μL) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was basified with 1N aqueous sodium hydroxide solution at 0° C., and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (1.11 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[C:14]([O:18][C:19](=[O:46])[CH2:20][N:21]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[Sn](C)(C)C)[C:22](=[O:35])[CH2:23][NH:24][C:25]([NH:27][C:28]1[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=1)=[O:26])([CH3:17])([CH3:16])[CH3:15].O>C1(C)C=CC=CC=1>[C:14]([O:18][C:19](=[O:46])[CH2:20][N:21]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:41]=1[C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1)[C:22](=[O:35])[CH2:23][NH:24][C:25]([NH:27][C:28]1[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=1)=[O:26])([CH3:17])([CH3:15])[CH3:16]
Reactant: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccccc2[Sn](C)(C)C)c1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccccc2C(=O)c2ccc(C(F)(F)F)cc2)c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 45.4 %

Procedure:
To a solution of 4-trifluoromethylbenzoyl chloride (53 μl, 0.36 mmol) in toluene (4 ml) is added dichlorobisacetonitrile palladium (12.5 mg, 0.036 mmol) at room temperature. Then, tert-butyl((2-trimethylstannylphenyl)-(2-(3-m-tolylureido)acetyl)amino)acetate (compound 25) (200 mg, 0.36 mmol) is added, and the mixture is stirred at 50° C. for 20 minutes. After addition of dichlorobisacetonitrile palladium (6.2 mg, 0.018 mmol), stirring is confinated for additional 10 minutes. To the reaction solution is added ice-cooled water. After stirring, the aqueous layer is extracted twice with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The residue is purified by subjecting to silica gel column chromatography to obtain the objective compound 26a (93 mg). Yield 46%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[C:26]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([C:30]1[CH:35]=[CH:34][C:33]([S:36]([N:20]2[CH2:21][CH2:22][CH:17]([N:15]3[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=4)=[N:16]3)[CH2:18][CH2:19]2)(=[O:38])=[O:37])=[CH:32][CH:31]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc(C(C)(C)C)cc4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 4-tert-butylbenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.