Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([N+:25]([O-])=O)[CH:23]=3)[NH:18][CH:17]=2)[CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].O.NN>CO.O.[Ni]>[C:5]([O:4][C:3](=[O:9])[N:2]([CH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH2:25])[CH:23]=3)[NH:18][CH:17]=2)[CH2:11]1)[CH3:1])([CH3:8])([CH3:6])[CH3:7]
Reactant: CN(C(=O)OC(C)(C)C)C1CCCC(c2c[nH]c3ccc([N+](=O)[O-])cc23)C1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C1CCCC(c2c[nH]c3ccc(N)cc23)C1
Yield: 97.1 %

Procedure:
To a solution of tert-butyl methyl-(3-(5-nitro-1H-indol-3-yl)cyclohexyl)carbamate (0.38, g 1.02 mmol) in dry MeOH (10 mL) was added Ra—Ni (0.1 g as a slurry in water) and hydrazine hydrate (0.50 mL, 10.20 mmol). The resulting mixture was immersed in a preheated oil bath and refluxed for 15 min. or until the solution became clear. The reaction was cooled and filtered trough celite, washed with MeOH (20 mL) and the solvent evaporated. The crude was purified on column chromatography (2 M NH3 in MeOH:CH2Cl2, 2:98) to give the title compound as a light brown solid (0.34 g, 97%). 1H-NMR (CDCl3) δ 1.31-1.66 (m, 4H), 1.48 (s, 9H), 1.75-1.80 (m, 1H), 1.89-1.96 (m, 1H), 2.03-2.11 (m, 2H), 2.74 (s, 3H), 2.84-2.93 (m, 1H), 3.52 (s, 2H, NH), 4.13-4.26 (m, 1H), 6.65 (dd, 1H, J=2.1, 8.4 Hz), 6.88 (d, 1H, J=2.4 Hz), 6.95 (s, 1H), 7.15 (d, 1H, J=8.4 Hz), 7.72 (s, 1H, NH); EI-MS (m/z, %), 343 (100).
Reaction SMILES: [CH:1]12[CH2:24][CH2:23][CH:4]([C:5]([C:7]3[N:12]=[C:11]4[N:13]([CH3:22])[C:14](=[O:21])[N:15]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:10]4=[CH:9][CH:8]=3)=[CH:6]1)[CH2:3][NH:2]2.CCN(C(C)C)C(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:18][C:17]([CH3:19])([CH3:20])[CH2:16][N:15]1[C:10]2[C:11](=[N:12][C:7]([C:5]3[CH:4]4[CH2:23][CH2:24][CH:1]([CH:6]=3)[N:2]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:3]4)=[CH:8][CH:9]=2)[N:13]([CH3:22])[C:14]1=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CCC3CN4)nc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CCC3CN4S(C)(=O)=O)nc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-(2-Azabicyclo[2.2.2]oct-5-en-5-yl)-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2-5, 25 mg, 0.08 mmol, 1.0 equiv) was added to anhydrous DCM (0.80 mL). To this solution was added DIPEA (40 μL, 0.23 mmol, 3.0 equiv) and methanesulfonyl chloride (12 μL, 0.15 mmol, 2.0 equiv) and the resulting mixture was allowed to stir at room temperature for 10 min. Following this duration, LCMS showed consumption of starting material. Saturated NaHCO3 (3 mL) and ethyl acetate (3 mL) were then added and the layers were separated. The aqueous layer was back-extracted with ethyl acetate (3×3 mL) and the combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give a yellow oil. Purification by reverse-phase HPLC (10-100% CH3CN:0.1% TFA in H2O) afforded 4-1 as a white solid. MS m/z (M+H): calculated=405.1955; observed=405.1952.
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][C@@H:14]3[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15]3)[CH:8]=[N:7][C:6]=2[N:5]([CH3:21])[C:4](=[O:22])[C:3]=1[F:23].[F:24][C:25]1[CH:31]=[C:30]([I:32])[CH:29]=[CH:28][C:26]=1[NH2:27].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].CC(N(C)C)=O>C1COCC1>[CH3:19][C:16]1([CH3:20])[O:15][C@H:14]([CH2:13][N:9]2[C:10](=[O:12])[C:11]3[C:2]([NH:27][C:26]4[CH:28]=[CH:29][C:30]([I:32])=[CH:31][C:25]=4[F:24])=[C:3]([F:23])[C:4](=[O:22])[N:5]([CH3:21])[C:6]=3[N:7]=[CH:8]2)[CH2:18][O:17]1
Reactant: Cn1c(=O)c(F)c(Cl)c2c(=O)n(C[C@@H]3COC(C)(C)O3)cnc21
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cn1c(=O)c(F)c(Nc2ccc(I)cc2F)c2c(=O)n(C[C@@H]3COC(C)(C)O3)cnc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Combine (R)-5-chloro-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (5.00 g, 14.5 mmol) and 2-fluoro-4-iodoaniline (3.45 g, 14.5 mmol) in THF (25 mL). Cool in an ice-bath. Add lithium hexamethyldisilazide (1.0 M in THF, 36.4 mL, 36.4 mmol) maintaining the temperature below about 10° C. After 10 minutes, warm to ambient temperature. After 30 minutes, heat to 55° C. After 20 hour, cool to ambient temperature, add dimethylacteamide (35 mL) and evaporate in vacuo to remove most of the THF. Cool the remaining mixture in an ice-bath then add water (17.5 mL) to form a solid. Add water (20 mL), then collect the solid by filtration, rinse with water (3×15 mL), heptane (15 mL), and dry in vacuo to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ10.14 (s, 1H), 8.60 (s, 1H), 7.68 (d, 1H, J=10.4, 2.0 Hz), 7.52 (d, 1H, J=8.8 Hz), 6.96 (td, 1H, J=8.8, 6.0 Hz), 4.41 (m, 1H), 4.25 (dd, 1H, J=13.6, 3.6 Hz), 4.06 (dd, 1H, J=8.8, 6.4 Hz), 3.98 (dd, 1H, J=13.6, 7.6 Hz), 3.78 (dd, 1H, J=9.2, 5.6 Hz), 3.58 (s, 3H), 1.37 (s, 3H), 1.23 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ161.1 (d, J=4.4 Hz), 155.7 (d, J=8.8 Hz), 155.4, 153.3, 151.1 (d, J=109 Hz), 135.6, 133.6 (d, J=7.3 Hz), 133.1 (d, J=3.7 Hz), 127.9 (d, J=13.2 Hz), 125.2 (d, J=6.5 Hz), 123.9 (d, J=21.9 Hz), 109.1, 95.1 (d, J=4.4 Hz), 87.1 (d, J=7.3 Hz), 72.2, 66.1, 48.9, 28.8, 26.6, 25.0; 19F NMR (376 MHz, DMSO-d6) δ-124.5, −149.3; MS (M+H)+m/z calcd 545.0. found 545.0.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21]>C(Cl)Cl.CN(C=O)C>[CH2:20]([N:22]([CH2:23][CH3:24])[C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[C:2]([F:1])([F:13])[F:12])[CH3:21]
Reactant: O=C(O)c1ccccc1C(F)(F)F
Reactant: CCNCC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.4 %

Procedure:
To a solution of 2-trifluoromethylbenzoic acid (20.0 g, 105 mmol) in 500 mL of methylene chloride was added oxalyl chloride (18.4 mL, 210 mmol) followed by ˜8 drops of DMF. The reaction was allowed to stir at ambient temperature for 4 h and then was concentrated in vacuo to a solid. The solid was taken up in 500 mL of methylene chloride and then there was added diethylamine (24 mL, 231 mmol) dropwise as a solution in 50 mL of methylene chloride. The resulting mixture was allowed to stir at ambient temperature for 18 h. The reaction was concentrated in vacuo. The residue was diluted with EtOAc, washed sequentially with 1N HCl, sat'd. aq. NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated to afford 22 g (85%) of the title compound as an oil. 1H NMR (CDCl3): δ 7.68 (d, 1H, J=7.7 Hz), 7.57 (t, 1H, J=7.4 Hz), 7.49 (t, 1H, J=7.7 Hz), 7.32 (d, 1H, J=7.1 Hz), 3.90-3.82 (m, 2H), 3.29-3.22 (m, 2H), 1.23 (t, 3H, J=7.2 Hz), 1.03 (t, 3H, J=7.2 Hz). LRMS (ESI): 246.12 (M+H)+.
Reaction SMILES: O.O.O.O.O.O.O.O.O.[S-2:10].[Na+].[Na+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[CH2:13]([S:10][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccccc1
Reactant: [S-2]
Agent: [Na+]
Solvent: O
Product: c1ccc(CSCc2ccccc2)cc1
Reaction time: 8 h
Yield: 188.5 %

Procedure:
Sodium sulphide nonahydrate (2.40 g, 0.01 mol), benzyl chloride (1.26 g, 0.01 mol), water (3 ml) and compound 1 (0.5 mmol) were stirred at 70°-78° C. for 20 minutes. The reaction mixture was poured into water and left overnight at room temperature. The white crystals thus obtained were filtered off and dried to give 2.02 g of benzyl sulphide.
Reaction SMILES: C([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])C.[H][H].[CH2:12]1COC[CH2:13]1>>[CH2:12]([CH:4]([OH:5])[CH2:3][CH2:6][CH2:7][CH2:8][CH3:9])[CH3:13]
Reactant: [H][H]
Reactant: C1CCOC1
Reactant: CCCCC(C=O)CC
Product: CCCCCC(O)CC
Yield: 99.5 %

Procedure:
3 g of catalyst A (3% Ru/SiO2) were placed in a 300 ml pressure reactor. The reactor was subsequently charged with 150 ml of a 33% strength solution of 2-ethylhexanal in THF. The hydrogenation was carried out at 130° C. and a pressure of 250 bar using pure hydrogen. The hydrogenation was continued until no more hydrogen was taken up and the reactor was subsequently vented. After distilling off the solvent, the reaction product was analyzed by gas chromatography. 2-Ethylhexanal had been reacted completely. 99.5% of ethylhexanol were obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH2:31][NH2:32].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:17][C:12]1[C:11]2[C:15](=[CH:16][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:32][CH2:31][CH2:30][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[O:23][CH3:22])[CH:5]=3)=[CH:9][CH:10]=2)[NH:14][N:13]=1
Reactant: CS(=O)(=O)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Reactant: COc1ccccc1CCN
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1CCNc1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 140 °C
Yield: 16.2 %

Procedure:
A mixture of 6-[2-amino-6-(methylsulfonyl)-4-pyrimidinyl]-1H-indazol-3-amine (500 mg, 1.64 mmol), 2-[2-(methyloxy)phenyl]ethanamine (500 mg, 3.31 mmol), and Hunig's base (2 mL) in NMP (3 mL) was heated for 4 hours at 140° C. in a BiotageInitiator® microwave synthesizer. Upon cooling, the mixture was decanted to remove the solids, and the resulting solution was concentrated to dryness. The crude material was purified by RPHPLC (gradient: 10% CH3CN/H2O to 30% CH3CN/H2O) to afford the title compound (100 mg) as a yellow solid. LC-MS (ES) m/z=376 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 2.81-2.84 (m, 2H), 3.52 (m, 2H), 3.74 (s, 3H), 5.37 (s, 2H), 6.01 (s, 2H), 6.28 (s, 1H), 6.76-6.86 (m, 4H), 7.22 (t, J=8.4 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.84 (s, 1H), 11.51 (s, 1H).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3](O)=O.[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[OH:19])C=O)[CH3:9].NC1C=CC=CC=1.S(=O)(=O)(O)O>N1C=CC=CC=1>[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[OH:19])[CH:3]=[CH:2][C:1]([OH:7])=[O:6])[CH3:9]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: O=C(O)CC(=O)O
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Solvent: Nc1ccccc1
Product: CCOc1cc(C=CC(=O)O)ccc1O
Reaction time: 3 h
Yield: 52.9 %

Procedure:
Malonic acid (1.56 g) and pyridine (3.0 ml) were placed in an egg-plant type flask (100 ml). Further, 3-ethoxy-4-hydroxybenzaldehyde (1.66 g) and aniline (30 μl) were added thereto and a reaction was performed at 55° C. for 3 hours. The reaction solution was acidified by adding dilute sulfuric acid. The crude crystals were obtained by filtration, washed with water, and then dried to obtain the above-identified compound (1.1 g, 56.1%) as a light yellowish crystal. Melting point: 157°-158° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[NH2:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)=[O:6].[CH3:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O>CO>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:5]([C:4]2[CH:15]=[CH:16][C:17]3[N:18]=[C:19]([C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=4[CH3:22])[NH:1][C:2]=3[CH:3]=2)=[O:6])[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccc(C(=O)Nc2cccc(Cl)c2)cc1N
Reactant: Cc1ccccc1C=O
Solvent: CO
Product: Cc1ccccc1-c1nc2ccc(C(=O)Nc3cccc(Cl)c3)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3,4-diamino-N-(3-chloro-phenyl)-benzamide (0.1 mL in 0.2 M DMSO solution), 2-methyl benzaldehyde (0.1 mL in 0.2 M toluene solution) and FeCl3 (0.05 mL in 0.02M THF solution) was stirred in open air at ambient temperature overnight. The mixture was then diluted by MeOH and the whole was loaded onto a solid phase extraction (SPE) cartridge that contained strong cation exchange (SCX) (1 g media in 6 mL cartridge, United Chemical Technology). Wash-to-waste (5 mL MeOH) was followed by elute-to-collect (5 mL 20:2:1 ethyl acetate-MeOH-Et3N) and, after evaporation of volatiles, the crude was further purified by silica gel column chromatography to give 2-o-tolyl-3H-benzoimidazole-5-carboxylic acid (3-chloro-phenyl)-amide as white powder: MS (m/z) 362 (M+1).
Reaction SMILES: C(O[CH:5]([C:17]1[N:21]([CH2:22][C:23]2S[C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:27]=2)[C:20]([CH2:32][CH2:33][CH2:34][CH3:35])=[N:19][CH:18]=1)[CH:6]([CH2:11][C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[C:7]([O:9][CH3:10])=[O:8])(=O)C.[N:36]12CCCN=C1CCCC[CH2:37]2>C1(C)C=CC=CC=1>[CH2:32]([C:20]1[N:21]([CH2:22][C:23]2[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:37][N:36]=2)[C:17](/[CH:5]=[C:6](\[CH2:11][C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)/[C:7]([O:9][CH3:10])=[O:8])=[CH:18][N:19]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCc1ncc(C(OC(C)=O)C(Cc2cccs2)C(=O)OC)n1Cc1ccc(C(=O)OC)s1
Reactant: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)OC)n1Cc1ccc(C(=O)OC)cn1
Temperature: 80 °C

Procedure:
A mixture of methyl 3-acetoxy-3-[2-n-butyl-1-{(5-carbomethoxy-2-thienyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methylpropanoate (1.99 g, 3.88 mmol) in dry toluene (150 ml) was treated with 17 ml of 1,8-diazabicyclo-[ 5.4.0]undec-7-ene (DBU) and the resulting solution was heated at 80° C. under argon for 1 hour. The solvent was evaporated, the residue triturated with diethyl ether and activated charcoal was added. After filtration, the filtrate was concentrated to give 6.29 g of an oil that was chromatographed over silica gel with hexane/ethyl acetate (1:1) to give 0.43 g (24%) of methyl (E)-3-[2-n-butyl-1-{(5-carbomethoxy-2-thienyl)methyl)-1H-imidazol-5-yl-2-(2-thienyl)methyl-2-propenoate.
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[F:5][C:6]1[C:11]2[NH:12][C:13](=[O:15])[O:14][C:10]=2[CH:9]=[C:8]([N+:16]([O-:18])=[O:17])[CH:7]=1.N12CCCN=C1CCCCC2>CN(C=O)C>[F:5][C:6]1[C:11]2[N:12]([CH:2]([CH3:4])[CH3:3])[C:13](=[O:15])[O:14][C:10]=2[CH:9]=[C:8]([N+:16]([O-:18])=[O:17])[CH:7]=1
Reactant: O=c1[nH]c2c(F)cc([N+](=O)[O-])cc2o1
Reactant: CC(C)I
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)n1c(=O)oc2cc([N+](=O)[O-])cc(F)c21

Procedure:
Prepared from 2-iodopropane (0.76 ml, 7.57 mmol), 4-fluoro-6-nitro-1,3-benzoxazol-2(3H)-one (EXAMPLE 86, Step 5, 1.2 g, 6.06 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.13 ml, 7.57 mmol) in DMF (10 ml) according to the method of EXAMPLE 86, Step 6 (0.87 g, 60%); mp 122-3° C.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([OH:12])[CH:8]=[CH:7][CH:6]=2)[CH3:2].[H-].[Na+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>CN(C)C=O.O>[CH3:27][O:26][C:24](=[O:25])[CH2:23][O:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[C:3]([CH2:1][CH3:2])[N:4]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)CBr
Reactant: CCc1cc2c(O)cccc2n1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc2c(OCC(=O)OC)cccc2n1Cc1ccccc1
Reaction time: 0.67 h
Yield: 68.3 %

Procedure:
2-ethyl-4-hydroxy-1-(phenylmethyl)-1H-indole (1.56 g, 6.2 mmol) is treated with 248 mg (6.2 mmol) of 60% NaH/mineral oil in dimethylformamide and the mixture stirred for 0.67 hours. 0.6 mL(6.2 mmol) of methyl bromoacetate is added and the mixture stirred for 17 hours. The reaction mixture is diluted with water and then extracted with ethyl acetate. The ethyl acetate solution is washed with brine, dried, and concentrated at reduced pressure. The product is purified by chromatography over silica gel eluting with 20% EtOAc/hexane, to give 1.37 g (69% yield) of [[2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid methyl ester, 89-92° C.
Reaction SMILES: O[C@@H]([C@@H:4]1[C@@H:7]([C@@H:8](C)[C:9](=O)[C:10](=[N+]=[N-])[C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])[NH:6][C:5]1=[O:21])C.[C:22]1([CH3:28])[CH:27]=[CH:26]C=CC=1>C(OCC)(=O)C>[C:5]([NH:6][C:9]1[CH2:8][C@@H:7]2[CH2:4][C:5](=[O:21])[N:6]2[C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:26][CH:27]=[CH:22][CH:28]=1)=[O:12])(=[O:21])[CH3:4]
Reactant: Cc1ccccc1
Reactant: C=CCOC(=O)C(=[N+]=[N-])C(=O)[C@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O
Solvent: CCOC(C)=O
Product: CC(=O)NC1=C(C(=O)OCc2ccccc2)N2C(=O)C[C@H]2C1
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture of crystalline diazo keto ester 4 (45 mg, 0.152 mmol) rhodium octanoate (1.2 mg, 0.00154 mmol) and anhydrous toluene (3.0 ml) was heated in an oil bath at 80° and under a nitrogen atmosphere for 15 minutes. (Note: gas evolution occurred at room temperature before heating). After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (3 ml), dried over magnesium sulfate, filtered, evaporated under vacuum and stripped with methylene chloride to afford 5 as a pale green oil (41 mg, 100%).
Reaction SMILES: ClCCCC([NH:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([S:24](=[O:27])(=[O:26])[NH2:25])[C:16]=1[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:11]([OH:13])=[O:12])=O.Cl[CH:29]([CH2:33][CH3:34])[C:30](N)=[O:31].[OH-:35].[K+].Cl>O>[O:17]([C:16]1[C:15]([S:24](=[O:26])(=[O:27])[NH2:25])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[NH:7][CH2:34][CH2:33][CH2:29][C:30]([OH:35])=[O:31])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(NC(=O)CCCCl)c1Oc1ccccc1
Reactant: [OH-]
Reactant: CCC(Cl)C(N)=O
Agent: Cl
Agent: [K+]
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)O)cc(NCCCC(=O)O)c1Oc1ccccc1
Yield: 120.7 %

Procedure:
The chlorobutyramide 3-(γ-chlorobutyrylamino)-4-phenoxy-5-sulfamylbenzoic acid (11.0 g) was added to a solution of KOH (40 g) in water 100 ml. The resulting solution was stirred and heated under reflux overnight. After cooling it was acidified with 3 N acqueous HCl, chilled by adding ice and the product collected, washed and air-dried. A recrystallization from aq. acetone gave 9.80 g (77% on two steps) of N-(2-phenoxy-3-sulfamyl-5-carboxyphenyl)-γ-aminobutyric acid as colorless crystals with m.p. 240°-241°; ir (Nujol) 3400, 3300, 2600 (broad), 1700, 1610, 1590, and 1550 cm-1 ; nmr (CDCl3 /d6 -DMSO) 1.4-2.3 (m, 4H), 3.15 (m, 2H), 4.2 (broad, NH), 6.43 (s, SO2NH2), 6.65-7.4 (m, C6H5), 7.57 (d, J=2, CH), and 7.92 ppm (d, CH); mass spectrum m/e 283 (100%) and 394 (M+ ).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)Cl>[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([C:19](=[O:21])[CH3:20])[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Cl
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCC(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Phenylpiperidine (87 mmol) and pyridine (96 mmol) are dissolved in dry CH2Cl2 (100 ml) and acetylchloride (96 mmol) in CH2Cl2 (40 ml) is added dropwise to the stirred solution at 10° C. The reaction is stirred for 1 hour at rt. The mixture is extracted three times with water and the water phase is extracted again with CH2Cl2. The combined organic phases are dried over sodium sulfate and evaporated. A pale brown oil with Rf=0.13 (ethyl acetate/hexane=1:1) is obtained.
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].Br[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=O>O>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([C:7]2[N:4]=[C:1]([CH3:2])[S:3][CH:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc(C(=O)CBr)c1
Reactant: CC(N)=S
Solvent: O
Product: COc1cccc(-c2csc(C)n2)c1
Temperature: 140 °C
Yield: 82.9 %

Procedure:
A mixture of thioacetamide (8.0 g, 106.0 mmol) and 2-bromo-1-(3-methoxy-phenyl)-ethanone (2.0 g, 8.81 mmol) was heated at 140° C. for 6 h under nitrogen atmosphere. After completion of the reaction mixture (TLC monitoring), water (50 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 2% EtOAc-Hexane) to get the desired product (1.5 g, 83%).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:19](OC)(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[SH:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:27]=[C:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[S:22][C:1]([C:3]2[N:8]=[C:7]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH:6]=[CH:5][CH:4]=2)=[N:2]1
Reactant: CC(C)(C)OC(=O)NCCc1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 64.4 %

Procedure:
tert-Butyl 2-(6-cyano-2-pyridyl)ethylcarbamate (2.0 g, 8.1 mmol) and methyl thiosalicylate (2.0 g, 12 mmol) were dissolved in toluene (10 ml), and triethylamine (5.0 ml, 36 mmol) was added thereto. The mixture was refluxed for 14 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (3:2, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (2.0 g, 64%) as white crystals.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:31]=[CH:30][C:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](OCCCC)=O)[CH2:19][CH2:18]3)=[CH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:32]([C:35]1[CH:36]=[N:37]C(Br)=[N:39][CH:40]=1)[CH2:33][CH3:34]>>[CH3:1][S:2]([C:5]1[CH:31]=[CH:30][C:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]4[N:39]=[CH:40][C:35]([CH2:32][CH2:33][CH3:34])=[CH:36][N:37]=4)[CH2:19][CH2:18]3)=[CH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CCCCOC(=O)N1CCC(c2ccc(COc3ccc(S(C)(=O)=O)cc3)nc2)CC1
Reactant: CCCc1cnc(Br)nc1
Product: CCCc1cnc(N2CCC(c3ccc(COc4ccc(S(C)(=O)=O)cc4)nc3)CC2)nc1

Procedure:
The title compound was prepared from tort-butyl 4-[2-(4-methanesulfonylphenoxymethyl)pyridin-5-yl]piperidine-1-carboxylate (Example 1) (50 mg, 0.11 mmol) and 5-propyl-2-bromopyrimidine (26 μL, 0.22 mmol) following a procedure analogous to that in Example 48 as a white crystal (31 mg, yield 60%).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[C:14]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[C:12]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:11]=1[C:34](=[O:36])[CH3:35])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=1.Cl>C(OCC)(=O)C>[OH:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=[CH:35][C:34]([C:11]2[C:12]([O:25][C:26](=[O:33])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:13][C:14]([O:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][C:10]=2[O:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:36])=[CH:40][CH:39]=1
Reactant: CC(=O)c1c(OC(=O)c2ccccc2)cc(OC(=O)c2ccccc2)cc1OC(=O)c1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(Oc1cc(OC(=O)c2ccccc2)c(C(=O)C=Cc2ccc(O)cc2)c(OC(=O)c2ccccc2)c1)c1ccccc1
Reaction time: 96 h

Procedure:
2',4',6'-tribenzoyloxyacetophenone (83.5 g) and 4-hydroxybenzaldehyde are dissolved in 850 ml of ethyl acetate. Hydrogen chloride is led in at a temperature of 0° for 6 h. The reaction mixture is then kept at about 5° for 4 days and then freed from most of the hydrogen chloride with nitrogen passed through the solution. The ethyl acetate is evaporated and the residue mixed with 300 ml benzene and evaporated to remove the remaining hydrogen chloride. The residue is mixed with abs. ethanol (460 ml). A crystalline solid is formed, collected by filtration and then suspended in ether and refluxed with stirring for 2 h. After cooling, filtration and washing with ether there is obtained 41 g of 4-hydroxy-2',4',6'-tribenzoyloxy-chalcone with m.p. 198°-200°. This compound is dissolved in 1400 ml dioxane and hydrogenated at room temperature and atmospheric pressure with 4 g of 10 percent Pd/C as catalyst. When the theoretical amount of hydrogen has been absorbed the reaction is stopped, the catalyst removed by filtration and the dioxane evaporated in vacuo. The residue is recrystallized twice from abs. ethanol and 28 g of 3-(4-hydroxyphenyl)-2',4',6'-tribenzoyloxypropiophenone is obtained with a m.p. of 156°-8°.