Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]([C:23](=[O:32])[C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[CH:25]=1)[NH:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[O:14][C:13]=2[C:21]=1[CH3:22])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:33][C:34]1[C:39](O)=[C:38]([F:41])[C:37]([F:42])=[C:36]([F:43])[C:35]=1[F:44].C1CCC(N=C=NC2CCCCC2)CC1>C(OCC)(=O)C>[F:33][C:34]1[C:39]([O:19][C:18]([CH:15]2[O:14][C:13]3[C:21]([CH3:22])=[C:9]([C:7]([NH:6][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:23](=[O:32])[C:24]4[CH:25]=[C:26]([CH3:31])[CH:27]=[C:28]([CH3:30])[CH:29]=4)=[O:8])[CH:10]=[CH:11][C:12]=3[O:17][CH2:16]2)=[O:20])=[C:38]([F:41])[C:37]([F:42])=[C:36]([F:43])[C:35]=1[F:44]
Reactant: Cc1cc(C)cc(C(=O)N(NC(=O)c2ccc3c(c2C)OC(C(=O)O)CO3)C(C)(C)C)c1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(C(=O)N(NC(=O)c2ccc3c(c2C)OC(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)CO3)C(C)(C)C)c1

Procedure:
In a vial, 97 mg (0.32 mm) of 7-[N′-tert-butyl-N′-(3,5-dimethyl-benzoyl)-hydrazinocarbonyl]-8-methyl-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid, 60 mg (0.35 mm) of pentafluorophenol, 60 mg (0.32 mm) of DCC and 3 mL of ethyl acetate were stirred at room temperature for 24 hours. The reaction mixture was transferred to a round bottom flask and evaporated to dryness. The residue was redissolved in CH2Cl2 and chromatographed on silica gel. Elution with 40% ethyl acetate in hexane yielded the pentafluorophenol ester, 7-[N′-tert-butyl-N′-(3,5-dimethyl-benzoyl)-hydrazinocarbonyl]-8-methyl-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid pentafluorophenyl ester, in a quantity of 80 mg. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.60 (d, 1H), 7.03 (s, 2H), 6.95 (d, 1H), 6.6 (q, 1H), 6.3 and 6.0 (d+d, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 2.251 and 2.230 (s+s, 6H), 2.052 and 1.903 (s+s, 3H), 1.58 and 1.574 (s+s, 9H) (many signals split); TLC. Rf=0.52 (1:1 hexane:ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=2[O:15][CH2:16][CH:17]2[CH2:19][O:18]2)=[CH:5][CH:4]=1.[C:24]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=2[O:15][CH2:16][CH:17]([OH:18])[CH2:19][N:33]2[CH2:34][CH2:35][N:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:31][CH2:32]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCCCc2ccccc2OCC2CO2)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CCCCc2ccccc2OCC(O)CN2CCN(c3ccccc3)CC2)cc1
Yield: 105.4 %

Procedure:
A solution of 185 mg of 2-{2-[4-(4-methoxyphenyl)butyl]phenoxymethyl}oxirane [prepared as described in Example 26(a)] and 96 mg of 1-phenylpiperazine in 5 ml of tetrahydrofuran was stirred at 60° C. for 24 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure. The oily residue thus obtained was purified by column chromatography through silica gel, using a 20:1 by volume mixture of methylene chloride and methanol as the eluent, to give 296 mg (yield 96%) of the title compound as a colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[C:11]([OH:14])=[N:12][CH:13]=1.[CH3:18][O:19][CH2:20][CH2:21]Br.O>CN(C)C=O>[Br:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[C:11](=[O:14])[N:12]([CH2:21][CH2:20][O:19][CH3:18])[CH:13]=1
Reactant: COCCBr
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1cc(Br)cc([N+](=O)[O-])c1=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 58.4 %

Procedure:
Cesium carbonate (14.88 g, 45.66 mmol) was added to a solution of 5-bromo-3-nitropyridin-2-ol (10.0 g, 45.7 mmol) and 2-bromoethyl methyl ether (4.29 mL, 45.66 mmol) in N,N-dimethylformamide (400 mL). After 3 h, additional 2-bromoethyl methyl ether (4.29 mL, 45.7 mmol) was added, and the reaction was heated to 60° C. After 4 h, water was added. The mixture was extracted with ethyl acetate (3×), and the combined organic extracts were washed with saturated brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→40% ethyl acetate/hexanes) gave the title compound (7.39 g). MS 277 (M).
Reaction SMILES: C(N(CC)CC)C.Br[CH:9]([N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12].[Cl:21][C:22]1[N:27]=[C:26]([OH:28])[CH:25]=[CH:24][CH:23]=1>C(#N)C>[Cl:21][C:22]1[N:27]=[C:26]([O:28][CH:9]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:25]=[CH:24][CH:23]=1
Reactant: Oc1cccc(Cl)n1
Reactant: CC(C)(C)C(=O)C(Br)n1cncn1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)C(Oc1cccc(Cl)n1)n1cncn1
Yield: 52 %

Procedure:
50.5 g (0.5 mol) of triethylamine were added dropwise to 123 g (0.5 mol) of crude 1-bromo-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one and 65 g (0.5 mol) of 6-chloro-2-hydroxy-pyridine in 250 ml of absolute acetonitrile at 24° to 30° C., while stirring. The mixture was stirred at room temperature for 3 hours and filtered and the filtrate was concentrated in vacuo. After treatment with water, the residue crystallized out. 76.6 g (52% of theory) of 1-(6-chloropyridin-2-yl-oxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one of melting point 103°-105° C. were obtained.
Reaction SMILES: [CH2:1]([N:8]([CH2:18][C:19]1(O)[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)[CH2:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:9]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[O:17][C:19]2([CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:23][CH2:24]2)[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CN(CC(=O)c2ccccn2)Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1ccccc1)C=C(c1ccccn1)O2
Temperature: 80 °C
Yield: 47.4 %

Procedure:
To tert-butyl 4-[[benzyl-[2-oxo-2-(2-pyridyl)ethyl]amino]methyl]-4-hydroxy-piperidine-1-carboxylate (190 mg, 0.43 mmol) in benzene (11 mL) was added 4-methylbenzenesulfonic acid (99 mg, 0.52 mmol) and reaction mixture was heated at 80° C. for 30 minutes. The reaction mixture was cooled, diluted with ethyl acetate and washed sequentially with sat. NaHCO3 and brine solution. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give residue, which was purified using silica gel column chromatography using EtOAc/DCM (10-100%) as eluent to give tert-butyl 8-benzyl-10-(2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undec-9-ene-3-carboxylate (86 mg, 45%). ESI-MS m/z calc. 421.5. found 422.2 (M+1)+; Retention time: 1.42 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 8.40-8.34 (m, 1H), 7.56 (dd, J=4.0, 3.5 Hz, 1H), 7.37-7.27 (m, 6H), 7.07 (s, 1H), 6.92 (d, J=1.5 Hz, 1H), 4.22 (s, 2H), 3.99-3.76 (m, 2H), 3.17 (t, J=11.8 Hz, 2H), 2.78 (s, 2H), 1.83 (s, 2H), 1.44 (s, 9H), 1.40 (d, J=4.4 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:19][CH2:18][CH2:17][C:16]3[C:15](=[NH:20])[NH:14][C:13](=N)[C:12]2=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[ClH:22].[CH3:23][O:24][C:25]1[CH:37]=[CH:36][CH:35]=[CH:34][C:26]=1[NH:27][C:28]1[S:29][CH2:30][C:31](=[NH:33])[N:32]=1.N=C1C2CCCCC=2C(=N)N1.Cl.N=C1NC(=N)CS1>>[ClH:22].[NH:20]=[C:15]1[C:16]2[CH2:17][CH2:18][CH2:19][CH:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:12]=2[C:13](=[C:30]2[S:29][C:28]([NH:27][C:26]3[CH:34]=[CH:35][CH:36]=[CH:37][C:25]=3[O:24][CH3:23])=[N:32][C:31]2=[NH:33])[NH:14]1
Reactant: COc1ccc(C2CCCC3=C2C(=N)NC3=N)cc1OC
Reactant: COc1ccccc1NC1=NC(=N)CS1
Agent: Cl
Agent: N=C1CSC(=N)N1
Agent: N=C1NC(=N)C2=C1CCCC2
Product: COc1ccccc1NC1=NC(=N)C(=C2NC(=N)C3=C2C(c2ccc(OC)c(OC)c2)CCC3)S1

Procedure:
When equivalent amounts of 4-(3,4-dimethoxyphenyl)-4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2-(o-methoxyanilino)-4-imino-2-thiazoline hydrochloride are substituted for the 4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2,4-diiminothiazolidine hydrochloride respectively, in the procedure described in Example 10, part A above, there is obtained as the product 1-imino-4-(3,4-dimethoxyphenyl)-4,5,6,7-tetrahydro-3-[2-(o-methoxyanilino)-4-imino-2-thiazolin-5-ylidene]isoindoline hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][S:10][CH3:11])=[CH:4][C:3]=1[NH2:12].[CH3:13][O:14][C:15]([N:17]=[C:18]=[S:19])=[O:16]>CC(C)=O>[CH3:13][O:14][C:15]([NH:17][C:18](=[S:19])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][S:10][CH3:11])=[CH:4][C:3]=1[NH:12][C:18]([NH:17][C:15]([O:14][CH3:13])=[O:16])=[S:19])=[O:16]
Reactant: COC(=O)N=C=S
Reactant: CSCOc1ccc(N)c(N)c1
Solvent: CC(C)=O
Product: COC(=O)NC(=S)Nc1ccc(OCSC)cc1NC(=S)NC(=O)OC

Procedure:
The 1,2-diamino-4-methylthiomethoxybenzene prepared above is dissolved in 60 ml. acetone and treated overnight with 6 g. methoxycarbonyl isothiocyanate at room temperature. The mixture is concentrated and the residue stirred with 500 ml. water and the brown solid filtered off. The residue is extracted with 250 ml. dichloromethane, filtered, treated with charcoal, and recrystallized from dichloromethanebenzene to afford 1,2-bis(3-methoxycarbonyl-2-thioureido)-4-methylthiomethoxybenzene.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:23][CH2:24][NH:25]C(OC(C)(C)C)=O)[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3].Cl>CCOC(C)=O>[ClH:22].[NH2:25][CH2:24][CH2:23][N:13]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[CH:10]1[CH2:9][CH2:8][N:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH2:12][CH2:11]1
Reactant: C=CCOC(=O)N1CCC(N(CCNC(=O)OC(C)(C)C)CCc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1CCC(N(CCN)CCc2ccc(Cl)cc2)CC1

Procedure:
1-Allyloxycarbonyl-N-[2-(tert-butoxycarbonylamino)ethyl]-N-[2-(4-chlorophenyl)ethyl]-piperidin-4-amine obtained in Step 1 was subjected to the deprotection reaction as described in Procedure 2 (4 N HCl in EtOAc). The crude product that was obtained in this step was used in the synthesis of Examples 8-13 without any further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:13](O)[CH2:14][OH:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[O:5]1[CH2:13][CH2:14][O:15][CH:4]1[C:3]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:2]=1[OH:1]
Reactant: OCCO
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(O)c(C2OCCO2)c1

Procedure:
The solution of 25 g (149.6 mmol) of 2-hydroxy-5-nitrobenzaldehyde in 500 ml of toluene is mixed with 100 ml of ethylene glycol, 2.85 g of p-toluenesulfonic acid monohydrate, and it is refluxed in a water separator for 5 hours. After cooling, it is poured into saturated sodium bicarbonate solution, extracted several times with ethyl acetate, the combined organic extracts are washed with saturated sodium chloride solution and dried on sodium sulfate. The residue that is obtained after filtration and removal of the solvent is further reacted without being purified.
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.Br[C:15]1[C:20]([F:21])=[C:19]([F:22])[C:18]([C:23]2[C:28]([F:29])=[C:27]([F:30])[C:26]([Br:31])=[C:25]([F:32])[C:24]=2[F:33])=[C:17]([F:34])[C:16]=1[F:35].[CH:36]1[C:49]2[C:40](=[CH:41][C:42]3[C:47]([C:48]=2[NH:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:39]=[CH:38][CH:37]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(=CC(=O)C)C1C=CC=CC=1.C(=CC(=O)C)C1C=CC=CC=1.[Pd].O>[Br:31][C:26]1[C:27]([F:30])=[C:28]([F:29])[C:23]([C:18]2[C:17]([F:34])=[C:16]([F:35])[C:15]([N:50]([C:48]3[C:49]4[C:40]([CH:41]=[C:42]5[C:47]=3[CH:46]=[CH:45][CH:44]=[CH:43]5)=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)=[C:20]([F:21])[C:19]=2[F:22])=[C:24]([F:33])[C:25]=1[F:32]
Reactant: c1ccc(Nc2c3ccccc3cc3ccccc23)cc1
Reactant: Fc1c(F)c(-c2c(F)c(F)c(Br)c(F)c2F)c(F)c(F)c1Br
Agent: [Pd]
Agent: CC(=O)C=Cc1ccccc1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1c(F)c(-c2c(F)c(F)c(N(c3ccccc3)c3c4ccccc4cc4ccccc34)c(F)c2F)c(F)c(F)c1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
In a nitrogen flow, 160 mg (0.282 mmol) of palladium bis(benzylideneacetone) and 170 mg (0.846 mmol) of tri-tert-butylphosphine were dissolved in 40 ml of toluene and then stirred for 15 minutes at room temperature. Then, 0.58 g (1.27 mmol) of 4,4′-dibromo-2,2′,3,3′,5,5′,6,6′-octafluoro-1,1′-biphenyl dissolved in 50 ml of toluene was dropped into the mixture and it was stirred for 30 minutes. Furthermore, 0.34 g (1.27 mmol) of N-(9-anthracenyl)-N-phenylamine was dissolved in 50 ml of toluene and was then dropped therein, followed by the addition of 0.18 g (1.91 mmol) of sodium tert-butoxide. Then, the mixture was heated and stirred for about 8 hours in an oil bath heated at 120° C. After returning the reaction solution to room temperature, 50 ml of water was added thereto and the resultant solution was then separated into an aqueous layer and an organic layer. Furthermore, the aqueous layer was extracted with toluene and ethyl acetate, and was then combined with the previous organic layer and dried with magnesium sulfate. The solvent was evaporated and then the residue was purified by silicagel-column chromatography (toluene:hexane=1:2) to obtain 0.55 g of 4-bromo-4′-[N-(9-anthracenyl)-N-phenylamino]-2,2′,3,3′,5,5′,6,6′-octafluoro-1,1′-biphenyl.
Reaction SMILES: S(O)(C)(=O)=O.[Cl:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([Cl:15])=[CH:9][C:8]=1[S:16][CH2:17][C:18](=O)[CH2:19][C:20]([O:22][CH3:23])=[O:21]>>[CH3:23][O:22][C:20](=[O:21])[CH2:19][C:18]1[C:9]2[C:10]([Cl:15])=[CH:11][C:12]([O:13][CH3:14])=[C:7]([Cl:6])[C:8]=2[S:16][CH:17]=1
Reactant: COC(=O)CC(=O)CSc1cc(Cl)cc(OC)c1Cl
Agent: CS(=O)(=O)O
Product: COC(=O)Cc1csc2c(Cl)c(OC)cc(Cl)c12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
MsOH (4.5 mL) was added to methyl 4-((2,5-dichloro-3-methoxyphenyl)sulfanyl)-3-oxobutanoate (1.03 g) at 0° C. The mixture was stirred at 0° C. for 10 min and then at room temperature for 1.5 h. The mixture was poured into ice water and extracted with EtOAc. The organic layer was separated, washed successively with saturated aqueous NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give a solid. The solid was washed with hexane to give the title compound (0.827 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:49])([CH3:48])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:47])([C@@:17]4([CH3:46])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([C:36]([O:38]CC2C=CC=CC=2)=[O:37])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4].C(O)(=O)C>C(O)C.O1CCOCC1.[Pd]>[CH:33]([C@H:30]1[C@@H:21]2[C@@H:22]3[C@@:17]([CH3:46])([CH2:18][CH2:19][C@@:20]2([C:36]([OH:38])=[O:37])[CH2:32][CH2:31]1)[C@@:16]1([CH3:47])[C@@H:25]([C@:26]2([CH3:29])[C@@H:13]([CH2:14][CH2:15]1)[C:12]([CH3:49])([CH3:48])[C@@H:11]([C:8]1[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=1)[CH2:28][CH2:27]2)[CH2:24][CH2:23]3)([CH3:35])[CH3:34]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COC(=O)c1ccc([C@H]2CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(C(=O)O)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-benzyl 9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate (0.2 g, 0.302 mmol) in ethanol (5 mL), 1,4-dioxane (7 mL), and acetic acid (0.5 mL, 8.73 mmol) was added Pd/C (10% by wt.) (0.1 g, 0.094 mmol). The mixture was flushed with N2 and was put on the Parr shaker under 30 psi H2. After 2 h, the reaction was checked by 1H NMR. The benzyl group had been removed, but the alkene still remained. The mixture was again flushed with N2. An additional 50 mg of 10% Pd/C was added and the mixture was pressurized to 40 psi H2. After stirring the mixture overnight, it reaction was removed from the Parr shaker and the palladium catalyst was removed by filtration. The filtrate was concentrated under reduced pressure to give the expected product, (1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-1-isopropyl-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (0.174 g, 100% yield), as a white solid. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.91 (d, J=8.24 Hz, 2H), 7.22 (d, J=8.55 Hz, 2H), 3.89 (s, 3H), 2.39 (dd, J=13.12, 3.05 Hz, 1H), 2.19-2.29 (m, 3H), 2.01-2.13 (m, 1H), 0.99 (s, 3H), 0.96 (s, 3H), 0.95 (s, 3H), 0.86 (d, J=6.71 Hz, 3H), 0.79-1.92 (m, 22H), 0.76 (d, J=6.71 Hz, 3H), 0.75 (s, 3H), 0.68 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[CH3:32][CH:33]([OH:37])[CH:34]([OH:36])[CH3:35].C([O-])([O-])=O.[K+].[K+].[I-].[Na+]>>[OH:36][CH:34]([CH3:35])[CH:33]([O:37][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6])[CH3:32]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Reactant: CC(O)C(C)O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CC(O)C(C)OCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Yield: 9 %

Procedure:
Following the general procedure of example 159, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indole-7-carboxamide (40.0 mg, 0.087 mmol), 2,3-butanediol (72 mg, 0.87 mmol), K2CO3 (35.0 mg, 0.35 mmol) and sodium iodide (0.5 mg) were reacted to give the title compound (4.0 mg, 8.9%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[N:22]=[C:23]=[O:24]>CN(C)C=O>[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[NH:22][C:23](=[O:24])[NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccc(F)cc2F)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 5 g of ethyl 2-aminothiazol-4-ylglyoxylate, 5.8 g of 2,4-difluorophenyl isocyanate and 30 ml of dimethylformamide. The resulting product was a white powder having the following physical properties.
Reaction SMILES: CC[N:3]=C=NCCCN(C)C.O.ON1C2C=CC=CC=2N=N1.N.O1CCOCC1.[C:30]([C:33]1[CH:34]=[C:35]([CH:61]=[CH:62][CH:63]=1)[CH2:36][N:37]1[CH2:42][CH2:41][CH:40]([CH2:43][NH:44][C:45](=[O:60])[CH2:46][NH:47][C:48](=[O:59])[C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([C:55]([F:58])([F:57])[F:56])[CH:50]=2)[CH2:39][CH2:38]1)(O)=[O:31]>CN(C=O)C.C(Cl)(Cl)Cl.CCN(CC)CC>[C:30]([C:33]1[CH:34]=[C:35]([CH:61]=[CH:62][CH:63]=1)[CH2:36][N:37]1[CH2:42][CH2:41][CH:40]([CH2:43][NH:44][C:45](=[O:60])[CH2:46][NH:47][C:48](=[O:59])[C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([C:55]([F:58])([F:57])[F:56])[CH:50]=2)[CH2:39][CH2:38]1)(=[O:31])[NH2:3]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCN(Cc2cccc(C(=O)O)c2)CC1
Reactant: CCN=C=NCCCN(C)C
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)c1cccc(CN2CCC(CNC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)CC2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
EDCI (10.7 mg), 1-hydroxybenzotriazole hydrate (7.5 mg), Et3N (15.4 mg), 0.5 M NH3 in dioxane (0.1 mL, 0.05 mmol) and DMF (0.5 mL) were added to a solution of 1-(3-carboxybenzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (19.4 mg, 0.041 mmol) in CHCl3 (2.5 mL). The reaction mixture was stirred at 25° C. for 20 h, washed with 2 N aqueous NaOH (2×2 mL) and brine (1 mL). After filtration through PTFE membrane filter, the solvent was removed under reduced pressure to afford 1-(3-carbamoylbenzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (compound No. 924) as a pale yellow solid (17.9 mg, 92%): The purity was determined by RPLC/MS (89%); ESI/MS m/e 447.3 (M++H, C24H27F3N4O3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[C:15]([CH2:30][N:31]([CH2:33][CH2:34][O:35][CH3:36])[CH3:32])=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:19]=4)[S:17][C:11]=3[N:10]([CH2:37][C:38]3[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=3[F:45])[C:9]2=[O:46])=[CH:4][CH:3]=1>N1C=CC=CC=1>[CH2:5]([NH:8][C:9]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[C:15]([CH2:30][N:31]([CH2:33][CH2:34][O:35][CH3:36])[CH3:32])=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:19]=4)[S:17][C:11]=3[N:10]([CH2:37][C:38]3[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=3[F:45])[C:9]2=[O:46])=[CH:6][CH:7]=1)=[O:46])[CH3:4]
Reactant: CCNC(=O)Nc1ccc(-c2sc3c(c2CN(C)CCOC)c(=O)n(-c2ccc(N)cc2)c(=O)n3Cc2c(F)cccc2F)cc1
Solvent: c1ccncc1
Product: CCNC(=O)Nc1ccc(-c2sc3c(c2CN(C)CCOC)c(=O)n(-c2ccc(NC(=O)NCC)cc2)c(=O)n3Cc2c(F)cccc2F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 108.2 %

Procedure:
Ethyl isothianate (36 mg) was added dropwise to a solution of the compound of Example 97 (0.10 g) in pyridine (1.00 ml) and the mixture was stirred at room temperature for 18 hours. After distilling off the solvent under reduced pressure, the obtained residue was partitioned between ethyl acetate and water, and the organic layer was washed with saturated brine and then dried over anhydride magnesium sulfate. The residue obtained by distilling off the solvent under the reduced pressure was recrystallized from methanol to give the title compound (0.06 g, 56%).
Reaction SMILES: C(OC(=O)C)(=O)C.C(OC(=O)CC)(=O)CC.[C:17]([O:25]C(=O)C1C=CC=CC=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:17]([OH:25])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(OC(=O)c1ccccc1)c1ccccc1
Agent: CCC(=O)OC(=O)CC
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1ccccc1

Procedure:
Acetic anhydride, propanoic anhydride, benzoic anhydride, monochloroacetyl anhydride, dichloroacetyl anhydride and benzoyl chlorides are preferred acylation agents.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:12]([O:19][CH2:20]Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CN(C=O)C>[CH2:12]([O:19][CH2:20][N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1cn[nH]c1
Reactant: ClCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COCn2cccn2)cc1
Reaction time: 96 h

Procedure:
To a solution of pyrazole (2.0 g, 29 mmol) in DMF (20 mL) is added potassium carbonate (12.4 g, 90 mmol) and benzyloxymethylchloride (4 mL, 32.3 mmol). The reaction is stirred for four days, then poured into water and extracted with EtOAc . The organic layer is washed with 1 N NaOH, dried over MgSO4 and concentrated. The residue is purified by column chromatography using EtOAc as eluent to afford the title compound as a light yellow oil: (M+1)+=189.