Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])/[CH:6]=[CH:7]/[C:8]([OH:10])=O.[C:22]([O:25][CH2:26][CH3:27])(=[S:24])[CH3:23]>C(OCC)(=O)C>[CH2:26]([O:25][C:22](=[S:24])[CH2:23][C:8](=[O:10])/[CH:7]=[CH:6]/[C:5]1[CH:11]=[CH:12][C:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:27]
Reactant: CCOC(C)=S
Reactant: COc1cc(/C=C/C(=O)O)ccc1O[Si](C)(C)C(C)(C)C
Solvent: CCOC(C)=O
Product: CCOC(=S)CC(=O)/C=C/c1ccc(O[Si](C)(C)C(C)(C)C)c(OC)c1
Yield: 60 %

Procedure:
The title compound was prepared in the same manner as in Step 1 of Example C-1, except that an equimolar amount of each of trans-3-methoxy-4-tert-butyldimethylsilyloxy-cinnamic acid prepared in Step 1 of Example C-10 and ethyl thioacetate was used in place of trans-cinnamic acid and ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].I[CH2:14][CH2:15][CH3:16]>O1CCCC1>[CH3:1][C:2]1[N:6]([CH2:14][CH2:15][CH3:16])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCn1c(C)nc2ccccc21
Reaction time: 0.33 h

Procedure:
To a flask were added 2.0 g 2-methylbenzimidazole and 40 ml tetrahydrofuran and the mixture was cooled to 10 C under nitrogen. 0.9 g Sodium hydride were added in portions and the reaction mixture was stirred for 20 minutes. 3.9 g 1-iodopropane were added and the mixture was heated to 45 C for 6 hours. The mixture was quenched slowly with 40 ml water, extracted twice with ethyl acetate and washed with water. Following solvent removal, the product was purified by silica gel chromatography using pure ethyl acetate to 5% methanol in ethyl acetate. A pale yellow oil was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][CH3:22])[CH:17]=2)[CH:12]([C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[CH:11]1[C:32]([O:34][CH3:35])=[O:33].[H-].[Na+].Br[CH2:39][CH2:40][CH2:41][OH:42]>CN(C=O)C>[OH:42][CH2:41][CH2:40][CH2:39][O:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][CH3:22])[CH:17]=2)[CH:12]([C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[CH:11]1[C:32]([O:34][CH3:35])=[O:33]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1O)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Reactant: OCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCCCO)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.5 %

Procedure:
Methyl (1RS,2RS,3RS)-3-(2-Hydroxy-4-methoxy-phenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylate (0.14 g, 0.29 mmol) in dry DMF (1 ml) was added to NaH (9 mg, 0.38 mmol) in a small volume of dry DMF. The mixture was stirred at ambient temperature for 20 min. then 3-bromopropan-1-ol (37 μl, 0.41 mmol) was added. After stirring for 1 h. the product was partitioned between 3 M aqueous HCl and ethyl acetate. The organic layer was washed with water then brine, then dried (MgSO4 anhyd.) filtered and evaporated to give an oil. The product was purified by column chromatography to provide methyl (1RS,2RS,3RS)-3-[2-(3-Hydroxyprop-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (0.1 g, 65%)(1H-NMR indicated some epimerization had occurred at C-2). This material was used without further purification. Methyl (1RS,2RS,3RS)-3-[2-(3-Hydroxyprop-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylate (0.04 g, 0.075 mmol) was dissolved in methanol (2 ml) and aqueous potassium hydroxide added (2 M, 0.22 ml, 0.44 mmol). The mixture was stirred under reflux overnight then cooled, diluted with water, acidified with 3 M aqueous hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with water and brine, dried (MgSO4 anhydrous), filtered and evaporated to give an oil. The product was purified by chromatography on silica-gel (eluant: ethyl acetate/hexane/3% acetic acid) to give 12 mg of free acid which was converted to its dicyclohexylamine salt. m.p. 110-112° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9](=[O:11])[NH:8][C:7]=2[CH:12]=1.Cl.Cl[CH2:17][C:18]1[CH:19]=[C:20]([C:24]2[N:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:26][N:25]=2)[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[N:33]1([CH2:32][CH2:31][O:30][C:27]2[CH:28]=[N:29][C:24]([C:20]3[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=3)[CH2:17][N:8]3[C:7]4[CH:12]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=[CH:5][C:6]=4[S:10][C:9]3=[O:11])=[N:25][CH:26]=2)[CH2:34][CH2:35][O:36][CH2:37][CH2:38]1
Reactant: ClCc1cccc(-c2ncc(OCCN3CCOCC3)cn2)c1
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=c1sc2ccc(C(F)(F)F)cc2n1Cc1cccc(-c2ncc(OCCN3CCOCC3)cn2)c1
Temperature: 70 °C
Reaction time: 120 h

Procedure:
A suspension of 89 mg (0.405 mmol) of 5-trifluoromethyl-3H-benzothiazol-2-one, 150 mg (0.405 mmol) of 4-{2-[2-(3-chloromethylphenyl)pyrimidin-5-yl-oxy]ethyl}morpholine hydrochloride and 286 mg (2.02 mmol) of potassium carbonate in 8 ml of acetonitrile are stirred at 70° C. for 5 days. 30 ml of water are added to the reaction mixture, with a precipitate slowly forming. The precipitate is filtered off with suction, washed with water and dried.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:21][C:22]1([CH3:25])[CH2:24][O:23]1>C(#N)C>[CH3:21][C:22]([OH:23])([CH3:25])[CH2:24][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CC1(C)CO1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
A suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (514.3 mg, 2.65 mmol), cesium carbonate (1.295 g, 3.98 mmol) and 2,2-dimethyloxirane (0.589 mL, 6.63 mmol) in acetonitrile (5 mL) was heated at 130° C. under microwave for 1 h. The resulting mixture was concentrated. The residue was triturated with dichloromethane and stirred at room temperature for 30 min and filtered. The filtrate was concentrated to give 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (0.4289 g). This material was used in subsequent Suzuki coupling reactions without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.84 (d, J=0.4 Hz, 1H), 7.55 (d, J=0.7 Hz, 1H), 4.02 (s, 2H), 4.01 (s, 1H), 1.25 (s, 12H), 1.04 (s, 6H).
Reaction SMILES: [NH2:1][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])=[CH:3][C:4]([O:6]CC)=O.[H-].[Na+].[F:18][C:19]([F:32])([F:31])[C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27](=O)[O:28]C)=[N:24][CH:25]=1>CN(C)C=O>[F:31][C:19]([F:18])([F:32])[C:20]1[CH:21]=[CH:22][C:23]([N:26]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:15])[NH:1][C:27]2=[O:28])=[N:24][CH:25]=1
Reactant: CCOC(=O)C=C(N)c1ccccc1Cl
Reactant: COC(=O)Nc1ccc(C(F)(F)F)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccccc2Cl)[nH]c(=O)n1-c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 10.1 %

Procedure:
1.27 g of ethyl 3-amino-3-(2-chlorophenyl)-2-propenoate was added dropwise to a 20 ml of dimethylformamide solution of 0.26 g of sodium hydride (purity: 55%). The solution was stirred t room temperature for 15 minutes, then cooled to 0° C. and added with 1.24 g of methyl (5-trifluoromethyl-2-pyridyl)carbamate. The resulting solution was further stirred at 120° C. for 5 hours and then the solvent was distilled away under reduced pressure. The residue was dissolved with 100 ml of water and washed with diethyl ether. The obtained aqueous layer was added into a mixed solution of 20 ml of concentrated hydrochloric acid and 50 g of ice, and the precipitated crystals were filtered out and dried to obtain 0.21 g of the objective compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([O:31][C:32]([NH:34][C@@H:35]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:36]([OH:38])=O)=[O:33])[CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30].CCN(C(C)C)C(C)C.[CH3:52][O:53][C@:54]1([C:63]2[CH:68]=[CH:67][C:66]([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=3[CH:75]=[CH2:76])=[CH:65][CH:64]=2)[CH2:58][NH:57][C@H:56]([C:59]([O:61][CH3:62])=[O:60])[CH2:55]1>C(Cl)Cl>[CH2:25]([O:31][C:32]([NH:34][C@@H:35]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:36]([N:57]1[CH2:58][C@:54]([O:53][CH3:52])([C:63]2[CH:64]=[CH:65][C:66]([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=3[CH:75]=[CH2:76])=[CH:67][CH:68]=2)[CH2:55][C@H:56]1[C:59]([O:61][CH3:62])=[O:60])=[O:38])=[O:33])[CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30]
Reactant: C=CCCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: C=Cc1ccccc1-c1ccc([C@@]2(OC)CN[C@H](C(=O)OC)C2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCCCOC(=O)N[C@H](C(=O)N1C[C@](OC)(c2ccc(-c3ccccc3C=C)cc2)C[C@H]1C(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
HATU (139 mg, 0.365 mmol) was added to a solution of (S)-2-((hex-5-enyloxy)carbonylamino)-3,3-dimethylbutanoic acid (128 mg, 0.498 mmol), DIEA (0.174 mL, 0.996 mmol) and (2S,4R)-methyl 4-methoxy-4-(2′-vinylbiphenyl-4-yl)pyrrolidine-2-carboxylate (112 mg, 0.332 mmol) in DCM (5 mL). The reaction was stirred at r.t. overnight. The reaction was evaporated and purified on the Biotage (10-40% EtOAc in hexanes) to give (2S,4R)-methyl 1-((S)-2-((hex-5-enyloxy)carbonylamino)-3,3-dimethylbutanoyl)-4-methoxy-4-(2′-vinylbiphenyl-4-yl)pyrrolidine-2-carboxylate (151 mg, 79% yield) as a clear oil. LCMS: rt=2.05 min. [M+Na]30 =599; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[C:20]([F:23])([F:22])[F:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:17][C:16]1[CH:18]=[CH:19][C:13]([F:12])=[C:14]([C:20]([F:23])([F:21])[F:22])[CH:15]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Product: O=C(Nc1ccc(F)c(C(F)(F)F)c1)c1cc(Cl)ccc1O
Yield: 72.1 %

Procedure:
Using 5-chlorosalicylic acid and 4-fluoro-3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[NH:33]1[CH2:37][CH2:36][CH:35]([CH2:38][C:39]([OH:41])=[O:40])[CH2:34]1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:33]5[CH2:37][CH2:36][CH:35]([CH2:38][C:39]([OH:41])=[O:40])[CH2:34]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:30])([F:32])[F:31])[CH:3]=1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: O=C(O)CC1CCNC1
Product: O=C(O)CC1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C1

Procedure:
(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidin-3-yl)-acetic acid was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and pyrrolidin-3-yl-acetic acid following General Procedure B.
Reaction SMILES: C([NH:8][C@H:9]([C:18]([NH:20][C@@H:21]([C:26]([NH:28][CH2:29][C:30]([NH:32][C@H:33]([C:41]([CH:43]1[C:50]2([NH2:52])[CH2:51][CH:46]3[CH2:47][CH:48]([CH2:53][C:44]1([C:54]([NH2:56])=[O:55])[CH2:45]3)[CH2:49]2)=[O:42])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:31])=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)(OC(C)(C)C)=O.[ClH:57]>C(O)(=O)C.O1CCOCC1>[ClH:57].[NH2:8][C@H:9]([C:18]([NH:20][C@@H:21]([C:26]([NH:28][CH2:29][C:30]([NH:32][C@H:33]([C:41]([CH:43]1[C:50]2([NH2:52])[CH2:51][CH:46]3[CH2:47][CH:48]([CH2:53][C:44]1([C:54]([NH2:56])=[O:55])[CH2:45]3)[CH2:49]2)=[O:42])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:31])=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1
Reactant: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)C1C2(N)CC3CC(C2)CC1(C(N)=O)C3
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CSCC[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)C1C2(N)CC3CC(C2)CC1(C(N)=O)C3
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1.0 g of Boc-L-tyrosyl-D-methionyl-glycyl-L-phenylalanyl-3-amino-1-adamantanecarboxamide in 5.0 ml of glacial acetic acid is added 5.0 ml of a 6 N solution of hydrogen chloride in dioxane. The reaction mixture is stirred for 20 minutes at room temperature. The solvent is removed under reduced pressure, and the residue is dissolved in 125 ml of water. The solution is lyophilized to give L-tyrosyl-D-methionyl-glycyl-L-phenylalanyl-3-amino-1-adamantanecarboxamide hydrochloride which is represented by the following formula ##STR29##
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:10][NH2:11]>C(O)C>[CH3:1][C:2]([NH:11][CH3:10])([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C=C(C)C
Reactant: CN
Solvent: CCO
Product: CCOC(=O)CC(C)(C)NC

Procedure:
A mixture containing ethyl 3,3-dimethylacrylate (100 g) and methylamine (140 ml of a 33% solution in ethanol) in ethanol (400 ml) was allowed to stand at room temperature for 2 weeks. The mixture was concentrated in vacuo to give an oil which was fractionally distilled in vacuo to give the title compound as a colourless, mobile oil, yield, 95.0 g, b.p. 68°-75°/20 mm.Hg.
Reaction SMILES: [CH2:1]([S:9][S:10]Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:12][NH:13][C:14]([F:16])=[O:15]>C(N(CC)CC)C>[CH3:12][N:13]([S:10][S:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:14]([F:16])=[O:15]
Reactant: CNC(=O)F
Reactant: CCCCCCCCSSCl
Solvent: CCN(CC)CC
Product: CCCCCCCCSSN(C)C(=O)F

Procedure:
Prepared as above by adding 25.2 g triethylamine to a solution of 48.0 g. n-octylthiosulfenylchloride and 19.26 g N-methylcarbamoyl fluoride. b.p. 110-118° C/0.2 Torr. ND21 1.4900.
Reaction SMILES: C([O:11][C@@H:12]1[CH2:20][C:19]2[C:14](=[CH:15][C:16]([N+:21]([O-:23])=[O:22])=[CH:17][CH:18]=2)[C@H:13]1[NH2:24])(=O)C(C1C=CC=CC=1)O.[OH-].[Na+].[C:27]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=[CH:31][C:30]([C:33](Cl)=[O:34])=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[N+:21]([C:16]1[CH:15]=[C:14]2[C:19]([CH2:20][CH:12]([OH:11])[C@@H:13]2[NH:24][C:33]([C:30]2[CH:31]=[CH:32][C:27]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:28][CH:29]=2)=[O:34])=[CH:18][CH:17]=1)([O-:23])=[O:22]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: N[C@@H]1c2cc([N+](=O)[O-])ccc2C[C@H]1OC(=O)C(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(N[C@@H]1c2cc([N+](=O)[O-])ccc2CC1O)c1ccc(-c2ccccc2)cc1
Reaction time: 1 h
Yield: 106.8 %

Procedure:
Add (1R,2R)-1-amino-6-nitroindan-2-ol mandelate (0.64 kg, 1.85 mol) to a mixture of toluene (9.6 L) and aqueous 1 N NaOH (4.8 L, 4.8 mol, 2.6 equiv). After 1 h, add 4-biphenylcarbonyl chloride (0.44 kg, 2.0 mol, 1.1 equiv) in portions over 20–30 min. After 22 hours, filter the solids under vacuum and rinse sequentially with 0.5 L of toluene, 2 L of water, and 2 L of toluene. Dry the cake to afford 0.74 kg of biphenyl-4-carboxylic acid (R)-(6-nitro-2-hydroxyindan-1-yl)amide. Add 38.2 L of ethyl acetate to 1.914 kg of biphenyl-4-carboxylic acid (R)-(6-nitro-2(R)-hydroxyindan-1-yl)amide prepared in a similar manner. Stir the slurry for 18 h, collect the solid by filtration, dry to afford 1.76 kg of biphenyl-4-carboxylic acid (R)-(6-nitro-2(R)-hydroxyindan-1-yl)amide as a white solid.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[Br:9]Br>>[Br:9][CH:2]1[C:3](=[O:7])[CH2:4][CH2:5][CH2:6][C:1]1=[O:8]
Reactant: BrBr
Reactant: O=C1CCCC(=O)C1
Product: O=C1CCCC(=O)C1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Cyclohexane-1,3-dione (11.2 g, 0.1 mol) was suspended in ice water (70 mL) and bromine (5.16 mL, 0.1 mol) was added dropwise over 5 minutes. The resulting suspension was stirred at room temperature for 3 hours. The suspension was filtered and the solid was stirred in water (200 mL) for 30 minutes. The solid was collected by vacuum filtration, rinsed with water, and dried to render crude product. The crude product was recrystallized from ethanol to produce the title compound.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([OH:14])=O)[NH:9]2)=[CH:5][C:4]=1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1.[C:25]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(=[O:27])[CH3:26]>>[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([N:31]3[CH2:32][CH2:33][N:28]([C:25](=[O:27])[CH3:26])[CH2:29][CH2:30]3)=[O:14])[NH:9]2)=[CH:5][C:4]=1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:23])[CH3:24])[CH2:18][CH2:17]1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)O)[nH]c3cc2Br)CC1
Reactant: CC(=O)N1CCNCC1
Agent: Cl
Product: CC(=O)N1CCN(C(=O)c2cc3cc(OC4CCN(C(C)C)CC4)c(Br)cc3[nH]2)CC1
Yield: 52 %

Procedure:
The title compound was synthesized in analogy to example 1, from 6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indole-2-carboxylic acid hydrochloride (example 1, intermediate a) and 1-acetylpiperazine to afford the title compound as a light-yellow foam (52%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH3:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C@@H:29](O)[CH3:30]>C(O)C>[CH3:23][CH:24]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCC[C@H](C)O
Reactant: O=Cc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCC(C)Oc1ccc(C=O)cc1

Procedure:
p-Hydroxy-benzaldehyde (15 g), ethanol (200 ml) and 50% NaOH (12 g) were mixed with stirring, followed by pouring in the mixture, a tosylate (26 g) derived from S-(+)-2-octanol, heating the resulting mixture under reflux for 6 hours, distilling off most of ethanol, adding 6N-HCl (100 ml), extracting with toluene, washing the toluene layer with acid, washing with alkali, washing with water to make it neutral, drying, concentrating, and further concentrating the resulting concentrate according to column chromatography with Al2O3 (40 g) to obtain oily p-(1-methylheptyloxy)benzaldehyde (13.0 g). Next, sodium boron hydride (1.0 g) was suspended in isopropyl alcohol (50 ml), followed by dropwise adding to the suspension, a solution of p-(1-methylheptyloxy)benzaldehyde obtained above in isopropyl alcohol (100 ml) so that the liquid temperature might not exceed 40° C., stirring the mixture at 60° C. for 4 hours, adding 6N-HCl (30 ml) and water (20 ml), further heating with stirring at 60° C., distilling off the solvent, extracting the residue with toluene, washing the toluene layer with acid, washing with alkali, washing with water to make it neutral, drying and concentrating to obtain raw p-(1-methylheptyloxy)benzyl alcohol (13 g), which was then heated together with thionyl chloride for 6 hours, followed by distilling off excess thionyl chloride under reduced pressure to obtain raw p-(1-methylheptyloxy)benzyl chloride (IIIb-2) (13 g), which was used, as it was, in the following reaction.
Reaction SMILES: C[O:2][C:3](=[S:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:2])=[S:12])=[N:6][CH:7]=2)=[O:31])=[CH:25][CH:24]=1
Reactant: COC(=S)Cc1ccc(N)cn1
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)Nc2ccc(CC(O)=S)nc2)cc1

Procedure:
A mixture of 5-amino-(pyrid-2-yl)-thioacetic acid methyl ester [930 mg, Reference Example 1(a)], 4-[3-(2-methylphenyl)ureido]phenylacetic acid (1.26 g, prepared as described in Example 21 of International Patent Application Publication No. WO 96/22966), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.69 g) and diisopropylethylamine (1.2 g) in dimethylformamide (50 ml) was stirred at ambient temperature for 1 hour. The mixture was evaporated then poured into water (500 ml). The resultant solid was washed with water (50 ml) and then washed twice with diethyl ether (50 ml). The solid was suspended in methanol (100 ml), then treated with sodium hydroxide solution (10 ml, 1M). The mixture was heated at reflux for 5 hours, then cooled, then evaporated. The residue was treated with hydrochloric acid (200 ml, 1M). The resultant solid was filtered, washed with water (20 ml), then washed twice with diethyl ether (20 ml), then recrystallised from ethanol to give the title compound (220 mg) as a yellow solid, m.p. >235° C. (with decomposition). MS: MH+ 451.
Reaction SMILES: [CH2:1]([O:7][C:8]1[C:9]([NH:21][C:22]2[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=2)=[CH:10][C:11]2[C:12]([CH3:20])=[CH:13][CH2:14][C:15]([CH3:19])([CH3:18])[C:16]=2[CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:33](=O)[CH2:34][CH3:35]>>[CH2:1]([O:7][C:8]1[C:9]([N:21]([CH2:33][CH2:34][CH3:35])[C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:31][CH:32]=2)=[CH:10][C:11]2[C:12]([CH3:20])=[CH:13][CH2:14][C:15]([CH3:19])([CH3:18])[C:16]=2[CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1cc2c(cc1Nc1ccc(C(=O)OCC)cc1)C(C)=CCC2(C)C
Reactant: CCC=O
Product: CCCCCCOc1cc2c(cc1N(CCC)c1ccc(C(=O)OCC)cc1)C(C)=CCC2(C)C
Yield: 100 %

Procedure:
Following General Procedure P, (Compound 112, 0.030 g, 0.07 mmol) was reacted with propionaldehyde to afford 0.032 g (100%) of the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]([O:4][CH:5]=[CH2:6])=[O:3].C(N(CC)CC)C.[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[S:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>ClCCl>[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[S:24][CH:25]1[CH2:30][CH2:29][N:28]([C:2]([O:4][CH:5]=[CH2:6])=[O:3])[CH2:27][CH2:26]1
Reactant: Brc1ccc2[nH]cc(SC3CCNCC3)c2c1
Reactant: C=COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=COC(=O)N1CCC(Sc2c[nH]c3ccc(Br)cc23)CC1
Reaction time: 2 h

Procedure:
Vinyl chloroformate (0.75 ml) is added dropwise to a solution of triethylamine (1.2 ml) and 5-bromo-3-(piperidin-4-ylthio)-1H-indole (2.5 g, prepared in Example 49) in dichloromethane (25 ml) at 0° C. After 2 hours at room temperature, the solution is washed with water. The organic phase is dried over magnesium sulfate and concentrated. Vinyl 4-[(5-bromo-1H-indol-3-yl)thio]piperidine-1-carboxylate (1.8 g) is obtained after chromatography on silica gel (eluent: cyclohexane/AcOEt 70/30).