Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][C:9]#[N:10].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:10][CH2:9][CH2:8][N:4]1[CH2:5][CH2:6][CH2:7][CH:3]1[CH2:2][OH:1]
Reactant: N#CCN1CCCC1CO
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCN1CCCC1CO
Yield: 62.4 %

Procedure:
The method follows that of S6 using 2-hydroxymethyl-pyrrolidin-1-yl-acetonitrile (19.5 g, 0.139 mol), LiAlH4 (15.84 g, 0.417 mol) and dry THF (150 mL). The title-compound (12.5 g, 63%) was afforded as straw-coloured oil by kugelrohr distillation (142° C., 0.3 mbar). δH (250 MHz; CDCl3); 1.6-1.9 (m, 4H, CH2CH2CH2, CH2CH2CH), 1.98 (s (broad), 3H, NH2, OH), 2.3 (m, 1H), 2.45 (m, 1H), 2.55 (m, 1H), 2.75-2.85 (m, 3H), 3.19 (m, 1H, NCHCH2), 3.4 (2×d, 1H, J=3 Hz and J=11 Hz, 1×CHCH2OH), 3.6 (2×d, 1H, J=3 Hz and J=11 Hz, 1×CHCH2OH); IR υmax/cm−1; 3375 (NH2), 3300 (NH2), 3200 (OH), 2970-2800 (CH2, CH3), 1600, 1475, 1375, 1230 and 1060; FAB MS, m/z(M+H)+ 145.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C[O:20][C:21](=[O:64])[CH2:22][CH2:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([C:41]3[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][CH:49]([O:54][Si](C(C)(C)C)(C)C)[C:50]([CH3:53])([CH3:52])[CH3:51])=[C:43]([CH3:62])[CH:42]=3)([CH2:39][CH3:40])[CH2:37][CH3:38])=[CH:32][C:31]=2[CH3:63])[CH:27]=[CH:28][CH:29]=1.P([O-])(O)(O)=O.[Na+]>O1CCCC1>[CH2:37]([C:36]([C:33]1[CH:34]=[CH:35][C:30]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([CH2:23][CH2:22][C:21]([OH:64])=[O:20])[CH:25]=2)=[C:31]([CH3:63])[CH:32]=1)([C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][CH:49]([OH:54])[C:50]([CH3:52])([CH3:53])[CH3:51])=[C:43]([CH3:62])[CH:42]=1)[CH2:39][CH3:40])[CH3:38]
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2cccc(CCC(=O)OC)c2)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P([O-])(O)O
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2cccc(CCC(=O)O)c2)c(C)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 93.3 %

Procedure:
Tetra-n-butylammonium fluoride (1 M solution in tetrahydrofuran, 0.2 mL, 0.2 mmol) and tetrahydrofuran (1 mL) were added to 3-[4′-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2′-methyl-biphenyl-3-yl]-propionic acid methyl ester (Example 12-(2); 0.016 g, 0.025 mmol), and the mixture was stirred at 60° C. for four hours. A 30% sodium dihydrogenphosphate aqueous solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (hexane/ethyl acetate=1/1) to give the title compound (0.012 g, 93%).
Reaction SMILES: C([O:5][C:6]1[N:18]=[C:17]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[CH:23]=[CH:22]3)[C:16]([CH:29]=[CH2:30])=[C:15]([O:31]C(C)(C)C)[C:7]=1[C:8]([O:10]C(C)(C)C)=[O:9])(C)(C)C.Cl>O1CCOCC1>[OH:31][C:15]1[CH:16]([CH:29]=[CH2:30])[CH:17]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[CH:23]=[CH:22]3)[NH:18][C:6](=[O:5])[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: C=Cc1c(-c2ccc3c(ccn3C)c2)nc(OC(C)(C)C)c(C(=O)OC(C)(C)C)c1OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C=CC1C(O)=C(C(=O)O)C(=O)NC1c1ccc2c(ccn2C)c1
Reaction time: 0.02 h

Procedure:
Into a solution of tert-butyl 2,4-di-tert-butoxy-6-(1-methyl-1H-indol-5-yl)-5-vinylnicotinate (44 mg, 0.092 mmol) in dioxane (1.0 mL) was added a solution of HCl in dioxane (4.0 M×1.0 mL, 4.0 mmol). After 1 min, the mixture was evaporated to dryness. The residue was treated with ether and filtered. The solid was collected as 4-hydroxy-6-(1-methyl-1H-indol-5-yl)-2-oxo-5-vinyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid (26 mg, 97%).
Reaction SMILES: ClC(Cl)=C[C@H]1[C@H](C(Cl)=O)C1(C)C.[CH:13]1[C:25]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1.[Cl:26][C:27]([Cl:38])=[CH:28][C@H:29]1[C@H:31]([C:32]([O:34][CH3:35])=[O:33])[C:30]1([CH3:37])[CH3:36]>>[CH:13]1[C:25]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1.[Cl:26][C:27]([Cl:38])=[CH:28][CH:29]1[CH:31]([C:32]([O:34][CH3:35])=[O:33])[C:30]1([CH3:36])[CH3:37]
Reactant: COC(=O)[C@H]1[C@H](C=C(Cl)Cl)C1(C)C
Agent: CC1(C)[C@@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Agent: c1ccc2c(c1)Cc1ccccc1-2
Product: COC(=O)C1C(C=C(Cl)Cl)C1(C)C

Procedure:
Similarly, but employing trans-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride, 9H-fluorene-1-methyl trans-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate was prepared.
Reaction SMILES: CO.[F:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].C(N(CC)CC)C.ClN[C:20](=[O:24])[O:21][CH2:22][CH3:23]>C1C=CC=CC=1.O>[F:3][C:4]1[CH:5]=[C:6]([NH:7][C:20](=[O:24])[O:21][CH2:22][CH3:23])[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)NCl
Reactant: Nc1cccc(F)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)Nc1cccc(F)c1
Yield: 30.3 %

Procedure:
The mixture of 150 ml of methanol, 25 g of m-fluoroaniline, 30 g of triethylamine and 32.5 g of ethyl chlorocarbamate was heated under reflux condition. After the completion of the reaction, the solvent was evaporated under reduced pressure to obtain the residue, to which was added 100 ml of water and 100 ml of benzene. The benzene layer was separated, washed twice with water and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain the residue, which was distilled under reduced pressure, and there was obtained 12.5 g (yield 34.8%) of ethyl m-fluorophenylcarbamate as colourless oil having a boiling point of 102° C/1.5 mmHg.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)(=[O:4])=[O:3].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([O:27][C:28]2[CH:33]=[CH:32][C:31](Br)=[CH:30][N:29]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([N:10]3[C:11]4[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=4)[CH:8]=[CH:9]3)=[CH:30][N:29]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cn2)CC1
Reactant: CS(=O)(=O)c1ccc2[nH]ccc2c1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(S(C)(=O)=O)ccc43)cn2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using 5-(methylsulfonyl)-1H-indole (intermediate 21) and tert-butyl-4-((5-bromopyridin-2-yl)oxy)piperidine-1-carboxylate (intermediate 65) (0.610 g, 46%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[OH:15][C:16]1[CH:21]=[C:20](O)[CH:19]=[C:18]([OH:23])[CH:17]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CCCCCC>[OH:15][C:16]1[C:21]2[C:12](=[O:14])[C:3]3[CH:4]=[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:10]4=[CH:11][C:2]=3[NH:1][C:20]=2[CH:19]=[C:18]([OH:23])[CH:17]=1
Reactant: Oc1cc(O)cc(O)c1
Reactant: Nc1cc2ccccc2cc1C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCCCO
Product: O=c1c2cc3ccccc3cc2[nH]c2cc(O)cc(O)c12
Reaction time: 48 h

Procedure:
To a solution of 5 g of 3-amino-2-naphthalenecarboxylic acid in 50 ml of heptan-1-ol there are added 3.5 g of 1,3,5-trihydroxybenzene and 62.5 mg of para-toluenesulphonic acid. The mixture is stirred for 48 hours under reflux using a Dean-Stark apparatus, and the reaction mixture is then concentrated in vacuo. The residue is chromatographed over silica gel (eluant: cyclohexane/acetone: 90/10). The isolated product is crystallised from a cyclohexane/acetone mixture, allowing 5.2 g of the expected product to be obtained.
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([C:16](=[O:18])[CH3:17])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)([O-:5])=[O:4].Cl>CO>[N+:3]([C:6]1[CH:7]=[C:8]([CH:16]([OH:18])[CH3:17])[CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=1)([O-:5])=[O:4]
Reactant: CC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
Add sodium borohydride (95 mg, 2.44 mmol) to a solution of 1-(3-nitro-5-(trifluoromethyl)phenyl)ethanone (570 mg, 2.44 mmol) in methanol (5 mL), stir the mixture for 15 min at ambient temperature. Quench the reaction with water, adjust pH=7 with 1N hydrochloric acid, extract with ethyl acetate (50 mL×3), combine the organic layers, wash with brine, dry over sodium sulfate. Concentrate under reduced pressure to provide the crude product. Purify by flash chromatography (silica gel, EtOAc:PE=1:10) to afford the title compound (520 mg, 91.2%).
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1>O.CCO>[CH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[CH2:5][C:1]#[N:2]
Reactant: BrCc1ccc2ccccc2c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccc2ccccc2c1
Reaction time: 16 h
Yield: 81.9 %

Procedure:
To a stirred solution of sodium cyanide (10.5 g, 0.214 mol) in H2O (20 mL) was added a solution of 2-(bromomethyl)naphthalene (40.0 g, 0.181 mol) in EtOH (170 mL). The resulting mixture was heated at reflux for 3 h, then spin-evaporated in vacuo. The residue was partitioned between H2O (175 mL) and CH2Cl2 (200 mL). The aqueous layer was further extracted with CH2Cl2 (3×200 mL). The combined organic layers were dried over MgSO4 (5 g) and spin-evaporated in vacuo to a solid. The solid was dissolved in refluxing EtOH (100 mL). The clarified solution was stored at 3° C. for 16 h. Solids were collected by filtration and dried to constant weight in vacuo to give 24.8 g (81.9%) of product suitable for further transformation. A total of 257.2 g of material was prepared in this fashion.
Reaction SMILES: C[O:2][C:3](=[O:29])[C@@H:4]([NH:14][C:15]([NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([OH:28])=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:16])[CH2:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[OH-].[K+]>O>[C:10]([O:9][C:7](=[O:8])[CH2:6][CH2:5][C@H:4]([NH:14][C:15]([NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([OH:28])=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:16])[C:3]([OH:29])=[O:2])([CH3:13])([CH3:11])[CH3:12]
Reactant: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)Nc1cccc2cc(O)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)Nc1cccc2cc(O)ccc12)C(=O)O
Temperature: 50 °C
Reaction time: 36 h
Yield: 62 %

Procedure:
To the methyl ester from Step 1 above (5 mmol, 2.0 g) was added potassium hydroxide (5 mmol, 0.28 g) in water (7 mL), and heated at 50° C. After stirring for 36 hours, the reaction mixture was evaporated to dryness, the residue was dissolved in water (15 mL), acidified to pH≈5 using 0.50 N hydrochloric acid, extracted with the ethyl acetate (4×50 mL), and dried to provide product as a light brown oil (1.20 g, 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:9]2)=[CH:4][C:3]=1[CH2:47]O.P(Br)(Br)[Br:50].N1C=CC=CC=1>CCOCC>[CH2:31]([O:30][C@H:11]1[C@H:12]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:47][Br:50])[CH:4]=2)[O:9][C@@H:10]1[CH2:38][O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: OCc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: c1ccncc1
Product: Clc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1CBr
Temperature: 25 °C
Reaction time: 15 h
Yield: 203.6 %

Procedure:
To a solution of alcohol 105 (5.33 g, 8.01 mmol) in ether (50 mL) were added phosphorus tribromide (0.26 mL, 2.80 mmol) and catalytic amount of pyridine at 0° C. The mixture was allowed to warm to room temperature and stirred at room temperature for 15 hours. The mixture was extracted with EtOAc/H2O (100 mL/150 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the title bromide 106 (4.15 g, 71%).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[Cl:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([O:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(O)cc1
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(Oc2cccc(Cl)c2C=O)cc1
Yield: 81.2 %

Procedure:
In a manner similar to the method described in Example 50a, 2,6-dichlorobenzaldehyde (2.7 g, 15 mmol) (Aldrich) was reacted with 4-methoxyphenol (1.8 g, 15 mmol) and K2CO3 in N,N-dimethylacetamide to give 2-chloro-6-(4-methoxy-phenoxy)-benzaldehyde as a yellow oil (Yield 3.2 g, 80%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[C:12]1(C2NCCN=2)C=CC=C[CH:13]=1.C(=O)(OCC)OCC>CCCCCCCCCC>[CH2:12]([O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3])[CH3:13]
Reactant: c1ccc(C2=NCCN2)cc1
Reactant: CC(C)(C)c1ccccc1O
Solvent: CCOC(=O)OCC
Solvent: CCCCCCCCCC
Product: CCOc1ccccc1C(C)(C)C
Temperature: 140 °C

Procedure:
5 mol of o-tert-butylphenol was charged into a reactor, along with 400 ml of decane and 5% of 4,5-dihydro-2-phenylimidazole, and the mixture was heated to 140° C. Then 5.5 mol of diethyl carbonate was added portionwise over a period of 4 hr. The resulting ethanol was continuously removed by distillation from the reaction mixture. After completion of the reaction, 4.6 mol of o-tert-butylphenyl ethyl ether was obtained from the mixture by distillation. The yield corresponded to 92% of theoretical, based on the starting amount of o-tert-butylphenol.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][O:15][C:16](=[O:42])[C@@H:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([N:28]2[C:36]3[C:31](=[CH:32][C:33]([C:37](O)=[O:38])=[CH:34][CH:35]=3)[C:30]([CH3:40])=[C:29]2[CH3:41])[CH3:27])=[CH:22][CH:21]=1)[CH3:18]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([NH:13][C:37]([C:33]2[CH:32]=[C:31]3[C:36](=[CH:35][CH:34]=2)[N:28]([CH:26]([C:23]2[CH:24]=[CH:25][C:20]([O:19][C@@H:17]([CH3:18])[C:16]([O:15][CH3:14])=[O:42])=[CH:21][CH:22]=2)[CH3:27])[C:29]([CH3:41])=[C:30]3[CH3:40])=[O:38])[CH3:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](C)Oc1ccc(C(C)n2c(C)c(C)c3cc(C(=O)O)ccc32)cc1
Reactant: C[C@H](N)c1ccc(C(C)(C)C)cc1
Product: COC(=O)[C@H](C)Oc1ccc(C(C)n2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4ccc(C(C)(C)C)cc4)ccc32)cc1

Procedure:
The title compound was prepared following the same general protocol as described in Step 5, Example 35, using (S)-1-(4-(tert-butyl)phenyl)ethanamine instead of (S)-1-(3-bromophenyl)ethylamine and 1-(1-(4-(((S)-1-methoxy-1-oxopropan-2-yl)oxy)phenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of 1-(4-(1-(methoxycarbonyl)cyclopropyl)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid′
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[N:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:6]([CH3:22])([CH3:21])[CH2:5]1.[CH2:23](Br)[CH:24]=[CH2:25].CCCCCCC>O1CCCC1.C(OCC)(=O)C>[CH2:25]([O:3][CH:4]1[CH2:9][C:8]([CH3:10])([CH3:11])[N:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:6]([CH3:21])([CH3:22])[CH2:5]1)[CH:24]=[CH2:23]
Reactant: C=CCBr
Reactant: CCCCCCCCON1C(C)(C)CC(O)CC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: C=CCOC1CC(C)(C)N(OCCCCCCCC)C(C)(C)C1
Temperature: 35 °C
Yield: 69.9 %

Procedure:
Sodium hydride (2.65 grams, 110 mmol) is added to a solution of 30.0 grams (105 mmol) of 4-hydroxy-1-octyloxy-2,2,6,6-tetramethylpiperidine in 150 ml of tetrahydrofuran under nitrogen. The reaction mixture is heated at reflux for three hours, cooled to 35° C., and treated with 12.7 grams (110 mmol) of allyl bromide. The reaction mixture is heated at reflux for one hour, then partitioned between ethyl acetate (150 ml) and water (50 ml). The organic layer is washed with saturated sodium chloride solution (100 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is dissolved in heptane (50 ml) and passed through a pad of silica gel (eluent 5:1 heptane:ethyl acetate). The crude product is purified by flash chromatography (silica gel; 9:1 heptane:ethyl acetate to afford 23.9 grams (70% yield) of the title compound as a colorless oil.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:4]2[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[C:5]=2[S:6][CH:7]=1.[Br:13]N1C(=O)CCC1=O>CN(C)C=O>[ClH:1].[NH2:2][C:3]1[C:4]2[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[C:5]=2[S:6][C:7]=1[Br:13]
Reactant: Nc1csc2c1CCCC2=O
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: CN(C)C=O
Product: Nc1c(Br)sc2c1CCCC2=O
Reaction time: 0.5 h

Procedure:
To a suspension of 3-Amino-5,6-dihydro-4H-benzo[b]thiophene-7-one hydrochloride (the compound of Preparation Example 6) (1.2 g) in N,N-dimethylformamide (33 mL) was added 1.05 g of N-bromosuccinimide (1.05 g) on an ice bath. After stirring for 30 minutes, the solvent was evaporated at reduced pressure, the pH was adjusted to 10 with an aqueous solution of sodium bicarbonate. After extracting with ethyl acetate, and washing the organic layer with water, drying with anhydrous magnesium sulfate was carried out and the solvent was evaporated at reduced pressure. The residue was dissolved in ethyl acetate, and the pH was brought to 1 by adding 4N hydrochloric acid/ethyl acetate. The resulting solid was collected by filtration, washed with ethyl acetate to provide the title compound (1.55 g) as an ocher solid.
Reaction SMILES: CN(C)[CH2:3][C:4]1[C:5]([CH3:16])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[Cl:18]C(OCC)=O>C1(C)C=CC=CC=1>[Cl:18][CH2:3][C:4]1[C:5]([CH3:16])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1c(CN(C)C)cccc1-c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1c(CCl)cccc1-c1ccccc1
Temperature: 80 °C
Yield: 104.9 %

Procedure:
Under a dry nitrogen atmosphere, 0.5 g (0.0022 mole) of N,N,2-trimethyl-[1,1'-biphenyl]-3-methanamine was dissolved in 5.5 ml of dry toluene with stirring and the solution was heated to 80° C. A solution of 0.36 g (0.0033 mole) of ethyl chloroformate in 1.1 ml of dry toluene was added dropwise during 5 minutes. The reaction mixture was stirred for 3.3 hours at 80° C., then cooled to room temperature and filtered. The solvent was removed from the filtrate under reduced pressure to give 0.5 g (100% yield) of 3-chloromethyl-2-methyl-[1,1'-biphenyl] as a light orange oil.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C@H:11]([C:13]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH3:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.Cl[Si:25]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:26][CH3:27]>CN(C)C=O>[C:1]1([S:7]([CH2:10][C@H:11]([C:13]2([O:18][Si:25]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH3:12])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC[Si](Cl)(CC)CC
Reactant: C[C@H](CS(=O)(=O)c1ccccc1)C1(O)CCCC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)OC1([C@H](C)CS(=O)(=O)c2ccccc2)CCCC1
Temperature: 0 °C
Yield: 123.9 %

Procedure:
To a solution of 6a (2.40 g, 8.94 mmol) and imidazole (1.22 g, 17.9 mmol) in N,N-dimethylformamide (20 mL) was added chlorotriethylsilane (2.2 mL, 13.1 mmol) in one portion. The mixture was stirred at ambient temperature for 3d. The mixture was poured into ice water, and extracted with diethyl ether. The combined organic layers were washed with water and brine, and dried over sodium sulfate. Filtration and concentration gave 4.24 g of an oily material, which was purified by column chromatography (silica gel 40 g, ethyl acetate in n-hexane, 10%) to give 3.67 g (quantitative) of 7a, as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].I.[NH:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>>[CH3:33][O:32][C:28]1[CH:27]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:48]2[CH2:47][CH2:46][CH:45]([NH:44][C:36]3[NH:35][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[N:37]=3)[CH2:50][CH2:49]2)([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:9]1)=[O:7]
Reactant: c1ccc2[nH]c(NC3CCNCC3)nc2c1
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(Cc3ccccc3)C2)cc(OC)c1OC
Agent: I
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(Cc3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 4.1 using 1-(3,4,5-trimethoxybenzoyl)-3-(phenylmethyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine (0.8 g, 1.67 mmol) and (1H-benzimidazol-2-yl)(piperidin-4-yl)amine hydriodic acid salt (0.8 g, 1.67 mmol). Purify by chromatography on silica gel eluting with 2% triethylamine/30% methanol/ethyl acetate to give the title compound: Rf=0.21 (silica gel, 2% triethylamine/30% methanol/ethyl acetate).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[H][H]>CO.[Pd]>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6]
Reactant: [H][H]
Agent: [Pd]
Agent: O=C(CCCBr)c1ccccc1
Solvent: CO
Product: BrCCCCc1ccccc1

Procedure:
In this Example, 0.45 g of the 4-bromobutyrophenone (purity: 94%, 1.86 mmol) obtained in Example 1 was dissolved in 2.2 g of methanol, and 0.14 g of 5% Pd-C (50% wet) was added, followed by stirring the mixture in a hydrogen atmosphere at 20° C. for four hours. The catalyst was filtered off and the solvent was removed by distillation under reduced pressure to give 1-bromo-4-phenylbutane in a 98.2% yield from 4-bromobutyrophenone.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:12](Cl)(=[O:22])[C:13]1[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:15](Cl)=[O:16].Cl>N1C=CC=CC=1>[O:16]=[C:15]1[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[C:12](=[O:22])[N:1]1[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccc(N2C(=O)c3ccccc3C2=O)cc1
Temperature: 60 °C
Yield: 90.1 %

Procedure:
A solution of 1.0 g (5.8 mmol) of p-aminophenylsulfonamide in 3.6 mL of pyridine was added 878 μL (6.1 mmol) of phthalic dichoride. After heating to 60° C. for 18 h, the solution was poured into 1N HCl, cooled to 0° C., the precipitate was collected by filtration, and dried under vacuum to give 1.58 g (90%) of the titled compound.