Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[C:9]([C@@:11]1([CH2:25][CH3:26])[CH2:15][CH2:14][C@@H:13]([NH:16][C@@H:17]2[CH2:22][CH2:21][O:20][CH2:19][C@H:18]2[O:23][CH3:24])[CH2:12]1)=[O:10].C(N(CC)CC)C.Cl[C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][N:36]=1>CS(C)=O>[CH2:25]([C@:11]1([C:9]([N:3]2[CH2:4][C@@H:5]3[CH2:8][C@H:2]2[CH2:7][N:6]3[C:35]2[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][N:36]=2)=[O:10])[CH2:15][CH2:14][C@@H:13]([NH:16][C@@H:17]2[C@H:18]([O:23][CH3:24])[CH2:19][O:20][CH2:21][CH2:22]2)[CH2:12]1)[CH3:26]
Reactant: FC(F)(F)c1ccnc(Cl)c1
Reactant: CC[C@]1(C(=O)N2C[C@@H]3C[C@H]2CN3)CC[C@@H](N[C@@H]2CCOC[C@H]2OC)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC[C@]1(C(=O)N2C[C@@H]3C[C@H]2CN3c2cc(C(F)(F)F)ccn2)CC[C@@H](N[C@H]2CCOC[C@H]2OC)C1
Temperature: 120 °C
Yield: 24.4 %

Procedure:
To a solution of HCl salt of (1S,4S)-2,5-diaza-bicyclo[2.2.1]heptan-2-yl((1S,3R)-1-ethyl-3-((3S,4R)-3-methoxy-tetrahydro-2H-pyran-4-ylamino)cyclopentyl)methanone (118 mg, 0.33 mmol) in DMSO (2 ml) was added triethylamine (0.15 ml, 1.08 mmol) and the 2-chloro-4-(trifluoromethyl)pyridine (183 mg, 1.01 mmol). The reaction was heated to 120° C. for 15 hours. The reaction was cooled to room temperature, and added to stirring ice water. The mixture was extracted with ethyl acetate (3x). The combined organics were washed with brine, dried over MgSO4 concentrated under reduced pressure and purified with the Biotage (0-100% methanol/ethyl acetate, 15 column volumes) to give the product as a brown foam (40 mg 26%). LC/MS (M+H)=497.2739 exp, 497.2884 obs; 1H NMR (400 MHz, CDCl3) δ ppm 8.25-8.24 (1H), 6.75-6.74 (1H), 6.51-6.45 (1H), 5.13-4.76 (2H), 4.10-4.03 (1H), 3.95-3.90 (1H), 3.72-3.16 (11H), 2.82-2.67 (1H), 2.58-2.36 (1H), 2.06-1.36 (12H), 0.86-0.67 (3H)
Reaction SMILES: [CH3:1][C:2]([C:6]1([OH:11])[CH2:10][CH2:9][NH:8][CH2:7]1)([CH3:5])[CH2:3][CH3:4].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:22](O)=[O:23])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2([C:22]([N:8]3[CH2:9][CH2:10][C:6]([C:2]([CH3:1])([CH3:5])[CH2:3][CH3:4])([OH:11])[CH2:7]3)=[O:23])[CH2:20][CH2:21]2)=[CH:17][CH:18]=1
Reactant: CCC(C)(C)C1(O)CCNC1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(C)(C)C1(O)CCN(C(=O)C2(c3ccc(Cl)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(1,1-Dimethylpropyl)pyrrolidin-3-ol (29.5 mg, 0.000188 mol) was dissolved in DMF and to this solution were added 1-(4-chlorophenyl)cyclopropanecarboxylic acid (44.3 mg, 0.000225 mol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (99.6 mg, 0.000225 mol) and N,N-diisopropylethylamine (49 μL, 0.00028 mol), and the resulting solution was stirred at rt overnight. The product was purified by prep-HPLC. LCMS (M+H)=336
Reaction SMILES: C(O[C:4](=[O:8])[CH2:5][C:6]#[N:7])C.[CH2:9]([CH:11]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][NH2:13])[CH3:10]>C(O)C>[CH2:9]([CH:11]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][NH:13][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:10]
Reactant: CCCCC(CC)CN
Reactant: CCOC(=O)CC#N
Solvent: CCO
Product: CCCCC(CC)CNC(=O)CC#N
Temperature: 154 °C

Procedure:
To ethylcyanoacetate (141 g., 1.25 mole) is slowly added 2-ethylhexylamine (129 g., 1.0 mole) over a period of 0.5 hours. The solution is then gradually heated to 154° C. and the ethanol formed is collected over a period of 1.75 hours. The solution is then stripped of all volatiles boiling at or below 88° C./3.0 mm to give N-(2-ethylhexyl)cyanoacetamide, 201.5 g.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.N1C=CN=C1.[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17]>ClCCl>[Si:20]([O:10][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][N:2]=[CH:3]2)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2[nH]ncc2c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a stirred solution of 1H-indazol-5-ol (5.0 g, 37.3 mol) and imidazole (12.7 g, 186.5 mmol) in dichloromethane (200 mL) was added tert-butylchlorodimethylsilane (16.8 g, 112 mol) and the mixture stirred at room temperature overnight. Then the reaction mixture was washed with brine (3×50 mL) and dried over Na2SO4. The crude mixture was purified by column chromatography (silica gel, 200-300 mesh, EtOAc:petroleum ether=1:10, v/v) to give 5-(tert-Butyldimethylsilyloxy)-1H-indazole (9.5 g, yield 100%) as yellow oil. MS: (M+H)+=249.2; 1H NMR (300 MHz, CDCl3): δ 7.95 (d, 1H, J=1.2 Hz), 7.34 (dt, 1H, J=8.7, 0.75 Hz), 7.12 (s, 1H), 6.97 (dd, 1H, J=8.7, 2.1 Hz), 1.01 (s, 9H), 0.23 (s, 6H).
Reaction SMILES: F[C:2]1[C:7](F)=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:32]CS(C)(=O)=O)C(=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=[C:4](OC)[CH:3]=1.[CH2:40](C1C=CC=CC=1B(O)O)[CH3:41]>CCCCCCC.CCOC(C)=O>[CH2:40]([C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][C:5]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH:15][CH3:32])[CH3:41]
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: CCc1ccccc1B(O)O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCc1ccccc1-c1ccncc1NC

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-methyl-amine (example 36, intermediate b) and 2-ethylphenylboronic acid (CAS RN 90002-36-1) and using a gradient of n-heptane:EtOAc (100:0 to 40:60) for the chromatographic purification. Light yellow solid (87%). MS (ESI): m/z=213.138 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:22]([N:29]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[C:35](=O)[O:34][CH2:33]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(COC)OC.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:35]1[C:36]2[C:32](=[CH:31][C:30]([N:29]([CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:38][CH:37]=2)[CH2:33][O:34]1
Reactant: O=C1OCc2cc(N(Cc3ccccc3)Cc3ccccc3)ccc21
Reactant: O=C1Cc2cc(Cl)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: O=C1Nc2ccc(Cl)cc2C1=C1OCc2cc(N(Cc3ccccc3)Cc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.5 %

Procedure:
To a solution of 5-chlorooxindole (63 mg, 0.371 mmol) in dimethoxyethane (2.0 ml) at room temperature was added 1.0M LiHMDS in THF (742 μl). After the mixture was stirred for 10 minutes at room temperature, 5-dibenzylamino-3H-isobenzofuran-1-one (110 mg, 0.334 mmol) was added, and the reaction was rapidly stirred at room temperature for 1.5 hours. The mixture was quenched into 4% HCl (20 ml), and then stirred with EtOAc. The mixture was basified with saturated NaHCO3 aqueous solution. The organic layer was diluted with MeOH, followed by addition of HCl in MeOH to give a yellow precipitant. The yellow precipitant was separated, and rinsed with MeOH and 20% EtOAc/hexane to yield 5-chloro-3-(5-dibenzylamino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one as a yellow solid (36 mg, 23%).
Reaction SMILES: I[CH2:2][CH2:3][CH:4]1[CH2:10][CH2:9][C:8]2[C:11]([O:21][CH3:22])=[C:12]([O:19][CH3:20])[C:13]([O:17][CH3:18])=[C:14]([O:15][CH3:16])[C:7]=2[CH2:6][CH2:5]1.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[C:30]1([C:27]2[CH:26]=[CH:25][C:24]([O:23][CH2:2][CH2:3][CH:4]3[CH2:10][CH2:9][C:8]4[C:11]([O:21][CH3:22])=[C:12]([O:19][CH3:20])[C:13]([O:17][CH3:18])=[C:14]([O:15][CH3:16])[C:7]=4[CH2:6][CH2:5]3)=[CH:29][CH:28]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: COc1c2c(c(OC)c(OC)c1OC)CCC(CCI)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c2c(c(OC)c(OC)c1OC)CCC(CCOc1ccc(-c3ccccc3)cc1)CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.8 %

Procedure:
The mixture of 7-(2-iodoethyl)-1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene(1.64 g),4-hydroxybiphenyl (797 mg), potassium carbonate (1.08 g), and DMF (16 ml) was stirred at room temperature for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by alumina column chromatography (toluene) to yield the entitled compound (1.73 g) as crystals.
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([C:24]4[CH:29]=[CH:28][C:27]([CH:30]=[CH:31][C:32]([OH:34])=[O:33])=[CH:26][CH:25]=4)[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].[N+:35]([C:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=1)([O-:37])=[O:36]>CCOCC>[N+:35]([C:38]1[CH:43]=[CH:42][C:41]([O:33][C:32](=[O:34])[CH:31]=[CH:30][C:27]2[CH:26]=[CH:25][C:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([C:16]4[CH:17]=[C:8]([C:5]([S:2]([CH3:1])(=[O:4])=[O:3])([CH3:7])[CH3:6])[CH:9]=[C:10]5[C:15]=4[N:14]=[CH:13][CH:12]=[CH:11]5)[CH:19]=3)=[CH:29][CH:28]=2)=[CH:40][CH:39]=1)([O-:37])=[O:36]
Reactant: CC(C)(c1cc(-c2cccc(-c3ccc(C=CC(=O)O)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: CCOCC
Product: CC(C)(c1cc(-c2cccc(-c3ccc(C=CC(=O)Oc4ccc([N+](=O)[O-])cc4)cc3)c2)c2ncccc2c1)S(C)(=O)=O

Procedure:
Prepared according to the procedure described in EXAMPLE 11, Step 3 but using 3-(3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl)-acrylic acid and 4-nitro-phenol as starting materials. Stirring in Et2O afforded the title compound after filtration.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:42][C:43]([N:45]([CH3:47])[CH3:46])=[O:44].O>CN(C)C=O>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1)[C:13]([N:15]1[CH2:20][CH2:19][C@H:18]([N:21]2[CH2:26][CH2:25][N:24]([CH2:42][C:43]([N:45]([CH3:47])[CH3:46])=[O:44])[CH2:23][CH2:22]2)[C@H:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:16]1)=[O:14]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccccc2)C1
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)CN1CCN([C@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
Rac-cis-(3,5-Bis-trifluoromethyl-phenyl)-(3-phenyl-4-piperazin-1-yl-piperidin-1-yl)-methanone (200 mg, 0.41 mmol) was dissolved in N,N-dimethylforamide (5 mL). Potassium carbonate (171 mg, 1.24 mmol) and 2-chloro-N,N-dimethylacetamide (0.042 mL, 0.41 mmol) were added and the reaction mixture was stirred at room temperature overnight. Water (50 mL) was added and the mixture was extracted twice with 100 mL ethyl acetate. Organic phases were pooled, dried with magnesium sulfate and evaporated. Chromatography on silica gel with methylen chloride/methanol/triethyl amine 90:10:1 gave the desired product (200 mg, 85%) as an off-white solid, MS: m/e=571.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([N+]([O-])=O)[CH:3]=1.F[C:16]1C=C(C=CC=1F)C(O)=O>>[CH3:16][C:6]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]([F:11])[CH:9]=1)=[O:8]
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: O=C(O)c1cc(F)c(F)cc1[N+](=O)[O-]
Product: CC(=O)c1ccc(F)c(F)c1

Procedure:
Briefly, the benzoyl ester derivatives of formula II are prepared by reacting 5-fluoro-4-halo-2-nitrobenzoic acid with a chlorinating agent, such as thionyl chloride or trichlorophosphorous, followed by reacting the acid chloride so formed with a dialkylmalonate. The 4,5-difluoro-2-nitrobenzoic acid starting material can be prepared by nitration in mixed acid of 3,4-difluorobenzoic acid, which is obtained by oxidation 3,4-difluoroacetophenone. The 4- chloro-5-fluoro-2-nitrobenzoic acid starting material can be obtained by the following process:
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([O:17][CH2:18][CH3:19])=O)=[CH:4][NH:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[CH2:18]([O:17][C:15]([C:5]1[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH2:1][CH2:2][NH:3][CH:4]=1)=[S:29])[CH3:19]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1ccccc21
Solvent: Cc1ccccc1
Product: CCOC(=S)C1=CNCCc2c1[nH]c1ccccc21
Yield: 5 %

Procedure:
To a solution of ethyl 1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate (0.51 g, 2 mmol) in toluene (20 mL) was added Lawesson's reagent (1.45 g, 3.6 mmol). The resulting suspension was heated to reflux under nitrogen for 24 hours. Solvent was evaporated to give the crude product, which was purified by column chromatography on silica gel eluting with MeOH-DCM (1:19) to give 1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carbothioic acid O-ethyl ester (27 mg); MS (ES): 273 (MH+).
Reaction SMILES: [CH3:1][N:2]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[N:3]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].Cl.[CH:35]1([NH2:38])[CH2:37][CH2:36]1.C(N(CC)CC)C>C1C=CC=CC=1>[CH:35]1([NH:38][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:15]([CH2:14][N:3]([C:4]([O:6][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:5])[N:2]([CH3:1])[C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[CH:16][CH:17]=2)[CH2:37][CH2:36]1
Reactant: CN(C(=O)OCc1ccccc1)N(Cc1ccc(C(=O)Cl)cc1)C(=O)OCc1ccccc1
Reactant: NC1CC1
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN(C(=O)OCc1ccccc1)N(Cc1ccc(C(=O)NC2CC2)cc1)C(=O)OCc1ccccc1

Procedure:
16.5 g. of 4-[(2-methyl-1,2-dicarbobenzoxy-hydrazino)methyl]-benzoyl chloride were added to 100 ml. of absolute benzene and treated with 3.1 g. of cyclopropylamine hydrochloride. 7.5 g. of triethylamine and 50 ml. of benzene were then dropped into the reaction mixture at 20°-30° with stirring. The reaction mixture was worked up as in Example 3, yielding 4-[(2-methyl-1,2-dicarbobenzoxy-hydrazino)-methyl]-benzoic acid cyclopropylamide, the carbobenzoxy groups of which were then removed by treatment with hydrogen bromide/glacial acetic acid. The product, 4-[(2-methyl-hydrazino)-methyl]-benzoic acid cyclopropylamide hydrobromide, melted at 180°-182°.
Reaction SMILES: C[O:2][C:3]1[CH:20]=[C:19]([O:21]C)[CH:18]=[C:17]2[C:4]=1[C@@:5]1([CH3:26])[C@H:14]([CH2:15][S:16]2)[C@:13]2([CH3:23])[C@H:8]([C:9]([CH3:25])([CH3:24])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1.B(Br)(Br)Br>C(Cl)Cl>[CH3:26][C@@:5]12[CH2:6][CH2:7][C@@H:8]3[C@:13]([CH3:23])([CH2:12][CH2:11][CH2:10][C:9]3([CH3:24])[CH3:25])[C@H:14]1[CH2:15][S:16][C:17]1[C:4]2=[C:3]([OH:2])[CH:20]=[C:19]([OH:21])[CH:18]=1
Reactant: COc1cc(OC)c2c(c1)SC[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)CCC[C@]2(C)[C@H]3CSc4cc(O)cc(O)c4[C@]3(C)CC[C@@H]12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (1R,10R,11S,16S)-3,5-dimethoxy-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene (Compound No. 22) (3.75 g, 10 mmol) in CH2Cl2 (200 mL) was added BBr3 (1.0 M in CH2Cl2, 60 mL, 60 mmol) dropwise at 0° C., and the resulting mixture was stirred at room temperature for 48 h, then concentrated to dryness. Water (100 mL) was added at 0° C., followed by EtOAc (500 mL). The organic layer was separated, washed with brine (2×50 mL), dried (Na2SO4), and concentrated. Purification by chromatography on silica gel (Hexanes/EtOAc, 3:1) followed by dilution with MeOH, concentration and trituration with water gave (1R,10R,11S,16S)-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3,5-diol (Compound No. 26) (620 mg, 18%) as an off-white solid. 1H NMR (CDCl3): δ 6.18 (d, 1H), 5.90 (d, 1H), 4.70 (s, 1H), 4.42 (s, 1H), 3.30 (m, 1H), 2.90 (m, 1H), 2.76 (m, 1H), 1.84-1.40 (m, 8H), 1.39 (s, 3H), 1.20-1.00 (m, 2H), 0.96 (s, 3H), 0.95 (m, 1H), 0.85 (s, 3H), 0.85 (s, 3H). MS m/z 345 (C21H30O2S−H+).
Reaction SMILES: C(OC(=O)C)(=O)C.[N:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:15].[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=1)=O.[OH-].[Na+]>O>[CH3:14][C:13]1[N:8]=[C:9](/[CH:15]=[CH:16]/[C:18]2[CH:19]=[CH:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:23]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: Cc1cccc(C)n1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc(/C=C/c2cccc(C)n2)cc1
Yield: 65.1 %

Procedure:
An acetic anhydride solution (100 mL) of 2,6-lutidine (65 g) and methyl 4-formylbenzenecarboxylate (20 g) was stirred overnight at 180° C. The reaction solution was poured into water with ice, and aqueous 5 N sodium hydroxide solution was added thereto until it became alkaline. The resulting mixture was extracted with ethyl acetate, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated off, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=9/1 to 4/1) to obtain the entitled compound (20.1 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:46]([C:50]([OH:52])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:59]([O:65][CH2:66]I)(=[O:64])[C:60]([CH3:63])([CH3:62])[CH3:61].O>CN(C=O)C>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[C:7]2[C:46]([C:50]([O:52][CH2:66][O:65][C:59](=[O:64])[C:60]([CH3:63])([CH3:62])[CH3:61])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2]
Reactant: CC(C)(C)C(=O)OCI
Reactant: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nc2cccc(C(=O)OCOC(=O)C(C)(C)C)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-ethoxy-1-[[2'-(N-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (2.2 g) in DMF (10 ml) were added potassium carbonate (0.53 g) and pivaloyloxymethyl iodide (0.94 g), and the mixture was stirred for 30 minutes at room temperature. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried. After removal of the solvent, the residue was dissolved in methanol (30 ml) and 1N-HCl (6 ml). The mixture was stirred for one hour at room temperature. The reaction mixture was concentrated to dryness and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and dried. After removal of the solvent, the residue was purified by column chromatography on silica gel to give crystals. The crystals were recrystallized from ethyl acetate-hexane to give colorless crystals (1.13 g. 63%), m.p. 104°-106° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:21]=[C:20]([Si](C)(C)C)[C:11]2[C:12]3[CH:18]=[C:17]([CH3:19])[CH:16]=[N:15][C:13]=3[NH:14][C:10]=2[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:27]I>C(O)C.F[B-](F)(F)F.[Ag+]>[CH2:1]([N:8]1[CH:21]=[C:20]([I:27])[C:11]2[C:12]3[CH:18]=[C:17]([CH3:19])[CH:16]=[N:15][C:13]=3[NH:14][C:10]=2[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: II
Reactant: Cc1cnc2[nH]c3c(=O)n(Cc4ccccc4)cc([Si](C)(C)C)c3c2c1
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: Cc1cnc2[nH]c3c(=O)n(Cc4ccccc4)cc(I)c3c2c1
Temperature: 0 °C
Yield: 86.9 %

Procedure:
Compound 28 (2.5 g, 6.93 mmol) dissolved in dry ethanol (200 mL) and stirred under nitrogen at 0° C. Silver tetrafluoroborate (1.45 g, 7.45 mmol) was added, and the solution stirred for 10 minutes. Iodine (1.85 g, 7.3 mmol) was added, and the reaction stirred 1 h as a precipitate began to form. After evaporation of the solvent, the solid was taken up in CH2Cl2 and washed with water, which caused an insoluble precipitate to form. The solid was collected by filtration and washed with ethyl acetate to leave 2.5 g (87%) of intended product. 1H NMR (400 MHz, DMSO-d6): δ 12.74 (s, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 7.90 (s, 1H), 7.25-7.36 (m, 5H), 5.26 (s, 2H), 2.46 (s, 3H). MS (ES) [m+H] calc'd for C18H14IN3O, 416; found 416.
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:35]([O:38][CH3:39])[O:36][CH3:37])[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1)=[CH:18][C:17]=2[OH:34])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.[CH3:53][O:54][CH2:55][CH:56](O)[CH3:57].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH2:1]([S:8][CH:9]([CH:35]([O:38][CH3:39])[O:36][CH3:37])[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][CH:25]=1)=[CH:18][C:17]=2[O:34][CH:56]([CH3:57])[CH2:55][O:54][CH3:53])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)C(CNC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O)c2[nH]1)SCc1ccccc1
Reactant: COCC(C)O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(=O)NCC(SCc3ccccc3)C(OC)OC)[nH]c12
Temperature: 50 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
To a stirred solution of N-[2-(benzylsulfanyl)-3,3-dimethoxypropyl]-7-hydroxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxamide (1.73 g), tributylphosphine (1.4 mL) and 1-methoxypropan-2-ol (0.59 mL) in tetrahydrofuran (50 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.53 g) at room temperature under argon atmosphere. The whole mixture was stirred at 50° C. for 4 h, and tributylphosphine (1.4 mL), and 1-methoxypropan-2-ol (0.59 mL) and 1,1′-(azodicarbonyl)dipiperidine (1.53 g) were added thereto. After stirred at 50° C. for 3 h, the reaction mixture was concentrated in vacuo. The residue was diluted with diethyl ether and the insoluble materials were removed by filtration and washed with diethyl ether. The combined filtrate and washings were concentrated in vacuo and the residue was purified by silica gel chromatography (ethyl acetate:hexane=35:65 to 60:40) to give a light yellow oil. The oil was partitioned between ethyl acetate and water. The organic layer was washed with successively water and brine, dried (MgSO4), filtered, and concentrated to give a yellow oil, which was purified by silica gel chromatography (ethyl acetate:hexane=35:65 to 70:30, volume ratio) to give the title compound (1.6 g, 82%) as a pale yellow oil. MS 641 (MH+).