Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:11][C:12](=O)[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1.[NH2:15][CH:16]([CH3:26])[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[OH:18].Cl>CO>[OH:25][C:22]1[CH:21]=[CH:20][C:19]([CH:17]([OH:18])[CH:16]([NH:15][CH:12]([CH3:13])[CH2:11][CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][O:2]2)[CH3:26])=[CH:24][CH:23]=1
Reactant: CC(N)C(O)c1ccc(O)cc1
Reactant: CC(=O)CC1OCCc2ccccc21
Agent: Cl
Solvent: CO
Product: CC(CC1OCCc2ccccc21)NC(C)C(O)c1ccc(O)cc1
Yield: 72 %

Procedure:
An oily product was obtained in the same manner as in Example 1, using (isochroman-1-yl)acetone and 2-amino-1-(4-hydroxyphenyl)-1-propanol [J. Med. Chem., 14, 148 (1971)]. The product was dissolved in anhydrous methanol, and concentrated hydrochloric acid was added thereto. The solvent was evaporated off to give a hydrochloride. The hydrochloride was then washed with ether to give Compound 24 as crystals in a yield of 72%.
Reaction SMILES: C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1.[NH2:27][CH:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:34]=2)[CH2:29]1.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1>>[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([S:49]([NH:27][CH:28]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[C:33]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:34]=3)[CH2:29]2)(=[O:51])=[O:50])=[CH:45][CH:44]=1
Reactant: COC(=O)Cc1ccc2c(c1)CC(N)C2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=C(O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)O)C(=O)c1ccccc1
Product: COC(=O)Cc1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2

Procedure:
In the same manner as described in Examples 50-(1), methyl (+)-(2-aminoindan-5-yl)acetate (+)-dibenzoyl-D-tartaric acid salt and 4-chlorophenylsulfonyl chloride are treated to give methyl (+)-[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetate.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[OH:15][CH2:16][C@@H:17]([NH:25][C:26](=[O:30])[C:27](O)=[O:28])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:27](=[O:28])[C:26]([NH:25][C@@H:17]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:16][OH:15])=[O:30]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)C(=O)N[C@H](CO)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C(=O)N[C@H](CO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
The mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.256 g; 1.09 mmol), (S)-2-(1-hydroxy-3-phenylpropan-2-ylamino)-2-oxoacetic acid (0.267 g; 1.19 mmol), HATU (0.413 g: 1.09 mmol) and N,N-diisopropylethylamine (0.474 mL; 2.71 mmol) in DMF (5 mL) was stirred at room temperature overnight and concentrated under reduced pressure. The residue was dissolved in dichloromethane and the organic layer was washed with water and was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 1 to 10% methanol in dichloromethane) to yield 0.251 g (58%) of (S)-N1-(2-(5-chloro-1H-indol-3-yl)ethyl)-N2-(1-hydroxy-3-phenylpropan-2-yl)oxalamide as a white solid.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH:39][C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:31])([F:1])[F:32])=[CH:8][CH:7]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:29])=[CH:36][CH:35]=1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccc(F)cc1)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with 4-fluorobenzylamine (34 mg, 0.27 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was concentrated, the residue was suspended in water, and the solid was collected by vacuum filtration to afford 96 mg of the title compound as a colorless solid.
Reaction SMILES: OOS([O-])=O.[K+].C(=O)([O-])[O-:8].[K+].[K+].[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([NH:18][C:19](=[O:21])[CH3:20])=[CH:16][CH:15]=1>O>[N:13]([C:14]1[CH:15]=[CH:16][C:17]([NH:18][C:19](=[O:21])[CH3:20])=[CH:22][CH:23]=1)=[O:8]
Reactant: CC(=O)Nc1ccc(N)cc1
Reactant: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: CC(=O)Nc1ccc(N=O)cc1
Reaction time: 0.17 h
Yield: 64.6 %

Procedure:
After oxone (potassium peroxymonosulfate, from Sigma-Aldrich®; 12.28 g, 20.0 mmol) had dissolved completely in water (100 mL), potassium carbonate (4.14 g, 30 mmol) was added slowly to neutralize the solution to a weak acidity. The solution was added quickly into a solution of 4′-aminoacetanilide (from Sigma-Aldrich®; 1.50 g, 10.0 mmol) in water (150 mL). The mixture immediately turned green, and greenish-gray solids started to fall out of solution. After the mixture had been stirred for another 10 minutes, the precipitates were collected on a filter funnel, air dried, and recrystallized from hot ethanol. Two batches of products were collected to give a total yield of 1.06 g (65%) greenish crystals, mp 179-180° C. (lit. 179-180° C.).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4][S:5][CH2:6][CH2:7]Cl.[CH3:9][C:10]1[CH:22]=[CH:21][C:13]([CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:12][CH:11]=1.[OH-].[K+]>CS(C)=O>[CH2:2]([N:18]1[CH2:19][CH2:20][N:15]([CH2:14][C:13]2[CH:21]=[CH:22][C:10]([CH3:9])=[CH:11][CH:12]=2)[CH2:16][CH2:17]1)[CH2:3][S:4][S:5][CH2:6][CH2:7][N:18]1[CH2:19][CH2:20][N:15]([CH2:14][C:13]2[CH:12]=[CH:11][C:10]([CH3:9])=[CH:22][CH:21]=2)[CH2:16][CH2:17]1
Reactant: Cc1ccc(CN2CCNCC2)cc1
Reactant: ClCCSSCCCl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1ccc(CN2CCN(CCSSCCN3CCN(Cc4ccc(C)cc4)CC3)CC2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of bis(2-chloroethyl)disulfide (2.9 g) in dimethylsulfoxide (5 ml) is added dropwise to a warmed mixture of (4-methylbenzyl)piperazine (5.7 g), potassium hydroxide (5.0 g), and dimethylsulfoxide (55 ml). The resulting mixture is stirred an additional 4 hours after which it is poured over ice/water and the product extracted with methylene chloride, dried and concentrated. The resulting oil (6.5 g) is purified on a silica gel column (methylene chloride:methanol, 95:5), and the salt precipitated with ethereal hydrochloric acid to provide, after recrystallization from ethanol/water, 1,1'-(dithiodi-2,1-ethanediyl)bis[4-(4-methylbenzyl)piperazine] tetrahydrochloride as a white crystalline solid, m.p. 280°-282° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.Cl[C:10]([F:15])([F:14])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:10]([F:15])[F:14])=[CH:4][N:3]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: Oc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)Oc1ccc(Br)nc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 58 %

Procedure:
A mixture of 2-bromo-5-hydroxypyridine (1.2 g, 6.9 mmol), sodium chlorodifluoroacetate (2.1 g, 13.8 mmol), and potassium carbonate (1.24 g, 8.97 mmol) in anhydrous DMF (10 ml) was stirred at 80° C. for 20 h. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was back extracted with EtOAc and the combined organics was dried (Na2SO4) and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 10% EtOAc in hexane, to provide 2-bromo-5-(difluoromethoxy)pyridine (0.89 g, 4.0 mmol, 58% yield) as colorless oil. ESI (M+1) 225.8.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[C:15]([F:23])[CH:14]=1>CN(C1C=CN=CC=1)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)(=[O:20])=[O:21])=[C:15]([F:23])[CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1F
Reactant: Nc1cccc2cccnc12
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cccc2cccnc12)c1ccc(Cl)cc1F
Yield: 81.8 %

Procedure:
In the similar fashion using route 14 general procedure 27, 8-aminoquinoline (100 mg, 0.69 mmol), 4-chloro-2-fluorobenzenesulfonyl chloride (200 mg, 0.83 mmol) and DMAP (cat.) gave the title compound (190 mg, 82%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [Na:1].[Na].[C:3]([NH:6][C@@H:7]1[C@@H:12]([O:13]CC2C=CC=CC=2)[C@H:11]([O:21]CC2C=CC=CC=2)[C@@H:10]([CH2:29][O:30][S:31]([OH:34])(=[O:33])=[O:32])[O:9][C@H:8]1[O:35][C@H:36]1[C@@H:50]([O:51]CC2C=CC=CC=2)[C@@H:49]([CH2:59][O:60][S:61]([OH:64])(=[O:63])=[O:62])[O:48][C@@H:38]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C@@H:37]1[O:65]CC1C=CC=CC=1)(=[O:5])[CH3:4].[H][H]>CO.O.[OH-].[OH-].[Pd+2]>[Na:1].[Na:1].[C:3]([NH:6][C@@H:7]1[C@@H:12]([OH:13])[C@H:11]([OH:21])[C@@H:10]([CH2:29][O:30][S:31]([OH:34])(=[O:33])=[O:32])[O:9][C@H:8]1[O:35][C@H:36]1[C@@H:50]([OH:51])[C@@H:49]([CH2:59][O:60][S:61]([OH:64])(=[O:63])=[O:62])[O:48][C@@H:38]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C@@H:37]1[OH:65])(=[O:5])[CH3:4]
Reactant: [H][H]
Reactant: CCCCCCCCO[C@@H]1O[C@H](COS(=O)(=O)O)[C@H](OCc2ccccc2)[C@H](O[C@@H]2O[C@H](COS(=O)(=O)O)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2NC(C)=O)[C@H]1OCc1ccccc1
Agent: [Pd+2]
Agent: [Na]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCO[C@@H]1O[C@H](COS(=O)(=O)O)[C@H](O)[C@H](O[C@@H]2O[C@H](COS(=O)(=O)O)[C@@H](O)[C@H](O)[C@H]2NC(C)=O)[C@H]1O
Reaction time: 4 h
Yield: 180.6 %

Procedure:
Compound 21 (170 mg, 0.160 mmol) was dissolved in a mixture of methanol and water (3:1, 15 mL) and palladium hydroxide/carbon (180 mg) was added thereto. Inside of the reaction system was replaced with hydrogen gas, and catalytic reduction was performed at room temperature for 4 hours. The reaction mixture was filtered through Celite, and the filtrate was evaporated. The residue was purified with a column of Sephadex LH-20 (CHCl3:MeOH:H2O=5:10:3), further purified with a column of Dowex-50 (Na+) type (CHCl3:MeOH:H2O=1:3:1), and finally purified with a column of Sephadex LH-20 (CHCl3:MeOH:H2O=5:10:3) again to obtain Compound 22 (101.4 mg, 90.6%).
Reaction SMILES: [H-].[Na+].[CH:3]1([CH:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH2:7][OH:8])[CH2:5][CH2:4]1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Cl)=[CH:19][C:18]=1[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>O1CCCC1>[CH:3]1([CH:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH2:7][O:8][CH2:23][C:20]2[CH:21]=[CH:22][C:17]([F:16])=[C:18]([O:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:19]=2)[CH2:5][CH2:4]1
Reactant: Fc1ccc(CCl)cc1Oc1ccccc1
Reactant: OCC(c1ccc(Cl)cc1)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(COCC(c2ccc(Cl)cc2)C2CC2)cc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
A stirred suspension of 0.1 gram (0.0044 mole) of sodium hydride in 5 mL of tetrahydrofuran was cooled to 0° C., and a solution of 0.8 gram (0.0041 mole) of 2-cyclopropyl-2-(4-chlorophenyl)ethanol in 2.5 mL of tetrahydrofuran was added via syringe during a two minute period. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for 30 minutes and then was heated to 55° C. where it stirred for 1.5 hours. The reaction mixture was cooled to ambient temperature, and a solution of 1.0 gram (0.0043 mole) of (4-fluoro-3-phenoxyphenyl)methyl chloride in 2.5 mL of tetrahydrofuran was added via syringe. Upon completion of addition, the reaction mixture stirred at ambient temperature for 20 hours and then was warmed to 60° C. where it stirred for 30 minutes. The reaction mixture was cooled, and 15 mL of water was added. The aqueous layer was removed and extracted with three 25 mL portions of hexanes. The organic materials were combined and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residual oil. The oil was purified by rotating disk thin layer chromatography using 5-10% ethyl acetate in hexanes for elution. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.65 gram of (4-fluoro3-phenoxyphenyl)methyl 2-cyclopropyl-2-(4-chlorophenyl)ethyl ether. The nmr and the ir spectra were consistent with the proposed structure.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([O:23][C@@H:24]([C@H:26]3[CH2:30][NH:29][C:28](=[O:31])[CH2:27]3)[CH3:25])=[N:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)=[CH:13][N:12]=3)=[CH:10][C:5]=2[N:4]=[CH:3]1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([N:20]1[CH2:21][CH2:22][N:17]([C:14]2[CH:15]=[CH:16][C:11]([C:9]3[N:8]=[C:7]([O:23][C@@H:24]([C@H:26]4[CH2:30][NH:29][C:28](=[O:31])[CH2:27]4)[CH3:25])[C:6]4[N:2]([CH3:1])[CH:3]=[N:4][C:5]=4[CH:10]=3)=[N:12][CH:13]=2)[CH2:18][CH2:19]1)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)cn2)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(-c3cc4ncn(C)c4c(O[C@H](C)[C@H]4CNC(=O)C4)n3)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
Into a solution of (R)-4-((R)-1-((3-methyl-6-(5-(piperazin-1-yl)pyridin-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one 3.39 (50 mg, 0.119 mmol) and TEA (0.12 g) in DCM (2 mL) was added acetic anhydride (0.02 g, 0.18 mmol) at 0° C. The reaction mixture was warmed to rt and stirred for 2 h. Then the reaction mixture was extracted with ethyl acetate and washed with brine. After drying, the solvent was removed, the residue was purified by silica chromatographgy to provide 36 mg of (R)-4-((R)-1-((6-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-3-methyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one 3.40.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]([C:22](=[O:26])[C@H:23]([CH3:25])[NH2:24])[CH:9]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].C(O)(=O)C.O=[C:38]([CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:39]([O:41][CH2:42][CH3:43])=[O:40]>C(O)C.[Ni]>[C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]([C:22](=[O:26])[C@H:23]([CH3:25])[NH:24][CH:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[CH:9]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1cc2c(cc1OC)C(N(CC(=O)OC(C)(C)C)C(=O)[C@H](C)N)CC2
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: [Ni]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)N(CC(=O)OC(C)(C)C)C1CCc2cc(OC)c(OC)cc21
Yield: 33.3 %

Procedure:
L-Alanyl-N-(5,6-dimethoxyindan-1-yl)glycine tert-butyl ester (4.0 g) is dissolved in 80 ml of ethanol, and 0.77 g of sodium acetate, 4.0 g of acetic acid, 4.0 g of ethyl 2-oxo-4-phenyl-butyrate, 12 g of molecular sieve 3A and 6.0 g of Raney nickel are added. Thereafter, the reaction and treatment are carried out as in Example 2 to give 2.0 g of N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-N-(5,6-dimethoxyindan-1-yl)glycine tert-butyl ester as slightly yellow oil.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17].CCOC(C)=O>C1COCC1>[CH3:8][C:7]1[C:2]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH2:15][CH2:16][CH3:17])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1cccnc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)c1ncccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.8 %

Procedure:
To 2-bromo-3-methylpyridine (1.3 mL, 11.7 mmol) in THF (35 mL) at −78° C. was added n-BuLi (2.5 M in hexanes, 5.6 mL, 14 mmol). After 30 min, tri-n-butyltin chloride (3.8 mL, 14 mmol) was added. After 1 h at −78° C., the reaction was allowed to warm to rt. EtOAc was added and the reaction mixture was washed with 10% aq KF. The organic layer was dried (MgSO4). Purification via silica gel chromatography (0-15% EtOAc in heptane) gave the title compound (1.2 g, 27%). MS (ESI) mass calcd. for C18H33NSn, 382.2; m/z found 384.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH2:17][OH:18])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.C(N(CC)CC)C.[CH3:26][Si:27](Cl)([CH3:29])[CH3:28]>ClCCl>[CH3:1][O:2][CH2:3][C:4]1([CH2:17][O:18][Si:27]([CH3:29])([CH3:28])[CH3:26])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: COCC1(CO)c2ccccc2-c2ccccc21
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC1(CO[Si](C)(C)C)c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 86 %

Procedure:
1 g of 9-methoxymethyl-9-hydroxymethyl-fluorene was dissolved in 20 ml of dichloromethane. The solution was cooled in ice-water bath to below 5° C., and 0.7 ml of triethyl amine was added thereto. After stirring for 5 minutes, 0.6 ml of trimethylsilyl chloride was added drop-wise, and the mixture was stirred for further 2 hours, followed by stirring at room temperature for 1 hour. The reaction mixture was washed with water, and the organic layer separated was dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to give 1.41 g of concentrate (yield 86%). MS(EI) m/e: 312(M+).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[C:10]([C:12]1[CH:32]=[CH:31][C:15]2[N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[N:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH:20]=3)[CH:17]=[N:18][C:14]=2[CH:13]=1)#N.C(Cl)Cl.[NH4+].[Cl-].[OH2:38]>C1(C)C=CC=CC=1>[CH:10]([C:12]1[CH:32]=[CH:31][C:15]2[N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[N:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH:20]=3)[CH:17]=[N:18][C:14]=2[CH:13]=1)=[O:38]
Reactant: N#Cc1ccc2c(c1)ncn2-c1cccc(-c2ncccn2)c1
Reactant: O
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)ncn2-c1cccc(-c2ncccn2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
A solution of DIBAL-H in toluene (2.5 ml, 1.0 M) was added to a mixture of (67) (367 mg, 1.2 mmol) and CH2Cl2 (60 ml) at -78° C. The reaction mixture was stirred for 1 hr at -78° C. and for 1 hr at room temperature. A saturated NH4Cl solution was added to the reaction mixture and stirring was continued for 0.5 hr. The mixture was poured into water and extracted with CH2Cl2. The organic extract was dried over MgSO4, and the solvent was evaporated under reduced pressure to give (68) (142 mg, 38%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:10]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: Cc1cc(O)cc(Br)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(C)cc(Br)c1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a mixture of 3-bromo-5-methyl-phenol (185 g; 0.940 mol) and K2CO3 (437 g, 3.17 mol) in acetone (2 L) is added MeI (424 g, 2.99 mol). The mixture is stirred at 40° C. for 16 h. The mixture is cooled to ambient temperature, filtered, and concentrated under reduced pressure. After filtration, the mixture is purified by flash silica gel chromatography to afford 1-Bromo-3-methoxy-5-methyl-benzene, D-4-1 (189 g, quant. yield) as a light yellow oil.
Reaction SMILES: C(S[C:6](=[O:24])[CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][CH:13]=1)[C:8](=[O:10])[CH3:9])(C)(C)C.[NH2:25][C:26]1[CH:27]=[C:28]([OH:33])[CH:29]=[CH:30][C:31]=1[Cl:32]>>[Cl:32][C:31]1[CH:30]=[CH:29][C:28]([OH:33])=[CH:27][C:26]=1[NH:25][C:6](=[O:24])[CH:7]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](=[O:23])[C:19]([CH3:20])([CH3:21])[CH3:22])=[CH:16][CH:17]=1)[C:8](=[O:10])[CH3:9]
Reactant: Nc1cc(O)ccc1Cl
Reactant: CC(=O)C(Cc1ccc(C(=O)C(C)(C)C)cc1)C(=O)SC(C)(C)C
Product: CC(=O)C(Cc1ccc(C(=O)C(C)(C)C)cc1)C(=O)Nc1cc(O)ccc1Cl

Procedure:
The title compound was prepared by the method of Preparation 11b using 2-[4-(2,2-dimethylpropionyl)benzyl]-3-oxothiobutyric acid S-tert-butyl ester and 3-amino-4-chlorophenol.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH:5]=[O:6].[CH2:7](O)[CH2:8][OH:9].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][S:2][CH2:3][CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1
Reactant: CSCCC=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CSCCC1OCCO1

Procedure:
A solution of 3-(methylthio)propanal (5.2 g, 0.05 mol) and ethyleneglycol (3.4 g. 0.055 mol) in 100 mL of benzene was treated with 300 mg p-toluenesulfonic acid and heated at reflux for 4 hrs. The solution was cooled and decanted. Concentration and drying in vacuo provided the title compound as a light yellow oil. 1H NMR (300 MHz, CDCl3) δ ppm: 4.93 (1H, t, J=4.76 Hz) 3.74–4.03 (4H, m) 2.46–2.68 (2H, m) 2.08 (3H, s) 1.83–2.00 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:4]=2[S:5][CH:6]=1.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[F:20].O>CN1CCCC1=O>[F:11][C:8]1[CH:9]=[CH:10][C:3]2[C:2]([NH:1][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[CH:6][S:5][C:4]=2[CH:7]=1
Reactant: Nc1csc2cc(F)ccc12
Reactant: Fc1cnccc1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: Fc1ccc2c(Nc3ccncc3F)csc2c1
Yield: 82.6 %

Procedure:
A solution of 3-amino-6-fluorobenzo[b]thiophene (10 g, 60 mmol) and 4-chloro-3-fluoropyridine hydrochloride (12 g, 71 mmol) in 150 mL of 1-methyl-2-pyrrolidinone was stirred at 90-95° for 2.5 h, and thereafter cooled, stirred with water and extracted with ether. The aqueous layer was basified with 30% aqueous ammonium hydroxide and extracted with ether. The organic extract was washed with water and saturated sodium chloride solution, and dried (anhydrous magnesium sulfate), filtered and concentrated to give 13 g of a solid. Elution through silica with 10% ethyl acetate in dichloromethane via flash column chromatography yielded 7 g (44.6%) of a white solid, mp 155-157° C. Recrystallization of 2 g from acetonitrile afforded 1.3 g (29%) of white needles, mp 158-159° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6](O)=O)([O-:3])=[O:2].C1(S([NH2:25])(=O)=O)C=CC=CC=1>>[N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]#[N:25])([O-:3])=[O:2]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Product: N#Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
2,4-dinitrobenzonitrile was prepared from 2,4-dinitrobenzoic acid and benzenesulfonamide by the method of Oxley, Partridge, Robson and Short, J. Chem. Soc., 1946, 763. The product was purified by chromatography on alumina, using tetrahydrofuran as a solvent: yield, 56%; m.p. 102° C.