Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=2)=[N:10][O:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:30][C:29]3[CH:28]=[CH:27][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:32][CH:31]=3)=[CH:15][CH:14]=2)=[N:10][O:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)Nc1conc1-c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)Nc1conc1-c1ccc(CNc2ccc(S(C)(=O)=O)cc2)cc1
Reaction time: 14 h

Procedure:
To a solution of [3-(4-formyl-phenyl)-isoxazol-4-yl]-carbamic acid tert-butyl ester (30 mg, 0.1 mmol) and 4-methanesulfonylaniline (30 mg, 0.17 mmol) in 1,2-dichloroethane (1 mL) was added sodium trisacetoxy borohydride (50 mg, 0.23 mmol). The reaction mixture was stirred for 14 h and then loaded directly on a silica gel column. Elution with 33% hexane in ethyl acetate provided (3-{4-[(4-methanesulfonyl-phenylamino)-methyl]-phenyl}-isoxazol-4-yl)-carbamic acid tert-butyl ester as a waxy solid. This was dissolved in 4M HCl in dioxane and stirred for 1 h. Removal of volatiles under reduced pressure afforded 3-{4-[(4-methanesulfonyl-phenylamino)-methyl]-phenyl}-isoxazol-4-ylamine hydrochloride as a white solid. MH+=344.3
Reaction SMILES: [CH3:1][C:2]([OH:16])([CH3:15])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]([CH3:12])=[O:11])[C:4]=1[CH2:13][OH:14]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:15][C:2]1([CH3:1])[C:3]2[C:4](=[C:5]([NH:9][C:10]([CH3:12])=[O:11])[CH:6]=[CH:7][CH:8]=2)[C:13](=[O:14])[O:16]1
Reactant: CC(=O)Nc1cccc(C(C)(C)O)c1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cccc2c1C(=O)OC2(C)C
Yield: 62.2 %

Procedure:
To a solution of 7.2 g of α,α-dimethyl-2-hydroxymethyl-3-acetaminobenzyl alcohol in 300 ml of chloroform was added 28 g of activated manganese dioxide and the mixture was allowed to react for 6 hours under refluxing. After the reaction was over, the reaction mixture was left to stand for cooling and filtered on a glass filter having a bed of celite. The residue was washed with 100 ml of chloroform. The filtrate and the washed solution were combined and concentrated to obtain an oily substance. The oily substance was purified by silica gel column chromatography to obtain 4.4 g of 3,3-dimethyl-7-acetaminophthalide in the white crystal form. m.p. 124.1 ° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[N:11]/O)/[CH2:6][CH2:5]2.C(OCC)(=O)C>C(O)(=O)C.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH2:11])[CH2:6][CH2:5]2
Reactant: O/N=C1\CCc2cc(Br)ccc21
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: NC1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.2 %

Procedure:
Zinc dust (28.0 g, 428 mmol) was added to a suspension of (E)-5-bromo-2,3-dihydro-1H-inden-1-one oxime (19.4 g, 86 mmol) in acetic acid (30 mL). The suspension was stirred at rt for 48 h. The reaction was filtered over Kiezelguhr gel. The residue was rinsed with ethyl acetate (2×100 mL). The combined filtrates were concentrated under reduced pressure to obtain a yellow oil. The yellow oil was partitioned between ethyl acetate (200 mL) and 2 N aq. HCl (200 mL). The acidic layer was separated before being basified using aq. 4 N NaOH and a white suspension was formed. Ethyl acetate (200 mL) was added and the milky mixture was filtered over Kiezelguhr gel. The organic phase was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound as a clear light yellow oil (10.8 g, 59%). MS (ESI): m/z [M−NH2]+ 198.0
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([CH:11]1[CH2:22][CH2:21][C:14]2([O:18][CH2:17][CH:16]([C:19]#[N:20])[CH2:15]2)[CH2:13][CH2:12]1)([CH3:10])([CH3:9])[CH3:8]>C1COCC1>[C:7]([CH:11]1[CH2:22][CH2:21][C:14]2([O:18][CH2:17][CH:16]([CH2:19][NH2:20])[CH2:15]2)[CH2:13][CH2:12]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)C1CCC2(CC1)CC(C#N)CO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)C1CCC2(CC1)CC(CN)CO2
Yield: 65.7 %

Procedure:
To a solution of lithium aluminum hydride (LAH) (2.19 g, 58 mmol) in THF (100 ml) was added 8-t-butyl-3-cyano-1-oxaspiro-(4,5)decane (8.5 g, 38.5 mmol) in THF (25 ml). The reaction mixture was refluxed for 3 hours. After cooling excess LAH was carefully destroyed by addition of saturated, aqueous sodium sulfate solution. The reaction mixture was filtrated from insoluble material and the filtrate was evaporated in vacuo. The pale yellow oil (8.6 g) was purified by Kugelrohr distillation (125°-135° C., 0.05 mbar) to yield the product as a colourless liquid (5.7 g nD22 : 1.4817).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[CH:22]=1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][O:30][CH3:31]>>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:27]([CH2:28][CH2:29][O:30][CH3:31])[CH2:26][CH2:25][O:24][CH3:23])=[CH:22][C:11]=3[S:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)csc2c1
Reactant: COCCNCCOC
Product: COCCN(CCCCOc1ccc2c(-c3ccc(Br)cc3)csc2c1)CCOC

Procedure:
According to the method in example 29, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[b]thiophene and bis(2-methoxyethyl)amine were converted to yield {4-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-bis-(2-methoxy-ethyl)-amine as light brown oil, MS: 492 (MH+,1Br).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[CH:7]=[C:6]([N:18]=[CH:17][C:16]2[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: NCc1ccc(F)cc1
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Nc1cc(N=Cc2ccc(F)cc2)ccc1[N+](=O)[O-]
Reaction time: 30 h

Procedure:
A solution of 15.6 g (100 mmol) 2-amino-4-fluoronitrobenzene, 22.5 g (180 mmol) 4-fluorobenzylamine and 20.2 g (220 mmol) triethylamine in 150 ml dimethylsulfoxide is heated with stirring and under an inert gas atmosphere for 30 hours to 60°-70° C. When the reaction time is completed, the solvent is distilled off in a vacuum, the residue is taken up in 500 ml 0.5N hydrochloric acid and the mixture is stirred intensively at room temperature for 30 minutes. The precipitated solid is suction filtered and subjected to hot steam extraction with toluene. The product crystallizing out of the toluene after the mixture has been allowed to stand for twelve hours at 0°-4° C. is suction filtered and dried in a vacuum. 22.2 g (85 % of theory) are obtained. After being left to stand for 12 hours at 0°-4° C., 2-amino-4-(4-fluorobenzylamino)-nitrobenzene crystallizes out of the toluene phase as orange-yellow crystals.
Reaction SMILES: Br[CH:2]([CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([S:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1)[CH:8]([CH3:10])[CH3:9])[CH3:7]
Reactant: COc1ccc(S)cc1
Reactant: CCOC(=O)C(Br)C(C)C
Product: CCOC(=O)C(Sc1ccc(OC)cc1)C(C)C
Yield: 99 %

Procedure:
2-(4Methoxy-phenylsulfanyl)-3-methyl-butyric acid ethyl ester was prepared according to the general method of Example 1. Starting from ethyl 2-bromo-3-methyl-butanoate (20.9 g, 100 mmol) and 4-methoxybenzenethiol (14.0 g, 100 mmol), 30 g of the product was isolated. Yield 99%; Light yellow oil; MS: 271 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=O)[C@H:9]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:39]2)=CC=1>C1(C)C=CC=CC=1>[C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[S:39])[C@H:9]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(N[C@@H]1N=C(c2ccccc2)c2ccccc2NC1=O)OCc1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: O=C(N[C@@H]1N=C(c2ccccc2)c2ccccc2NC1=S)OCc1ccccc1

Procedure:
A mixture of (+)-phenylmethyl N-[(3R)-2,3-dihydro-5-phenyl-2-oxo-1H-1,4-benzodiazepin-3-yl]carbamate (4.0 g, 10 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (4.5 g 11 mmol) in toluene (100 mL) was heated under reflux for 75 min. The mixture was cooled and the volume was reduced to 30 mL by evaporation under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/Hexane (75:25) to give phenylmethyl N-[(3R)-2,3-dihydro-5-phenyl-2-thioxo-1H-1,4-benzodiazepin-3-yl]carbamate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[O:16][C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:26]([O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][C:31]=1[CH3:39])([CH3:28])[CH3:27].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([N:8]1[CH2:18][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[O:16][C:10]2([CH2:15][CH2:14][N:13]([C:34]([C:33]3[CH:37]=[CH:38][C:30]([O:29][CH:26]([CH3:27])[CH3:28])=[C:31]([CH3:39])[CH:32]=3)=[O:35])[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)O)ccc1OC(C)C
Reactant: Clc1ccc(C2CN(Cc3ccccc3)CC3(CCNCC3)O2)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: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(c2ccc(Cl)cc2)O3)ccc1OC(C)C
Reaction time: 0.17 h
Yield: 29.5 %

Procedure:
To a solution of 8-benzyl-10-(4-chlorophenyl)-11-oxa-3,8-diazaspiro[5.5]undecane (100 mg, 0.28 mmol) and 4-isopropoxy-3-methyl-benzoic acid (54 mg, 0.28 mmol) in DMF (1 mL) was added DIEA (98 μL, 0.56 mmol) followed by the addition of HATU (128 mg, 0.34 mmol). The reaction mixture was stirred for 10 minutes, then quenched with water and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water (twice). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography using 0 to 50% EtOAc/hexanes as eluent to obtain [8-benzyl-10-(4-chlorophenyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (44 mg, 29%). ESI-MS m/z calc. 532.2. found 533.3 (M+1)+; Retention time: 2.17 minutes (3 min run).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:11]=[C:10]([C:12]([O:14]CC)=[O:13])[O:9][N:8]=2)[CH:2]=1.O.[OH-].[Na+]>O1CCOCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[O:9][N:8]=2)[CH:2]=1
Reactant: CCOC(=O)c1cc(-c2cccnc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(-c2cccnc2)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
300 mg (1.38 mmol) of ethyl 3-(pyridin-3-yl)-1,2-oxazole-5-carboxylate (for preparation see Chem. Heterocyclic Comp. 2000, 36, 1226-1231) were dissolved in 20 ml of dioxane. While cooling with ice, 7 ml of water and 0.35 ml of 45% aqueous sodium hydroxide solution were added to the solution. The mixture was stirred at room temperature for two hours, then the dioxane was removed on a rotary evaporator under reduced pressure. Ice-water was added to the residue, and it was acidified with concentrated hydrochloric acid. The solution was stirred at room temperature overnight, and the precipitated solid was filtered off with suction and dried.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([C:19]#[N:20])[C:16](=[O:21])[NH:15][C:14]=2[CH3:22])=[CH:9][CH:8]=1)C.O.[OH-].[Li+]>O1CCOCC1.O>[C:19]([C:17]1[C:16](=[O:21])[NH:15][C:14]([CH3:22])=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:23])=[O:3])=[CH:8][CH:9]=2)[CH:18]=1)#[N:20]
Reactant: CCOC(=O)COc1ccc(-c2cc(C#N)c(=O)[nH]c2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1[nH]c(=O)c(C#N)cc1-c1ccc(OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a stirred solution of [4-(5-Cyano-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)phenoxy]-acetic acid ethyl ester (7, 1.3 g, 4.16 mmol) in a mixture of 1,4-dioxane (25 mL) and water (25 mL) was added lithium hydroxide mono hydrate (700 mg, 16.7 mmol). The reaction mixture was stirred for 2 h at ambient temperature, diluted with water (50 mL), washed with diethylether (2×25 mL), cooled to 0° C. and acidified to pH 2 with aqueous hydrochloric acid (5 N). After standing at ambient temperature overnight the formed precipitate was filtered off with suction, washed with water and dried under vacuum to give [4-(5-Cyano-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-phenoxy]-acetic acid (8) as light yellow crystalline solid (758 mg, 64% yield, 97% pure by LC-MS and 1H NMR), 1H NMR (400 MHz; CDCl3): δ 7.70 (d, 1H); 7.20 (m, 2H); 6.73 (m, 2H); 4.88 (s, 2H); 1.71 (s, 3H).
Reaction SMILES: [N:1]([C:4]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)([CH3:6])[CH3:5])=[N+]=[N-].[H][H]>C(O)C.[Pd]>[N:13]1[C:14]2[C:9](=[CH:8][C:7]([C:4]([NH2:1])([CH3:5])[CH3:6])=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(N=[N+]=[N-])c1ccc2ncccc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(N)c1ccc2ncccc2c1
Reaction time: 6 h
Yield: 15.9 %

Procedure:
To 6-(2-azidopropan-2-yl)quinoline (0.100 g, 2.67 mmol) in ethanol (3 ml), palladium on carbon (10 mg, 10% w/w) was added and stirred under a hydrogen atmosphere using hydrogen filled balloon. After 6 h, the reaction mass was filtered through celite, washed with methanol and concentrated to afford the title compound as brown liquid (0.079 g, 90%). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.82 (dd J=4.2, 1.6 Hz, 1H), 8.31 (d, J=8.9 Hz, 1H), 8.02 (d, J=1.9 Hz, 1H), 7.99 (dd, J=8.9, 2.1 Hz, 1H), 7.93 (d, J=8.9 Hz, 1H), 7.49 (q, J=4.2 Hz, 1H), 2.06 (s, 2H), 1.46 (s, 6H).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:9]([O:24][CH3:25])[CH:8]=1>C1C=CC=CC=1.C(OCC)(=O)C>[Cl:4][C:12]1[C:7]([OH:6])=[CH:8][C:9]([O:24][CH3:25])=[C:10]([CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:11]=1
Reactant: CCCCCC(CC(=O)OC)c1ccc(O)cc1OC
Reactant: O=S(=O)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCCCCC(CC(=O)OC)c1cc(Cl)c(O)cc1OC
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 88 %

Procedure:
604 mg (4.48 mmol) of sulfuryl chloride were added to a solution of 1.26 g (4.48 mmol) of methyl 3-(4-hydroxy-2-methoxyphenyl)octanoate (prepared as described in Preparation 44) in 10 ml of benzene, and the resulting mixture was stirred at 70° C. for 3.5 hours. At the end of this time, the reaction mixture was diluted with ethyl acetate, and the diluted solution was washed with an aqueous solution of sodium carbonate, with water and with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 100 g of silica gel, using a 1:2 by volume mixture of ethyl acetate and hexane as the eluent, to give the title compound as an oily substance in a 88% yield.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]1[C@@H:11]([CH2:12][CH2:13][CH3:14])[C@@H:10]([CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]1=[O:24].[OH-].[Na+].S(=O)(=O)(O)[O-:28].[Na+]>C1COCC1.CO>[C:18]1([CH2:17][CH2:16][CH2:15][C@H:10]([C@@H:11]([NH:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH2:12][CH2:13][CH3:14])[C:9]([OH:24])=[O:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCC[C@H]1[C@@H](CCCc2ccccc2)C(=O)N1OC1CCCCO1
Reactant: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC[C@H](NOC1CCCCO1)[C@@H](CCCc1ccccc1)C(=O)O
Temperature: 23 °C
Reaction time: 36 h
Yield: 72 %

Procedure:
To a solution of (3R,4S)-1-(2-tetrahydropyranyloxy)-3-(3-phenyl-1-propyl)-4-propylazetidin-2-one (1.22 g, 3.69 mmol) in THF-methanol (2:1, 15 mL) is added 1 N aqueous sodium hydroxide (5.5 mL). The solution is stirred at 23° C. for 36 h, is acidified to pH 3 with saturated aqueous sodium bisulfate solution, and is extracted with two 100-mL portions of EtCOAc. The combined organics are dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide (2R,3s)-2-(3-phenyl-1-propyl)-3-(2-tetrahydropyranyloxyamino)hexanoic acid as an oil (0.93 g, 72% yield).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:13])=[CH:5][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:8]=1.[CH3:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17](O)=O.CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][C:6]([C:9]([F:11])([F:10])[F:12])=[CH:5][C:4]=2[N:13]=[C:17]1[C:16]1[CH:20]=[CH:21][N:22]=[CH:23][C:15]=1[CH3:14]
Reactant: Cc1cnccc1C(=O)O
Reactant: CNc1ccc(C(F)(F)F)cc1N
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: Cc1cnccc1-c1nc2cc(C(F)(F)F)ccc2n1C
Temperature: 120 °C
Reaction time: 5 h
Yield: 82.5 %

Procedure:
A mixture of 0.38 g of N1-methyl-4-trifluoromethylbenzene-1,2-diamine, 0.33 g of 3-methylisonicotinic acid, 0.46 g of WSC and 10 ml of pyridine was stirred for 5 hours while heating at 120° C. After cooling down to room temperature, water was poured, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, then, concentrated under reduced pressure. To the residue were added a mixture of 0.57 g of p-toluenesulfonic acid monohydrate and 10 ml of toluene, and the mixture was stirred for 1 hour while heating at 80° C., and stirred for 2 hours while heating at 120° C. After cooling down to room temperature, a saturated sodium hydrogen carbonate aqueous solution was poured, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.48 g of 1-methyl-2-(3-methylpyridin-4-yl)-5-trifluoromethyl-1H-benzimidazole (hereinafter, referred to as present active compound 6).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2].B(F)(F)F.CCOCC.[N+](=[C:67]([CH3:69])[CH3:68])=[N-]>CCOCC>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH:67]([CH3:69])[CH3:68])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CC(C)=[N+]=[N-]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: FB(F)F
Solvent: CCOCC
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC(C)C)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg) in ether (6 ml) is added boron trifluoride etherate (10 μl) followed by freshly prepared 2-diazopropane (100 fold excess). The mixture is stirred at room temperature for 15 min and quenched with sat'd. aqueous sodium bicarbonate solution. The organic layer is separated, washed (sat'd. aqueous NaCl) and dried over anhydrous magnesium sulfate. Removal of solvent followed by preparative tlc on silica gives the title compound and its 4"-isomer.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH3:18])[C:9]=1[SH:19].[CH:20]1([CH2:23]Br)[CH2:22][CH2:21]1>C(#N)C>[Cl:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH3:18])[C:9]=1[S:19][CH2:23][CH:20]1[CH2:22][CH2:21]1
Reactant: BrCC1CC1
Reactant: COC(=O)c1ccc(Cl)c(S)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1ccc(Cl)c(SCC2CC2)c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.66 g (5.09 mmol) of cesium carbonate in 20 ml of acetonitrile were added to 1.05 g (4.85 mmol) of methyl 4-chloro-3-mercapto-2-methylbenzoate. 687 mg (5.09 mmol) of cyclopropylmethyl bromide were slowly added dropwise, and the reaction mixture was stirred at RT for 16 h. For work-up, the solvent was removed, and water was added to the residue. The mixture was extracted three times with ethyl acetate, the combined organic phases were dried and filtered and the solvent was removed. What was isolated were 1.2 g of pure product.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([N:6]1[C:5]2[CH:12]=[CH:13][C:2]([CH3:1])=[CH:3][C:4]=2[C:9](=[O:10])[O:8][C:7]1=[O:11])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c(=O)oc(=O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
A solution of Compound 11 (25 g, 141 mmol) in DMF was added slowly to a suspension of NaH (60% in mineral oil, 6.21 g, 155 mmol) in DMF and further stirred at room temperature for 1 h. Then, neat benzyl bromide (19.53 mL, 155 mmol) was added and the solution further stirred at room temperature for 3 h. The solution was poured into ice water, and the solids formed were filtered, washed several times by water, and dried. The solid was suspended in hexane, sonicated briefly, filtered, and washed by hexane to yield 36.5 g (97%) of white solids. M.P. 150° C. 1H NMR (DMSO-d6): δ 2.32 (s, 3H), 5.27 (s, 2H), 7.15 (d, J=8.7 Hz, 1H), 7.26–7.39 (m, 5H), 7.54 (dd, J=1.5, 8.7 Hz, 1H), 7.83 (d, J=1.5 Hz, 1H). Anal. (C16H13NO3) C, H, N.