Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:10][CH:9]=[C:8]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[N:7]=1.[OH-].[Na+]>CO>[OH:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:8]1[N:7]=[C:6]([CH2:5][CH2:4][C:3]([OH:33])=[O:2])[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)CCc1nc(CCCCCO)ccc1OCCCC/C=C/c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C=C/CCCCOc2ccc(CCCCCO)nc2CCC(=O)O)cc1
Yield: 83.1 %

Procedure:
Under the conditions of example 3 C, 400 mg of 3-{6-(5-hydroxypentyl)-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester in 20 ml of methanol is saponified with 12 ml of 2n sodium hydroxide solution and worked up. 322 mg of the title compound is obtained as oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5])C.CO.O.O.[OH-].[Li+]>C1COCC1>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:7]2[C:6]([C:4]([OH:5])=[O:3])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:13][CH:14]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)c1ccccc1-c1ccc(C(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.8 %

Procedure:
Crude 4′-tert-butylbiphenyl-2-carboxylic acid ethyl ester (33 g, ˜117 mmol) was taken up in a mixture of THF (100 mL), methanol (50 mL) and water (40 mL). Lithium hydroxide monohydrate (7.36 g, 176 mmol) was added and the reaction mixture was allowed to stir at room temperature for 3 days. The mixture was extracted three times with diethyl ether. The aqueous phase was then acidified using aq. 6N HCl and extracted three times with EtOAc. The combined EtOAc layers were dried over MgSO4, filtered and concentrated. The solid residue was triturated with hexane to afford the title compound as a white solid (18.7 g, 63%). 1H NMR (selected signals, DMSO-d6): 7.66 (dd, 1H), 7.53 (m, 1H), 7.41 (d, 2H), 7.25 (d, 2H), 1.29 (s, 9 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][P:12]([OH:14])[OH:13])=[CH:4][CH:3]=1.[OH-].[Na+].[O-:17][Mn](=O)(=O)=O.[K+].P(O)O.Cl.S(=O)(O)[O-].[Na+]>CC(C)=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][P:12](=[O:17])([OH:14])[OH:13])=[CH:6][CH:7]=1
Reactant: OP(O)CCCCc1ccc(F)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: O=S([O-])O
Agent: OPO
Solvent: O
Solvent: CC(C)=O
Product: O=P(O)(O)CCCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of p-fluorophenylbutyl phosponous acid (1 g, 0.0046 mole) in acetone (10 ml) and water (10 ml) was added a solution of sodium hydroxide (0.185 g, 0.0046 mole) in water (5 ml) until a pH of 7 was reached. A solution of KMnO4 (0.44 gm, 0.0028 mole) in water (50 ml) was added slowly to the vigorously stirred solution of phosphonous acid at 20-25° C. After the addition (20 min), the reaction mixture was stirred for 10 min at ambient temperature and acidified with concentrated HCl acid until a pH 1 was reached. Saturated sodium bisulphite solution was added to the reaction mixture thereby resulting in formation of a cloudy white precipitate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5](O)=[O:6].[OH-].[NH4+:30]>S(Cl)(Cl)=O.C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5]([NH2:30])=[O:6]
Reactant: [NH4+]
Reactant: O=C(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: NC(=O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reaction time: 16 h

Procedure:
3-Fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzoic acid (107 mg, 0.274 mmol) was dissolved in thionyl chloride at 65° C. for 1 h before it was concentrated. The reaction mixture was dissolved in THF (1.4 mL) before ammonium hydroxide (1.07 mL, 27.40 mmol) was added and stirred at ambient temp. for 16 h. The reaction mixture was diluted with EtOAc, added to a separatory funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed with sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated via rotovap to give the title compound after preparatory LC. MS (ESI) m/z: Calculated: 389; Observed: 390.1 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:12]=2)=[CH:4][CH:3]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2oc(-c3ccc(F)cc3)nc2-c2ccccn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(-c2nc(-c3ccccn3)c(C3CCNCC3)o2)cc1

Procedure:
tert-Butyl 4-[2-(4-fluorophenyl)-4-(pyridin-2-yl)-1,3-oxazol-5-yl]piperidine-1-carboxylate (50 mg. 0.12 mmol) was stirred in 4:1 DCM/TFA (5 ml) at room temperature for 3 h. Then the volatiles were removed under vacuum, and the resulting residue was purified by reverse phase HPLC (0.05% TFA-water-acetonitrile) to give the title compound. LC-MS m/e 324.15 [M+1]+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][S:11](Cl)(=[O:13])=[O:12].[CH3:15][O:16][C:17]1[CH:18]=[C:19](/[CH:29]=[C:30]2\[CH2:31][CH2:32][C@H:33]3[CH2:38][NH:37][CH2:36][C@@H:35]([C:39]4[CH:44]=[C:43]([F:45])[C:42]([F:46])=[C:41]([F:47])[CH:40]=4)[N:34]3[C:48]\2=[O:49])[CH:20]=[CH:21][C:22]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH3:10][S:11]([N:37]1[CH2:36][C@@H:35]([C:39]2[CH:44]=[C:43]([F:45])[C:42]([F:46])=[C:41]([F:47])[CH:40]=2)[N:34]2[C:48](=[O:49])/[C:30](=[CH:29]/[C:19]3[CH:20]=[CH:21][C:22]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:17]([O:16][CH3:15])[CH:18]=3)/[CH2:31][CH2:32][C@H:33]2[CH2:38]1)(=[O:13])=[O:12]
Reactant: COc1cc(/C=C2\CC[C@H]3CNC[C@@H](c4cc(F)c(F)c(F)c4)N3C2=O)ccc1-n1cnc(C)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C2\CC[C@H]3CN(S(C)(=O)=O)C[C@@H](c4cc(F)c(F)c(F)c4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
IPEA (0.02 mL) and methanesulfonyl chloride (0.004 mL) were sequentially added to a solution of (4R*,9aS*)-7-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene}-4-(3,4,5-trifluorophenyl)octahydropyrido[1,2-a]pyrazin-6-one (20 mg) in methylene chloride (3 mL), and the reaction solution was stirred at 0° C. for one hour. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate 1:1->ethyl acetate->ethyl acetate:methanol 4:1) to obtain 24 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C([O:22][C@@H:23]1[C@H:27]([O:28]C(=O)C2C=CC=CC=2)[C@@H:26]([CH2:37][O:38]C(=O)C2C=CC=CC=2)[O:25][C@H:24]1[N:47]1[CH:55]=[N:54][C:53]2[C:48]1=[N:49][C:50]([Cl:57])=[N:51][C:52]=2Cl)(=O)C1C=CC=CC=1.N>>[Cl:57][C:50]1[N:51]=[C:52]([NH:1][N:2]2[CH2:3][CH:4]=[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:6][CH2:7]2)[C:53]2[N:54]=[CH:55][N:47]([C:48]=2[N:49]=1)[C@@H:24]1[O:25][C@H:26]([CH2:37][OH:38])[C@@H:27]([OH:28])[C@H:23]1[OH:22]
Reactant: NN1CC=C(c2ccccc2)CC1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: N
Product: OC[C@H]1O[C@@H](n2cnc3c(NN4CC=C(c5ccccc5)CC4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Yield: 12 %

Procedure:
The title compound was prepared according to method A as described above by reacting crude 1-amino-4-phenyl-1,2,3,6-tetrahydropyridine (prepared by the procedure outlined in Example 6) (1.25 g) with 9-(2',3',5'-tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.50 g, 3.9 mmol), followed by debenzoylation of the purified product using methanolic ammonia to provide the title 2-Chloro-N-(4-phenyl-1,2,3,6-tetrahydro-1-pyridinyl)adenosine (0.20 g 12%) (after column chromatography) as a foam, 1H NMR (DMSO-d6) δ 3.53-3.70 (4H, m, H-5'a, H-5'b and --CH2 --), 3.94 (1H, q, H-4'), 4.14 (1H, q, H-3'), 4.52 (1H, q, H-2'), 5.07 (1H, t, 5'-0H), 5.22, 5.50 (2H, 2d, 2'- and 3'-OH), 5.85 (1H, d, H-1'), 6.15 (1H, br s, vinylic C--H), 7.24-7.51 (5H, m, Ar--H), 8.43 (1H, s, H-8), 9.55 (1H, s, N--H).
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[SH:11][C:12]1[N:13]=[N:14][NH:15][CH:16]=1.[Na]>CN(C)C=O.C(OCC)(=O)C>[CH2:5]([C:4]([O:3][CH2:2][S:11][C:12]1[N:13]=[N:14][NH:15][CH:16]=1)=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC(=O)OCCl
Reactant: Sc1c[nH]nn1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCC(=O)OCSc1c[nH]nn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
23.1 g hexanoic acid chloromethyl ester are added over a period of 30 minutes with stirring to 17.2 g 4-mercapto-1,2,3-triazole, sodium salt, in 100 ml dimethyl formamide. After 2 h, the mixture is added to 600 ml ice water and the oil formed is taken up in ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:26])[N:6]2[CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1.O1CCOCC1.C(Cl)CCl.O[N:38]1[C:42](=[O:43])[CH2:41][CH2:40][C:39]1=[O:44]>ClCCl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:26])[N:6]2[CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([O:23][N:38]2[C:42](=[O:43])[CH2:41][CH2:40][C:39]2=[O:44])=[O:22])=[CH:19][CH:18]=1
Reactant: COCCOc1nc(N)c2nc(O)n(Cc3ccc(C(=O)O)cc3)c2n1
Reactant: O=C1CCC(=O)N1O
Solvent: ClCCCl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COCCOc1nc(N)c2nc(O)n(Cc3ccc(C(=O)ON4C(=O)CCC4=O)cc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
The product of example 10 (2 mmol) is dissolved in dichloromethane or dioxane (10 mL) and EDC (2 mmol) is added. To this solution is added N-hydroxysuccinimide (2 mmol) and resulting mixture is stirred at room temperature for 1 h. The mixture is taken to dryness in vacuo and the crude product is purified by silica gel chromatography to yield 2 mmol of product that is suitable for conjugation reactions involving primary amines.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>ClCCCl>[C:7]([N:3]1[CH2:4][CH2:5][O:1][C:2]1=[O:6])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1NCCO1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C1OCCN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
To a solution of 2-oxazolidinone (4.68 g; 0.05 mol) in 1,2-dichlorethane (60 ml), there is added benzoyl chloride (5.6 ml, 0.05 mol) and triethylamine (7.0 ml; 0.05 mol), with stirring at ambient temperature for 30 mins. The solution is then concentrated at reduced pressure and ethyl acetate is added, thereafter it is filtered to remove the base hydrochloride; the filtrate is partly evaporated and diluted with n-heptane and the precipitated solid is removed by filtration. After washing with water and drying, it gives 3-benzoyl-2-oxazolidinone (5.94 g; 90%). From absolute ethanol it crystallizes in nacar scales with m.p. = 166°-170°C. A portion of the substance in ethanol, with a catalytic amount of sodium ethoxide at room temperature immediately gives ethyl benzoate and, with aniline, benzanilide.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:10](=[O:13])[CH:11]=[CH2:12])=[N:7][CH:8]=1.[OH:21][CH:22]([C:27]1[CH:28]=[CH:29][C:30]([CH:33]=[O:34])=[N:31][CH:32]=1)[C:23]([OH:26])([CH3:25])[CH3:24].C(N(CC)CC)C.O1CCCC1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[OH:21][CH:22]([C:27]1[CH:28]=[CH:29][C:30]([C:33](=[O:34])[CH2:12][CH2:11][C:10](=[O:13])[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][N:7]=2)[CH2:14][CH:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[N:31][CH:32]=1)[C:23]([OH:26])([CH3:24])[CH3:25]
Reactant: CC(C)(O)C(O)c1ccc(C=O)nc1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(SC)cn1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: C1CCOC1
Product: CSc1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ccc(C(O)C(C)(C)O)cn2)nc1
Yield: 63.9 %

Procedure:
A mixture of 4-[5-(methylsulfanyl)pyridin-2-yl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (0.50 g), 5-(1,2-dihydroxy-2-methylpropyl)pyridine-2-carbaldehyde (0.32 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (43 mg), triethylamine (0.09 mL), tetrahydrofuran (6 mL) and ethanol (6 mL) was stirred with heating under reflux for 1 hr. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography, and the title compound (0.51 g, yield 61%) was obtained as a colorless oil from a fraction eluted with ethyl acetate. MS: 524 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:13])[CH:5]([CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)[CH3:6])C.[OH-].[Na+].Cl>O1CCOCC1.O>[O:10]1[CH2:11][CH2:12][CH:7]([CH:5]([CH3:6])[C:4]([OH:13])=[O:3])[CH2:8][CH2:9]1
Reactant: CCOC(=O)C(C)C1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C(=O)O)C1CCOCC1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
To a solution of (Tetrahydro-pyran-4-yl)-acetic acid ethyl ester (2.0 g, 11.6 mmol) in 50 mL of THF at −78° C. LDA (1.0 M, 17.4 mL, 34.8 mmol) is added dropwise. The solution is stirred for 0.5 h and treated with HMPA (3.2 mL, 9.3 mmol) and MeI (4.94 g, 34.8 mmol). The reaction mixture is stirred at the same temperature for 0.5 h and for 1.5 h at 0° C., acidified with aqueous 1 N aqueous HCl solution, and extracted twice with ether (2×40 mL). The organic phase is washed with saturated aqueous NaCl solution, dried (MgSO4), and concentrated in vacuo to give 1.8 g of 2-(Tetrahydro-pyran-4-yl)-propionic acid ethyl ester which is hydrolyzed without further purification. A solution of the crude ester (500 mg, 2.68 mmol) and 5 N aqueous NaOH solution (2.68 mL, 13.4 mmol) in dioxane-water (4 mL/2 mL) is heated at 60° C. for 2 h. The solution is cooled to room temperature, acidified with 1 N aqueous HCl solution, and extracted with ether. The ether layer is washed with saturated aqueous NaCl solution, dried over anhydrous MgSO4, and concentrated in vacuo to give 400 mg of the title compound. MS: 159 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 2 min then 100% CH3CN+0.1% TFA for 1 min, flow 0.5 ml/min): 1.27 min.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.CN(C)C=O.[F:14][C:15]1[CH:38]=[CH:37][C:18]([O:19][C:20]2[C:28]3[N:27]=[C:26]([SH:29])[NH:25][C:24]=3[CH:23]=[C:22]([O:30][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH:21]=2)=[CH:17][CH:16]=1>C(OCC)(=O)C>[F:14][C:15]1[CH:38]=[CH:37][C:18]([O:19][C:20]2[C:28]3[N:27]=[C:26]([S:29][CH3:1])[NH:25][C:24]=3[CH:23]=[C:22]([O:30][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH:21]=2)=[CH:17][CH:16]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(Oc2cc(Oc3cccnc3)cc3[nH]c(S)nc23)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: CSc1nc2c(Oc3ccc(F)cc3)cc(Oc3cccnc3)cc2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
30 mg of potassium carbonate and 0.014 ml of methyl iodide were added to a dimethylformamide (1.0 ml) solution of 78 mg of 4-(4-fluoro-phenoxy)-6-(pyridin-3-yloxy)-1H-benzimidazole-2-thiol produced in Example 115, and the reaction liquid was stirred at 0° C. for 30 minutes. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)[CH3:2].[Li+].C1CCCCC1.[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][C:26]2[C:29]([S:34][CH2:35][C:36]#[N:37])=[C:30]([Cl:33])[CH:31]=[CH:32][C:25]=2[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(I)C>C1COCC1>[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][C:26]2[C:29]([S:34][CH:35]([C:36]#[N:37])[CH2:1][CH3:2])=[C:30]([Cl:33])[CH:31]=[CH:32][C:25]=2[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCC#N)c2CC1
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CCI
Product: CCC(C#N)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 2 h
Yield: 68 %

Procedure:
To a stirred solution of 1.5M lithium diisopropylamide in cyclohexane (1.37 mL, 2.05 mmol) in dry THF (5 mL) at −78° C. under dry nitrogen, add a solution of 3-tert-butoxycarbonyl-7-chloro-6-cyanomethylthio-2,3,4,5-tetrahydro-1H-benzo[d]-azepine (600 mg, 1.70 mmol) in THF (5 mL) and continue stirring for 2 h. Rapidly transfer the above solution via cannula to a solution of ethyl iodide (13.2 g, 84.9 mmol) in THF (5 mL) and continue stirring for 1 h. Quench with aqueous saturated ammonium chloride solution, extract three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give (±)-3-tert-butoxycarbonyl-7-chloro-6-(1-cyanopropylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a pale oil (350 mg, 68%). Use a method similar to the General Procedure 1-4 to give the title compound as an off-white solid. MS (ES+) m/z: 281 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[C:21](OCC)=[O:22].S([O-])([O-])(=O)=O.[Na+].[Na+]>CCOCC>[OH:22][CH2:21][C:9]1[CH:10]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:12]=[CH:13][C:8]=1[CH3:7]
Reactant: CCOC(=O)c1cc(-c2ccc(C)cc2)ccc1C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: Cc1ccc(-c2ccc(C)c(CO)c2)cc1
Reaction time: 2 h

Procedure:
To a suspension of lithium aluminum hydride (0.2 g) in 50 ml of ether at 0° C. was added dropwise a solution of ethyl 4,4'-dimethylbiphenyl-3-carboxylate (2 g) in ether. After the addition was complete, the mixture was allowed to slowly rise to room temperature, and stirred for 2 hours. Excess reagent was hydrolysed with wet sodium sulfate. The mixture was filtered, the solvent evaporated from the filtrate under reduced pressure, and the residue flash-chromatographed on silica gel, eluting with 25% ethyl acetate in heptane, to yield 3-hydroxymethyl-4,4'-dimethylbiphenyl as an oil.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([C:16]([O:18][CH3:19])=[O:17])=[C:13]([CH3:20])[C:12]=2[CH3:21])=[CH:7][CH:6]=1>C(O)(=O)C>[Br:1][C:6]1[CH:7]=[C:8]([C:11]2[S:15][C:14]([C:16]([O:18][CH3:19])=[O:17])=[C:13]([CH3:20])[C:12]=2[CH3:21])[CH:9]=[CH:10][C:5]=1[O:4][CH3:3]
Reactant: COC(=O)c1sc(-c2ccc(OC)cc2)c(C)c1C
Reactant: BrBr
Solvent: CC(=O)O
Product: COC(=O)c1sc(-c2ccc(OC)c(Br)c2)c(C)c1C
Temperature: 25 °C
Yield: 85.4 %

Procedure:
Liquid bromine (0.58 g, 0.19 ml, 3.60 mmol) was added to a solution of methyl 5-(4-methoxyphenyl)-3,4-dimethylthiophene-2-carboxylate (step-3, 0.83 g, 3.00 mmol) in acetic acid (20 ml) under stirring at 25° C. The reaction mixture was then stirred at 25° C. for 3 hrs. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 ml). The resulting mixture was washed with saturated sodium bicarbonate solution (30 ml). The separated organic layer was concentrated under reduced pressure to obtain a crude product. The crude product obtained was purified by flash column chromatography using 5% ethyl acetate in hexanes as an eluent to obtain the title compound 9d (0.91 g, 83.0%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[CH2:3][N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([CH2:28][CH2:29][OH:30])[CH:27]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1.C(Cl)Cl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O>[F:31][C:2]([F:1])([F:32])[CH2:3][N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([CH2:28][CH:29]=[O:30])[CH:27]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1
Reactant: OCCn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=CCn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a reaction vial charged with 2-(4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-ethanol 150 (0.250 g, 0.540 mmol) was added 4 mL DCM to give a slurry. Next, Dess-Martin periodinane (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, 0.2522 g, 0.594 mmol) was added portion-wise and the reaction mixture was stirred at room temperature with LCMS monitor. Full conversion was seen after 30 minutes reaction time. The reaction mixture was diluted with water to give a white precipitate. This solid was collected by vacuum filtration, washed with EtOAc and dried on high vacuum to give the intermediate aldehyde, 2-(4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-ethanal. To a suspension of the aldehyde (0.160 g, 0.347 mmol) and diethylamine (0.127 g, 1.74 mmol) in 1.0 ml of DCM was added acetic acid (0.0198 mL, 0.347 mmol) and the reaction mixture was heated at 40 C for 1 hour. Finally sodium cyanoborohydride (0.0350 g, 0.556 mmol) was added in portions. The reaction mixture was heated at 40° C. for 45 minutes with complete conversion to product as determined by LCMS. The cooled reaction mixture was diluted with DCM, washed with water and saline, and concentrated to a solid which was purified by RP-HPLC to give 484. MS: (ESI+)=518.2
Reaction SMILES: [C:1]1(=[C:8]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([CH3:23])([CH3:22])[C:17](OCC)=[O:18])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]1(=[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([CH3:23])([CH3:22])[CH2:17][OH:18])=[CH:11][CH:10]=2)[C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CO)Oc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Yield: 75.7 %

Procedure:
The reduction procedure described for 224 was used. Ethyl 2-({4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}oxy)-2-methylpropanoate (225) (0.125 g, 0.31 mmol) was treated with LiAlH4 (0.8 mL) in THF (5 mL). Standard work-up followed by purification afforded 0.086 g (76%) of the title compound 230 as white foam. 1H NMR (300 MHz, DMSO-d6): δ 9.27 (s, 1H), 7.00 (d, J=7.8 Hz, 2H), 6.91 (d, J=4.5 Hz, 4H), 6.68 (d, J=8.4 Hz, 2H), 4.84 (t, J=5.7 Hz, 1H), 3.34 (d, J=3.6 Hz, 2H), 2.21 (br s, 4H), 1.52 (br s, 8H), 1.17 (s, 6H). LCMS (ESI): m/z 367 (M−H)−.