Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4](O)=[O:5].[CH2:10]([NH:17][C:18]([NH2:20])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[CH2:10]([N:17]1[C:4](=[O:5])[CH:3]([C:2]([F:9])([F:8])[F:1])[CH2:7][NH:20][C:18]1=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(=O)NCc1ccccc1
Reactant: C=C(C(=O)O)C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C1NCC(C(F)(F)F)C(=O)N1Cc1ccccc1
Temperature: 90 °C
Reaction time: 5 h
Yield: 71.9 %

Procedure:
A mixture of α-trifluoromethylacrylic acid (700 mg; 5.0 mmoles) and benzylurea (796 mg; 5.3 mmoles) in DMF (5 ml) was heated at 90° C. with stirring for 5 hours. After the reaction mixture was cooled to 0° C., a solution of DCC (1.13 g; 5.5 mmoles) in DMF (3 ml) was added dropwise. The mixture was stirred for 1 hour, and the precipitated solid was filtered off and washed with ethyl acetate. The solvents were evaporated under reduced pressure from the combined filtrates. The residue was purified by a column chromatography on silica gel (ethyl acetate:chloroform=1:1) to give 979 mg (yield: 72%) of 3-benzyl-5-trifluoromethyl-5,6-dihydrouracil. m.p.: 129.2°-129.7° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH2:25][C:26]2[CH:27]=[C:28]([CH:35]=[CH:36][CH:37]=2)[O:29][C@@H:30]([CH3:34])[C:31](O)=[O:32])[C:20]([CH3:38])=[C:19]3[CH3:39])=[O:15])[CH3:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH4+:40].[Cl-].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:40][C:31](=[O:32])[C@@H:30]([O:29][C:28]1[CH:27]=[C:26]([CH:37]=[CH:36][CH:35]=1)[CH2:25][N:21]1[C:22]2[C:18](=[CH:17][C:16]([C:14]([NH:13][C@H:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:10][CH:9]=3)[CH3:12])=[O:15])=[CH:24][CH:23]=2)[C:19]([CH3:39])=[C:20]1[CH3:38])[CH3:34]
Reactant: [NH4+]
Reactant: Cc1c(C)n(Cc2cccc(O[C@@H](C)C(=O)O)c2)c2ccc(C(=O)N[C@@H](C)c3ccc(C(C)(C)C)cc3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C)n(Cc2cccc(O[C@@H](C)C(N)=O)c2)c2ccc(C(=O)N[C@@H](C)c3ccc(C(C)(C)C)cc3)cc12
Yield: 95.1 %

Procedure:
A solution of (S)-2-(3-((5-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoic acid (20 mg, 0.036 mmol), NH4Cl (19 mg, 0.36 mmol), HATU (14 mg, 0.036 mmol) and DIEA (25 μl, 0.144 mmol) in DCM (0.5 ml) was stirred at rt for 1 h. After concentration, the obtained oil was purified by reverse phase prep-HPLC (MeOH/Acetonitrile/water) to afford a white powder (18 mg). ESI-MS (m/z): 526 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:31])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:30])[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25](OC)=[CH:24][CH:23]=2)[CH2:14][CH2:13]1.[Cl:32]C1C=CC=CC=1CCl.COC1C=CC(CCl)=CC=1>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:31])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:30])[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:32])[CH2:14][CH2:13]1
Reactant: ClCc1ccccc1Cl
Reactant: COc1ccc(CCC(O)CN2CCN(CC(=O)Nc3c(C)cccc3C)CC2)cc1
Agent: COc1ccc(CCl)cc1
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)CCc2ccccc2Cl)CC1

Procedure:
Compound 18 was prepared in a manner similar to that of compound 16 substituting 2-chlorobenzyl chloride for 4-methoxybenzyl chloride. (M+1)=430.2
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([S:14]([CH2:16][C:17]3[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=3)=[O:15])[NH:11][C:10]=2[CH:27]=1>CN(C=O)C>[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([S@:14]([CH2:16][C:17]3[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=3)=[O:15])[NH:11][C:10]=2[CH:27]=1
Reactant: COc1ccc2nc(S(=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1ccc2nc([S@@](=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1

Procedure:
The procedure set forth in Example 2 is repeated except that ethanol is employed as a solvent in place of DMF and the resulting structure is shown by various X-ray crystal diffraction and/or Raman spectroscopy to contain between about 82 and 85 percent (w/w) of 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole and between about 15 and 18 percent (w/w) of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-methyl]sulfinyl]-1H-benzimidazole.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C@@H:7]([CH3:8])[CH2:6][N:5]([C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH3:20])[N:12]=2)=[O:10])[CH2:4]1.C(N(CC)CC)C.[C:28](O)(=[O:31])[CH2:29][CH3:30].C1N=CN(C(N2C=NC=C2)=O)C=1>CN(C=O)C>[C:28]([NH:2][C@H:3]1[C@@H:7]([CH3:8])[CH2:6][N:5]([C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH3:20])[N:12]=2)=[O:10])[CH2:4]1)(=[O:31])[CH2:29][CH3:30]
Reactant: CCC(=O)O
Reactant: C[C@H]1CN(C(=O)c2nn(C)c3ccccc23)C[C@H]1N
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(=O)N[C@@H]1CN(C(=O)c2nn(C)c3ccccc23)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.3 %

Procedure:
Into 2 ml of DMF were dissolved 200 mg (0.68 mmol) of cis-3-amino-4-methyl-1-(l-methylindazol-3-ylcarbonyl)pyrrolidine hydrochloride and 0.09 ml (0.68 mmol) of triethylamine, and the solution was stirred for 0.5 hours at room temperature. This solution was added to another solution which was separately prepared by dissolving 0.05 ml (0.68 mmol) of propionic acid and 112 mg (0.68 mmol) of CDI into 2 ml of DMF, followed by stirring for 2 hours at room temperature. Resultant mixture was stirred overnight at room temperature. After DMF was distilled off, to the residue was added water and the solution was made alkaline with sodium bicarbonate, which was then extracted with methylene chloride. After washed with saturated saline solution and dried over anhydrous magnesium sulfate, the solution was concentrated under reduced pressure to obtain crude oil. This was subjected to silica gel column chromatographic purification (methylene chloride:acetone=5:1) to obtain 37 mg (17.3%) of aimed compound. m.p. 139°-141° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[C@@H:10]([NH:15][C:16]2[C:21]([CH:22]=[O:23])=[CH:20][N:19]=[C:18]3[NH:24][CH:25]=[CH:26][C:17]=23)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35].O>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[C@@H:10]([NH:15][C:16]2[C:21]([CH:22]=[O:23])=[CH:20][N:19]=[C:18]3[N:24]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:25]=[CH:26][C:17]=23)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CCN(Cc2ccccc2)C[C@@H]1Nc1c(C=O)cnc2[nH]ccc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CCN(Cc2ccccc2)C[C@@H]1Nc1c(C=O)cnc2c1ccn2COCC[Si](C)(C)C
Yield: 41.7 %

Procedure:
rac-4-{[(3R,4R)-1-Benzyl-4-methylpiperidin-3-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (118 mg, 0.338 mmol) in N,N-dimethylformamide (3 mL) was cooled to 0° C. and stirred with sodium hydride (55 wt % dispersion in mineral oil, 126 mg, 0.586 mmol) for 30 minutes and then with [2-(chloromethoxy)ethyl]trimethylsilane (104 μL. 0.586 mmol) at room temperature for one day. After addition of water, the reaction mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 (v/v)) to give the title compound as a brown oil (67.5 mg, yield 42%).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:23]=[C:22]4[C:17]([CH2:18][CH2:19][CH:20]([NH:24]C(=O)OC(C)(C)C)[CH2:21]4)=[CH:16][CH:15]=3)[CH:10]=[CH:9][N:8]=2)=[O:5])[CH2:3][CH2:2]1.Cl>O1CCOCC1>[NH2:24][CH:20]1[CH2:21][C:22]2[CH:23]=[C:14]([O:13][C:11]3[CH:10]=[CH:9][N:8]=[C:7]([NH:6][C:4]([CH:1]4[CH2:2][CH2:3]4)=[O:5])[CH:12]=3)[CH:15]=[CH:16][C:17]=2[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(Oc3ccnc(NC(=O)C4CC4)c3)cc2C1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCc2ccc(Oc3ccnc(NC(=O)C4CC4)c3)cc2C1
Reaction time: 2 h

Procedure:
To tert-butyl [7-({2-[(cyclopropylcarbonyl)amino]pyridin-4-yl}oxy)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate (4.0 g, 0.0071 mol) was added HCl in dioxane (4M, 15 ml). After 2 h at rt, the solvent was removed. N-{4-[(7-amino-5,6,7,8-tetrahydronaphthalen-2-yl)oxy]pyridin-2-yl}cyclopropanecarboxamide was obtained as off white solid and was used without further purification (2.8 g). 1H NMR (d6-DMSO, 400MHz, HCl salt) δ: 11.50 (s, 1H); 8.25 (s, 2H); 7.40 (s, 1H); 7.24 (d, 1H); 7.04 (d, 1H); 6.80 (dd, 1H); 6.82 (dd, 1H); 4.35 (s, 1H); 3.45 (s, 1H); 2.90 (dd, 1H); 2.85 (m, 3H); 2.14 (m, 1H); 1.95 (m, 1H); 1.77 (m, 1H); and 0.83 (m, 4H). LCMS ES+ 324.4, ES− 322.5
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15]([NH:17][CH2:18][C:19]([O:21]C)=[O:20])=[O:16])=[C:5]2[OH:23].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])=[C:5]2[OH:23]
Reactant: COC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2cc(Cl)ccc21
Reaction time: 0.33 h

Procedure:
Methyl N-((6-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-yl)carbonyl)glycinate (0.256 g, 0.760 mmol) was suspended in water (3.0 mL) and treated with a 5N NaOH solution (0.38 mL, 1.90 mmol). After 20 minutes at ambient temperature, the resulting homogeneous mixture was quenched with a 1N HCl solution to pH=2. The white solid that precipitated upon acidification was collected by vacuum filtration and washed with 1:1 H2O/acetone (2×2.0 mL). The product was subsequently dried at 80° C. under vacuum for 24 hours. MS m/e=324.0 (M+H)+. Calculated for C15H14ClNO5 323.06.
Reaction SMILES: [F:1][CH:2]([C:7]1[CH:8]=[C:9]([CH:29]=[CH:30][CH:31]=1)[CH2:10][CH:11]([NH:21]C(=O)OC(C)(C)C)[CH:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[OH:13])[C:3]([F:6])([CH3:5])[CH3:4]>FC(F)(F)C(O)=O>[NH2:21][CH:11]([CH2:10][C:9]1[CH:29]=[CH:30][CH:31]=[C:7]([CH:2]([F:1])[C:3]([F:6])([CH3:5])[CH3:4])[CH:8]=1)[CH:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[OH:13]
Reactant: CC(C)(C)OC(=O)NC(Cc1cccc(C(F)C(C)(C)F)c1)C(O)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(F)C(F)c1cccc(CC(N)C(O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl N-[(1RS,2SR)-1-[3-(1,2-difluoro-2-methylpropyl)benzyl]-2-(4-fluorophenyl)-2-hydroxyethyl]carbamate (2.139 g, 4.889 mmol) and trifluoroacetic acid (10 ml) was stirred at room temperature for 1 hr. The reaction solution was evaporated under reduced pressure, diluted with water, alkalified with potassium carbonate, and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate and passed through APS-silica gel. The solvent was evaporated under reduced pressure to give the objective substance.
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[CH2:9][C@H:8]([N:10]([CH:12]([CH3:14])[CH3:13])[CH3:11])[CH2:7][CH2:6][C@@H:5]1[N:15]1[CH2:19][CH2:18][C@H:17]([NH:20]C(=O)OCC2C=CC=CC=2)[C:16]1=[O:31])=[O:2]>CO.[Pd]>[NH2:20][C@H:17]1[CH2:18][CH2:19][N:15]([C@H:5]2[CH2:6][CH2:7][C@@H:8]([N:10]([CH:12]([CH3:14])[CH3:13])[CH3:11])[CH2:9][C@H:4]2[NH:3][CH:1]=[O:2])[C:16]1=[O:31]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](NC=O)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](NC=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
To a solution of benzyl (S)-1-((1S,2R,4R)-2-formamido-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (50 mg, 0.116 mmol) in methanol (3 mL) was added 10% Pd/C (40 mg of 50% wet catalyst). The flask was evacuated and back-filled with hydrogen from a hydrogen balloon. The mixture was stirred at room temperature for 1 h and the catalyst was removed by filtration. The filtrate was concentrated in vacuo to provide N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)cyclohexyl)formamide (35 mg, 100%) which was taken on to the next step without further purification. LC/MS found [M+H]+=297.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][C:23]([OH:25])=O)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20].[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C.[NH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[OH:49]>C(#N)C.O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][C:23]([NH:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[OH:49])=[O:25])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20]
Reactant: Nc1ccccc1O
Reactant: COCCOCOc1ccc(C=CC(=O)O)cc1OCOCCOC
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: COCCOCOc1ccc(C=CC(=O)Nc2ccccc2O)cc1OCOCCOC
Yield: 12.4 %

Procedure:
To a solution of 1.21 g (3.40 mmol) of 3-{3,4-di-(β-methoxyethoxymethoxy)phenyl}-2-propenic acid in dry acetonitrile (30 ml) were added in an argon atmosphere 1.73 g (6.76 mmol) of 2-chloro-1-methylpyridinium iodide and 2.40 ml (17.2 mmol) of triethylamine and 799 mg (7.32 mmol) of o-aminophenol, successively. The mixture was reacted at room temperature for 60 hours, followed by addition of water. The mixture was extracted with ethyl acetate, and the organic layer was successively washed with 1N-aqueous hydrochloric acid, water, aqueous solution of sodium carbonate and water. The organic layer was concentrated under reduced pressure, and the residue thus obtained was subjected to silica gel column chromatography. There was obtained 188 mg (0.420 mmol) of N-[3-{3,4-di(β-methoxyethoxymethoxy)phenyl}-2-propenoyl]-o-aminophenol.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@@H:9](O)[CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1)=[N+:2]=[N-:3].C(N(S(F)(F)[F:24])CC)C.C(=O)([O-])O.[Na+]>ClCCl>[N:1]([CH2:4][C@@H:5]1[C@@H:9]([F:24])[CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC[C@H]1CN(Cc2ccccc2)C[C@@H]1O
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: [N-]=[N+]=NC[C@H]1CN(Cc2ccccc2)C[C@@H]1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(3R,4R)-3-Azidomethyl-1-benzyl-4-hydroxypyrrolidine (566 mg) was dissolved in dichloromethane (9 mL). While this solution was cooled on an ice bath, diethylaminosulfur trifluoride (0.39 mL) was added dropwise and the mixture was stirred at room temperature for 2 hours. While the reaction vessel was cooled on an ice bath, a saturated aqueous solution of sodium hydrogen carbonate (9 mL) was added, and the mixture was diluted with dichloromethane (15 mL). The dichloromethane layer was collected and the collected dichloromethane layer was washed with a saturated aqueous solution of sodium hydrogen carbonate (10 mL) and then water (10 mL), was dried over anhydrous sodium sulfate, and was concentrated under reduced pressure. The resulting residue was purified on a silica gel column (eluant=hexane:ethyl acetate=4:1). From the first half fraction, 76.7 mg of (3R,4R)-3-azidomethyl-1-benzyl-4-fluoropyrrolidine was obtained as a pale brown oil.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][CH:4]=1)=[O:2].[C:20]([C:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=1)#[CH:21]>CCCCCCC.C(Cl)Cl>[C:22]1([C:20]#[C:21][C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:8][CH:7]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(C=O)cc2)cc1
Reactant: C#CC1=CCCCC1
Solvent: ClCCl
Solvent: CCCCCCC
Product: O=Cc1ccc(C#CC2=CCCCC2)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 4-formyl-phenyl ester and 1-ethynyl-cyclohexene following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/DCM 1:1; yield (71 mg, 68%); 1H NMR δ (CDCl3): 9.99 (s, 1H), 8.02 (d, J=8.51 Hz, 2H), 7.52 (d, J=8.60 Hz, 2H), 6.31-6.27 (m, 1H), 2.14-2.22 (m, 4H), 1.58-1.73 (m, 4H); LCMS m/z: 210.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[CH2:8]Cl>CO>[F:3][C:4]([F:18])([F:17])[C:5]1[CH:6]=[C:7]([CH2:8][NH:2][CH3:1])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1
Reactant: FC(F)(F)c1cc(CCl)cc(C(F)(F)F)c1
Reactant: CN
Solvent: CO
Product: CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C
Yield: 40.9 %

Procedure:
Methylamine (3 g, 40% aqueous solution) was dissolved in 30 mL of MeOH. The reaction mixture was heated at 50° C. under stirring. 3,5-Bis(trifluoromethyl)-benzyl chloride (2 g, 7.6 mmol) dissolved in 10 mL of MeOH, was added. The solution was left stirring at this temperature for 5 h. The solution was concentrated carefully to remove MeOH as much as possible, then an aqueous solution of NaOH 1M was added and the aqueous layer was extracted with DCM. The two phases were separated; the organic phase was filtered through a phase separator and removed carefully in vacuo obtaining the title compound (0.8 g) as a yellow oil. UPLC-MS: m/z (ES+): 258.01 [M+H]+ Rt=0.60. 1H NMR (400 MHz, CDCl3) δ ppm 7.83 (s, 2H), 7.79 (s, 1H), 3.91 (s, 2H), 3.30 (m, 1H), 2.50 (s, 3H); UPLC-MS: Rt=1.30; m/z (ES+): 586 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[CH2:10][CH2:9][N:8]([C@@H:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]([O:14]C(C)(C)C)=[O:13])[C:7]1=[O:23].FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[CH2:10][CH2:9][N:8]([C@@H:11]([C:19]([CH3:20])([CH3:21])[CH3:22])[C:12]([OH:14])=[O:13])[C:7]1=[O:23]
Reactant: CC(C)(C)OC(=O)[C@@H](N1CCN(Cc2cccc(F)c2)C1=O)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2cccc(F)c2)C1=O
Yield: 74 %

Procedure:
A solution of Example 137B in dichloromethane (1.5 mL) was treated with trifluoroacetic acid (1.5 mL) at 25° C. for 16 h. The solvents were evaporated, and the crude residue was purified using reverse phase chromatography eluting with a gradient of 95% water (0.1% trifluoroacetic acid)/5% acetonitrile to 100% acetonitrile to give the title compound (0.14 g, 74%).
Reaction SMILES: C1COCC1.CC(O)=O.O.[C:11]([O:15][C:16]([N:18]1[C:24]2[CH:25]=[C:26]([O:31]C3C(O)=C(O)C(O)=C(O)O3)[C:27]([O:29][CH3:30])=[CH:28][C:23]=2[C:22](=[O:42])[N:21]2[CH2:43][C:44](=[CH2:46])[CH2:45][C@H:20]2[C@@H:19]1[O:47][CH:48]1[C:53]([OH:54])=[C:52]([OH:55])[C:51]([OH:56])=[C:50]([OH:57])[O:49]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])(O)=O.[Na+]>CCOC(C)=O.CCCCCC>[C:11]([O:15][C:16]([N:18]1[C:24]2[CH:25]=[C:26]([OH:31])[C:27]([O:29][CH3:30])=[CH:28][C:23]=2[C:22](=[O:42])[N:21]2[CH2:43][C:44](=[CH2:46])[CH2:45][C@H:20]2[C@@H:19]1[O:47][CH:48]1[C:53]([OH:54])=[C:52]([OH:55])[C:51]([OH:56])=[C:50]([OH:57])[O:49]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: C=C1C[C@H]2[C@H](OC3OC(O)=C(O)C(O)=C3O)N(C(=O)OC(C)(C)C)c3cc(OC4OC(O)=C(O)C(O)=C4O)c(OC)cc3C(=O)N2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C1C[C@H]2[C@H](OC3OC(O)=C(O)C(O)=C3O)N(C(=O)OC(C)(C)C)c3cc(O)c(OC)cc3C(=O)N2C1
Yield: 87.9 %

Procedure:
A solution of THF/AcOH/H2O (2:1:1, 5 mL) was added to the olefin 26 (1.8 g, 3.3 mmol) and the resulting mixture was stirred for 3 h at which point TLC (SiO2, 50% EtOAc-hexane) revealed complete reaction. The mixture was then neutralized with saturated NaHCO3 and extracted with EtOAc (3×30 mL) and the combined organic layers were washed with brine (50 mL) and dried (MgSO4). Removal of excess solvent under reduced pressure gave the crude product. The residue was subjected to flash chromatography (SiO2, 50% EtOAc-hexane) to afford the product 27 (1.34 g, 2.9 mmol, 87% yield, mixture of diastereomers from THP protecting group): [α]27D=+81° (c=0.16, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.32 (s, 18H, Boc), 1.45-1.64 (m, 8H, THP), 1.66-1.84 (m, 4H, THP), 2.50-2.58 (m, 1H, 1-H), 2.68-2.80 (m, 1H, 1-H), 2.84-2.96 (m, 2H, 1-H), 3.51-3.67 (m, 4H, 11a-H, THP), 3.87-4.00 (m, 8H, 7-OMe, THP), 4.04-4.18 (m, 2H, 3-H), 4.23-4.38 (m, 2H, 3-H), 4.96-5.19 (m, 6H, 2a-H, THP), 5.65-5.72 (d, 1H, 11-H), 5.75-5.88 (d, 1H, 11-H), 5.97 (s, 1H, 8-OH), 6.00 (s, 1H, 8-OH), 6.63 (s, 1H, 9-H), 6.92 (s, 1H, 9-H), 7.17 (s, 1H, 6-H), 7.21 (s, 1H, 6-H); 13C NMR (CDCl3, 100 MHz): δ 20.0, 20.7, 25.1, 25.2, 28.0, 28.1, 29.7, 30.8, 31.3, 35.1, 35.4, 50.7, 56.1, 56.2, 59.8, 60.0, 63.6, 64.6, 88.0, 91.0, 96.1, 100.7, 109.4, 109.8, 116.4, 117.0, 130.3, 130.5, 142.0, 145.8, 146.0, 147.5, 147.7, 167.3, 167.5; IR (neat): 2940, 2851, 1703, 1630, 1512, 1467, 1440, 1407, 1391, 1367, 1326, 1200, 1161, 1118, 1072, 1019, 910, 730 cm−1; MS (ES+) m/z (relative intensity) 461 (M+., 75), 462 ([M+2H]+., 20), 259 (100), 260 (30), 359 (21).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:21]=[CH:20][C:19]3[S:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11](=[O:22])[C:10]=3[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(#N)C.S(=O)(=O)(O)[OH:27].OO>O>[C:1]1([S:7]([C:8]2[CH:21]=[CH:20][C:19]3[S:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11](=[O:22])[C:10]=3[CH:9]=2)=[O:27])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1c2ccccc2sc2ccc(Sc3ccccc3)cc12
Reactant: O=S(=O)(O)O
Agent: OO
Solvent: CC#N
Solvent: O
Product: O=c1c2ccccc2sc2ccc(S(=O)c3ccccc3)cc12
Temperature: 40 °C
Reaction time: 14 h
Yield: 83 %

Procedure:
While 11.2 parts of 2-(phenylthio)thioxanthone synthesized in Production Example 1, 215 parts of acetonitrile, and 0.02 parts of sulfuric acid were stirred at 40° C., 4.0 parts of a 30% aqueous hydrogen peroxide solution was dropped thereto slowly and then a reaction was performed at 40 to 45° C. for 14 hours. Subsequently, the reaction solution was cooled to room temperature (about 25° C.) and then was poured into 200 parts of distilled water, so that the product was precipitated. This was filtered and the residue was washed with water until the pH of the filtrate became neutral. Then the residue was dried under reduced pressure, affording a yellow powdery product. The product was purified by column chromatography (eluate: ethyl acetate/toluene=⅓:volume ratio) to afford 2-[(phenyl)sulfinyl]thioxanthone in a yield of 83%. The product was identified by 1H-NMR {d6-dimethyl sulfoxide, δ (ppm) 8.75 (1H, s), 8.45 (1H, d), 8.01 (2H, d), 7.75-7.85 (4H, m), 7.53-7.62 (4H, m)}.