Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][CH2:34][CH2:35][Br:36])[C:27]([O:29]CC)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[OH-].[K+:44]>C(O)C>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][CH2:34][CH2:35][Br:36])[C:27]([O-:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+:44]
Reactant: CCOC(=O)C(=NOCCBr)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: O=C([O-])C(=NOCCBr)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
A mixture of 2.88 g of the said ester and 4.3 ml of dioxane was stirred under an inert atmosphere at room temperature until dissolution occured and then 30.6 ml of a solution of 0.5 M potassium hydroxide in ethanol were added thereto over 3 minutes at 20°-25° C. The mixture was stirred at room temperature under an inert atmosphere for 24 hours and after 2 or 3 hours a potassium salt crystallized. The mixture was vacuum filtered at room temperature and the recovered product was rinsed with 1 ml of ether and 3 times with 2 ml of methylene chloride to obtain 1.6 g of the syn isomer of potassium 2-(2-tritylamino-4-thiazolyl)-2-(2-bromoethoxyimino)-acetate.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)C=CC=CC=1.[O-]CC.[Na+]>C(O)C>[C:5]1([C:3]([C:2]([F:12])([F:11])[F:1])=[CH:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(c1ccccc1)C(F)(F)F
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: Fc1ccc(C=C(c2ccccc2)C(F)(F)F)cc1
Yield: 90 %

Procedure:
2,2,2-Trifluoroacetophenone is reacted with triphenyl-(4-fluorobenzyl)-phosphonium chloride (R. A. Jones: Australian J. Chem. 18, 903-6 (1965) in ethanol in the presence of sodium ethoxide. 2-Phenyl-3,3,3-trifluoro-1-(4-fluorophenyl)-propene is obtained with a yield of 90%; b.p.: 105°-107° C./0.2 mm Hg, m.p.: 35°-41° C.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8](S(C)(=O)=O)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:32]([O:39]CC1C=CC=CC=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[Na].[Na].[NH4+].[OH-]>C(O)C1C=CC=CC=1>[CH2:32]([O:39][C:8]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][N:7]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCCCc1nnc(S(C)(=O)=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: c1ccc(COCc2ccccc2)cc1
Agent: [NH4+]
Agent: [Na]
Agent: [OH-]
Solvent: OCc1ccccc1
Product: CCCCc1nnc(OCc2ccccc2)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 12 %

Procedure:
A solution of 35 mg (0.08 mmole) of 3-n-butyl-5-methylsulfonyl-4-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-4M-1,2,4-triazole (from Example 24) in 300 μl (0.21 mmole) of 0.71 M sodium benzyloxide in benzyl alcohol (freshly prepared from sodium and benzyl alcohol) was stirred at 60° C. for 20 hours, by which time TLC (90:10:1CH2Cl2 --MeOH-concd. NH4OH, developed 3×) indicated complete reaction. The mixture was partitioned between 20 ml of ethyl acetate and 15 ml of 0.2 N HCl. The organic phase was washed with 2×10 ml of 0.2 N HCl, then dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution with 19:1 and then 9:1CH2Cl2 --MeOH). Concentration of clean product fractions yielded 4.4 mg (12%) of the title compound as a residual glass, homogeneous by TLC in 90:10:1 CH2Cl2 --MeOH-concd. NH4OH; mass spectrum (FAB) m/e 466 (M+1)+.
Reaction SMILES: Cl.Cl.[CH3:3][CH:4]([CH3:18])[CH2:5][N:6]([CH2:11][C@H:12]1[CH2:17][NH:16][CH2:15][CH2:14][NH:13]1)[S:7]([CH3:10])(=[O:9])=[O:8].C(N(CC)CC)C.[N+:26]([C:29]1[S:33][C:32]([S:34](Cl)(=[O:36])=[O:35])=[CH:31][CH:30]=1)([O-:28])=[O:27]>C(Cl)Cl>[N+:26]([C:29]1[S:33][C:32]([S:34]([N:16]2[CH2:15][CH2:14][NH:13][C@@H:12]([CH2:11][N:6]([CH2:5][CH:4]([CH3:18])[CH3:3])[S:7]([CH3:10])(=[O:8])=[O:9])[CH2:17]2)(=[O:36])=[O:35])=[CH:31][CH:30]=1)([O-:28])=[O:27]
Reactant: CC(C)CN(C[C@H]1CNCCN1)S(C)(=O)=O
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)s1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CN(C[C@H]1CN(S(=O)(=O)c2ccc([N+](=O)[O-])s2)CCN1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
A 5-mL vial was charged with N-(2-methylpropyl)-N-((2R)-2-piperazinylmethyl)methanesulfonamide dihydrochloride (0.144 g, 0.446 mmol) and CH2Cl2 (2 mL). To this was added triethylamine (0.650 mL, 4.66 mmol) in potions at room temperature followed by drop wise addition of 5-nitrothiophene-2-sulfonyl chloride (0.120 g, 0.525 mmol, Enamine LLC, Monmouth Jct. NJ) in CH2Cl2 (1 mL). The mixture was stirred at room temperature for 15 min and then the reaction mixture was partitioned between water (20 mL) and CH2Cl2 (20 mL). The aqueous phase was extracted with CH2Cl2 (2×20 mL) and the combined organic extracts were washed with saturated aqueous NaCl (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (25 g of silica gel, 0 to 10% (2 M NH3 in MeOH) in CH2Cl2) to afford N-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-piperazinyl)methyl)-N-(2-methylpropyl)methanesulfonamide (0.173 g) as a light-brown foam.
Reaction SMILES: [F:1][C:2]([F:24])=[C:3]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH2:5][CH3:6])[C:18]1[CH:17]=[CH:16][C:15]([O:22]C)=[CH:14][C:13]=1[CH2:12][CH2:11]3.[H-].C([Al+]CC(C)C)C(C)C.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[F:1][C:2]([F:24])=[C:3]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH2:5][CH3:6])[C:18]1[CH:17]=[CH:16][C:15]([OH:22])=[CH:14][C:13]=1[CH2:12][CH2:11]3
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CCC2=C(F)F
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)(O)O
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A solution of 5 g of 17-difluoromethylene-3-methoxy-18-methyl-estra-1,3,5(10)-triene in 95 ml of toluene is refluxed with 95 ml of a 1.6 M diisobutylaluminum hydride solution in toluene for 3 hours at a bath temperature of 140° C. Then, it is cooled to room temperature, slowly added to 200 g of ice, mixed with 400 ml of 1 M sulfuric acid, stirred for 1 hour at room temperature, extracted three times with ethyl acetate, the organic phases are washed with water as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 4.5 g of 17-difluoromethylene-18-methyl-estra -1,3,5(10)-trien-3-ol is obtained as colorless crystals with a melting point of 120-121° C., [α]D22 =+37.8° (c=0.5% in pyridine).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[Br:22][C:23]1[CH:31]=[C:30]([NH:32][C:33](=[O:46])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26].O>ClCCl>[Br:22][C:23]1[CH:31]=[C:30]([NH:32][C:33](=[O:46])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH:29]=[CH:28][C:24]=1[C:25]([N:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[CH2:10][N:4]2[CH:3]=[CH:2][CH:1]=[C:5]2[CH2:6]1)=[O:26]
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccn2)cc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Br)c1)c1ccccc1-c1ccccn1
Temperature: 25 °C
Yield: 104.8 %

Procedure:
To a stirred solution of the product from Reference Example 6, 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.54 g. 2.93 mmol) in dichloromethane (35 ml), under nitrogen, was added triethylamine (0.49 ml, 3.52 mmol). The mixture was cooled to 0° C. before a suspension of the crude 2-bromo-4-[(2-pyridin-2-ylbenzoyl)amino]benzoyl chloride (1.4 g) in dichloromethane (5 ml) was added dropwise. After the addition was complete, the reaction mixture was allowed to warm to room temperature. After 18 hours the reaction mixture was poured into water and sequentially washed with water, saturated aqueous sodium bicarbonate, twice with 10% aqueous acetic acid, once with saturated aqueous sodium bicarbonate and once with water. The organic solution was dried (Na2SO4), filtered and in vacuo to yield a dark purple foam (1.73 g). Purification by flash chromatography on silica gel with hexane-ethyl acetate (1:2) as the mobile phase, followed by concentration in vacuo, resulted in a colorless solid (1.23 g, 75%), m.p. 227.5°-229° C. MS (ESI),m/z: 563 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH:29]([CH3:31])[CH3:30])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22](CO)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[CH3:37][O:38][CH2:39][CH2:40][NH:41][CH3:42].Cl[CH2:44]Cl>CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH:29]([CH3:31])[CH3:30])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:42][N:41]([CH2:40][CH2:39][O:38][CH3:37])[CH3:44])=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: ClCCl
Reactant: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Reactant: CNCCOC
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COCCN(C)Cc1cnnn1-c1cccc(C2=Nc3cc(N(C)C(C)C)c(Cl)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isopropyl-methyl-amino)-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 96) (220 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with N-(2-methoxyethyl)methylamine in DMF according to the method described in Example 45. Obtained as a light yellow solid (120 mg, 47%).
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:18]([OH:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:33](O)=[O:34].[C:38](=O)([O-])[O-:39].[K+].[K+].Cl>CO.CCOC(C)=O.O>[OH:20][C:9]1[C:8]([CH:33]=[O:34])=[CH:7][C:6]2[C@@H:5]3[C@H:14]([C@H:15]4[C@@:2]([CH2:3][CH2:4]3)([CH3:1])[C@@H:18]([OH:19])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1.[OH:20][C:9]1[CH:8]=[CH:7][C:6]2[C@@H:5]3[C@H:14]([C@H:15]4[C@@:2]([CH2:3][CH2:4]3)([CH3:1])[C@@H:18]([OH:19])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[C:10]=1[CH:38]=[O:39]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reactant: O=C(O)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@]12CC[C@@H]3c4cc(C=O)c(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Product: C[C@]12CC[C@@H]3c4ccc(O)c(C=O)c4CC[C@H]3[C@@H]1CC[C@@H]2O
Temperature: 100 °C
Reaction time: 6 h
Yield: 4 %
Yield: 13 %

Procedure:
To a mixture of estradiol (1, 13.6 g, 50 mmol) and hexamethylenetetramine (21.0 g, 150 mmol) was added trifluoroacetic acid (100 mL) at room temperature. The reaction mixture was stirred for 6 h at 100° C., poured into H2O (300 mL), and extracted with Et2O. The combined organic layers were washed with H2O, then with saturated aqueous NaCl, and dried (MgSO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was dissolved in THF (50 mL) and MeOH (50 mL), potassium carbonate (6.9 g, 50 mmol) was added, and the mixture stirred for 1 h at room temperature. The reaction mixture was then diluted with EtOAc, acidified with 1N HCl, and extracted with EtOAc. The combined organic layers were washed with H2O, then with saturated aqueous NaCl, and dried (MgSO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was purified by column chromatography (silica gel) using n-hexane:THF (5:1→3:1, v/v) to afford 1.91 g of 2a (13% yield), m.p. 219°-221° C., and 0.552 g of 2b (4% yield), m.p. 146°-147° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])/[C:5](/[OH:17])=[CH:6]/[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][N:10]=[C:9](Cl)[CH:8]=1)[CH3:2].[CH:19]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH2:1]([O:3][C:4](=[O:18])/[C:5](/[OH:17])=[CH:6]/[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][N:10]=[C:9]([N:27]2[CH2:28][CH2:29][N:24]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:25][CH2:26]2)[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)/C(O)=C/c1cc(Cl)ncc1[N+](=O)[O-]
Reactant: C1CCC(N2CCNCC2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(O)=C/c1cc(N2CCN(C3CCCC3)CC2)ncc1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
A mixture of 3.16 g (Z)-3-(2-chloro-5-nitro-pyridin-4-yl)-2-hydroxy-acrylic acid ethyl ester in 40 mL DMF was treated with 2.96 g (192 mmol) 1-cyclopentyl-piperazine and heated to 110° C. for 1.5 h. The mixture was diluted with 1N NaHCO3 aq. and extracted with DCM. The combined organic layers were dried with MgSO4 and evaporated to dryness to yield the title compound which was used without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[CH:5]([NH2:16])[CH2:6][CH2:7][CH2:8][C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11].C(=O)([O-])[O-].[K+].[K+].[C:24](Cl)(=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1.O>[CH3:2][O:3][C:4](=[O:17])[CH:5]([NH:16][C:24]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:33])[CH2:6][CH2:7][CH2:8][C:9]([F:14])([F:15])[C:10]([F:11])([F:12])[F:13]
Reactant: COC(=O)C(N)CCCC(F)(F)C(F)(F)F
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(CCCC(F)(F)C(F)(F)F)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, 16.9 g (59.2 mmol) of rac-methyl-2-amino-6,6,7,7,7-pentafluoroheptanoate hydrochloride (racemate) from Example 139A were initially charged in 775 ml of THF and 99 ml of water, and 25.37 g (183.6 mmol) of potassium carbonate were added carefully at RT. 11.0 ml (65.1 mmol) of benzyl chlorocarbonate were then added dropwise at 0° C., and the suspension was stirred at RT overnight. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered and concentrated. The crude product was purified by silica gel chromatography (mobile phase: cyclohexane/ethyl acetate gradient: 100/0 to 10/1 to 8/1 to 5/1). The product fraction was then re-purified by preparative RP-HPLC (acetonitrile/water gradient with 0.1% TFA). This gave 13.34 g (56% of theory, purity 94%) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:3]=1[C:4]([NH:6][CH:7]([CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:30])[CH:17]=[CH:16]2)[C:8]([O:10]C)=[O:9])=[O:5].Cl[C:37]1C=CC=C(Cl)[C:38]=1C1C=CC2C(=CC=C(CC(NC([C@@H]3CCCCN3S(C3C=CC(C)=CC=3)(=O)=O)=O)C(OC)=O)C=2)N=1.ClC1C=CC=C(Cl)C=1C1C=CC2C(=CC=C(CC(NC([C@@H]3CCCCN3S(C3C=CC(C)=CC=3)(=O)=O)=O)C(O)=O)C=2)N=1>>[Cl:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:2]([Cl:1])[C:3]=1[C:4](=[N:6][CH:7]([CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([C:23]1[C:24]([Cl:30])=[CH:25][CH:26]=[CH:27][C:28]=1[Cl:29])[CH:17]=[CH:16]2)[C:8]([OH:10])=[O:9])[O:5][CH2:37][CH3:38]
Reactant: COC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NC(=O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NC(=O)c1c(Cl)cccc1Cl
Agent: Cc1ccc(S(=O)(=O)N2CCCC[C@H]2C(=O)NC(Cc2ccc3nc(-c4c(Cl)cccc4Cl)ccc3c2)C(=O)O)cc1
Product: CCOC(=NC(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)C(=O)O)c1c(Cl)cccc1Cl

Procedure:
Compound 64 is synthesized according to Chem. Pharm. Bull. (1984), 32, (11), 4466-4477 starting from compound 35 followed by basic hydrolysis, as described for the transformation of compound 46 into compound 90.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[CH3:8][O:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:30][C:31]([F:49])([F:48])[C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([C:44](=O)[CH2:45][CH3:46])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1>C1(C)C=CC=CC=1>[CH3:8][O:9][CH:10]=[C:44]([C:41]1[CH:42]=[CH:43][C:38]([C:35]2[CH:36]=[CH:37][C:32]([C:31]([F:49])([F:48])[F:30])=[CH:33][CH:34]=2)=[CH:39][CH:40]=1)[CH2:45][CH3:46]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCC(=COC)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.3 %

Procedure:
To a an ambient temperature suspension of potassium tert-butoxide (670 mg, 5.39 mmol) in toluene (36 mL) is added (methoxymethyl)triphenylphosphonium chloride (1.85 g, 5.56 mmol) and is stirred at room temperature for 30 min. 1-(4′-trifluoromethylbiphenyl-4-yl)-propan-1-one (1 g, 3.59 mmol) is added, and the reaction mixture continues to stir at room temperature overnight. The reaction mixture is filtered, using dichloromethane to aid rinsing, concentrated to ⅓ volume, then loaded onto silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 25% giving 4-(1-methoxymethylene-propyl)-4′-trifluoromethylbiphenyl (278 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7]([C:13]([OH:15])=[O:14])=[C:6]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:5]2=O.O.[NH2:26][NH2:27]>C(O)C.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]([OH:8])=[C:4]([C:5]2[C:6]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:7]([C:13]([OH:15])=[O:14])[NH:26][N:27]=2)[CH:3]=1
Reactant: NN
Reactant: COc1ccc(-c2c(C(=O)O)oc3cc(O)c(Cl)cc3c2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2c(-c3cc(Cl)c(O)cc3O)n[nH]c2C(=O)O)cc1
Temperature: 70 °C

Procedure:
6-Chloro-7-hydroxy-3-(4-methoxy-phenyl)-4-oxo-4H-chromene-2-carboxylic acid (1 eq) was taken up in ethanol and hydrazine hydrate (3 eq) was added. To aid dissolution a few drops of NaHCO3 (aq) was added, and then all was heated at 70° C. under nitrogen for 2 hours. The solution was cooled to room temperature and concentrated in vacuo to a brown oil. This was partitioned between 1M HCl (aq) and diethyl ether. The organic phases were combined, washed with 1M HCl (aq), dried over MgSO4, filtered and concentrated in vacuo to give 5-(5-chloro-2,4-dihydroxy-phenyl)-4-(4-methoxy-phenyl)-2H-pyrazole-3-carboxylic acid as a yellow foam.
Reaction SMILES: B(O)(O)[OH:2].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1O>>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:2])=[CH:9][CH:8]=1
Reactant: OB(O)O
Reactant: COc1ccccc1O
Product: COc1ccc(O)cc1

Procedure:
The reaction was carried out in the same manner as in Example 4 except that orthoboric acid was replaced by 1.2 g. of anhydrous boric acid and 2.60 g. (21.0 m.moles) of o-methoxyphenol and 1.74 g. (14.0 m.moles) of p-methoxyphenol were obtained. The yield of these hydroxyphenyl ethers was 49.4 %.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:22])([F:21])[C:8]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)([OH:13])[C:9]([F:12])([F:11])[F:10].O>N1C=CC=CC=1>[F:6][C:7]([F:21])([F:22])[C:8]([C:14]1[CH:20]=[CH:19][C:17]([NH:18][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:16][CH:15]=1)([OH:13])[C:9]([F:10])([F:12])[F:11]
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 8 h

Procedure:
Add 2.50 g (22 mmole) of methanesulfonyl chloride dropwise to 5.06 g (15 mmole) 4-(hexafluoro-2-hydroxy-2-propyl)-aniline in 25 ml of pyridine and allow to stand overnight. Pour the reaction into H2O and extract with Et2O. Wash the Et2O with 1N HCl and extract with 1N NaOH. Acidify the NaOH and extract with Et2O. Dry, concentrate and recrystallize from Et2O-hexane to obtain 4'-(hexafluoro-2-hydroxy-2-propyl)methanesulfonanilide; m.p. 137°-139° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[CH:15]=[CH:14][O:13][C:12]=1[NH:16][C:17](=[O:23])OC(C)(C)C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:25](Cl)(=O)[CH2:26][CH2:27]C>>[CH2:1]([NH:8][C:9]([C:11]1[CH:15]=[CH:14][O:13][C:12]=1[NH:16][C:17](=[O:23])[CH2:25][CH2:26][CH3:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1occc1C(=O)NCc1ccccc1
Reactant: CCCC(=O)Cl
Agent: Cl
Product: CCCC(=O)Nc1occc1C(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl 3-[(benzylamino)carbonyl]-2-furylcarbamate (1-1, 1 equiv) is saturated with HCl gas at 0° C., and the resulting solution is stirred at 0° C. for 1 h, then allowed to warm to 23° C. and stirred for 1 h. The reaction mixture is concentrated and the residue is dissolved in pyridine. The resulting solution is cooled to 0° C., and butyryl chloride (3 equiv) is added in three equal portions over 1 h. The reaction mixture is partitioned between aqueous sodium bicarbonate solution and ethyl acetate. The organic layer is dried over sodium sulfate and concentrated. The residue is purified by flash column (hexanes initially, grading to 100% ethyl acetate) to give N-benzyl-2-(butyrylamino)-3-furamide (1-2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[C@@H:14]([NH:15]C(=O)OC(C)(C)C)[CH2:13][C@@H:12]([N:23]2[CH2:30][C:29]3[C:25](=[N:26][NH:27][CH:28]=3)[CH2:24]2)[CH2:11][S:10]1.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>C(Cl)Cl>[F:34][C:33]([F:36])([F:35])[C:31]([OH:37])=[O:32].[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[C@@H:14]([NH2:15])[CH2:13][C@@H:12]([N:23]2[CH2:30][C:29]3[C:25](=[N:26][NH:27][CH:28]=3)[CH2:24]2)[CH2:11][S:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3c[nH]nc3C2)CSC1c1cc(F)ccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1C[C@@H](N2Cc3c[nH]nc3C2)CSC1c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl N-[(3S,5R)-2-(2,5-difluorophenyl)-5-(4,6-dihydro-2H-pyrrolo[3,4-c]pyrazol-5-yl)tetrahydrothiopyran-3-yl]carbamate (3.2 mg, 0.007 mmol) was dissolved in a mixture of TFA (0.5 mL) and methylene chloride (1.0 mL) and stirred at RT for 1 h. The solvents were evaporated and the residue was freeze-dried from a mixture of benzene and ethanol to give the title compound as a white solid.