Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH2:14][C:13]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:17])[CH2:12]2)=[C:4]2[CH2:10][CH2:9][CH2:8][C:5]2=[N:6][CH:7]=1.[C:26]([O:30][C:31]([NH:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47](O)=[O:48])=[O:32])([CH3:29])([CH3:28])[CH3:27].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>CN(C=O)C.CO>[C:26]([O:30][C:31]([NH:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47]([NH:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH2:14][C:13]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:17])[CH2:12]2)=[C:4]2[CH2:10][CH2:9][CH2:8][C:5]2=[N:6][CH:7]=1)=[O:48])=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC1(NC(=O)OC(C)(C)C)CCCN(c2c(N)cnc3c2CCC3)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: CC1(NC(=O)OC(C)(C)C)CCCN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)cnc3c2CCC3)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.3 %

Procedure:
A mixture of tert-butyl [1-(3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-3-methylpiperidin-3-yl]carbamate (8.0 mg, 0.023 mmol), 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (9.1 mg, 0.025 mmol), HATU (21.9 mg, 0.058 mmol) in DMF (0.05 mL) and DIPEA (0.012 mL, 0.069 mmol) was stirred at room temperature for 2 h. The reaction mixture was diluted with MeOH and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a white powder (8.4 mg, 53%). LCMS calc. for C34H43F2N6O5S (M+H)+: m/z=685.3. Found: 685.3.
Reaction SMILES: C(OC(=O)[N:10]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26]2[S:27][C:28]([C:34]3[C:39]([F:40])=[CH:38][C:37]([C:41]([OH:44])([CH3:43])[CH3:42])=[CH:36][C:35]=3[F:45])=[CH:29][C:30]=2[C:31]([NH2:33])=[O:32])[N:20]=1)[CH2:11][C:12]([NH:14][CH:15]([CH3:17])[CH3:16])=[O:13])C1C=CC=CC=1.[H][H]>CO.[Pd]>[F:40][C:39]1[CH:38]=[C:37]([C:41]([OH:44])([CH3:43])[CH3:42])[CH:36]=[C:35]([F:45])[C:34]=1[C:28]1[S:27][C:26]([NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([CH2:18][NH:10][CH2:11][C:12]([NH:14][CH:15]([CH3:17])[CH3:16])=[O:13])[N:20]=2)=[C:30]([C:31]([NH2:33])=[O:32])[CH:29]=1
Reactant: [H][H]
Reactant: CC(C)NC(=O)CN(Cc1cccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)NC(=O)CNCc1cccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1
Reaction time: 3 h

Procedure:
Benzyl{[6-({3-(aminocarbonyl)-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-thienyl}amino)pyridin-2-yl]methyl}[2-(isopropylamino)-2-oxoethyl]carbamate (83 mg, 0.13 mmol) was dissolved in methanol. Palladium on carbon (0.68 mg, 6.4 μmol) was added and a hydrogen balloon was placed on top. The solution was evacuated and then charged with hydrogen several times. The reaction was stirred for 3 hours. The solution was filtered through celite and concentrated. The crude residue was purified by reverse phase HPLC (10-100% acetonitrile/water+0.05% TFA modifier) to yield the title compound.
Reaction SMILES: [F:1][C:2]1([F:19])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](SC)[N:12]=3)[C:4]=2[O:3]1.O[O:21][S:22]([O-:24])=O.[K+].[C:26]([O-])(O)=O.[Na+]>CO>[F:19][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:22]([CH3:26])(=[O:24])=[O:21])[N:12]=3)[C:4]=2[O:3]1
Reactant: CSc1nccc(-c2cccc3c2OC(F)(F)O3)n1
Reactant: O=S([O-])OO
Reactant: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)c1nccc(-c2cccc3c2OC(F)(F)O3)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2-methylsulfanyl-pyrimidine (326 mg, 1.15 mmol) in MeOH (8 ml) was cooled at 0° C. and then an aqueous solution of oxone (2.31 g, 3.76 mmol in 8 ml of water) was slowly added. After stirring 2 hours at room temperature, the mixture was basified with 5% NaHCO3 and the product was extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated to give 364 mg of the title compound that was used in the next step without further purification (quantitative yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][C:3]=1[Cl:21].ClC(Cl)(O[C:26](=[O:32])OC(Cl)(Cl)Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+].[NH2:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][CH:48]=1)[C:44]#[N:45]>ClCCl.O>[Cl:21][C:3]1[CH:4]=[C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:9]2)[CH:6]=[CH:7][C:2]=1[NH:1][C:26]([NH:40][C:41]1[CH:48]=[CH:47][CH:46]=[C:43]([C:44]#[N:45])[CH:42]=1)=[O:32]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)c(Cl)c2)C1
Reactant: N#Cc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(NC(=O)Nc3cccc(C#N)c3)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 296.1 %

Procedure:
To a stirred solution of tert-butyl (RS)-2-(4-amino-3-chlorophenyl)morpholine-4-carboxylate (70 mg) in dichloromethane (2 ml) was added triphosgene (25 mg). A solution of sodium carbonate (47 mg) in water (2 ml) was then added. The reaction mixture was stirred at room temperature for 2.5 hours. TLC showed all the starting material had reacted. 3-Aminobenzonitrile (53 mg, CAS 2237-30-1) was then added and the reaction mixture was stirred at room temperature for a further 2 hours. TLC showed the reaction was complete. The reaction mixture was poured into dichloromethane and extracted with water. The organic phase was separated, dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: 0% to 30% EtOAc in hexanes) to give tert-butyl (RS)-2-(3-chloro-4-(3-(3-cyanophenyl)ureido)phenyl)morpholine-4-carboxylate (114 mg, quant.) as an amorphous white solid. MS (ISP): 457.2 ([{37Cl}M−H]−), 455.2 ([{35Cl}M−H]−).
Reaction SMILES: [C:1]([C@H:5]1[CH2:9][O:8][S:7](=[O:10])[N:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:19].[Na+]>C(#N)C.O.O.[Ru](Cl)(Cl)Cl>[C:1]([C@H:5]1[CH2:9][O:8][S:7](=[O:19])(=[O:10])[N:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(C)(C)[C@H]1COS(=O)N1Cc1ccccc1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)[C@H]1COS(=O)(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.5 %

Procedure:
To a solution of (4S)-4-(tert-butyl)-3-(phenylmethyl)-1,2,3-oxathiazolidine-2-oxide (6.26 g, 24.71 mmol) in acetonitrile (30 mL) and water (30 mL) at 0° C. was added ruthenium chloride hydrate (5.13 mg, 0.025 mmol), followed by sodium periodate (7.93 g, 37.1 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 3 h, diluted with water, extracted with ethyl acetate. The combined organics were washed with water, dried over anhydrous Na2SO4, filtered then concentrated to give the title compound (6.22 g) as an off-white solid. LCMS m/z=270.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 1.00 (s, 9H), 3.25-3.30 (m, 1H), 4.31-4.40 (m, 2H), 4.47 and 4.55 (dd, J=15.2 Hz, 2H), 7.30-7.48 (m, 5H).
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:9]([O:14]C)([O:12][CH3:13])(=[O:11])=[O:10].[CH2:16](OCC)C>O>[S:9]([O-:14])([O-:12])(=[O:11])=[O:10].[CH3:8][S+:7]([CH3:13])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][S+:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:16]
Reactant: COS(=O)(=O)OC
Reactant: CSc1ccccc1
Reactant: CCOCC
Solvent: O
Product: C[S+](C)c1ccccc1
Product: O=S(=O)([O-])[O-]

Procedure:
At room temperature, 6.2 g (0.05 mole) of thioanisole and 6.9 g (0.055 mole) of dimethyl sulfate were stirred for 12 hours. To the reaction solution were added 100 g of water and 50 ml of diethyl ether. The water layer was taken out, obtaining an aqueous solution of the desired dimethylphenylsulfonium sulfate.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([O:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[C:7]([O:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:6][C:3]=1[CH:4]=[CH2:5].ClC1C=CC=C(C(OO)=[O:33])C=1>CCOC(C)=O.C1CCCCC1>[Cl:1][C:2]12[O:33][C:3]1([CH:6]=[C:7]([O:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[C:8]([O:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:9]2[Cl:10])[CH:4]=[CH2:5]
Reactant: C=Cc1cc(OCOCCOC)c(OCOCCOC)c(Cl)c1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: C=CC12C=C(OCOCCOC)C(OCOCCOC)=C(Cl)C1(Cl)O2
Yield: 99.6 %

Procedure:
Using the procedure of Stage D of Example 40, 13.2 g of thee allylic alcohol of Step C and 10.3 g of m-chloro perbenzoic acid were reacted to obtain 13.7 g of the expected product with a Rf =0.25 (AcOEt-cyclohexane 6-4)
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:12])([CH3:11])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6]1.N1C(C)=CC=CC=1C.[Cl:21][C:22]1[CH:23]=[C:24]([CH:32]([CH2:36][C@H:37]2[CH2:41][CH2:40][C:39]([F:43])([F:42])[CH2:38]2)[C:33](Cl)=[O:34])[CH:25]=[CH:26][C:27]=1[S:28]([CH3:31])(=[O:30])=[O:29]>C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[C:24]([CH:32]([CH2:36][C@H:37]2[CH2:41][CH2:40][C:39]([F:43])([F:42])[CH2:38]2)[C:33]([NH:10][C:7]2[CH:8]=[CH:9][N:5]([CH2:4][C:3]([O:2][CH3:1])([CH3:12])[CH3:11])[N:6]=2)=[O:34])[CH:25]=[CH:26][C:27]=1[S:28]([CH3:31])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)c1ccc(C(C[C@H]2CCC(F)(F)C2)C(=O)Cl)cc1Cl
Reactant: COC(C)(C)Cn1ccc(N)n1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(C)(C)Cn1ccc(NC(=O)C(C[C@H]2CCC(F)(F)C2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a round bottom flask was placed 1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-ylamine (prepared as in Example 94, 61 mg, 0.36 mmol), 2,6-lutidine (54 μL, 0.49 mmol) and methylene chloride (10 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise a solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3,3-difluoro-cyclopentyl)-propionyl chloride (prepared as in Example 106, ˜0.16 M solution, 2 mL, 0.33 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution (10 mL) and then diluted with methylene chloride (10 mL) transferred to a separatory funnel and the layers separated. The aqueous layer was then extracted methylene chloride (3×10 mL). The organics were combined and then washed with a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (12 g column, 35% ethyl acetate/hexanes to 70% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3,3-difluoro-cyclopentyl)-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (as a mixture of two diastereomers, 130 mg, 77%) as an off-white foam: ES-HRMS m/e calcd for C23H30N3O4SClF2 (M+H)+ 518.1687, observed 518.1684; 1H NMR (300 MHz, DMSO-d6) δ 1.04 (s, 3H, CH3), 1.05 (s, 3H, CH3), 1.42 (m, 1H, CH), 1.64-2.31 (m, 8H, 4×CH2), 3.14 (s, 3H, OCH3), 3.34 (s, 3H, SO2CH3), 3.91 (m, 1 H, ArCHCO), 3.97 (s, 2 H, NCH2), 6.45 (d, J=2.2 Hz, 1H, Ar), 7.48 (d, J=2.2 Hz, 1H, Ar), 7.60 (d, Jo=8.2 Hz, 1H, Ar), 7.71 (s, 1H, Ar), 8.02 (d, Jo=8.2 Hz, 1H, Ar), 10.84 (s, 1H, NH).
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:44]2[C:39](=[CH:40][C:41]([F:45])=[CH:42][CH:43]=2)[C:7]2([CH2:12][CH2:11][N:10]([C:13]([C@H:15]([NH:25][C:26](=[O:38])[C:27]([NH:30]C(OC(C)(C)C)=O)([CH3:29])[CH3:28])[CH2:16][O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:14])[CH2:9][CH2:8]2)[CH2:6]1)(=[O:4])=[O:3].FC(F)(F)C(O)=O.[Cl:53]CCl>>[ClH:53].[CH3:1][S:2]([N:5]1[C:44]2[C:39](=[CH:40][C:41]([F:45])=[CH:42][CH:43]=2)[C:7]2([CH2:12][CH2:11][N:10]([C:13]([C@H:15]([NH:25][C:26](=[O:38])[C:27]([NH2:30])([CH3:29])[CH3:28])[CH2:16][O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:14])[CH2:9][CH2:8]2)[CH2:6]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)N1CCC2(CC1)CN(S(C)(=O)=O)c1ccc(F)cc12
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)C(=O)N[C@H](COCc1ccccc1)C(=O)N1CCC2(CC1)CN(S(C)(=O)=O)c1ccc(F)cc12
Product: Cl
Temperature: 25 °C

Procedure:
To a solution of 0.101 g the intermediate from Step C in 1 mL of dichloromethane was added 1.0 mL of trifluoroacetic acid and maintained at RT for 30 min. The reaction mixture was evaporated to dryness, basified with 10% aqueous sodium carbonate solution (10 mL), and extracted with dichloromethane (3×5 mL). The combined organics were washed with brine (5 mL), dried over potassium carbonate, and concentrated. This material was dissolved in 2 mL of ethyl acetate and 0.10 mL of 4M HCl in EtOAc was added at 0° C. The precipitate was filtered under nitrogen and washed with EtOAc/ether (1:1) and dried to give 62 mg of the product as a white solid.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])=[CH:8][CH2:7]1)(=O)=O.C1CCN2C(=NCCC2)CC1>O1CCCC1.C(OCC)(=O)C>[C:9]1([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[CH2:10][CH2:11][CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)OC1CC=C(c2ccncc2[N+](=O)[O-])CC1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cnccc1C1=CC=CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(3-nitropyridin-4-yl)cyclohex-3-enyl methanesulfonate (1.0 equiv) in tetrahydrofuran (0.1 M) was added DBU (1.8 equiv.) at room temperature. The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with ethyl acetate (200 mL), and washed with sat NaCl (30 mL). The organic was dried with MgSO4, filtered and concentrated. The residue was purified by column (5% methanol in 1:1 ethyl acetate and hexanes) to give 4-(cyclohexa-1,3-dienyl)-3-nitropyridine. LC/MS (m/z): MH+=203.2, Rt=0.85.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:17]4[CH:18]=[C:19]([CH:33]=[CH:34][C:35]=4[CH3:36])[C:20]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[O:21])=[CH:13][CH:14]=3)[N:9](COCC[Si](C)(C)C)[N:8]=2)=[O:5])[CH2:3][CH2:2]1.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]>C(Cl)Cl>[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46].[CH:1]1([C:4]([NH:6][C:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:17]4[CH:18]=[C:19]([CH:33]=[CH:34][C:35]=4[CH3:36])[C:20]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:30])[F:32])[CH:24]=4)=[O:21])=[CH:13][CH:14]=3)[NH:9][N:8]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1Nc1ccc2c(NC(=O)C3CC3)nn(COCC[Si](C)(C)C)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1Nc1ccc2c(NC(=O)C3CC3)n[nH]c2c1
Reaction time: 2 h
Yield: 66 %

Procedure:
To a solution of 3-(3-(cyclopropanecarboxamido)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-ylamino)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide (25 mg) in CH2Cl2 (1 mL) was added TFA (0.25 mL) at room temperature. The reaction mixture was stirred for 2 hours and the organic solvent was concentrated under reduced pressure. To a solution of the resulting mixture in THF (0.5 mL) and MeOH (0.5 mL) was added LiOH aqueous solution (1.0 M, 1.0 mL). The resulting mixture was stirred for another 2 hours at room temperature. The organic solvent was removed under reduced pressure and the aqueous layer was extracted with ethyl acetate. The organic extracts were washed with brine, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by Prep HPLC and acetonitrile was removed under reduced pressure. The remained water was freeze-dried to afford TFA salt of title compound (16 mg, 66%), MS (ESI) m/z 494 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C:11]([OH:25])([CH3:24])[CH2:12]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[F:26][C:27]([F:42])([F:41])[C:28]1[CH:40]=[CH:39][C:31]([O:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:30][CH:29]=1.[I-].[Na+].C(N(CC)CC)C>CN(C=O)C.O>[Cl:1][C:2]1[N:3]([CH2:10][C:11]([CH3:24])([OH:25])[CH2:12][N:36]2[CH2:35][CH2:34][CH:33]([O:32][C:31]3[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:41])[F:42])=[CH:40][CH:39]=3)[CH2:38][CH2:37]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: FC(F)(F)c1ccc(OC2CCNCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC(C)(O)Cn2cc([N+](=O)[O-])nc2Cl)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(O)(CN1CCC(Oc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 80 °C
Reaction time: 7 h
Yield: 64.5 %

Procedure:
To a solution of 2-chloro-1-[2-hydroxy-2-methyl-3-(4-methylbenzenesulfonyloxy)propyl]-4-nitroimidazole prepared in Example 5 (0.30 g, 0.77 mmol) and 4-(4-trifluoromethylphenoxy)piperidine (0.21 g, 0.85 mmol) in DMF (6 ml), sodium iodide (0.13 g, 0.77 mmol) and triethylamine (0.12 ml, 0.77 mmol) were added followed by stirring at 80° C. for 7 hours. To the reaction mixture, water was added, and the resulting solution was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=9/1) to afford 1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-trifluoromethylphenoxy)piperidin-1-yl]propan-2-ol (0.23 g, yield 63%) as a yellow oil.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[NH:3])[CH3:2].Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])=O.C(N(CC)C(C)C)(C)C>C(#N)C.CC1CCCO1>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:3]=[C:1]([CH3:2])[N:4]([NH:5][C:6](=[O:7])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:14]=1
Reactant: O=C(CBr)c1ccccc1F
Reactant: CC(=N)NNC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC1CCCO1
Solvent: CC#N
Product: Cc1nc(-c2ccccc2F)cn1NC(=O)OC(C)(C)C

Procedure:
Compound C1 (11.4 g, 65.8 mmol), 2-bromo-1-(2-fluorophenyl)ethanone (13.0 g, 59.9 mmol) and N,N-diisopropylethylamine (23.0 mL, 132 mmol) were combined in a mixture of acetonitrile (100 mL) and 2-methyltetrahydrofuran (300 mL) and heated at reflux for 18 hours. After cooling, the reaction mixture was concentrated in vacuo; the residue was mixed with ethyl acetate, then washed sequentially with saturated aqueous ammonium chloride solution and with saturated aqueous sodium bicarbonate solution. The combined aqueous layers were extracted with ethyl acetate, and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide the product as a pale brown foam. Yield: 18.1 g, assumed quantitative. LCMS m/z 292.4 [M+H]+. 1H NMR (500 MHz, CDCl3), presumed to be a mixture of rotamers: δ 8.15 (v br s, 1H), 8.03-8.07 (m, 1H), 7.30 and 7.31 (2 s, 1H), 7.13-7.20 (m, 2H), 7.02-7.08 (m, 1H), 2.31 (s, 3H), 1.49 (br s, 9H).
Reaction SMILES: [CH3:1][N:2]([CH3:41])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:32]3[CH:37]=[CH:36][C:35]([N:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=3)[O:14][C:13]3[C:15]4[C:20]([CH:21]=[C:22]([C:23]([O:25][CH2:26][CH2:27][OH:28])=[O:24])[C:12]=3[CH:11]=[CH:10]2)=[CH:19][CH:18]=[C:17]([N:29]([CH3:31])[CH3:30])[CH:16]=4)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:49](Cl)(=[O:52])[CH2:50][CH3:51]>C(Cl)Cl>[CH3:39][N:38]([CH3:40])[C:35]1[CH:36]=[CH:37][C:32]([C:9]2([C:6]3[CH:5]=[CH:4][C:3]([N:2]([CH3:41])[CH3:1])=[CH:8][CH:7]=3)[O:14][C:13]3[C:15]4[C:20]([CH:21]=[C:22]([C:23]([O:25][CH2:26][CH2:27][O:28][C:49](=[O:52])[CH2:50][CH3:51])=[O:24])[C:12]=3[CH:11]=[CH:10]2)=[CH:19][CH:18]=[C:17]([N:29]([CH3:30])[CH3:31])[CH:16]=4)=[CH:33][CH:34]=1
Reactant: CCC(=O)Cl
Reactant: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3)C=Cc3c(C(=O)OCCO)cc4ccc(N(C)C)cc4c3O2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)OCCOC(=O)c1cc2ccc(N(C)C)cc2c2c1C=CC(c1ccc(N(C)C)cc1)(c1ccc(N(C)C)cc1)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A solution of 2,2-bis(4-dimethylaminophenyl)-5-(2-hydroxyethoxycarbonyl)-9-dimethylamino-[2H]-naphtho[1,2-b]pyran (Example 9, Step 5) (0.045 g, 0.082 mmol) and triethylamine (0.05 ml) in dry DCM (5 ml) was added propionyl chloride in one portion (0.0075 g, 0.082 mmol) and the mixture stirred at RT for 30 minutes. The solvent was then evaporated in vacuo and the crude residue purified by column chromatography (silica gel, DCM/diethyl ether, 10:1), giving the pure product, 2,2-bis(4-dimethylaminophenyl)-5-(2-propionyloxy-ethoxycarbonyl)-9-dimethylamino-[2H]-naphtho[1,2-b]pyran (0.044 g, 89%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[C:16]2[O:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:13]([CH3:23])[C:12](=[O:24])[C:11]=2[CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.O>O1CCCC1>[C:1]([NH:6][C:7]1[C:16]2[O:15][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[C:13]([CH3:23])[C:12](=[O:24])[C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: Cc1c(-c2ccccc2)oc2c(N)cccc2c1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: C=CC(=O)Nc1cccc2c(=O)c(C)c(-c3ccccc3)oc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1.75 ml of acryloyl chloride in 15 ml of anhydrous tetrahydrofuran was added dropwise at -10° C. to a stirred mixture of 5 g of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 3 ml of triethylamine in 60 ml of anhydrous tetrahydrofuran. After stirring at 0° C. for 1 hour and at ambient temperature for 1 hour, the reaction mixture was poured into water and filtered under suction. The filter cake was washed with water. Desiccation gave 5.5 g of the title compound, m.p. 229°-230° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([P:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[ClH:23]>O>[Cl-:23].[Cl-:23].[Cl-:23].[NH3+:1][C:2]1[CH:3]=[C:4]([P:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH3+:22])[CH:17]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH3+:15])[CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(P(c2cccc(N)c2)c2cccc(N)c2)c1
Reactant: Cl
Solvent: O
Product: [Cl-]
Product: [NH3+]c1cccc(P(c2cccc([NH3+])c2)c2cccc([NH3+])c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
An aqueous solution of 3.04 g (9.90 mmol) of tris(3-aminophenyl)phosphine in 100 ml of water was treated with 13.5 ml of hydrochloric acid (2 N) and the clear solution was stirred at room temperature for 30 minutes. The solvent was distilled off at 60° C. under reduced pressure, giving 3.21 g of tris(3-ammoniophenyl)phosphine trichloride as a colorless solid (yield: 78%).
Reaction SMILES: Cl.[OH:2][C:3]1[C:4]([O:20][CH3:21])=[C:5]([C:10](=[O:19])[CH2:11][NH:12][C:13]2([CH3:18])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=[CH:7][C:8]=1[OH:9].C[OH:23]>[Pt](=O)=O>[OH:19][CH:10]([C:5]1[C:4]([O:20][CH3:21])=[C:3]([OH:2])[C:8]([OH:9])=[CH:7][CH:6]=1)[CH2:11][NH:12][C:13]1([CH3:18])[CH2:14][CH2:15][CH2:16][CH2:17]1.[C:10]([O-:19])(=[O:23])[C:5]1[CH:4]=[CH:3][CH:8]=[CH:7][CH:6]=1
Reactant: CO
Reactant: COc1c(C(=O)CNC2(C)CCCC2)ccc(O)c1O
Agent: O=[Pt]=O
Agent: Cl
Product: COc1c(C(O)CNC2(C)CCCC2)ccc(O)c1O
Product: O=C([O-])c1ccccc1

Procedure:
5 g of 1-(3,4-dihydroxy-2-methoxyphenyl)-2-(1-methylcyclopentylamino)ethanone hydrochloride is hydrogenated with 0.2 g of platinum(IV) oxide in 200 mL methanol. The catalyst is suction filtered and the solvent is distilled off under reduced pressure. The residue remaining is dissolved in ethanol and combined with 5 g of sodium benzoate. The title compound is isolated in the form of its benzoate. Yield: 4.5 g (70.5%; benzoate); melting point: 179° C.-180° C.