Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]2=[O:25])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH2:13]O)[N:10]=[CH:9]1.C1(P([N:40]=[N+:41]=[N-:42])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]2=[O:25])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH2:13][N:40]=[N+:41]=[N-:42])[N:10]=[CH:9]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-n3cnc(CO)c3)c(F)c2)C(=O)O1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(-n3cnc(CN=[N+]=[N-])c3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 48 h
Yield: 94.4 %

Procedure:
N-[(5 S)-3-(3-Fluoro-4-(4-hydroxymethylimidazol-1-yl)phenyl)-2-oxooxazolidin-5-yl-methyl]acetamide (1.74 g, 5 mM) was suspended in dry dichloromethane (60 ml), diphenylphosphoryl azide (2.47 g, 9 mM) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.82 g, 12 mM) added, and the mixture stirred under argon at ambient temperature for 48 hours. The resulting solution was columned on silica (75 g) through a sinter funnel, eluting with a gradient increasing in polarity from 0 to 10% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the title product (1.76 g).
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:11][CH:10]1[CH2:9][N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:7]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:5])C.C>[OH-].[Na+].C(O)C>[C:22]1([CH:7]2[N:8]([S:12]([C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=3)(=[O:14])=[O:13])[CH2:9][CH:10]3[C:6]2([C:4]([OH:5])=[O:3])[CH2:11]3)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C12CC1CN(S(=O)(=O)c1ccc(C)cc1)C2c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N2CC3CC3(C(=O)O)C2c2ccccc2)cc1
Reaction time: 1 h

Procedure:
A solution of racemic 2-phenyl-3-(toluene-4-sulfonyl)-3-aza-bicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester (Intermediate 1) in 400 mL 10% NaOH and 80 mL ethanol was refluxed for 6 hours. The solution was allowed to cool, treated with decolorizing charcoal, and filtered thru supercel. The ethanol was evaporated at reduced pressure and the residual solution was cooled in an ice bath and acidified with concentrated HCl to pH 1. The product precipitated and was granulated for one hour, then collected by filtration to give 2-phenyl-3-(toluene-4-sulfonyl)-3-aza-bicyclo[3.1.0]hexane-1-carboxylic acid as a white solid (19.38 g, quantitative).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:25]=[C:24]([CH3:26])[O:23][N:22]=3)=[CH:17][CH:16]=2)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1COCC1.[NH4+]=[S:33].C(OCC)(=O)C>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:25]=[C:24]([CH3:26])[O:23][N:22]=3)=[CH:17][CH:16]=2)[C:12]([NH2:13])=[S:33])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(C#N)Nc2ccc(-c3noc(C)n3)cc2)cc1OC
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(Nc2ccc(-c3noc(C)n3)cc2)C(N)=S)cc1OC
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of 1.25 g of (3,4-dimethoxyphenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]acetonitrile in 120 ml of an ethanol:THF=2:1 mixed solvent there was added 10 ml of a 20% aqueous solution of ammonium sulfide, and the mixture was stirred at room temperature for 60 hours. Next, 500 ml of ethyl acetate and 400 ml of water were added to the reaction solution, and the organic layer was washed twice with 300 ml of water and once with 300 ml of saturated brine, and was then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and after concentrating the filtrate under reduced pressure, 10 ml of t-butyl methyl ether was added to the residue prior to filtration. The solid was washed with 10 ml of t-butyl methyl ether to give the title compound (1.34 g) as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([N:12]([CH2:14][C@@H:15]2[CH2:17][C@H:16]2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH3:13])[CH:5]=[CH:4][N:3]=1.O.[NH2:26][NH2:27]>O1CCOCC1>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C@@H:16]2[CH2:17][C@H:15]2[CH2:14][N:12]([CH3:13])[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:26][NH2:27])[C:7]=2[C:8]([F:11])([F:10])[F:9])=[CH:19][CH:20]=1
Reactant: CN(C[C@@H]1C[C@H]1c1ccc(F)cc1)c1ccnc(Cl)c1C(F)(F)F
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Product: CN(C[C@@H]1C[C@H]1c1ccc(F)cc1)c1ccnc(NN)c1C(F)(F)F
Yield: 92.9 %

Procedure:
A mixture of trans 2-chloro-N-((2-(4-fluorophenyl)cyclopropyl)methyl)-N-methyl-3-(trifluoromethyl)pyridin-4-amine (1.2 g, 3.34 mmol) and hydrazine hydrate (3.32 mL, 66.9 mmol) in dioxane (20 mL) was heated to reflux under nitrogen for 6 h. The reaction mixture was concentrated. The reaction mixture was diluted with EtOAc and washed with aqueous sodium bicarbonate. The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with aqueous sodium bicarbonate (2×20 mL) and brine (20 mL), dried over magnesium sulfate, and concentrated to give trans-N-((2-(4-fluorophenyl)cyclopropyl)methyl)-2-hydrazinyl-N-methyl-3-(trifluoromethyl)pyridin-4-amine (1.1 g, 80% yield), which was used for the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:6][C:5]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17]
Reactant: COCCCCOc1cc(C)ccc1C(=O)OC
Reactant: C1CCNCC1
Product: COCCCCOc1cc(CN2CCCCC2)ccc1C(=O)OC

Procedure:
The 2-(4-methoxybutoxy)-4-(piperidin-1-ylmethyl)-benzoic acid methyl ester that is used is prepared in a manner analogous to that described in Example 30 An) from 2-(4-methoxybutoxy)-4-methyl-benzoic acid methyl ester and piperidine, with subsequent purification of the crude product by FC (eluants C and M): brown oil, Rf (N)=0.34.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15].C(N(CC)CC)C>ClCCl>[S:2]([O:6][CH2:7][CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15])([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)CCCCC=CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)CCCCC=CCOS(C)(=O)=O
Reaction time: 0.33 h
Yield: 84.7 %

Procedure:
Methane sulphonylchloride (8.07 g; 1.1 eq) was added dropwise over 30 minutes to a stirred solution of 9-hydroxy-non-7-en-2-one (10 g) in dry dichloromethane (60 ml) containing an excess of triethylamine (9.71 g; 1.5 eq), at -10° C. The solution was stirred for a further 20 minutes. The reaction mixture was washed with cold water, cold 5 N hydrochloric acid, cold 5% sodium bicarbonate solution and cold brine then was dried and evaporated in vacuo at <30° to give 9-mesyloxy-non-7-en-2-one (12.7 g) as a deep red oil.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH2:12][CH:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8]1.[CH3:19][C:20]([CH3:22])=[O:21].Cl>O1CCCC1>[C:13]1([C:10]23[CH2:9][CH:8]([O:21][C:20]2([CH3:22])[CH3:19])[N:7]([CH3:6])[CH2:12][CH2:11]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN1CC=C(c2ccccc2)CC1
Reactant: CC(C)=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC2(c3ccccc3)CC1OC2(C)C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (15 ml of 1.5M solution in hexane) was added under nitrogen to a solution of 4.7 g of commercially available 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (II: R1 =Me; R2, R3 =H; R4 =phenyl) in 50 mL of tetrahydrofuran, kept at -10°. The deep red solution was stirred at -10° for 15 min and then transferred in a slow stream into a stirred mixture of 15 mL of acetone and 25 mL of tetrahydrofuran and kept at -70°. Excess 10% hydrochloric acid was added after stirring at -70° for 5 min; the mixture was allowed to come to room temperature, and then washed with toluene. The aqueous layer was made basic with sodium hydroxide and extracted with methylene chloride. Removal of the solvent from the dried solution and short-path distillation of the residue (90°-135° bath temperature, 5×10-4 mm Hg [0.07 Pa]) gave 2.79 g of 5-phenyl-2,6,6-trimethyl-7-oxa-2-azabicyclo[3.2.1]octane (III: R1, R5, R6 =Me; R2, R3 =H, R4 =phenyl) as an oil of ca. 85% purity.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([N+:16]([O-:18])=[O:17])=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[N:19]12[CH2:26][CH2:25][CH2:24][C:23]1([CH2:27][NH2:28])[CH2:22][CH2:21][CH2:20]2>>[N:19]12[CH2:26][CH2:25][CH2:24][C:23]1([CH2:27][NH:28][C:2]1[C:3]3[C:8]([C:9]([N+:16]([O-:18])=[O:17])=[C:10]4[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]4)=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:22][CH2:21][CH2:20]2
Reactant: NCC12CCCN1CCC2
Reactant: O=[N+]([O-])c1c2ccccc2c(Br)c2ccccc12
Product: O=[N+]([O-])c1c2ccccc2c(NCC23CCCN2CCC3)c2ccccc12
Yield: 51.5 %

Procedure:
9-Bromo-10-nitroanthracene and (1-azabicyclo[3.3.0]octan-5-yl)methylamine were reacted in the same manner as in Example 1 to obtain the titled compound in a yield of 51.5%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH:6]1[CH2:10][CH:9]=[CH:8][NH:7]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([N:7]1[CH2:8][CH:9]=[CH:10][NH:6]1)(=[O:4])=[O:3]
Reactant: C1=CNNC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CC=CN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
114.5 g of methanesulphonic acid chloride were added dropwise to 70 g of pyrazoline and 101 g of triethylamine in 300 ml of methylene chloride at room temperature. The mixture was subsequently stirred at room temperature for 3 hours and was filtered. The filtrate was washed with water, dried over sodium sulphate and concentrated. 114 g (77% of theory) of methanesulphonylpyrazoline of melting point 62° C. were obtained.
Reaction SMILES: C(OP(=O)(OCC)O[C:6]([CH3:26])([CH3:25])[C:7]#[C:8][C:9]1[CH:24]=[CH:23][C:12]2[C:13]([C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=3)=[N:14][S:15][C:11]=2[CH:10]=1)C.[CH2:31]([NH:33][CH2:34][CH2:35][OH:36])[CH3:32].C1COCC1.C([O-])(O)=O.[Na+]>CCOC(C)=O>[Br:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[C:12]3[CH:23]=[CH:24][C:9]([C:8]#[C:7][C:6]([N:33]([CH2:31][CH3:32])[CH2:34][CH2:35][OH:36])([CH3:25])[CH3:26])=[CH:10][C:11]=3[S:15][N:14]=2)=[CH:21][CH:20]=1
Reactant: CCOP(=O)(OCC)OC(C)(C)C#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: CCNCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN(CCO)C(C)(C)C#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Temperature: 50 °C

Procedure:
To 45 mg (0.09 mmol) Phosphoric acid 3-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-1,1-dimethyl-prop-2-ynyl ester diethyl ester and 16 μl (0.18 mmol) 2-Ethylaminoethanol in 0.5 ml THF 10.2 mg (0.01 mmol) tetrakis(triphenylphosphine)palladium was added and the suspension stirred at 50° C. over night. The mixture was added to a saturated aqueous solution of NaHCO3 and EtOAc, the phases were separated and the inorganic one was extracted with EtOAc. The combined organic phases were washed with brine and dried over Na2SO4. Column chromatography on silica gel with CH2Cl2:MeOH 95:5 gave 2-((3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6 yl]-1,1-dimethyl-prop-2-ynyl)-ethyl-amino)-ethanol as yellow semisolid, MS: 443 (MH+, 1Br).
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[CH:10][C:11]=2[CH3:13])[NH:6][C:5]=1[C:15]([O:17][CH3:18])=[O:16].C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27]>C1COCC1>[C:26]([O:1][N:2]=[CH:3][C:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[CH:10][C:11]=2[CH3:13])[NH:6][C:5]=1[C:15]([O:17][CH3:18])=[O:16])(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1[nH]c2c(C)ccc(C)c2c1C=NO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1[nH]c2c(C)ccc(C)c2c1C=NOC(C)=O
Temperature: 0 °C
Yield: 89.3 %

Procedure:
A solution of 0.8 g (3.3 mmol) of methyl 3-(hydroxyiminomethyl)-4,7-dimethylindole-2-carboxylate in 15 ml of anhydrous THF was cooled to 0° C., and then 0.5 ml (3.6 mmol) of triethylamine was added. While the reaction mixture was stirred at 0° C., a solution of 0.25 ml (3.6 mmol) of acetyl chloride in 5 ml of THF was added dropwise over a period of 15 minutes. The reaction mixture was stirred at room temperature for 1 hour and then poured into 100 ml of ice water. The crystals were separated by filtration and dried to provide 0.85 g of yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:20]=[C:21]([CH3:23])[CH:22]=2)[O:15][CH2:16][CH2:17][CH2:18][OH:19])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:20]=[C:21]([CH3:23])[CH:22]=2)[O:15][CH2:16][CH2:17][CH:18]=[O:19])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc(Br)c2)c1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2cccc(Br)c2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 68.1 %

Procedure:
To a cooled (0° C.), stirred solution of 914 mg (2.28 mmol) 3-[3-(3-bromophenylsulfonyloxy)-5-methylphenoxy]propanol, as prepared in the preceding step, 795 μL of N,N-diisopropylethylamine and 485 μL of anhydrous dimethyl sulfoxide in 15 mL of anhydrous dichloromethane was added 732 mg (4.60 mmol) of sulfur trioxide pyridine complex. The mixture was warmed to ambient temperature over 30 min and stirred for 3 h. The mixture was poured into 15 mL of dichloromethane and washed with 5% (w/v) aqueous citric acid (2×25 mL). Each wash was extracted with 5 mL of dichloromethane and the combined extracts were washed with brine (25 mL) and dried over Na2SO4 to give, after concentration, a white semisolid. This material was chromatographed on 80 g of silica gel with 3% ethyl acetate-dichloromethane to afford 620 mg (68%) of the title compound as a colorless oil: 1H-NMR (300 MHz; CDCl3) δ 9.84 (t, 1H, J=1.4 Hz), 8.01 (t, 1H, J=1.8 Hz), 7.79 (m, 2H), 7.43 (t, 1H, J=8.0 Hz), 6.64 (m, 1H), 6.44 (m, 1H), 6.37 (t, 1H, J=2.0 Hz), 4.20 (t, 2H, J=6.1 Hz), 2.87 (td, 2H, J=6.1, 1.4 Hz) and 2.26 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C16H15BrO5S: 423.0 (M+2+Na, 81Br ion). Found: 423.1.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][C:15]2[N:19]([CH3:20])[C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[N:16]=2)[C:8]=1[CH3:25].ClC1C=CC=C(C(OO)=[O:34])C=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14]([C:15]2[N:19]([CH3:20])[C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[N:16]=2)=[O:34])[C:8]=1[CH3:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCCCOc1ccnc(CSc2nc3ccccc3n2C)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3n2C)c1C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
0.25 g of 2-{4-(3-methoxypropoxy)-3-methylpyridine-2-yl}methylthio-1-methylbenzimidazole was dissolved in 20 ml of dichloromethane to obtain a solution. 0.18 g of 80% m-chloroperbenzoic acid was added to the solution at -50° C. The obtained mixture was stirred for one hour, followed by the addition of 0.14 g of triethylamine and 20 ml of a saturated aqueous solution of sodium hydrogencarbonate. The obtained mixture was stirred at a room temperature for one hour. The dichloromethane layer was separated, washed with a saturated aqueous solution of sodium hydrogencarbonate twice, dried over magnesium sulfate and filtered. The filtrate was concentrated to obtain a residue. This residue was purified by silica gel column chromatography to obtain 0.12 g of the title compound as a pale yellow crystal.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([P:15](=O)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)([O:3][CH3:4])=[O:2].C(N(CC)CC)C.Cl[SiH](Cl)Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:11]([C:9]1[CH:8]=[C:7]([P:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=[C:5]([C:1]([O:3][CH3:4])=[O:2])[CH:10]=1)([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(C(=O)OC)cc(P(=O)(c2ccccc2)c2ccccc2)c1
Agent: Cl[SiH](Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C(=O)OC)cc(P(c2ccccc2)c2ccccc2)c1

Procedure:
To a mixture of 17.0 g (4.31×10-2 mol) of 3,5-dicarbomethoxyphenyldiphenylphosphine oxide (from Preparation 3), 4.71 g (4.65×10-2 mol) of triethylamine and 196 ml of dry toluene under nitrogen was added 6.76 g (4.74×10-2 mol) of trichlorosilane. The mixture was then heated at reflux for 15.25 hr and cooled. A solution of 20% sodium hydroxide (49 ml) was added and the mixture was stirred. The organic layer was separated, washed with two 250 ml portions of water, dried over MgSO4 and concentrated to an oil which crystallized. The solid was recrystallized twice from methanol and dried. The yield of 3,5-dicarbomethoxyphenyldiphenylphosphine was 14.0 g (85.8% of theory); mp=103-4.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:9]/[C:10](/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[C:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)([OH:30])=[O:29].O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.Cl[Pd]Cl.[Fe+2]>[OH:12]/[N:11]=[C:10](/[C:13]1[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1)\[CH2:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([C:28]([OH:30])=[O:29])[CH:32]=2)=[CH:3][CH:4]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27]
Reactant: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(-c2cccc(C(=O)O)c2)cc1

Procedure:
In analogy to example 166, step 1, 5-{3-(4-bromo-phenyl)-1-[(E)-hydroxyimino]-3-o-tolyl-propyl}-1-methyl-1H-pyridin-2-one (example 162, step 4) was reacted with 3-carboxyphenylboronic acid in the presence of dichloro(1,1′-bis(diphenylphosphino)ferrocene)-palladium(II) dichloromethane adduct in a mixture of 1,4-dioxane, water and 2 M aqueous sodium carbonate solution to give the title compound as a light yellow foam, MS (ESI−): m/z=465.1 [M−H]−.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:18])([F:17])[CH:14]([F:16])[F:15])=[CH:8][N:7]=1.S(=O)(=O)(O)[OH:20]>O>[F:17][C:13]([F:18])([O:12][C:9]1[CH:10]=[CH:11][C:6]([OH:20])=[N:7][CH:8]=1)[CH:14]([F:16])[F:15]
Reactant: O=S(=O)(O)O
Reactant: Nc1ccc(OC(F)(F)C(F)F)cn1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(OC(F)(F)C(F)F)cn1
Reaction time: 3 h

Procedure:
A solution of 10.3 g (149 mmol) of sodium nitrite in 16.5 ml of water was added dropwise with stirring to a solution of 23 g (109 mmol) of 2-amino-5-(1,1,2,2-tetrafluoroethoxy)pyridine in 103 ml of water and 21.9 g of concentrated sulfuric acid at 0° C. The mixture was stirred for 3 hours at 20°-25° C., and the colorless solid was filtered off under suction and washed with water until free of acid.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[NH:6][CH:7]=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11]CC)=O)([O-:3])=[O:2].C1(OC2C=CC=CC=2)C=CC=CC=1>C(OCC)C>[CH2:17]([O:16][C:14]([CH:8]1[C:9](=[O:11])[C:19]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:22]=[CH:21][CH:20]=2)[N:6]=[CH:7]1)=[O:15])[CH3:18]
Reactant: CCOC(=O)C(=CNc1ccccc1[N+](=O)[O-])C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Product: CCOC(=O)C1C=Nc2c(cccc2[N+](=O)[O-])C1=O
Temperature: 25 °C
Yield: 85 %

Procedure:
Diethyl (2-nitroanilino)methylenemalonate (43 g) was added to refluxing diphenyl ether (600 ml). The mixture was stirred at reflux for 1.5 hours, then cooled to ambient temperature. Diethyl ether (600 ml) was added and the mixture filtered. The solid so obtained was washed with diethyl ether to give 3-ethoxycarbonyl-8-nitro-4-oxo-3,4-dihydroquinoline in 85% yield, mp 241-243° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:34][C:35]1([C:41]([OH:43])=[O:42])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[F:32][C:2]([F:1])([F:33])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:38]4[CH2:39][CH2:40][C:35]([CH3:34])([C:41]([OH:43])=[O:42])[CH2:36][CH2:37]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CC1(C(=O)O)CCNCC1
Product: CC1(C(=O)O)CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC1

Procedure:
1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-4-methyl-piperidine-4-carboxylic acid was prepared from 5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 4-methyl-piperidine-4-carboxylic acid following General Procedure C.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C@@H:11]2[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]3[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=3)=[O:17])[CH2:12]2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH3:32][C:33]([O:36][C:37]([NH:39][C:40](=[N:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[NH:41][C:42]1[CH:50]=[CH:49][C:45]([C:46](O)=[O:47])=[CH:44][CH:43]=1)=[O:38])([CH3:35])[CH3:34]>>[CH3:58][C:55]([O:54][C:52]([NH:51][C:40](=[N:39][C:37]([O:36][C:33]([CH3:35])([CH3:34])[CH3:32])=[O:38])[NH:41][C:42]1[CH:50]=[CH:49][C:45]([C:46]([N:14]2[CH2:15][C@@H:11]([N:8]3[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]3)[CH2:12][C@H:13]2[C:16]([NH:18][C:19]2[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])=[CH:21][CH:20]=2)=[O:17])=[O:47])=[CH:44][CH:43]=1)=[O:53])([CH3:56])[CH3:57]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)[C@@H]2C[C@H](N3CCN(S(C)(=O)=O)CC3)CN2)cc1
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc(C(=O)N2C[C@@H](N3CCN(S(C)(=O)=O)CC3)C[C@H]2C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)cc1

Procedure:
Following the procedure described in Example 8, the compound prepared in Example 6 was treated with the compound prepared in Example 10 to give the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:15]([CH3:16])[N:14]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]=1[C:23]1[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH:24]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>C(O)C.O>[C:1]([O:5][CH:6]([C:11]1[N:15]([CH3:16])[N:14]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]=1[C:23]1[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH:24]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C2=CCC(C)(C)CC2)c(-c2ccccc2)nn1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1nc(-c2ccccc2)c(C2=CCC(C)(C)CC2)c1C(OC(C)(C)C)C(=O)O
Yield: 86.2 %

Procedure:
A mixture of methyl 2-(tert-butoxy)-2-[4-(4,4-dimethylcyclohex-1-en-1-yl)-1-methyl-3-phenyl-1H-pyrazol-5-yl]acetate (1f) (121 mg, 0.29 mmol) and potassium hydroxide (144 mg, 1.18 mmol) in a mixture of ethanol (1.5 mL) and water (1.5 mL) was refluxed for 6 hours. The reaction mixture was concentrated in vacuo. Water (2 mL) was added to the residue and the aqueous layer was washed with diethyl ether (2×2 mL), acidified with concentrated hydrochloric acid until pH 2 and extracted with diethyl ether (2×3 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide 2-(tert-butoxy)-2-[4-(4,4-dimethylcyclohex-1-en-1-yl)-1-methyl-3-phenyl-1H-pyrazol-5-yl]acetic acid (example 1) (101 mg, 0.25 mmol, 86%).