Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:18]([F:21])([F:20])[F:19])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=2I)=[O:5])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]([C:29]#[CH:30])[CH:26]=[CH:27][CH:28]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:18]([F:21])([F:20])[F:19])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=2[C:30]#[C:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([F:22])[CH:24]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(I)c2OC1C(F)(F)F
Reactant: C#Cc1cccc(F)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C1=Cc2cc(Cl)cc(C#Cc3cccc(F)c3)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
To 0.502 g (1.161 mmole) of ethyl-6-chloro-8-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate was added 67 mg (0.060 mmole) tetrakis(triphenylphosphine)palladium(0), 22 mg (0.116 mmole) copper (I) iodide, 10 mL degassed toluene, 0.484 mL (3.48 mmole) degassed TEA, and 0.199 mL (1.74 mmole) 3-fluorophenylacetylene. The mixture was stirred overnight at room temperature. The mixture was concd and the resulting oil was purified using reverse phase chromatography to afford 0.440 g (89%) of a crystalline solid: 1H NMR (CDCl3/400 MHz) 1.35 (t,3H, J=6.8 Hz), 4.28-4.37 (m, 2H), 5.83 (q, 1H, J=6.8 Hz), 7.04-7.09 (m, 1H), 7.18 (d, 1H, J=2.4 Hz), 7.20-7.23 (m, 1H), 7.30-7.33 (m, 2H), 7.44 (d, 1H, J=2.8 Hz), 7.63 (s, 1H); MS (ES+) 425 (M+1, 100).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC(=O)[N:14]([CH2:21][CH2:22][O:23][C:24]1[CH:29]=[C:28]([C:30](=[O:46])[N:31]([CH:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)[CH2:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH:27]=[C:26]([Cl:47])[CH:25]=1)[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:47][C:26]1[CH:27]=[C:28]([CH:29]=[C:24]([O:23][CH2:22][CH2:21][NH:14][C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)[CH:25]=1)[C:30]([N:31]([CH:41]1[CH2:42][CH2:43][CH2:44][CH2:45]1)[CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)=[O:46]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCN2CCOCC2)C2CCCC2)c1)c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc(Cl)cc(OCCNc2ccncc2)c1)N(CCCN1CCOCC1)C1CCCC1
Reaction time: 2 h
Yield: 111.1 %

Procedure:
A solution of (2-{3-chloro-5-[cyclopentyl-(3-morpholin-4-yl-propyl)-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester trifluoroacetate (0.060 g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 2 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.034 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][N:15]=[CH:14]2.S(OC)(O[CH3:22])(=O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[C:13](=[CH:14][N:15]([CH3:22])[N:16]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: COS(=O)(=O)OC
Reactant: Clc1ccc(-c2cccc3cn[nH]c23)c(Cl)c1
Solvent: Cc1ccccc1
Product: Cn1cc2cccc(-c3ccc(Cl)cc3Cl)c2n1
Temperature: 2.5 °C

Procedure:
A solution of 7-(2,4-dichloro-phenyl)-1H-indazole (4; 1.12 g, 4.27 mmol) and dimethyl sulfate (0.405 mL, 4.28 mmol) in 15 mL of toluene was stirred at 110° C. for 17 h, allowed to cool, then chilled at 0-5° C. The mixture was carefully washed with 15 mL of a saturated aqueous NaHCO3 solution, dried over MgSO4, filtered (rinsing with diethyl ether), and concentrated to an orange oil Column chromatography (0→33% EtOAc/hexanes) afforded 7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole as a viscous yellow oil (5; 0.92 g, 78%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1Br.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:10][O:11][C:12]1[C:13]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccccc1B(O)O
Reactant: Fc1cccc(F)c1Br
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1-c1c(F)cccc1F
Yield: 45.3 %

Procedure:
Treatment of 2,6-difluorobromobenzene (8.9 g, 46.1 mmol) with 2-methoxybenzeneboronic acid (10.51 g, 69.2 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (1.81 g, 2.3 mmol), and potassium carbonate (15.9 g, 115.3 mmol) generally according to the procedure described for Intermediate 37 provided 4.6 g (45%) of 2′,6′-difluoro-1,1′-biphenyl-2-yl methyl ether. To a solution of 2′,6′-difluoro-1,1′-biphenyl-2-yl methyl ether (4.5 g, 20.4 mmol) in dichloromethane (100 mL) cooled to −78° C. was added boron tribromide (5.11 g, 1.0 M in dichloromethane) and the reaction mixture was allowed to stir for 30 min. The reaction mixture was allowed to warn to room temperature and was quenched by the addition of ice (150 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (500 mL). The combined organic layers were washed with water (400 mL), saturated aqueous sodium chloride (100 mL), dried (magnesium sulfate), and the solvent removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, hexanes:ethyl acetate 95:5) provided 3.95 g (94%) of 2′,6′-difluoro-1,1′-biphenyl-2-ol as a colorless oil. Anal. calcd. for C12H8F2O: C, 69.9; H, 3.91. Found: C, 68.51; H, 4.06.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=2)[CH3:10])[N:3]=1.[Cl-].[NH4+].[In]>C(O)C.O>[Cl:1][C:2]1[N:3]=[C:4]([O:8][C@@H:9]([C:11]2[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=2)[NH2:17])[CH3:10])[CH:5]=[N:6][CH:7]=1
Reactant: C[C@@H](Oc1cncc(Cl)n1)c1cccc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [In]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: C[C@@H](Oc1cncc(Cl)n1)c1cccc(N)c1
Temperature: 25 °C
Yield: 74.5 %

Procedure:
To a solution of (R)-2-chloro-6-(1-(3-nitrophenyl)ethoxy)pyrazine (240 mg, 0.86 mmol) in ethanol (12 mL) was added a solution of ammonium chloride (460 mg, 8.6 mmol) in water (6 mL), then indium powder (394 mg, mesh 100, 3.4 mmol). The mixture was heated at reflux for 20 hours, was allowed to cool to room temperature and was filtered through Celite. The filter cake was washed with ethanol and the combined filtrates were concentrated under reduced pressure. The residue was dissolved in ethyl acetate (25 mL) and was washed with water (15 mL), brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure to give (R)-3-(1-(6-chloropyrazin-2-yloxy)ethyl)aniline as a dark yellow liquid (160 mg).
Reaction SMILES: [CH2:1]1[CH:8]2[C:4]3([C:10]([NH:12][C:13]4[S:21][C:16]5[CH2:17][O:18][CH2:19][CH2:20][C:15]=5[C:14]=4[C:22](O)=[O:23])=[O:11])[CH2:5][CH:6]([CH2:9][CH:2]1[CH2:3]3)[CH2:7]2.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[N:25]1([C:22]([C:14]2[C:15]3[CH2:20][CH2:19][O:18][CH2:17][C:16]=3[S:21][C:13]=2[NH:12][C:10]([C:4]23[CH2:5][CH:6]4[CH2:9][CH:2]([CH2:1][CH:8]2[CH2:7]4)[CH2:3]3)=[O:11])=[O:23])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: O=C(O)c1c(NC(=O)C23CC4CC(CC2C4)C3)sc2c1CCOC2
Reactant: C1COCCN1
Product: O=C(c1c(NC(=O)C23CC4CC(CC2C4)C3)sc2c1CCOC2)N1CCOCC1

Procedure:
The title compound was prepared from 2-[(hexahydro-2,5-methano-pentalene-3a-carbonyl)-amino]-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid (Example 167B) and morpholine according to the procedure described for Example 166C. 1H NMR (dimethylsulfoxide-d6) δ 1.58-1.62 (m, 4H), 1.75-1.81 (m, 2H), 1.88-1.97 (m, 4H), 2.29 (br s, 2H), 2.66 (t, J=7.0 Hz, 1H), 3.29-3.31 (m, 2H), 3.41 (br s, 4H), 3.71 (br s, 4H), 3.83 (t, J=5.6 Hz, 2H), 4.64 (br s, 2H), 9.74 (br s, 1H). MS (ESI+) m/z 417.2 (M+H)+. Anal. calcd. for C22H28N2O4S: C, 63.44; H, 6.78; N, 7.21. Found: C, 63.29; H, 6.77; N, 6.65.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6](=[O:13])[CH2:5][C:4](=O)[CH2:3]1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[SH:22]>CS(C)=O>[C:8]([CH:7]1[C:6](=[O:13])[C:5]2[S:22][C:17]3[C:16](=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:15][C:4]=2[CH2:3][CH:2]1[CH3:1])([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1C(=O)CC(=O)CC1C
Reactant: Nc1ccccc1S
Solvent: CS(C)=O
Product: CCOC(=O)C1C(=O)C2=C(CC1C)Nc1ccccc1S2

Procedure:
A mixture of ethyl 6-methyl-2,4-dioxocyclohexane-1-carboxylate, 7b (5.94 g, 30 mmole) and 2-aminothiophenol, 6 (X=H, 3.75 g, 30 mmole) in DMSO (10 mL) is placed in a preheated heating mantle. The reaction mixture is stirred and refluxed for 0.5 h. Upon cooling, the reaction mixture forms a solid. The crystals are filtered and the remaining mother liquid is poured into cold water, whereupon further precipitation occurs. Each precipitate is separately recrystallized twice from EtOH and proves to be identical. An analytical sample of 4b, (R=H), mp 201-202° C. occurs as light orange crystals; yield: 1.80 g (30.8%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[F:11].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl>[F:11][C:3]1[C:4]([N+:8]([O-:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[F:12]
Reactant: O=[N+]([O-])c1cccc(Br)c1F
Reactant: OB(O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cccc(-c2ccccc2F)c1F
Temperature: 100 °C

Procedure:
To a solution of 1-bromo-2-fluoro-3-nitrobenzene [58534-94-4] (150 mg, 0.68 mmol) and 2-fluorophenylboronic acid [1193-03-9] (191 mg, 1.36 mmol) in dioxane (4 mL) and water (1 mL) was added potassium carbonate (236 mg, 1.70 mmol) and Pd(dppf)Cl2CH2Cl2 adduct (55.7 mg, 0.068 mmol). The solution was heated for 30 min at 100° C. under microwave irradiation. The reaction mixture was diluted with CH2Cl2 and the resulting solution was washed successively with saturated aqueous NaHCO3 solution, 1N HCl solution and brine, then dried (Phase separator) and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 20-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA) to give after lyophilization of the purified fractions the title compound. MS (LC-MS): 236 [M+H]+; tR (HPLC conditions k): 3.81 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH:21]=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:31]CC)(=O)[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:28]([O:27][C:25]([C:24]1[C:23](=[O:31])[N:14]([CH:11]2[CH2:10][CH2:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:13][CH2:12]2)[C:15]2[C:16]([CH:21]=1)=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:26])[CH3:29]
Reactant: O=Cc1ccccc1NC1CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2ccccc2n(C2CCN(Cc3ccccc3)CC2)c1=O
Yield: 64.1 %

Procedure:
A mixture of N-(1-benzyl-4-piperidinyl)-o-formylaniline (32.0 g), diethyl malonate (35.4 g), piperidine (5 ml), acetic acid (2.5 ml), anhydrous toluene (320 ml) and molecular sieves (32 g) is refluxed for 8 hours. After concentrating the reaction mixture, dichloromethane is added to the residue and the mixture is filtered. Water is added to the filtrate and the mixture is extracted with dichloromethane. After concentrating the extract, the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane/methanol=50/1) to give 3-ethoxycarbonyl-1-(1-benzyl-4-piperidinyl)carbostyril (27.2 g).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:26])=[CH:20][C:21](OCC)=[O:22])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>CCOCC>[CH:7]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]([CH3:26])=[CH:20][CH2:21][OH:22])=[CH:17][CH:18]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CCOC(=O)C=C(C)c1ccc(C2CCCCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(=CCO)c1ccc(C2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
To an ice-cooled slurry of LiAlH4 (3.8 g) in dry ether (200 ml) was added a solution of ethyl 3-(4′-cyclohexylphenyl)-but-2-enoate (3b, 12.7 g) in dry ether (50 ml) dropwise. The reaction mixture was stirred for 3 h at 0° C. The reaction mixture was quenched with water (20 ml). A solution of 10% NaOH (10 ml) was added and the ether layer was decanted. The precipitate was washed with ether and combined extracts were concentrated. The crude product was purified by column chromatography on silica gel as adsorbent and hexane/ethylacetate as eluant to furnish 9.5 g (88.7% yield) of 3-(4′-cyclohexylphenyl)-2-butenol (4b) m.p. 54-55° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.[F:17][C:18]([F:35])([F:34])[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]2[N:31]=[C:30]([CH:32]=[CH2:33])[N:29]=[CH:28][N:27]=2)=[CH:21][CH:20]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:7]1[C:8]2[C:4](=[CH:3][C:2](/[CH:33]=[CH:32]/[C:30]3[N:29]=[CH:28][N:27]=[C:26]([NH:25][C:22]4[CH:21]=[CH:20][C:19]([C:18]([F:34])([F:17])[F:35])=[CH:24][CH:23]=4)[N:31]=3)=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: Ic1ccc2c(cnn2C2CCCCO2)c1
Reactant: C=Cc1ncnc(Nc2ccc(C(F)(F)F)cc2)n1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: FC(F)(F)c1ccc(Nc2ncnc(/C=C/c3ccc4c(cnn4C4CCCCO4)c3)n2)cc1
Temperature: 90 °C
Yield: 56.4 %

Procedure:
To a stirred solution of 5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.05 g, 0.152 mmol) in ACN (5 mL) were added N-(4-(trifluoromethyl)phenyl)-4-vinyl-1,3,5-triazin-2-amine (0.041 g, 0.152 mmol), tri-o-tolylphosphine (0.019 g, 0.061 mmol) and triethylamine (0.064 mL, 0.457 mmol). Nitrogen was purged for 5 minutes. Tris(dibenzylideneacetone)dipalladium(0) (0.014 g, 0.015 mmol) was added and the reaction mixture was heated at 90° C. overnight. The reaction mixture was filtered through a pad of celite, washed with ethyl acetate, and the organic layer was concentrated. The crude product was purified by flash chromatography on silica gel using 25% ethyl acetate in hexane to give (E)-4-(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)vinyl)-N-(4-(trifluoromethyl)phenyl)-1,3,5-triazin-2-amine as a pale yellow solid (0.04 g, 42% yield). LCMS: R.T.=1.21 min; [M+H]+=467.33.
Reaction SMILES: C(O)(=O)CCC(O)=O.C([O-])(=O)C([O-])=O.[Na+].[Na+].C([O-])(=O)C1C=CC=CC=1.[Na+].[CH:27]1[CH:28]=[CH:29][C:30]([S:50]([OH:53])(=[O:52])=[O:51])=[C:31](/[C:33](/[C:42]2[CH:43]=[CH:44][C:45]([OH:49])=[C:46]([OH:48])[CH:47]=2)=[C:34]2\[CH:35]=[CH:36][C:37]([C:39]([OH:41])=[CH:40]\2)=[O:38])[CH:32]=1.[O-][Mo:55]([O-])(=O)=O.[Na+].[Na+].Cl>O>[CH:27]1[CH:28]=[CH:29][C:30]([S:50]([OH:53])(=[O:51])=[O:52])=[C:31](/[C:33](/[C:34]2[CH:35]=[CH:36][C:37]([OH:38])=[C:39]([OH:41])[CH:40]=2)=[C:42]2\[CH:43]=[CH:44][C:45]([C:46]([OH:48])=[CH:47]\2)=[O:49])[CH:32]=1.[Mo:55]
Reactant: O=[Mo](=O)([O-])[O-]
Agent: Cl
Agent: O=C(O)CCC(=O)O
Agent: O=C([O-])C(=O)[O-]
Solvent: O
Product: [Mo]
Reaction time: 8 h

Procedure:
In 940 ml of ultra pure water, 5.9 g succinic acid, 0.14 g sodium oxalate and 0.5 g sodium benzoate was dissolved. Pyrocatechol violet solution (100 mg dissolved in 40 ml methanol) was added followed by the addition of 16 ml sodium molybdate solution (120 mg dissolved in 50 ml ultrapure water). The pH was adjusted to 2.5 using 50% v/v HCl solution followed by the addition of 2 g polyvinyl alcohol (30-70 kD) and 1 g polyvinyl pyrrolidone (55 kD). The solution was stirred overnight at about 20° C. to about 25° C., e.g. room temperature.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][CH3:11].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].[NH4+].[Cl-]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:10]([C:3]1[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11]
Reactant: OB(O)c1ccccc1
Reactant: CCc1cc(C#N)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCc1cc(C#N)ccc1-c1ccccc1
Temperature: 120 °C

Procedure:
A mixture of 4-bromo-3-ethyl benzonitrile (1 g, 4.76 mmol), phenylboronic acid (1.16 g, 9.5 mmol), K2CO3 (1.97 g, 14.3 mmol), and Pd(PPh3)4 (543 mg, 0.48 mmol) in DMF (anhydrous, 15 mL) is heated in a sealed tube at 120° C. for 12 h. After cooling to room temperature, the reaction mixture is poured into a mixture of ice and saturated aqueous NH4Cl. The mixture is extracted with EtOAc (3×30 mL). The combined organic layers are washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated. The crude product obtained is purified by silica gel chromatography (5% EtOAc in hexanes) to give 2-ethyl-biphenyl-4-carbonitrile as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:32]([OH:34])=O)=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:35]([O:42][CH2:43][CH2:44][NH:45][CH:46]([CH3:48])[CH3:47])([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].[Si](OCCN(C(C)C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2(C3C=C(Cl)C=CC=3Cl)CCCC2)N=1)=O)(C(C)(C)C)(C)C>>[Si:35]([O:42][CH2:43][CH2:44][N:45]([CH:46]([CH3:48])[CH3:47])[C:32]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:26][CH:27]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)[N:11]=1)=[O:34])([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]
Reactant: O=C(O)c1nc(CC2(c3ccc(C(F)(F)F)cc3)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Agent: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3cc(Cl)ccc3Cl)CCCC2)nc(O)c1OCc1ccccc1
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccc(C(F)(F)F)cc3)CCCC2)nc(O)c1OCc1ccccc1
Yield: 52.55 %

Procedure:
5-Benzyloxy-6-hydroxy-2-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (245) (187 mg, 52.55%) as a yellow sticky solid was synthesized from 5-benzyloxy-6-hydroxy-2-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-pyrimidine-4-carboxylic acid (244) (250 mg, 0.53 mmol) and 2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamine (8b) following the procedure as described for 5-benzyloxy-2-[1-(2,5-dichlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]isopropylamide (206).
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11](F)[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH3:17].O>C1COCC1>[NH2:17][C:11]1[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([F:1])[CH:12]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Reactant: N
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc([N+](=O)[O-])c(N)cc1F

Procedure:
A mixture of ethyl 2,4-difluoro-5-nitrobenzoate (5.00 g; 21.6 mmol) (see Example 59 (d)) in THF (100 mL) was treated with NH3 in THF (2.7 mL; 8 M; 21.6 mmol) at 0° C. and the mixture was stirred over night. Another portion of NH3 in THF (1.0 mL; 8M; 8 mmol) was added and the mixture stirred over night. Water (100 mL) was added and the mixture was concentrated. The precipitate was filtered off and dried to give the sub-title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=2)(=[O:23])=[O:22])[CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=1
Reactant: O=Cc1c[nH]c(-c2ccccc2F)c1
Reactant: O=S(=O)(Cl)c1ccccn1
Product: O=Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2ccccn2)c1

Procedure:
By a similar reaction as in Reference Example 65 and using 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (190 mg) and pyridine-2-sulfonyl chloride (231 mg), the title compound was obtained as a pale-red solid (yield 183 mg, 55%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].BrC1C=CC(F)=CC=1[CH2:22][O:23][CH2:24]OC>>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][C:3]=1[CH2:4][O:5][CH2:22][O:23][CH3:24]
Reactant: COCOCc1cc(F)ccc1Br
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Product: COCOCc1cc(C(F)(F)F)ccc1Br

Procedure:
This compound was made from 2-bromo-5-trifluoromethylbenzaldehyde in the same manner as compound 5b and used for the next step without purification.