Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][C:5]([CH:6]=O)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([NH:21][C:22](=[O:26])[CH2:23][C:24]#[N:25])[CH:18]=[CH:19][CH:20]=1>>[Cl:14][C:15]1[CH:16]=[C:17]([NH:21][C:22](=[O:26])[C:23]([C:24]#[N:25])=[CH:6][C:5]2[CH:8]=[C:9]([OH:10])[C:2]([OH:1])=[CH:3][C:4]=2[N+:11]([O-:13])=[O:12])[CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1cc(O)c(O)cc1[N+](=O)[O-]
Reactant: N#CCC(=O)Nc1cccc(Cl)c1
Product: N#CC(=Cc1cc(O)c(O)cc1[N+](=O)[O-])C(=O)Nc1cccc(Cl)c1
Yield: 27.5 %

Procedure:
The reaction of 4, 5-dihydroxy-2-nitrobenzaldehyde (185 mg, 1.01 mmol) and N-(3-chlorophenyl) cyanoacetamide (197 mg, 1.01 mmol) was effected in the same manner as in Example 1 to give the objective N-(3-chlorophenyl)-2-cyano-3-(4, 5-dihydroxy-2-nitrophenyl)propenamide (100 mg, 28% in yield) as brown powdery crystals.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:12]1[CH:17]=[CH:16][C:15](/[C:18](/[C:35]2[CH:40]=[CH:39][C:38]([S:41][C:42]([F:45])([F:44])[F:43])=[CH:37][CH:36]=2)=[CH:19]\[CH2:20][O:21][C:22]2[CH:33]=[CH:32][C:25]([O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:24]([CH3:34])[CH:23]=2)=[CH:14][CH:13]=1.C(NC(C)C)(C)C>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:10][CH:7]1[CH2:8][CH2:9][N:4]([CH2:1][C:2]#[C:3][C:12]2[CH:13]=[CH:14][C:15](/[C:18](/[C:35]3[CH:36]=[CH:37][C:38]([S:41][C:42]([F:44])([F:43])[F:45])=[CH:39][CH:40]=3)=[CH:19]\[CH2:20][O:21][C:22]3[CH:33]=[CH:32][C:25]([O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:24]([CH3:34])[CH:23]=3)=[CH:16][CH:17]=2)[CH2:5][CH2:6]1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(SC(F)(F)F)cc2)cc1C
Reactant: C#CCN1CCC(O)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCC(O)CC3)cc2)c2ccc(SC(F)(F)F)cc2)cc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1-Propargylpiperidin-4-ol (154 mg, 1.10 mmol) was added to a solution of methyl (Z)-[4-[3-(4-iodophenyl)-3-[4-(trifluoromethyl-sulfanyl)phenyl]allyloxy]-2-methylphenoxy]-acetate (340 mg, 0.553 mmol; prepared as described in example 56) and diisopropylamine (0.35 mL, 2.49 mmol) in tetrahydrofuran (9 mL). The mixture was degassed and copper(I) iodide (8.4 mg, 0.044 mmol) and bis(triphenylphosphine)palladium(II) dichloride (19.3 mg, 0.027 mmol) were added. The reaction mixture was stirred under argon at ambient temperature for 20 h, filtered and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, chloroform/methanol 97:3) yielding methyl (E)-[4-[3-[4-[3-(4-hydroxypiperidin-1-yl)propynyl]phenyl]-3-[4-(trifluoromethylsulfanyl)phenyl]-allyloxy]-2-methylphenoxy]acetate.
Reaction SMILES: [CH:1]1([S:5](Cl)(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.[F:9][C:10]1[C:15]([F:16])=[C:14]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=2[F:25])[C:13]([NH2:26])=[C:12]([O:27][CH3:28])[CH:11]=1>>[F:16][C:15]1[C:14]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=2[F:25])=[C:13]([NH:26][S:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:7])=[O:6])[C:12]([O:27][CH3:28])=[CH:11][C:10]=1[F:9]
Reactant: COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1N
Reactant: O=S(=O)(Cl)C1CCC1
Product: COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1NS(=O)(=O)C1CCC1
Yield: 75 %

Procedure:
According to the general procedure B, the cyclobutylsulfonyl chloride prepared in the step above was reacted with 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)-3-methoxy-benzene-1,2-diamine to obtain the title product. Yield: 75%. 1H-NMR (300 MHz, CDCl3): δ=7.44 (s, 1H, br), 7.41-7.36 (dd, 1H), 7.24-7.23 (m, 1H), 6.54-6.38 (m, 2H), 5.90 (s, 1H, br), 3.85-3.75 (m, 5H), 2.60-2.40 (m, 2H), 2.25-2.15 (m, 1H), 2.15-1.95 (m, 2H); m/z=511 [M−1]−.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14](O)[CH3:15])=[CH:10][CH:9]=1)=[O:7].S(Cl)([Cl:19])=O>C1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]([Cl:19])[CH3:15])=[CH:10][CH:9]=1)=[O:7]
Reactant: CC(O)c1ccc(C(=O)c2cccs2)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(Cl)c1ccc(C(=O)c2cccs2)cc1
Reaction time: 8 h

Procedure:
To a stirred and cooled solution of 43.7 parts of p-(1-hydroxyethyl)phenyl 2-thienyl ketone in 180 parts of dry benzene are added dropwise 16 parts of thionyl chloride. Upon completion, stirring is continued overnight at room temperature. The reaction mixture is evaporated. The residue is taken up in toluene and the latter is evaporated once more. The latter residue is distilled and the distillate is crystallized from ethanol at room temperature, yielding p-(1-chloroethyl)phenyl 2-thienyl ketone; mp. 60° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:14]2[N:15]=[C:16]([O:19][CH2:20][CH2:21][CH2:22][S:23](=[N:26]C#N)([CH3:25])=[O:24])[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1.S(=O)(=O)(O)O.[OH-].[Na+]>O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:14]2[N:15]=[C:16]([O:19][CH2:20][CH2:21][CH2:22][S:23]([CH3:25])(=[NH:26])=[O:24])[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1
Reactant: CS(=O)(CCCOc1ccc2ncc(-c3cc4ccccc4o3)n2n1)=NC#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=N)(=O)CCCOc1ccc2ncc(-c3cc4ccccc4o3)n2n1
Temperature: 140 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
To 780 mg (1.97 mmol) [(3-{[3-(1-benzofuran-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}propyl)(methyl)oxido-lambda6-sulfanylidene]cyanamide were added 20 mL 50% aqueous sulfuric acid. It was stirred 2 hours at 140° C. bath temperature. The reaction was allowed to reach room temperature. The sulfuric acid was diluted with 20 mL water and the pH was adjusted to 12 with 50% aqueous sodium hydroxide on an ice bath. The aqueous phase was extracted with 30 mL dichloromethane. During the second extraction water had to be added to separate the layers. The first organic phase was combined with the reaction mixture and vigorously shaken. The layers were separated and the aqueous phase was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated yielding 530 mg (72%) of a yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Br:12].[CH2:13]([O:20]CC1C=CC=CC=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na]>O1CCCC1>[CH2:13]([O:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Br:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCCCCCCCCCCBr
Reactant: c1ccc(COCc2ccccc2)cc1
Agent: [Na]
Solvent: C1CCOC1
Product: BrCCCCCCCCCCOCc1ccccc1

Procedure:
10-Benzyloxydecanyl bromide was prepared by reacting 100 g of 1,10-dibromodecane with an equimolar amount of sodium benzyloxide in tetrahydrofuran under reflux conditions, filtering the precipitated material, concentrating the filtrate and distilling the concentrated filtrate under reduced pressure. Yield 46 g. B.P. 185° to 189° C./3 mmHg.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10](=[O:25])/[C:11](/[C:15]2[N:16]=[C:17]([N:20]=CN(C)C)[S:18][CH:19]=2)=[N:12]\[O:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(=O)([O-])O.[Na+].C(OCC)(=O)C>CO>[C:1]1([CH2:7][CH2:8][NH:9][C:10](=[O:25])/[C:11](/[C:15]2[N:16]=[C:17]([NH2:20])[S:18][CH:19]=2)=[N:12]\[O:13][CH3:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CO/N=C(\C(=O)NCCc1ccccc1)c1csc(N=CN(C)C)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CO/N=C(\C(=O)NCCc1ccccc1)c1csc(N)n1
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
(Z)-N-(2-Phenylethyl)-2-(2-dimethylaminomethylidenaminothiazol-4-yl)-2-methoxyiminoacetamide (130 mg, 0.36 mmol) was dissolved in 4 ml of methanol, followed by the addition of 1 ml of 2N hydrochloric acid. The mixture so obtained was stirred at 60 ml for 3 hours and 30 minutes. The reaction mixture was then added with 20 ml of a saturated aqueous solution of sodium hydrogencarbonate and 20 ml of ethyl acetate. The resulting mixture was then allowed to separate into an organic phase and an aqueous phase. The aqueous phase was further extracted twice with 10 ml portions of ethyl acetate. All the organic phases were combined, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, whereby 107 mg of the title compound were obtained (yield: 97.5%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=2)[N:3]=1.C(N(C(C)C)CC)(C)C.[F:30][C:31]([F:43])([F:42])[O:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]=[N:40][NH2:41])=[CH:35][CH:34]=1>O1CCOCC1>[Cl:8][C:6]1[N:7]=[C:2]([NH:41][N:40]=[CH:39][C:36]2[CH:35]=[CH:34][C:33]([O:32][C:31]([F:30])([F:43])[F:42])=[CH:38][CH:37]=2)[N:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=2)[N:5]=1
Reactant: NN=Cc1ccc(OC(F)(F)F)cc1
Reactant: Fc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1C(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(Nc2nc(Cl)nc(NN=Cc3ccc(OC(F)(F)F)cc3)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
4,6-Dichloro-N-(3-trifluoromethyl-4-fluorophenyl)-1,3,5-triazine-2-amine (XVII) (2.0 g, 6.2 mmol) was dissolved in dioxane (40 mL). Diisopropylethyl-amine (1.6 mL, 9.32 mmol) was added followed by [4-(trifluoromethoxy)-benzylidene]hydrazine (XX) (1.3 g, 6.2 mmol). The reaction was stirred at room temperature overnight. The solvent was removed under vacuum, and the residue diluted with ethyl ether (25 mL). The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to a yellow powder. This powder was washed with acetonitrile to give {4-chloro-6-[N′-(4-trifluoromethoxy-benzylidene)hydrazino]-1,3,5-triazin-2-yl}-(4-fluoro-3-trifluoromethylphenyl)-amine (XXI) as a white solid; (2.1 g, 67% yield): m.p. 109-111° C.; 1H NMR (CDCl3): δ 8.9, (bs, 1H); 8.5 (bs, 1H); 7.95 (s, 1H); 7.75 (bs, 2H); 7.45 (bs, 1H); 7.24 (m, 4H); ESI/MS 494 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:37][CH3:38])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=4)[CH2:17][CH:16]3[CH2:34][OH:35])=[O:14])=[CH:8][C:7]=2[CH:36]=1.[H-].[Na+].[CH2:41](I)[CH3:42]>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([O:37][CH3:38])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:23]=[C:24]([O:32][CH3:33])[C:25]([O:30][CH3:31])=[C:26]([O:28][CH3:29])[CH:27]=4)[CH2:17][CH:16]3[CH2:34][O:35][CH2:41][CH3:42])=[O:14])=[CH:8][C:7]=2[CH:36]=1
Reactant: CCI
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)N1CCN(Cc3cc(OC)c(OC)c(OC)c3)CC1CO)=C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCC1CN(Cc2cc(OC)c(OC)c(OC)c2)CCN1C(=O)C1=Cc2cc(OC)c(OC)cc2CCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -4-(3,4,5-trimethoxybenzyl)piperazine-2-methanol (500 mg) obtained by the method in Working Example 19 and N,N-dimethylformamide (3 ml) is cooled to 0° C., to which is added, in limited amounts, 60% oily sodium hydride (80 mg). The reaction mixture is stirred for 30 minutes and then cooled to -20° C., followed by adding thereto dropwise a mixture of ethyl iodide (200 mg) and N,N-dimethylformamide (1 ml). After stirring for 4 hours at -20° C., the reaction mixture is poured into ice-water, followed by extraction with methylene chloride. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by means of a silica gel column chromatography (eluent:ethyl acetate-hexane-methanol=50:45:5) to give 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -2-ethoxymethyl-4-(3,4,5trimethoxybenzyl)piperazine as a colorless oily product (420 mg). This product is dissolved in ethyl acetate and converted to its hydrochloride with 4N HCl (ethyl acetate solution). To the mixture is added ethyl ether, and left standing to give the hydrochloride as colorless crystals, m.p. 169-171° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH2:21][CH3:22])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[CH:4][CH:3]=1.C([Li])CCC.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:11]([CH2:21][CH3:22])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[CH:6][CH:7]=1
Reactant: CCn1cnc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1CC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-1-ethylimidazole (230 mg, 0.66 mmol) from Step A (higher Rf isomer) in THF (4 mL) cooled to −70° C. in a dry ice/acetone bath was added 1.6N n-butyl lithium in hexanes (0.500 mL, 0.80 mmol). The reaction was stirred for 1 hr and then ethyl chloroformate (0.130 mL, 1.3 mmol) was added via syringe. The reaction was allowed to warm to rt for 1 hr and was then quenched with aq. sodium bicarbonate and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by Prep TLC (3×1 mm, silica) (25% ethyl acetate in hexanes) to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]4[O:48][CH2:47][CH2:46][C:45]=4[CH:49]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH:50]=[O:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:52]=[O:53].[OH-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]4[O:48][CH2:47][CH2:46][C:45]=4[CH:49]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@:10]1([CH2:52][OH:53])[CH:50]=[O:51])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc4c(c3)CCO4)c2)O[C@H](C=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc4c(c3)CCO4)c2)O[C@@](C=O)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
(2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 51 (4.19 g, 5.9 mmol) was dissolved in 45 mL 1,4-dioxane, followed by addition of 9.6 mL 37% formaldehyde solution and dropwise addition of 17.82 mL 1 M sodium hydroxide solution. The reaction mixture was stirred for 16 hours at 70° C. Thereafter, the reaction mixture was concentrated under reduced pressure and partitioned after 100 mL ethyl acetate and 50 mL saturated sodium chloride solution were added. The aqueous phase was extracted with ethyl acetate (100 mL×2) and the organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 5j (4.36 g, pale yellow grease), which was used directly in the next step without purification.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[O:11]=[P:12](Cl)(Cl)Cl>BrCCBr.C1COCC1>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([P:12](=[O:11])([C:3]2[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=2)[C:3]2[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=2)=[CH:4][CH:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(Br)cc1
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COc1ccc(P(=O)(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Reaction time: 8 h
Yield: 89.1 %

Procedure:
A reaction flask under nitrogen containing magnesium turnings (223.9 g, 9.21 mol) and 1950 mL THF was charged with 1 drop of 1,2-dibromoethane and heated to reflux for 1 h. Heating was removed and p-bromoanisole (1683 g, 9.00 mol) was added dropwise at a rate to maintain reflux. After holding the reaction mixture overnight, POCl3 (460.0 g, 3.00 mol) was added slowly over 2 h at 50–79° C. and the resulting mixture was held overnight at 50° C. The product was isolated by aqueous workup to give 984.5 g of tris(4-methoxyphenyl)phosphine oxide (89.0% yield). Recrystallized analytical specimen (from ethyl acetate): mp 145.2° C. (DSC), lit. 143–144° C. (J. Org. Chem. 1960, 25, 2001).
Reaction SMILES: O[N:2]=[C:3]1[C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:6]=2[CH2:5][CH2:4]1.[OH-].[Na+]>CCO.O.[Ni]>[CH2:5]1[C:6]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[CH:3]([NH2:2])[CH2:4]1
Reactant: ON=C1CCc2c1[nH]c1ccccc21
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC1CCc2c1[nH]c1ccccc21
Yield: 90.1 %

Procedure:
To a stirred solution of 3-hydroxyimino-1,2,3,4-tetrahydrocyclopent[b]indole (6 g) in 150 ml of 95% EtOH at 0° C. was added a nickel alloy (Harshaw, Ni-1000P, 10 g) followed by 12.9 grams of sodium hydroxide in 150 ml water. The ice bath was removed after 0.5 hour and the mixture was stirred an additional hour and filtered. The EtOH was removed in vacuo and the product crystallized to provide 5.0 grams of solid. A sample was recrystallized from toluene to provide analytically pure material.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([C:17](O)=[O:18])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl.[CH3:21][O:22][C:23](=[O:43])[C@@H:24]([NH2:42])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:21][O:22][C:23](=[O:43])[CH:24]([NH:42][C:17]([C:11]1[CH:10]=[N:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]=1[C:13]([F:16])([F:14])[F:15])=[O:18])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:40])([F:39])[F:41])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1
Reactant: O=C(O)c1cnn(-c2ccc(F)cc2)c1C(F)(F)F
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)NC(=O)c1cnn(-c2ccc(F)cc2)c1C(F)(F)F
Yield: 47.2 %

Procedure:
A solution of 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (0.300 g, 1.097 mmol, prepared in example 635) in DMF (4.0 mL) was reacted with (2S)-amino-3-(4′-trifluoromethyl-biphenyl-4-yl)propionic acid methyl ester Hydrochloride (0.394 g, 1.097 mmol), HBTU (0.416 g, 1.097 mmol), and DIEA (0.585 mL, 3.29 mmol) as described in general procedure A. The crude compound was purified by washing with ethyl ether to give 0.300 g (47%) of 2-{[1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester. A solution of this ester (0.125 g, 0.215 mmol) in THF (4.0 mL) was treated with LiOH (0.031 g) by general procedure I to afford (0.105 g, 87%) the title compound 2-{[1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic acid as a white solid. LCMS: 565 (M+1)+. 1H NMR (DMSO-d6) 8.92 [d, 1H], 8.39 [s, 1H], 8.18 [d, 2H], 8.09 [d, 2H], 7.96 [d, 2H], 7.87 [m, 2H], 7.71 [m, 4H], 4.83 [m, 1H], 3.58 [m, 1H], 3.36 [m, 1H].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH2:4][N:5]([S:27](=[O:37])(=[O:36])[NH:28]C(OC(C)(C)C)=O)[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:12][C:11](=[O:24])[C:10]([O:25][CH3:26])=[CH:9]2>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3](=[O:38])[CH2:4][N:5]([S:27](=[O:37])(=[O:36])[NH2:28])[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:12][C:11](=[O:24])[C:10]([O:25][CH3:26])=[CH:9]2
Reactant: COC(=O)CN(c1cc2cc(OC)c(=O)oc2cc1OCc1ccccc1)S(=O)(=O)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CN(c1cc2cc(OC)c(=O)oc2cc1OCc1ccccc1)S(N)(=O)=O

Procedure:
A solution of N-(t-butoxycarbonylsulfamoyl)-N-(7-benzyloxy-3-methoxy-2-oxo-2H-chromen-6-yl)glycine methyl ester (0.550 g, 1 mmol) in 40 mL of CH2Cl2/TFA (3:1) is stirred for 40 min at ambient temperature. The solvent is removed under reduced pressure. Methylene chloride is added to the residue and the solvent removed under reduced pressure (4×). The residue is purified by flash chromatography using CH2Cl2/EtOAc (4:1) to afford N-sulfamoyl-N-(7-benzyloxy-3-methoxy-2-oxo-2H-chromen-6-yl)glycine methyl ester as a white solid: mp=178-179° C.; 1H NMR (DMSO-d6) δ 7.74 (s, 1H), 7.52-7.32 (m, 5H), 7.29 (s, 1H), 7.13 (s, 1H), 5.22 (s, 2H), 4.30 (s, 2H), 3.80 (s, 3H), 3.58 (s, 3H); (M−H)−=447.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[F:13].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH2:14]([O:12][C:9]1[C:10]2[C:5](=[CH:4][C:3]([F:13])=[C:2]([Cl:1])[CH:11]=2)[CH:6]=[CH:7][N:8]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=c1[nH]ccc2cc(F)c(Cl)cc12
Reactant: BrCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Fc1cc2ccnc(OCc3ccccc3)c2cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 54.2 %

Procedure:
14.7 g of 7-chloro-6-fluoro-2H-isoquinolin-1-one (7) were dissolved in 150 ml of toluene. After addition of 30.9 g of silver carbonate and 15.3 g of benzyl bromide, the mixture was stirred at 80° C. for 3 h. After cooling down to room temperature, the reaction mixture was filtered and the filtrate was evaporated. The residue was dissolved in dichloromethane and washed with water, dried with magnesium sulfate and evaporated. Final purification by preparative HPLC gave 11.6 g of the title compound. Rt=2.51 min (Method B). Detected mass: 288.1/290.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=2)[C:7]2[C:12]([C:13]=1[C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:10]([OH:18])=[CH:9][CH:8]=2)=[O:4].Cl[C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=1>>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:23][CH:24]=2)[C:7]2[C:12]([C:13]=1[C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:10]([O:18][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=1)=[CH:9][CH:8]=2)=[O:4]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: COC(=O)c1c(C(=O)OC)n(-c2ccc(OC(C)C)cc2)c2ccc(O)cc12
Product: COC(=O)c1c(C(=O)OC)n(-c2ccc(OC(C)C)cc2)c2ccc(Oc3ccc(C(F)(F)F)cn3)cc12

Procedure:
The sub-title compound was prepared in accordance with step (a) Example 18 from 5-hydroxyindole-1-(4-isopropoxyphenyl)-2,3-dicarboxylic acid dimethyl ester (104 mg, 0.27 mmol, see (a) above) and 2-chloro-5-trifluoromethylpyridine (74 mg, 0.41 mmol). Yield 100 mg (70%).