Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1I.[CH2:15]([Sn](CCCC)(CCCC)/C=C/C)[CH2:16][CH2:17]C>ClC(Cl)C.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>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1/[CH:15]=[CH:16]\[CH3:17]
Reactant: C/C=C/[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(Cl)Cl
Product: C/C=C\c1c(C(=O)OC)nc(Cl)c(F)c1N

Procedure:
Methyl 4-amino-6-chloro-5-fluoro-3-iodopicolinate (0.4 g, 1.210 mmol), (E)-tributyl(prop-1-en-1-yl)stannane (0.481 g, 1.452 mmol), and bis(triphenylphosphine)palladium(II) chloride (0.085 g, 0.121 mmol) in dichloroethane (2.42 mL) were irradiated at 120° C. for 30 min in a microwave reactor. Celite was then added to the reaction mixture and the solvent was removed under vacuum. The crude product was first purified by flash column chromatography (SiO2, hexane/EtOAc gradient) then by reverse phase HPLC to afford the title compound as an orange oil: 1H NMR (400 MHz, CDCl3) δ 6.39 (dq, J=11.1, 1.7 Hz, 1H), 6.07 (dq, J=11.2, 6.9 Hz, 1H), 4.64 (s, 2H), 3.89 (s, 3H), 1.55 (dd, J=6.9, 1.7 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −139.48; EIMS m/z 245 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][N:13]([CH3:28])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[C:23]([CH3:24])=[C:22]([CH:25]=O)[NH:21][C:20]=1[CH3:27])=[O:18]>>[CH3:12][N:13]([CH3:28])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[C:23]([CH3:24])=[C:22]([CH:25]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:21][C:20]=1[CH3:27])=[O:18]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN(C)C
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(C)c1C(=O)NCCN(C)C
Yield: 86.9 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (0.17 g, 0.8 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-dimethylaminoethyl)amide (0.2 g, prepared by method C) using method B to give 0.3 g (83%) of the title compound as a yellow solid.
Reaction SMILES: C([O:4][C@@H:5]1[CH2:9][C@@H:8]([CH2:10][O:11]C(=O)C)[CH2:7][C@H:6]1[N:15]1[C:19]2[CH:20]=[C:21]([Cl:25])[C:22]([Cl:24])=[CH:23][C:18]=2[N:17]=[C:16]1[Br:26])(=O)C.C(=O)([O-])[O-].[Na+].[Na+].C(O)C.CO>O.C(O)(=O)C>[Br:26][C:16]1[N:15]([C@@H:6]2[CH2:7][C@H:8]([CH2:10][OH:11])[CH2:9][C@H:5]2[OH:4])[C:19]2[CH:20]=[C:21]([Cl:25])[C:22]([Cl:24])=[CH:23][C:18]=2[N:17]=1
Reactant: CC(=O)OC[C@H]1C[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@H](OC(C)=O)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CO
Product: OC[C@@H]1C[C@@H](O)[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)C1
Reaction time: 2 h
Yield: 72 %

Procedure:
(±)-(1R*,2R*,4S*)-4-(Acetoxymethyl)-2-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-cyclopentyl acetate (2.75 g, 5.92 mmol) was added to a stirred mixture of sodium carbonate (0.63 g) in water (11 mL)-ethanol (55 mL)-methanol (55 mL). After 2 hours at ambient temperature, the pH was adjusted to 7 with glacial acetic acid. Volatiles were removed in vacuo and the residue triturated with water (30 mL) and filtered to give white solid. Recrystallization of the solid from 1:1 ethanol-methanol gave title compound as white powder (1.62 g, 72%), m.p. 218°-220° C.; 1H-NMR (DMSO-d6) δ: 8.18 (s, 1, benzimidazole H7), 7.97 (s, 1, benzimidazole H4), 5.20 (m, 1, OH), 4.95 (m, 1, OH), 4.80-4.60 (m, 2, OCH and NCH), 3.50-3.40 (m, 2, OCH2), 2.45-2.20 (m, 1, CH), 2.20-1.60 (m, 4,4CH); mass spectrum (CI): 379 (M+1).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]([C:15](O)=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH2:1]([NH:8][C:9]1[CH:10]=[CH:11][N:12]=[CH:13][C:14]=1[CH2:15][OH:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnccc1NCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1cnccc1NCc1ccccc1

Procedure:
Starting from 4-(benzylamino)nicotinic acid using 4 eq of LiAlH4 yielded the title compound. ESI-MS [M+H]+=215.1.
Reaction SMILES: Cl.[O:2]=[C:3]1[N:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH2:6][C:5]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:4]1.[Br:23][C:24]1[CH:29]=[C:28]([CH2:30]Br)[C:27]([Cl:32])=[CH:26][C:25]=1[Cl:33]>>[Br:23][C:24]1[C:25]([Cl:33])=[CH:26][C:27]([Cl:32])=[C:28]([CH:29]=1)[CH2:30][N:20]1[CH2:21][CH2:22][C:5]2([O:4][C:3](=[O:2])[N:7]([C:8]3[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=3)[CH2:6]2)[CH2:18][CH2:19]1
Reactant: Clc1cc(Cl)c(CBr)cc1Br
Reactant: COC(=O)c1ccc(N2CC3(CCNCC3)OC2=O)cc1
Agent: Cl
Product: COC(=O)c1ccc(N2CC3(CCN(Cc4cc(Br)c(Cl)cc4Cl)CC3)OC2=O)cc1

Procedure:
The title compound was prepared methyl 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoate hydrochloride salt (80 mg, 0.245 mmol; Example 1, Step 2) and 1-bromo-5-(bromomethyl)-2,4-dichlorobenzene (86 mg, 0.269 mmol) following essentially the same procedure described in Step 1 of Example 7-9. The title compound was obtained as an off-white solid (129 mg) and was used without further purification.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[C:5]([Si:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)Cl)([CH3:8])([CH3:7])[CH3:6].N1C=CN=C1>>[Si:9]([O:4][CH2:1][C:2]#[CH:3])([C:5]([CH3:8])([CH3:7])[CH3:6])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C#CCO
Agent: c1c[nH]cn1
Product: C#CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C

Procedure:
2.9 ml of 2-propyn-1-ol, 15.6 ml of tert-butyldiphenylchlorosilane and 4.1 g of imidazole were reacted in the manner described in Example 14c. Chromatography of the raw product on silica gel [Kieselgel 60 (0.063-0.200 mm)] with petroleum ether/diisopropylether (20:1) yielded 13.3 g of the title compound in the form of crystals melting at 55°-58° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][NH:12][CH3:13].N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]([CH3:13])[CH3:11])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CNC
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CN(C)C(=O)c1ccc(Cl)cc1

Procedure:
The procedure of Example 13 is followed, but the endcapper is 4-chloro-N,N-dimethylbenzamide (0.20 g, 1.09 mmol) to yield the amido-functionalized macromonomer. 4-Chloro-N,N-dimethylbenzamide is prepared by reacting 4-chlorobenzoyl chloride with dimethylamine in toluene with some pyridine (1 mol equivalent per acid chloride) to trap the HCl that is evolved. After aqueous extraction of the pyridinium salt and any excess starting materials, the product is crystallized from the toluene solution.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][C:35]=1[F:36])[NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH:13][C:14]1[CH:15]=[C:16]([CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1)=[O:12].FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][C:35]=1[F:36])[NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:15]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(NC(=O)CCCCCNc3ccc(F)c(F)c3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCCCCNc1ccc(F)c(F)c1)Nc1cccc(C2CCNCC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.9 %

Procedure:
Into a solution of tert-butyl 4-(3-{[6-(3,4-difluoroanilino)hexanoyl]amino}phenyl)-1-piperidine carboxylate (11.2 mg, 0.0224 mmol) in dichloromethane (0.500 mL) at 0° C. was slowly added trifluoroacetic acid (25.5 mg, 2.24 mmol). The reaction mixture was stirred at room temperature for 10 min and concentrated in vacuo. The residue was dissolved in i-PrOH/CHCl3 (1:3, 10 mL) and basified to pH 11 with 10% KOH, washed with H2O, followed by brine. The organic layer was dried over MgSO4 and concentrated in vacuo to give the desired product (8.98 mg, 99%): 1H NMR (400. MHz, CDCl3) δ 7.39-7.08 (m, 5H), 7.06-6.94 (m, 2H), 6.91-6.81 (m, 1H), 6.77-6.67 (m, 1H), 3.54-3.42 (m, 2H), 3.25-3.04 (m, 3H), 2.91-2.80 (m, 1H), 2.45-2.32 (m, 2H), 2.11-1.99 (m, 2H), 1.98-1.83 (m, 2H), 1.80-1.62 (m, 4H), 1.55-1.40 (m, 2H), 1.34-1.23 (m, 1H); ESMS m/e: 402.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[F:9][C:10]([F:15])([F:14])[CH:11]1[O:13][CH2:12]1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:12][CH:11]([OH:13])[C:10]([F:15])([F:14])[F:9])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: FC(F)(F)C1CO1
Product: OC(CNc1cccc(Br)c1)C(F)(F)F
Temperature: 70 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
EX-633A) 3-Bromoaniline (2.15 g, 12.5 mmol) and 1,1,1-trifluoro-2,3-epoxypropane (1.0 g, 8.9 mmol) were placed in a sealed vial, heated to 70° C. and stirred for 1 h under an atmosphere of nitrogen. The crude product was purified by flash column chromatography on silica gel eluting with CH2CH2:hexane (2:1) to give 2.11 g (84%) of the desired 3-[(3-bromophenyl)amino]-1,1,1-trifluoro-2-propanol product as a light amber oil, 98% pure by HPLC analysis. MS m/z=284/286 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][O:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(N2CCC(CO)CC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCN(c2ccc(C#N)cc2)CC1
Reaction time: 8 h

Procedure:
To a solution of 5.5 g of 1-(4-cyanophenyl)-4-hydroxymethyl-piperidine and 5.16 g of triethylamine in 150 ml of methylene chloride, 5.84 g of methanesulphonic acid chloride are slowly added dropwise at ambient temperature and with stirring. After it has all been added the mixture is left to stand overnight and the solvent is removed under reduced pressure. The residue is chromatographed with methylene chloride/methanol (50:1) over silica gel. Yield: 6.95 g (93% of theory), Mass spectrum: (M+H)+ =295
Reaction SMILES: [CH3:1][C@:2]1([NH:21][C:22]2[CH:27]=[N:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8]([C:10]1[C:15]([N:16]2[N:20]=[CH:19][CH:18]=[N:17]2)=[CH:14][CH:13]=[CH:12]N=1)=[O:9].C[C@]1(NC2C=NC(C(F)(F)F)=CN=2)CCC[C@@H]1N.[Cl:50][C:51]1C=CC=C(N2N=CC=N2)C=1C(O)=O>>[Cl:50][C:51]1[CH:12]=[CH:13][CH:14]=[C:15]([N:16]2[N:20]=[CH:19][CH:18]=[N:17]2)[C:10]=1[C:8]([NH:7][C@H:3]1[CH2:4][CH2:5][CH2:6][C@:2]1([CH3:1])[NH:21][C:22]1[CH:27]=[N:26][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:24][N:23]=1)=[O:9]
Reactant: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1ncccc1-n1nccn1
Reactant: O=C(O)c1c(Cl)cccc1-n1nccn1
Agent: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1N
Product: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1c(Cl)cccc1-n1nccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide (Example 77) from (1S,2S)-1-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine (Intermediate 25; 63 mg, 0.24 mmol) and 2-chloro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 15; 65 mg, 0.29 mmol) except this was purified by column chromatography (silica, 0-30% ethyl acetate/petrol) followed by trituration with diethyl ether/pentane to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.O>CN(C)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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:33]3[CH:34]=[CH:35][C:30]([CH2:29][O:28][CH3:27])=[CH:31][CH:32]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
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: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COCc1ccc(-c2nccnc2N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 110 °C
Yield: 105.3 %

Procedure:
Dissolve 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (1.00 g, 3.26 mmol) in N,N-dimethylacetamide (15 mL). Add potassium carbonate (1.29 g, 9.36 mmol), 4-methoxymethylbenzeneboronic acid (649 mg, 3.90 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.0225 g, 0.034 mmol), then water (5 mL) and degas with nitrogen for 30 min. Heat at 110° C. for 18 hr. under nitrogen. Cool to room temperature, add water (20 mL) and extract with DCM (3×20 mL). Combine the DCM extracts and pass through an IST Phase Separator Frit® and concentrate. Purify (silica gel chromatography, eluting with 20:80 ethyl acetate:isohexane), to give 3′-(4-methoxymethyl-phenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester as a yellow oil (1.32 g, 105%). MS (ES): m/z=385 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[OH:23][CH2:24][C:25]([C:28]1[O:32][N:31]=[C:30]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[CH:29]=1)([CH3:27])[CH3:26].C(C1C=C(NC(=O)N)ON=1)(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:34]([NH:33][C:30]2[CH:29]=[C:28]([C:25]([CH3:27])([CH3:26])[CH2:24][OH:23])[O:32][N:31]=2)=[O:35])[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(CO)c1cc(NC(=O)Oc2ccccc2)no1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: CC(C)c1cc(NC(N)=O)on1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)CO)on4)c3)c2cc1OC
Yield: 61 %

Procedure:
Prepared from 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (30 mg, 0.10 mmol) and phenyl 5-(1-hydroxy-2-methylpropan-2-yl)isoxazol-3-ylcarbamate from the previous step (41 mg, 0.15 mmol) according to the method described for 14346,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea in Example 122B. Purification via preparative TLC eluting with 10% methanol in dichloromethane afforded 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1-hydroxy-2-methylpropan-2-yl)isoxazol-3-yl)urea as a colorless solid (30 mg, 61%). 1H NMR (300 MHz, DMSO-d6) δ 9.57 (brs, 1H), 8.99 (brs, 1H), 8.56 (s, 1H), 7.56-7.58 (m, 2H), 7.38-7.42 (m, 2H), 7.23-7.26 (m, 1H), 6.95-6.98 (m, 1H), 6.49 (s, 1H), 4.95 (brs, 1H), 3.98-3.99 (2×s, 6H), 3.43 (s, 2H), 1.20 (s, 6H); LC-MS (ESI) m/z 480 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:14]([O-:16])=[O:15])[C:8]([O:12][CH3:13])=[C:9]([CH:11]=1)[NH2:10])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].Cl>O.N1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([N+:14]([O-:16])=[O:15])[C:8]([O:12][CH3:13])=[C:9]([NH:10][S:25]([CH3:24])(=[O:27])=[O:26])[CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(N)cc(C(C)(C)C)cc1[N+](=O)[O-]
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1c(NS(C)(=O)=O)cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 32.5 °C
Reaction time: 8 h

Procedure:
Under N2 was charged the product of step (vii) (471 g, 2.099 mol), toluene (1880 mL) and pyridine (471 mL), then methanesulfonyl chloride (179 mL) was added dropwise over 1 h while maintaining the temperature below 35° C. The reaction was stirred at 30-35° C. overnight, before being cooled to below 20° C., then water (1880 mL) and 2 M HCl (1880 mL) were charged (pH 3 achieved). The layers were separated and the organic phase was washed with 2.5% brine (1880 mL). Heptane (3760 mL) was then charged to the organic layer over 0.5 h to isolate a precipitate. The mixture was cooled to 0° C. and stirred for 1 h. The solid was collected via vacuum filtration and washed with heptane (1880 mL), before being dried, under vacuum, at 40° C. overnight. Yield=551 g (87%). HPLC purity 98.5%. Purity >97% by 1H NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:14][CH:15]([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])[C:11](O)=[O:12])[C:7](=[O:24])[CH:6]=1.[CH3:29][C:30]1([CH3:42])[O:34][C@H:33]([CH2:35][N:36]2[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]2)[CH2:32][O:31]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[CH3:29][C:30]1([CH3:42])[O:34][C@H:33]([CH2:35][N:36]2[CH:40]=[CH:39][C:38]([NH:41][C:11](=[O:12])[CH:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[CH:25]=[CH:26][CH:27]=[CH:28][C:2]=4[Cl:1])=[CH:6][C:7]3=[O:24])[CH2:14][CH:15]([C:20]([F:22])([F:23])[F:21])[C:16]([F:19])([F:17])[F:18])=[N:37]2)[CH2:32][O:31]1
Reactant: O=C(O)C(CC(C(F)(F)F)C(F)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC(C(F)(F)F)C(F)(F)F)N3CC(Oc4ccccc4Cl)=CC3=O)n2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
In a round bottom flask under argon was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-4-trifluoromethyl-pentanoic acid (31 mg, 0.072 mmol) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 20 mg, 0.086 mmol) in N,N-dimethylformamide (1 mL). To this mixture was added N,N-diisopropyethylamine (35 μL, 0.22 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (48 mg, 0.11 mmol) and stirred overnight at 25° C. After this time, the mixture was diluted with ethyl acetate (15 mL) and washed with a saturated aqueous solution of ammonium chloride (10 mL), saturated aqueous solution of sodium bicarbonate (10 mL) and a saturated aqueous solution of sodium chloride (10 mL), dried over sodium sulfate, and concentrated with silica gel (1.5 g). Purification by Biotage flash chromatography (AnaLogix 12 g column, 40% ethyl acetate/hexanes) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-4-trifluoromethyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (34 mg, 77%) as a cream colored foam: HR-ES-MS m/z calculated for C25H25N4O5ClF6 [M+H]+ 611.1491, observed 611.1487.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C1(C)C=CC=CC=1>[C:16]1([C:2]2[CH:15]=[CH:14][C:13]3[C:4](=[CH:5][C:6]4[C:11]([CH:12]=3)=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:3]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ccc2cc3ccccc3cc2c1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc3cc4ccccc4cc3c2)cc1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
Into a flask, 5.00 g of 2-chloroanthracene, 4.3 g of phenylboronic acid, 538 mg of tris(dibenzylieneacetone)dipalladium(0), 494 mg of tricyclohexyl phosphine, 9.98 g of tripotassium phosphate, and 75 ml of toluene were put, and the solution was stirred at reflux temperature for 2 hours under argon atmosphere. After heating, 1.5 liter of toluene was added to the reaction liquid, the liquid was cooled to room temperature and then filtrated, and thus the filtrates were purified by silica gel column chromatography. The filtrates were concentrated in an evaporator, the concentrates were recrystallized in toluene, and thus 5.0 g of 2-phenylanthracene was obtained.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]([O:15]CC)=[O:14])[CH:9]=[N:10]2)=[CH:5][CH:4]=1.Br>O.CC(O)=O>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]([OH:15])=[O:14])[CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cnc2cc(OC)ccc2c1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cnc2cc(O)ccc2c1
Reaction time: 2 h

Procedure:
According to Scheme A, ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate (VIII) is obtained in four steps from commercially available synthetically accessible m-anisidine (II). m-Anisidine is combined with diethyl ethoxymethylenemalonate at temperatures ranging from 100° C. to about 125° C., preferably 125° C. for a period of 1 to 5 h, preferably about 3 h to provide diethyl 2-(((3-methoxyphenyl)amino)methylene)malonate. Ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate (III) is obtained by heating Dowtherm™ at a temperature of 257° C. and diethyl 2-(((3-methoxyphenyl)amino)methylene)malonate for a period of 15 minutes to 2 h. Compound (IV) ethyl 7-methoxyquinoline-3-carboxylate is commercially available or synthetically accessible from ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate (III) in two steps. Chlorination of compound (III) under conditions known to one skilled in the art, for example, but not limited to, oxalyl chloride, thionyl chloride, or phosphorus oxychloride, with or without a catalytic amount of DMF, in the presence or absence of a solvent such as DCM or CHCl3, at temperatures ranging from 50° C. to about 70° C., for a period ranging from 2 to 4 h, preferably 2.5 h, provides ethyl 4-chloro-7-methoxyquinoline-3-carboxylate. Subsequent reduction of ethyl 4-chloro-7-methoxyquinoline-3-carboxylate, employing Pd/C under hydrogenation conditions, in a solvent such as MeOH or EtOH, in the presence or absence of an acid such as acetic or formic acid, provides ethyl 7-methoxyquinoline-3-carboxylate (IV). Commercially available or synthetically accessible ethyl 7-methoxyquinoline-3-carboxylate (IV) is reacted under demethylation conditions, for example, HBr in H2O or HOAc, at temperatures ranging from 80° C. to about 110° C., preferably 105° C. for a period of 0.5 h to 24 h, preferably about 2 h, to provide 7-hydroxyquinoline-3-carboxylic acid. Ethyl 7-hydroxyquinoline-3-carboxylate (V), where R3 is H, is obtained by esterification of 7-hydroxyquinoline-3-carboxylic acid, employing methods known to one skilled in the art, for example, but not limited to, reaction of 7-hydroxyquinoline-3-carboxylic acid with an acid such as H2SO4, and the like, in a solvent such as EtOH, at temperatures ranging from 60° C. to about 80° C., preferably 75° C. for a period of about 12 to 24 h, preferably 20 h.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[Br:13]Br>ClC(Cl)C>[Br:13][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([C:9]([F:10])([F:11])[F:12])[C:5]=1[OH:8]
Reactant: Oc1ccc(F)cc1C(F)(F)F
Reactant: BrBr
Solvent: CC(Cl)Cl
Product: Oc1c(Br)cc(F)cc1C(F)(F)F
Temperature: 50 °C

Procedure:
9 g (500 mmol) of 4-fluoro-2-(trifluoromethyl)-phenol is dissolved in 100 ml of dichloroethane, the solution is stirred at 50° C. and a solution of 9.6 g (60 mmol) of bromine in 30 ml of dichloroethane is instilled in the course of 2 hours. When the instillation is completed, it is stirred for 1 more hour at 50° C. and then concentrated by evaporation in a vacuum. The oily residue is dissolved in 100 ml of dichloroethane and shaken out three times with 20 ml of water each. The organic phase is dried on magnesium sulfate, filtered, concentrated by evaporation and the residue is chromatographed on silica gel 60 (Merck) ethyl acetate/hexane. 8.07 g (31.15 mmol)=62.3% of the theoretical yield is obtained as a partially crystalline solid.