Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:18]=[CH:17][NH:16][N:15]=3)[N:11]3[CH:19]=[CH:20][N:21]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.[CH:22]1([CH:25]=[CH:26][C:27]#[N:28])[CH2:24][CH2:23]1.C(#N)C.C1CCN2C(=NCCC2)CC1>>[CH:22]1([CH:25]([N:16]2[CH:17]=[CH:18][C:14]([C:12]3[N:11]4[CH:19]=[CH:20][N:21]=[C:10]4[CH:9]=[C:8]([C:6]4[CH:5]=[N:4][N:3]([CH3:2])[CH:7]=4)[N:13]=3)=[N:15]2)[CH2:26][C:27]#[N:28])[CH2:24][CH2:23]1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cc[nH]n3)n2)cn1
Reactant: N#CC=CC1CC1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cn1cc(-c2cc3nccn3c(-c3ccn(C(CC#N)C4CC4)n3)n2)cn1
Temperature: 45 °C
Yield: 17.5 %

Procedure:
7-(1-Methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-3-yl)imidazo[1,2-c]pyrimidine hydrochloride (Example 129, Step C, 50.2 mg, 0.148 mmol) and 3-cyclopropylacrylonitrile (Preparation B; 69.1 mg, 0.742 mmol) were suspended in acetonitrile (742 μL, 0.148 mmol). DBU (88.8 μL, 0.594 mmol) was added to the reaction mixture and heated at 45° C. for 15 hours. The reaction mixture was purified by reverse phase HPLC using a 0-100% acetonitrile/water gradient. The resultant solid was diluted in Et2O, sonicated, filtered and washed with Et2O to afford the title compound as a light yellow solid (9.3 mg, 17% yield). MS (apci) m/z=359.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1I.[CH:11]1(B(O)O)[CH2:13][CH2:12]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH:11]1[CH2:13][CH2:12]1
Reactant: OB(O)C1CC1
Reactant: N#Cc1ccc(N)c(I)c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(N)c(C2CC2)c1
Temperature: 100 °C

Procedure:
Palladium (II) acetate (798 mg, 3.55 mmol) was added to a stirred mixture of 4-amino-3-iodobenzonitrile (5.08 g, 20.8 mmol), cyclopropyl boronic acid (2.69 g, 31.3 mmol), potassium phosphate (22.9 g, 108 mmol) and tricyclohexylphosphine (1.17 g, 4.17 mmol) in toluene (40 mL)/water (2 mL). The reaction mixture was degassed and heated to 100° C. for 3 h. After cooling to rt, the reaction mixture was poured into water and extracted with EtOAc. The combined organics were washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel (gradient elution; 0-20% EtOAc/hexanes as eluent) to afford the title compound i-4-a. m/z (ES) 159 (MH)+
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH2:10]([O:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH:11]([CH3:13])[CH3:12].Cl[S:22]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([OH:30])=[O:29])(=[O:24])=[O:23]>C1COCC1>[CH2:10]([O:14][CH:15]1[CH2:20][CH2:19][N:18]([S:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28]([OH:30])=[O:29])(=[O:24])=[O:23])[CH2:17][CH2:16]1)[CH:11]([CH3:13])[CH3:12]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)COC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)COC1CCN(S(=O)(=O)c2cccc(C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of N,N-Diisopropylethylamine (0.0078 ml, 0.045 mmol) in THF (1 ml) is added to 4-Isobutoxy-piperidine (0.008 g, 0.05 mmol) followed by a solution of 3-(Chlorosulfonyl)benzoic acid (9.93 mg, 0.045 mmol) and shaken at room temperature for 48 hours. The solution is evaporated under vacuum to afford 3-(4-Isobutoxy-piperidine-1-sulfonyl)-benzoic acid which is used without purification; [M+H]+ 342.00
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([C:8]2[C:9]([C:17]([O:19][CH3:20])=[O:18])=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[CH:7]=1.BrC1C=CC([N+]([O-])=O)=CC=1[C:26](OC)=[O:27].COC1C=CC(OC)=CC=1B(O)O>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>[CH3:22][O:21][C:5]1[CH:4]=[CH:3][C:2]([O:27][CH3:26])=[CH:7][C:6]=1[C:8]1[C:9]([C:17]([O:19][CH3:20])=[O:18])=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(F)ccc1OC
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COc1ccc(OC)c(B(O)O)c1
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(OC)ccc1OC
Yield: 69 %

Procedure:
This compound was prepared in a manner similar to that of methyl 5'-fluoro-2'-methoxy-4-nitro-2-biphenylcarboxylate (EXAMPLE 107) from methyl 2-bromo-5-nitrobenzoate (2.46 g, 9.46 mmol), (PPh3)4Pd (0.33 g, 0.28 mmol), and 2,5-dimethoxyphenylboronic acid (2.42 g, 13.3 mmol) to afford 2.08 g (69%) of methyl (2',5'-dimethoxy-4-nitro-2-biphenylcarboxylate) as a white solid. Data for methyl (2',5'-dimethoxy-4-nitro-2-biphenylcarboxylate): 1H NMR (400 MHz, CDCl3) 8.70 (d, J=2.4, 1H), 8.37 (dd, J=8.4, 2.5, 1H), 7.52 (d, J=8.5, 1H), 6.92 (dd, J=8.8, 3.0, 1H), 6.84 (m, 1H), 3.82 (s, 3H), 3.75 (s, 3H), 3.67 (s, 3H).
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.BrC1C=CC(OCC(O)=O)=CC=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([C:39]3[S:40][CH:41]=[CH:42][C:43]=3[NH:44][S:45]([CH:48]([CH3:50])[CH3:49])(=[O:47])=[O:46])=[CH:35][CH:34]=2)O1.[OH-].[Ba+2].[OH-]>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.O>[CH3:50][CH:48]([S:45]([NH:44][C:43]1[CH:42]=[CH:41][S:40][C:39]=1[C:36]1[CH:37]=[CH:38][C:33]([C:2]2[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=2)=[CH:34][CH:35]=1)(=[O:46])=[O:47])[CH3:49]
Reactant: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: O=C(O)COc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C(O)COc1ccc(Br)cc1
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2ccc(OCC(=O)O)cc2)cc1
Yield: 65 %

Procedure:
Heat a solution of (4-Iodo-phenoxy)-acetic acid or (4-bromo-phenoxy)-acetic acid (0.25 mmol), propane-2-sulfonic acid {2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-thiophen-3-yl}-amide (122 mg, 0.30 mmol), PdCl2(dppf)(41 mg, 0.05 mmol) and barium hydroxide (158 mg, 0.50 mmol) in DMF-H2O (v/v 4:1, 2.5 mL) to 80° C. under nitrogen atmosphere for 20 h. Pour into H2O (50 mL) and dichloromethane (50 mL), then extract with H2O (4×50 mL) and dry the combined organic phases (MgSO4). Concentrate to furnish a crude mixture as a yellowish solid. Purification by flash chromatography (Silica gel-Hexane/EtOAc) affords the title compound as a pale yellow solid (65-80% yield). MS (ES−):430.1 (M−1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.CC1(C)C(C)(C)OC([C:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH:21]=2)O1.C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[C:29]([O:28][C:26]([N:23]1[CH2:22][CH:21]=[C:20]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=2)[CH2:25][CH2:24]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: COC(=O)c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CC=C(C2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cn1
Temperature: 140 °C
Yield: 64.4 %

Procedure:
To a microwave vial was charged with methyl 5-bromopicolinate (250 mg, 1.22 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (393 mg, 1.34 mmol), K2CO3 (400 mg, 3.03 mmol), and 3 mL of DMF. The vial was then flushed with argon while PdCl2(dppf)2 (42 mg, 0.060 mmol) was added. The resulting mixture was then capped and heated at 140° C. for 10 min in a microwave reactor. LC-MS indicated that the reaction was complete. The reaction mixture was then partitioned between EtOAc (25 mL) and water (10 mL). The organic layer was washed with brine (10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give an oil which was purified by silica gel column chromatography, eluting with 0-60% EtOAc in hexanes, to give methyl 5-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)picolinate (250 mg, 68%). LC-MS (ESI) m/z 319 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>CC.C(Cl)CCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[Cl:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 8.2 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-4-piperidone (8.01 g, 39.4 mmol), 2-chloroaniline (5.74 g, 44.1 mmol) and acetic acid (2.80 g, 46.6 mmol) in 200 ml ethylene chloride ethane was added sodium triacetoxyborohydride (8.37 g, 78.8 mmol). The mixture was stirred at room temp for 2.5 days. Added 2N NaOH solution to adjust pH to 10. The organic phase was separated and washed with water, then dried over Na2SO4. Solvent was removed under vacuum and crude product was purified with flash column chromatography to yield tert-butyl-4-(2-chlorophenylamino)piperidine-1-carboxylate in 8.2% yield (1.6 g) as white solid.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][CH2:13][CH3:14])(=[O:11])[CH:9]=[CH2:10].C1(C)C(C(P(C(C2C(C)=CC=CC=2)=O)C(C2C(C)=CC=CC=2)=O)=O)=CC=CC=1.Br.Br[C:45]1[S:54][C:53]2[C:52](=[C:55]3[CH2:60][CH2:59][N:58]([CH3:61])[CH2:57][CH2:56]3)[C:51]3[CH:62]=[CH:63][CH:64]=[CH:65][C:50]=3[CH2:49][CH2:48][C:47]=2[CH:46]=1.[Cl-].[NH4+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[CH3:61][N:58]1[CH2:59][CH2:60][C:55](=[C:52]2[C:51]3[CH:62]=[CH:63][CH:64]=[CH:65][C:50]=3[CH2:49][CH2:48][C:47]3[CH:46]=[C:45]([CH:10]=[CH:9][C:8]([O:12][CH2:13][CH3:14])=[O:11])[S:54][C:53]2=3)[CH2:56][CH2:57]1
Reactant: C=CC(=O)OCC
Reactant: CN1CCC(=C2c3ccccc3CCc3cc(Br)sc32)CC1
Agent: [Pd+2]
Agent: Br
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1cc2c(s1)C(=C1CCN(C)CC1)c1ccccc1CC2
Temperature: 80 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
Triethylamine (35.5 mL, 255 mmol), ethyl acrylate (26.8 mL, 246 mmol), palladium acetate (0.4 g, 1.8 mmol), and tri(o-toluoyl)phosphine (1.5 g, 5.0 mmol) were added to a DMF (160 mL) solution of Compound 2 (9.2 g, 24.5 mmol), and the mixture was stirred overnight at 80° C. in an argon atmosphere. A saturated aqueous ammonium chloride solution was added to the reaction mixture, the product was extracted with ethyl acetate, and the organic layer was then washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvents were distilled off under a reduced pressure, and the resulting residue was then purified by column chromatography (chloroform-methanol=9:1), to give 7.6 g (79%) of the captioned compound in the form of white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([O:11][CH2:12][CH:13]=C)=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[N:7]=1)=[O:5])[CH3:2].C[N+]1([O-])CC[O:33]CC1.I([O-])(=O)(=O)=O.[Na+]>O.O1CCOCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([O:11][CH2:12][CH:13]=[O:33])=[C:9]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[N:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[N:7]=1)=[O:5])[CH3:2]
Reactant: C=CCOc1c(C(=O)OCC)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Reactant: C[N+]1([O-])CCOCC1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1OCC=O
Reaction time: 3.5 h

Procedure:
To a stirred solution of 4-allyloxy-5-(4-chlorophenyl)-1-(2-chlorophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester I-1e (337 mg, 0.8 mmol) osmium tetroxide (53 microliters of a 0.15 M solution in water) and N-methylmorpholine-N-oxide (120 mg, 0.9 mmol) in dioxane (2.4 ml)/water (0.6 ml) was stirred at ambient temperature for 18 hours, then sodium periodate (1.7 g, 8.1 mmol) was added and stirring was continued for 3.5 hours. The thick slurry was diluted with ethyl acetate (100 ml), filtered and solids washed 2× with ethyl acetate. The combined filtrates were washed with water, brine, dried (Na2SO4) and concentrated in vacuo to afford an oil. Silica gel chromatography (25% ethyl acetate/hexanes) afforded the title compound (I-1f) as a colorless foam, 130 mg.
Reaction SMILES: [OH-].[K+].[C:3](=[S:5])=S.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([NH2:15])[CH:9]=1>C(O)C.O.C(Cl)Cl>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]2[N:14]=[C:3]([SH:5])[NH:15][C:10]=2[CH:9]=1
Reactant: COc1ccc(N)c(N)c1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc2nc(S)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.8 %

Procedure:
To potassium hydroxide (3.8 g, 0.067M) in ethanol (20 mL) and water (7 mL) was added 2.5 mL CS2 (3.09 g, 0.04M) (H2S trapped over clorox). The reaction mixture was stirred for 30 minutes at ambient temperature, cooled to 0° C., and 4-methoxy-o-phenylene diamine (5.23 g, 0.03M) was slowly added. This reaction mixture was then stirred at reflux for 4 hours, stirred at ambient temperature overnight (basic soln. with pH paper), evaporated in vacuo and diluted with CH2Cl2. Addition of water gave a precipitate which was suspended in CH2Cl2 and acidified to pH 4. Filtration of the suspension gave purple crystalline 5-methoxy-2-mercaptobenzimidazole (3.4 g, 63%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C1(C)C=CC=CC=1.[F-].[K+]>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.O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 96.8 %

Procedure:
To a solution of 4-bromobenzonitrile (4.0 g, 22 mmol) and 4-fluorophenylboronic acid (4.6 g, 32 mmol) in 4:1 toluene:water (100 mL) were added potassium fluoride (3.8 g, 66 mmol) and Pd(PPh3)4 (2.5 g, 2.2 mmol). The resulting mixture was stirred at reflux for 12 h. The mixture was cooled to room temperature and extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification of the crude residue by silica gel chromatography gave 4′-fluorobiphenyl-4-carbonitrile (4.2 g) as a colorless solid. 1H NMR (400 MHz, CD3OD) δ 7.69 (s, 4H), 7.63-7.60 (m, 2H), 7.15-7.10 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[Cl:15])[CH:3]=1.[F:16][C:17]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[Cl:15][C:10]1[CH:11]=[N:12][N:13]([CH3:14])[C:9]=1[C:4]1[CH:3]=[C:2]([NH:1][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:17]=2[F:16])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: Cn1ncc(Cl)c1-c1cc(N)ccc1O
Reactant: COc1ccc(C(=O)O)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccc(O)c(-c3c(Cl)cnn3C)c2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
4-Amino-2-(4-chloro-1-methyl-1H-pyrazol-5-yl)phenol (2.0 g, 8.94 mmol) was suspended in anhydrous CH2Cl2 (75 mL). The suspension was made to dissolve by the adding anhydrous DMF (5 mL) and briefly heating the solution using a heat gun (−50° C.). 2-Fluoro-4-methoxybenzoic acid (1.52 g, 8.94 mmol), DIEA (2.34 mL, 13.4 mmol) and HATU (4.08 g, 10.7 mmol) were added to the solution. The reaction was stirred at room temperature for 2 hours. After this time, the reaction was extracted (120 mL each of H2O/CH2Cl2). The aqueous layer was extracted once more with CH2Cl2 (120 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography (0, 20, 40, 50, 70% EtOAc/Hexanes) to yield N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-2-fluoro-4-methoxybenzamide (2.88 g, 7.66 mmol, 77.1%) as a colorless oil that turned solid upon standing. LCMS m/z 376.1 (M+H); 1H NMR (400 MHz, MeOH-d4) δ ppm 3.76 (s, 3H), 3.90 (s, 3H), 6.87 (dd, J=33.09, 2.53 Hz, 1H), 6.87 (dd, J=11.49, 2.40 Hz, 1H), 7.00 (d, J=8.59 Hz, 1H), 7.54 (s, 1H), 7.55 (d, J=2.53 Hz, 1H), 7.66 (dd, J=8.84, 2.53 Hz, 1H), 7.76 (t, J=8.72 Hz, 1H).
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[N:21]=[C:20]([N:31]4[CH2:35][CH2:34][CH2:33][CH:32]4[CH3:36])[N:19]=3)[CH2:14][CH2:13]2)=[N:7][CH:6]=1)C.O.O[Li].O.Cl>C1COCC1.CCO>[Cl:11][C:9]1[C:8]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[C:22]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)[N:21]=[C:20]([N:31]4[CH2:35][CH2:34][CH2:33][CH:32]4[CH3:36])[N:19]=3)[CH2:16][CH2:17]2)=[N:7][CH:6]=[C:5]([CH:10]=1)[C:4]([OH:37])=[O:3]
Reactant: CCOC(=O)c1cnc(N2CCN(c3cc(-c4ccc(F)cc4)nc(N4CCCC4C)n3)CC2)c(Cl)c1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC1CCCN1c1nc(-c2ccc(F)cc2)cc(N2CCN(c3ncc(C(=O)O)cc3Cl)CC2)n1
Temperature: 55 °C

Procedure:
To a solution of 5-chloro-6-{4-[6-(4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-nicotinic acid ethyl ester (427 mg, 0.813 mmol) in THF, add water dropwise until the cloudiness almost persists. To this mixture add LiOH.H2O (350 mg, 8.13 mmol) followed by a small amount of EtOH. Heat the mixture at 55° C. for 2 h, and then concentrate under reduced pressure. Add a small amount of water to the residue, followed by 8.13 mmol of HCl (3M solution). Adjust the final pH to 4 and collect the off-white solid via filtration. Wash the solid with water and dry to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:15])[CH:5]=[CH:6][C:7]=1[F:8].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[CH3:31][N:32]1[CH:36]=[C:35]([C:37](O)=[O:38])[C:34]([CH3:40])=[N:33]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:37]([C:35]2[C:34]([CH3:40])=[N:33][N:32]([CH3:31])[CH:36]=2)=[O:38])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1nn(C)cc1C(=O)O
Reactant: Nc1ccccc1-c1ccc(F)c(Cl)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nn(C)cc1C(=O)Nc1ccccc1-c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
At room temperature, 0.47 g of 3′-chloro-4′-fluoro-2-aminobiphenyl and 0.82 g of bis(2-oxo-3-oxazolidinyl)phosphoryl chloride were added to a solution of 0.30 g of 1,3-dimethyl-1H-pyrazole-4-carboxylic acid and 0.43 g of triethylamine in 30 ml of dichloromethane. The mixture was stirred at room temperature for 12 hours. The mixture was then washed successively twice with dilute hydrochloric acid, twice with aqueous sodium bicarbonate solution and once with water. The organic phase was dried and concentrated. The crude product was purified by silica gel column chromatography using cyclohexane/methyl tert-butyl ether 1:2. This gave 0.56 g of the desired product as white crystals of m.p. 177-180° C.
Reaction SMILES: Cl.[CH2:2]([C:5]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[CH:3]=[CH2:4].CCN(C(C)C)C(C)C.[Br:25][C:26]1[CH:27]=[N:28][C:29](Cl)=[N:30][CH:31]=1.CCCCCC>CCO>[CH2:2]([C:5]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9][N:8]([C:29]2[N:30]=[CH:31][C:26]([Br:25])=[CH:27][N:28]=2)[CH2:7][CH2:6]1)[CH:3]=[CH2:4]
Reactant: C=CCC1(C(=O)OCC)CCNCC1
Reactant: Clc1ncc(Br)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Solvent: CCO
Product: C=CCC1(C(=O)OCC)CCN(c2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.4 %

Procedure:
To a solution of ethyl 4-allylpiperidine-4-carboxylate hydrochloride (1.30 g, 6.59 mmol) in EtOH (20.0 mL) was added DIPEA (3.0 mL, 16.47 mmol) and the mixture stirred at rt for 10 min followed by addition of 5-bromo-2-chloropyrimidine (1.06 g, 5.49 mmol). The reaction was then heated up to 70° C. for 1 h. After reaction completion (by TLC), solvent was evaporated and the crude residue purified over 100-200 M silica-gel using 2.0% EtOAc:hexane to obtain the desired product as a yellow solid (1.0 g, 56% yield). 1H NMR (DMSO-d6): δ 1.19 (t, J=6.80 Hz, 3H), 1.44 (m, 2H), 2.02 (m, 2H), 2.27 (m, 2H), 3.10 (m, 2H), 4.13 (q, J=6.80 Hz, 2H), 4.29 (m, 2H), 5.06 (m, 2H), 5.66 (m, 1H) and 8.43 (s, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[H-].[Na+].[CH2:32](Br)[CH:33]([CH3:35])[CH3:34].[NH4+].[Cl-]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:5]=[C:6]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: CC(C)CBr
Reactant: CCOC(=O)Cc1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(C)C)c1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (0.75 g, 1.70 mmol) was dissolved in anhydrous DMF (20 mL), NaH (60% wt. in paraffin oil, 0.049 g, 2.04 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature, upon which isobutyl bromide (0.2 mL, 1.87 mmol), was added in a drop wise manner at 0° C. The reaction mixture was stirred an additional 1 h at 0° C. and then saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic layers were washed with water (2×10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a colorless oil, witch was purified by flash column chromatography to give ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (0.5 g, 59% yield) as a thick liquid.