Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:11]([F:14])([F:13])[F:12])=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[N:9]O>C(O)(=O)C.[Zn]>[F:1][C:2]1[C:3]([C:11]([F:13])([F:14])[F:12])=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][NH2:9]
Reactant: ON=Cc1ccnc(C(F)(F)F)c1F
Agent: [Zn]
Solvent: CC(=O)O
Product: NCc1ccnc(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Zinc dust (0.63 g, 9.62 mmol) was added at RT to a solution of 3-fluoro-2-trifluoromethyl-pyridine-4-carbaldehyde oxime (0.460 g, 1.57 mmol) in acetic acid (8 mL). The reaction mixture was stirred at RT for 3 h, then filtered through a 0.45 microns filter, and the filtrate was concentrated in vacuo. The colored oily residue was partitioned between CH2Cl2 and 1N HCl, the layers were separated and the aqueous phase was extracted twice with CH2Cl2. The pH of the aqueous layer was then adjusted to pH=9 by adding a saturated aqueous NaHCO3 solution, and the resulting white suspension was extracted four times with CH2Cl2. The combined organics were dried (phase separator) and concentrated in vacuo to afford the title compound as a yellow oil. MS (LC/MS): 195.0 [M+H]+; tR (HPLC conditions c): 2.47 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:19][S:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:27](=[O:28])[C:26]3[CH:25]=[CH:24][C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:31][CH:30]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(S(C)(=O)=O)cc2)cc1
Yield: 84.4 %

Procedure:
Using the procedure described in Example 55, Part B, N1-(4-methoxybenzoyl)-1,2-benzenediamine (399 mg, 1.65 mmol) and 4-methylsulfonylbenzoic acid (463 mg, 2.31 mmol) yielded 591 mg (84%) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:11][C:12]2[NH:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=3[N:21]=2)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31]>>[Br:1][C:2]1[C:3]([S:11][C:12]2[N:13]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])[C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=3[N:21]=2)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: Nc1nccc2[nH]c(Sc3cc4c(cc3Br)OCO4)nc12
Reactant: Clc1ccccc1CCBr
Product: Nc1nccc2c1nc(Sc1cc3c(cc1Br)OCO3)n2CCc1ccccc1Cl

Procedure:
The title compound was prepared by a similar procedure described for step 7 of example 1 using 2-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-1H-imidazo[4,5-c]pyridin-4-amine and 1-(2-bromoethyl)-2-chloro-benzene. 1H NMR (DMSO-d6) δ; 7.69 (d, J=6.0 Hz, 1H), 7.36 (dd, J=8.0, 1.6 Hz, 1H), 7.32 (s, 1H), 7.23 (td, J=8.0, 1.6 Hz, 1H), 7.06 (td, J=7.2, 1.6 Hz, 1H), 6.72 (d, J=6.0 Hz, 1H), 6.52 (s, 1H), 6.38 (s, 2H), 6.06 (s, 2H), 4.45 (t, J=6.8 Hz, 2H), 3.09 (t, J=6.8 Hz, 2H); LC-MS [M+H]+ 502.99.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH2:20]([NH2:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:20]([NH:28][C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: NCCc1ccccc1
Product: CCc1cc(-c2cncc(C(=O)NCCc3ccccc3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and phenethyl-amine to afford the title compound. MS: m/e=362 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[O:6]1)=[O:4].COC(C1OC(C#CCNC(OC(C)(C)C)=O)=CC=1)=O>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)C1CCC(CCCNC(=O)OC(C)(C)C)O1
Agent: [Pd]
Agent: COC(=O)c1ccc(C#CCNC(=O)OC(C)(C)C)o1
Solvent: CO
Product: COC(=O)c1ccc(CCCNC(=O)OC(C)(C)C)o1
Reaction time: 18 h

Procedure:
5-(3-tert-Butoxycarbonylamino-propyl)-tetrahydrofuran-2-carboxylic acid methyl ester and 5-(3-tert-Butoxycarbonylamino-proDyl)-furan-2-carboxylic acid methyl ester. To a solution of 5-(3-tert-butoxycarbonylamino-prop-1-ynyl)-furan-2-carboxylic acid methyl ester (1.69 g) in MeOH (50 mL) was added 10% palladium on carbon (850 mg) and the mixture was hydrogenated on a Parr shaker at 50 psi for 18 h. The catalyst was removed via filtration through Celite and the volatiles were concentrated in vacuo. Flash chromatography (hexanes:EtOAc 4:1) provided 5-(3-tert-butoxycarbonylamino- propyl)-furan-2-carboxylic acid methyl ester (422 mg, MS 284 M+) followed by 5-(3-tert-butoxycarbonylamino-propyl)-tetrahydrofuran-2-carboxylic acid methyl ester (903 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:47]1[CH:54]=[CH:53][C:50]([CH:51]=[O:52])=[C:49]([F:55])[C:48]=1[F:56]>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.C1(C)C=CC=CC=1>[F:56][C:48]1[C:49]([F:55])=[C:50]([CH:51]=[O:52])[CH:53]=[CH:54][C:47]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(Br)c(F)c1F
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc(-c2ccc(F)cc2)c(F)c1F
Temperature: 100 °C
Reaction time: 16 h
Yield: 80.1 %

Procedure:
(4-Fluorophenyl)boronic acid (6.67 g), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (1.96 g), a 2 M aqueous sodium carbonate solution (47.6 mL), and tris(dibenzylideneacetone)dipalladium(0) (2.04 g) were added at room temperature to a toluene (200 mL) solution of 4-bromo-2,3-difluorobenzaldehyde (7.02 g), and the mixture was stirred at 100° C. for 16 hours in an argon atmosphere. Water was added to the reaction mixture at room temperature, and the mixture was filtered through celite. Then, the filtrate was subjected to extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was passed through a short silica gel column (hexane/ethyl acetate), and the solvent was distilled off under reduced pressure. The obtained residue was crystallized (hexane/ethyl acetate) and further recrystallized (hexane/ethyl acetate) to obtain the title compound (6.01 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:29][CH2:28][CH2:27][N:26]([CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Product: CC(C)(C)OC(=O)N1CCCN(Cc2cccc(-c3ccnc(Cl)n3)c2)CC1

Procedure:
Intermediate 1 was coupled with [1,4]Diazepane-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 403.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.[C:11]1([CH3:19])[CH:16]=[CH:15][C:14]([NH:17][NH2:18])=[CH:13][CH:12]=1>CCO>[C:2]([C:3]1[CH:4]=[C:5]([NH2:6])[N:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:19])=[CH:12][CH:13]=2)[N:18]=1)([CH3:9])([CH3:8])[CH3:1]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Temperature: 90 °C
Yield: 98.9 %

Procedure:
A mixture of 4,4-dimethyl-3-oxopentanenitrile (2.503 g, 20 mmol) and p-tolylhydrazine hydrochloride (3.173 g, 20 mmol) in EtOH was heated at 90° C. for 8 hours. The reaction was quenched by adding water and extracted with DCM. Extracts were dried over MgSO4 and concentrated to give 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine as solid (4.537 g, 99%). 1H NMR (300 MHz, CDCl3) δ 1.31 (s, 9H), 2.36 (s, 3H), 3.69 (s, 2H), 5.51 (s, 1H), 7.25 (d, 2H), 7.44 (d, 2H); LC-MS (ESI) m/z 230 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=[CH:12]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[C:44]=1[C:50]1[C:54]([CH2:55]O)=[C:53]([CH:57]([CH3:59])[CH3:58])[O:52][N:51]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:55][C:54]2[C:50]([C:44]3[C:43]([Cl:42])=[CH:48][CH:47]=[CH:46][C:45]=3[Cl:49])=[N:51][O:52][C:53]=2[CH:57]([CH3:59])[CH3:58])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=[CH:12]2
Reactant: COC(=O)c1cccc2cc(-c3ccc(O)cc3Cl)ccc12
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3Cl)ccc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.6 %

Procedure:
A mixture of methyl 6-(2-chloro-4-hydroxyphenyl)-1-naphthalenecarboxylate (0.25 g, 0.799 mmol), polymer-bound triphenylphosphine (0.27 g, 0.799 mmol), [3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methanol (0.23 g, 0.799 mmol) and 10 mL of dichloromethane was cooled to 0° C. Diisopropyl azodicarboxylate (0.16 mL, 0.799 mmol) was slowly added to the reaction mixture. The reaction mixture was stirred for 10 minutes at the above temperature and then warmed to room temperature and stirred for 18 h. The reaction mixture was filtered and the filtrate was concentrated to give oil. The crude material was partially purified by flash chromatography over silica gel using 20% EtOAc in hexane to afford 0.36 g of the title compound. 1H NMR (DMSO-d6): 8.75 (d, J=9 Hz, 1H), 8.22 (d, J=8 Hz, 1H), 8.14 (d, J=7 Hz, 1H), 8.0 (s, 1H), 7.53-7.67 (m, 5H), 7.36 (d, J=8.6 Hz, 1H), 7.03-7.04 (m, 1H), 6.84-6.87 (m, 1H), 4.92 (s, 2H), 3.93 (s, 3H), 3.46 (m, 1H), 1.34 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]2)=[N:6][C:7]=1[O:8][CH3:9].[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][NH:23]2)=[CH:19][C:18]=1B1OCC(C)(C)CO1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C>[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][NH:23]2)=[CH:19][C:18]=1[C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5]([N:10]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]2)=[CH:4][CH:3]=1
Reactant: COc1nc(N2CCC(O)C2)ccc1Br
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(N4CCC(O)C4)nc3OC)cc12
Temperature: 80 °C
Yield: 35.3 %

Procedure:
A vial was charged with 1-(5-bromo-6-methoxypyridin-2-yl)pyrrolidin-3-ol (100.0 mg, 0.37 mmol), methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (176.4 mg, 0.55 mmol), Pd(dppf)C12 (26.8 mg, 0.04 mmol), potassium carbonate (152 mg, 1.10 mmol, 2M/L aqueous) and toluene/ethanol (1.5 mL/0.5 mL). The mixture was purged with nitrogen for 5 minutes and then sealed. The reaction was heated to 80° C. overnight. The mixture was cooled to room temperature and filtered. The filtrate was diluted with water (5 mL) and extracted with ethyl acetate (5 mL×3). The organic layer was dried (sodium sulfate) and concentrated. The resulting residue was purified through prep. TLC (petroleum ether: ethyl acetate, 2:1) to give the title compound (52.5 mg, 35.7%) as an off-white solid. 1H NMR (400 MHz, CDCl3) ppm: 8.62 (br. s), 8.05 (s, 1H), 7.89 (d, 1H), 7.50 (s, 1H), 7.35 (d, 1H), 6.00 (d, 1H), 4.61 (m, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.73-3.57 (m, 4H), 2.24-2.05 (m, 2H).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3[O:15][N:14]=[C:13]([CH3:16])[N:12]=3)=[N:10][C:5]2=[N:4][CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][C:19]=1[C:33]1[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=1>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]4[O:15][N:14]=[C:13]([CH3:16])[N:12]=4)=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:20][C:19]=1[C:33]1[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Cc1noc(-c2ccn3c(Br)cnc3n2)n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Product: Cc1noc(-c2ccn3c(-c4ccc(F)c(-c5ccccc5C#N)c4)cnc3n2)n1

Procedure:
3-Bromo-7-(3-methyl-[1,2,4]oxadiazol-5-yl)imidazo[1,2-α]pyrimidine was coupled with 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 2 to give 2′-fluoro-5′-[7-(3-methyl-[1,2,4]oxadiazol-5-yl)imidazo[1,2-α]pyrimidin-3-yl]biphenyl-2-carbonitrile as a yellow solid: δH (400 MHz, CDCl3) 2.55 (3H, s), 7.46 (1H, t, J 9), 7.56-7.59 (1H, m), 7.64 (2H, dd, J 7 and 2), 7.69-7.73 (2H, m), 7.81-7.87 (2H, m), 8.16 (1H, s), 9.05 (1H, s); m/z (ES+) 397 (M++H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=O)C.Cl>CO>[NH:4]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH2:16])(=[O:14])=[O:15])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: CC(=O)N1CCc2cc(S(N)(=O)=O)ccc21
Agent: Cl
Solvent: CO
Product: NS(=O)(=O)c1ccc2c(c1)CCN2
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.3 %

Procedure:
To a suspension of 1-acetylindoline-5-sulfonamide (Intermediate 52A, 1.00 g, 4.16 mmol) in MeOH (12.0 mL) was added conc. HCl (1.7 mL, 20.8 mmol). The resulting reaction mixture was stirred at room temperature for 18 h and then at 80° C. for 2 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The brown residue was dissolved in water and the solution was adjusted to a pH of 7-8 with 1 N aq. NaOH solution. The mixture was then extracted with EtOAc (2×), and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (720 mg, 87%) as a light brown solid. 1H NMR (DMSO-d6) δ 7.42-7.38 (m, 2H), 6.86 (s, 2H), 6.47 (d, J=8.1 Hz, 1H), 6.24-6.22 (m, 1H), 3.53-3.50 (m, 2H), 2.98-2.95 (m, 2H); MS(ESI+) m/z 199.1 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:7][CH:8]([O:10][C@H:11]([CH3:19])[C:12](OCC(C)C)=[O:13])[CH3:9])[CH2:4][CH2:5][CH3:6].CO.O>C1(C)C=CC=CC=1>[CH2:3]([O:7][CH:8]([O:10][C@H:11]([CH3:19])[CH2:12][OH:13])[CH3:9])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCOC(C)O[C@H](C)C(=O)OCC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: CCCCOC(C)O[C@H](C)CO
Yield: 91.4 %

Procedure:
8.4 g (0.204 mole) of sodium borohydride was suspended at room temperature in a solution of 44.1 g (0.17 mole) of the isobutyl (R)-(+)-2-(1-n-butoxyethoxy)propionate (obtained in Reference Example 6) dissolved in 170 ml of toluene. Thereto was dropwise added slowly 41.3 ml (1.02 mole) of methanol with stirring, so that the internal temperature of the reaction system could be kept at 40° C. After the completion of the dropwise addition, the resulting mixture was stirred at room temperature for 5 hours to give rise to a reaction. To the reaction mixture was added 50 ml of water, followed by stirring for 0.5 hour. The organic layer was separated. The water layer was subjected to extraction with 50 ml of toluene. The two organic layers were combined and washed with 50 ml of water and 50 ml of a saturated aqueous sodium chloride solution in this order. The washed solution was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove the solvent, whereby was obtained 27.4 g (yield: 91.3%) of an oily title compound (diastereomixture).
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[C:7]([Cl:13])[CH:6]=1.[Cl-].[NH4+]>O1CCCC1>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:12])[CH3:1])=[C:7]([Cl:13])[CH:6]=1
Reactant: OCc1ccc(Br)cc1Cl
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
A solution of methylmagnesium bromide (4.8 mL, 3M, 14.4 mmol) was added dropwise to the solution of (4-bromo-2-chlorophenyl)methanol (1.52 g, 7.0 mmol) in tetrahydrofuran at −40° C. Then the mixture was stirred at 25° C. for 3 hrs. Saturated ammonium chloride solution (10 mL) was added to the mixture. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1:1) to give 1-(4-bromo-2-chlorophenyl)ethanol as a white solid (1.32 g, 81%). 1H NMR (300 MHz, d6-DMSO): 7.69 (d, J=8.1, 1H), δ 7.53 (d, J=0.9, 1H), 7.19 (dd, J1=8.1, 1H J2=0.9, 1H), 5.38 (d, J=3.6, 1H), δ 4.70 (m, 1H), 1.30 (d, J=6.6, 3H).
Reaction SMILES: [CH3:1][S-:2].[Na+].F[C:5]1[N:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:6]=1[CH3:13].CCOC(C)=O.CCCCCC>CC(O)C.O>[CH3:13][C:6]1[CH:7]=[C:8]([C:11]#[N:12])[CH:9]=[N:10][C:5]=1[S:2][CH3:1]
Reactant: C[S-]
Reactant: Cc1cc(C#N)cnc1F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)O
Product: CSc1ncc(C#N)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a stirred suspension of sodium thiomethoxide (1.66 g, 23.71 mmol) in 2-propanol (20 mL) at room temperature under a nitrogen atmosphere was added a suspension of 6-fluoro-5-methyl-3-pyridinecarbonitrile (2.69 g, 19.76 mmol) in 2-propanol (10 mL). After one hour stirring at room temperature, TLC (25% EtOAc/hexane) indicated loss of starting material. The reaction mixture was diluted with water (20 mL) and filtered. The filtrate was extracted twice with ether (25 mL×2). The organic layers were combined, washed with water and evaporated in vacuo to give the desired product (2.57 g, 79.1%) as yellow fluffy crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[C:6]([N+:8]([O-])=[O:9])[CH:7]=1.O.NN>ClCCCl.C(O)C.[Ni]>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][OH:9])[CH:5]=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Br)cc([N+](=O)[O-])c1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: ClCCCl
Solvent: CCO
Product: COc1cc(Br)cc(NO)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-Bromo-5-nitroanisole (1.5 g, 6.46 mmol) was dissolved in 20 mL of 1,2-dichloroethane and 20 mL of ethanol, and the mixture was cooled to 0° C. Raney-Ni (30 mg) and hydrazine hydrate (0.79 mL, 12.9 mmol) were added within 10 minutes, and the reaction was stirred for 4 hours at room temperature, when 50 mg of Raney-Ni were added. After stirring for 16 hours, another 50 mg of Raney-Ni were added, and after further stirring for 4 hours, another 50 mg of Raney-Ni were added. Stirring was continued for 4 hours at room temperature, when the starting material had completely disappeared. The reaction mixture was filtered through celite, and the solvent was removed under reduced pressure to provide N-(3-bromo-5-methoxy-phenyl)-N-hydroxylamine as a solid, which was dissolved in 80 ml of toluene. Sodium bicarbonate (597 mg, 7.11 mmol) was added, followed by acetyl chloride (0.51 mL, 7.11 mol). Stirring at room temperature was continued for 20 hours. The reaction mixture was then filtered and concentrated under reduced pressure. The residue was purified by column chromatography (40 g SiO2; EtOAc/heptane in a gradient from 5/95 to 1/3) to yield the title compound as a solid (360 mg, 21% over 2 steps). LC-MS at 254 nm; [M+H] 260.0/262.1; Rt 0.82 min; (LCMS method 1). 1H-NMR (600 MHz; DMSO-d6): 10.85 (brs, 1H), 7.50 (dd, 1H), 7.26 (dd, 1H), 6.94 (dd, 1H), 3.77 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].[F:18][C:19]([F:40])([F:39])[O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:32]=[CH:31][C:30]([CH2:33]O)=[C:29]([C:35]([F:38])([F:37])[F:36])[CH:28]=2)=[CH:23][CH:22]=1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:6])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:33][C:30]2[CH:31]=[N:32][C:27]([C:24]3[CH:23]=[CH:22][C:21]([O:20][C:19]([F:39])([F:18])[F:40])=[CH:26][CH:25]=3)=[CH:28][C:29]=2[C:35]([F:38])([F:36])[F:37])=[CH:11][C:10]=1[CH3:16])[CH3:7])[CH3:2]
Reactant: OCc1cnc(-c2ccc(OC(F)(F)F)cc2)cc1C(F)(F)F
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2cnc(-c3ccc(OC(F)(F)F)cc3)cc2C(F)(F)F)cc1C

Procedure:
In analogy to the procedure described in example 43E], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with [6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-yl]-methanol in the presence of N,N,N′,N′-tetramethylazodicarboxamide and tributylphosphine to give the title compound as colorless oil.
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([NH:9][C:10]2[C:15]([O:16][CH3:17])=[CH:14][C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=3)=[C:12]([CH3:28])[CH:11]=2)[CH:3]=1.[CH:29]([S:32]([C:35]1[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=1[NH2:37])(=[O:34])=[O:33])([CH3:31])[CH3:30].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(CCC)=CC(CCC)=CC=2CCC)CCCCC1.CC(C)([O-])C.[Na+]>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].C1COCC1>[Cl:8][C:7]1[C:2]([NH:37][C:36]2[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=2[S:32]([CH:29]([CH3:31])[CH3:30])(=[O:34])=[O:33])=[CH:3][C:4]([NH:9][C:10]2[C:15]([O:16][CH3:17])=[CH:14][C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=3)=[C:12]([CH3:28])[CH:11]=2)=[N:5][CH:6]=1
Reactant: COC(=O)c1ccc(-c2cc(OC)c(Nc3cc(Br)c(Cl)cn3)cc2C)cc1
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CCCc1cc(CCC)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(CCC)c1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2cc(OC)c(Nc3cc(Nc4ccccc4S(=O)(=O)C(C)C)c(Cl)cn3)cc2C)cc1
Temperature: 150 °C

Procedure:
Methyl 4′-(4-bromo-5-chloropyridin-2-ylamino)-5′-methoxy-2′-methylbiphenyl-4-carboxylate generated in Step 2 (9 mg, 0.022 mmol), 2-(isopropylsulfonyl)aniline (4 mg, 0.022 mmol, 1 equiv), Pd2(dba)3 (1.7 mg, 0.002 mmol, 0.1 equiv.), 2-(Dicyclohexylphosphino)-2′,4′,6′-tri-1-propyl-1,1′-biphenyl (1.8 mg, 0.004 mmol, 0.2 equiv.), and Sodium tert-butoxide (2.7 mg, 0.028 mmol, 1.3 equiv.) are added to THF (1 mL). The resulting mixture is bubbled with N2 gas for 5 minutes and then heated at 150° C. for 4 hours. After cooling to room temperature, the reaction mixture is diluted into EtOAc and washed with H2O. The EtOAc layer is dried over Mg2SO4 and concentrated in vacuo. Silica gel chromatography (hexanes-EtOAc) affords Methyl 4′-(5-chloro-4-(2-(isopropylsulfonyl)phenylamino)pyridin-2-ylamino)-5′-methoxy-2′-methylbiphenyl-4-carboxylate (254); MS m/z 580.2 (M+1).