Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([S:19][CH3:20])[C:3]=1[C:21]#[N:22].[OH:23]O.[OH-].[NH4+].CO>O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([S:19][CH3:20])[C:3]=1[C:21]([NH2:22])=[O:23]
Reactant: CSc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C#N
Reactant: OO
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C(N)=O
Reaction time: 10 h

Procedure:
A mixture of 5-amino-3-methylsulfanyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole-4-carbonitrile (2.7 g, 7.35 mmol), 30% hydrogen peroxide (10 ml), ammonium hydroxide (90 ml), methanol (70 ml) and water (15 ml) was stirred in a pressure reactor for 10 hours. The mixture was filtered and washed with water to give an off-white solid. The filtrate was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated to recover more product as an off-white solid. Both portions of off-white solid were combined to give 1.400 g of the desired title compound which was identical to the first title compound of Preparation B.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[F:18])[C:12]([OH:14])=O)[CH:5]=[CH:4][N:3]=1.[F:19][C:20]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:21]=1[NH2:22].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[F:18])[C:12]([NH:22][C:21]2[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:20]=2[F:19])=[O:14])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(F)c(N)c1
Reactant: O=C(O)c1ccc(F)c(Oc2ccnc(Cl)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(Cl)c3)c2)c1

Procedure:
A solution of 3-(2-Chloropyridin-4-yloxy)-4-fluorobenzoic acid (2.22 g, 8.29 mmol), 2-fluoro-5-methylaniline (1.56 g, 12.4 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 3.78 g, 9.95 mmol) and N-methylmorpholine (2.00 mL, 18.2 mmol) in dimethylformamide (22 mL) was heated at 90° C. for 2 h. The solvent was evaporated in vacuo at 50° C. To the residue was added water resulting in a thick oil. The water was decanted and the oil dissolved in EtOAc then extracted twice with water, 1M hydrochloric acid and brine. The organic layer was dried (MgSO4), filtered and evaporated to crude 6 (3.37 g). Trituration with dichloromethane (25 mL) gave 3-(2-Chloropyridin-4-yloxy)-4-fluoro-N-(2-fluoro-5-methylphenyl)benzamide as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[C:3]=1[F:11].B1([O-])OO1.[OH2:16].[OH2:17].O.O.[Na+].O>C(O)(C(F)(F)F)=O.C(O)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N+:6]([O-:17])=[O:16])=[C:4]([O:9][CH3:10])[C:3]=1[F:11]
Reactant: O
Reactant: COc1c(N)ccc(Br)c1F
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: COc1c([N+](=O)[O-])ccc(Br)c1F
Temperature: 60 °C
Yield: 40 %

Procedure:
To 4-bromo-3-fluoro-2-methoxyaniline (1 g, 4.5 mmol) in a mixture of TFA and acetic acid (10 mL/10 mL) was added sodium perborate tetrahydrate (3.2 g, 21 mmol). The reaction mixture was warmed up to 60° C. and heated for 24 h. It was then diluted to water, extracted with ethyl acetate. The product was obtained by flash column as a yellow solid (450 mg, 40%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.11 (s, 3 H) 7.40 (dd, J=9.0, 6.2 Hz, 1 H) 7.54 (dd, J=9.0, 1.9 Hz, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=[O:10])=[CH:7][CH:8]=1.[C:12]1([CH:19]=[CH:18][C:16](O)=[CH:15][CH:14]=1)[OH:13].B(O)(O)O.S(=O)(=O)(O)O>O>[OH:13][C:12]1[CH:19]=[CH:18][C:16]([O:10][C:9](=[O:11])[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: Oc1ccc(O)cc1
Agent: O=S(=O)(O)O
Agent: OB(O)O
Solvent: O
Product: COc1ccc(C(=O)Oc2ccc(O)cc2)cc1

Procedure:
912 g p-methoxybenzoic acid and 660 g hydroquinone are heated under reflux in the presence of 12 g boric acid and ml sulfuric acid (98%) until the elimination of water is over. After cooling, the crystals precipitating are filtered under suction, washed and redried. Yield: 1250 g colorless crystals. Melting point: 162°-165° C. Mp. J. Org. Chem. 37, 1425 (1972) 156° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)=[CH:4][C:5]([NH:8][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:10][OH:11])=[N:6][CH:7]=1.[C:28](O)(=O)C.C(N)=N.C([O-])(O)=O.[Na+].CCOC(C)=O>CCO>[CH:25]1([C:23]2[NH:22][N:21]=[C:20]([N:19]3[C:3]4[CH:4]=[C:5]([NH:8][C@H:9]([C:12]5[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=5)[CH2:10][OH:11])[N:6]=[CH:7][C:2]=4[N:1]=[CH:28]3)[CH:24]=2)[CH2:27][CH2:26]1
Reactant: CC(=O)O
Reactant: Nc1cnc(N[C@@H](CO)c2ccc(F)cc2)cc1Nc1cc(C2CC2)[nH]n1
Agent: N=CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: OC[C@H](Nc1cc2c(cn1)ncn2-c1cc(C2CC2)[nH]n1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 153 %

Procedure:
A mixture of (R)-2-(5-amino-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyridin-2-ylamino)-2-(4-fluorophenyl)ethanol (Method 93, 0.14 g, 0.38 mmol) and formamidine acetate (0.079 g, 0.76 mmol) in EtOH (5 ml) was heated at reflux for 2 hours. After cooling to 25° C., the reaction mixture was treated with saturated NaHCO3 solution (10 ml) and EtOAc (30 ml). The organic layer was separated, washed with brine (10 ml), and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (EtOAc-MeOH=20:1) to give the title compound as an off-white solid (0.22 g, 32%). 1H NMR (400 MHz) 12.76 (s, 1H), 8.40 (s, 1H), 8.34 (s, 1H), 7.43 (m, 2H), 7.10 (m, 2H), 6.92 (s, 1H), 6.72 (d, J=7.2 Hz, 1H), 6.25 (s, 1H), 4.92 (m, 2H), 3.62 (m, 2H), 1.97 (m, 1H), 1.02 (m, 2H), 0.77 (m, 2H). MS: Calcd.: 378; Found: [M+H]+ 379.
Reaction SMILES: [C:1]1([C:6]([O:8][CH3:9])=[O:7])[CH2:5][CH2:4][CH2:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:18])C=1>ClCCl.CCOC(C)=O>[C:1]12([C:6]([O:8][CH3:9])=[O:7])[O:18][CH:5]1[CH2:4][CH2:3][CH2:2]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)C1=CCCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C12CCCC1O2
Reaction time: 2 h
Yield: 142 %

Procedure:
Methyl cyclopent-1-ene-1-carboxylate (30.0 g, 237.8 mmol) was dissolved in 20 mL of dichloromethane and 3-chloroperbenzoic acid (64.4 g, 373.3 mmol) was added. The reaction was allowed to stir vigorously for 2 hours. The reaction mixture was diluted with EtOAc and washed with 0.5 N NaOH. The organic layer was dried over sodium sulfate, filtered and concentrated to give 48.0 grams of methyl 6-oxabicyclo[3.1.0]hexane-1-carboxylate.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[CH2:5][CH2:4]1)[CH3:2].[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[C:24]1[C:33]2[N:32]=[CH:31][CH:30]=[N:29][C:28]=2[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.CC1C=CC=C(C)C=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>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:10]=[C:11]([NH:12][C:34]([C:27]3[C:28]4[N:29]=[CH:30][CH:31]=[N:32][C:33]=4[C:24]([C:18]4[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=4[CH3:16])=[CH:25][CH:26]=3)=[O:35])[CH:13]=[CH:14][CH:15]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)O)c2nccnc12
Reactant: CCN1CCN(c2cccc(N)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cccc(C)c1B(O)O
Product: CCN1CCN(c2cccc(NC(=O)c3ccc(-c4c(C)cccc4C)c4nccnc34)c2)CC1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 3-(4-ethylpiperazin-1-yl)-aniline (Step 2.1) and 8-(2,6-dimethyl-phenyl)-quinoxaline-5-carboxylic acid. The carboxylic acid was synthesized as described in Steps 1.2-1.7 but using 2,6-dimethylphenylboronic acid and Pd(PPh3)4 in Step 1.4. Title compound: ESI-MS: 466.2 [M+H]+; tR=3.74 min (System 3).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([N:13]=[C:14]=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:18]([O:20][P:21]([C:26]1[CH:32]=[C:31]([Br:33])[CH:30]=[CH:29][C:27]=1[NH2:28])([O:23][CH2:24][CH3:25])=[O:22])[CH3:19]>>[CH2:18]([O:20][P:21]([C:26]1[CH:32]=[C:31]([Br:33])[CH:30]=[CH:29][C:27]=1[NH:28][C:14]([NH:13][C:5]1[CH:4]=[C:3]([C:2]([F:16])([F:17])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:6]=1)=[O:15])([O:23][CH2:24][CH3:25])=[O:22])[CH3:19]
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOP(=O)(OCC)c1cc(Br)ccc1N
Product: CCOP(=O)(OCC)c1cc(Br)ccc1NC(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To an oven dried 30 mL vial containing a stirring bar 2 mL of pyridine was added followed by 3,5-bistrifluorometylphenylisocyanate (35 mg, 0.125) and 2-Diethylphosphono-4-bromoaniline (32 mg, 0.104 mmol). The resulting solution was stirred at 65° C. for 3 hours. Pyridine was removed by rotary evaporation and then the product was purified by silica column chromatography using mixtures of EtOAc and hexanes to give 1-(2-diethylphosphono-4-bromophenyl)-3-(3,5-bistrifluoromethylphenyl)urea. 1H-NMR (400 MHz, CDCl3): δ=1.32 (t, 6.8 Hz, 6H CH3), 4.10 (m, 4H, CH2), 7.52 (s, 1H, CCF3CHCCF3), 7,64 (m, 2H, CHCBRCH), 8.03 (s, 2H, CCF3CHCNH), 8.30 (m, 1H, CPCNCH), 8.62 (s, 1H, NH), 9.82 (s, 1H, PCCNH). 31P (400 Mz, CDCl3) δ=18.19 (s)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(Cl)(Cl)Cl.ClC1C=CC=C(C(OO)=[O:33])C=1>C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[N+:4]([O-:33])[CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][C:11]=2[N:12]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1c[n+]([O-])ccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
To a mixture of 0.20 g of 2-(3-methylpyridin-4-yl)-5-(trifluoromethyl)benzoxazole and 4 ml of chloroform, 0.30 g of 65% m-chloroperbenzoic acid was added while ice-cooling. The reaction mixture was stirred at room temperature for three hours, then diluted with ethyl acetate, and washed with 5% aqueous solution of sodium hydroxide and a saturated sodium chloride solution, sequentially. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 0.17 g of 3-methyl-4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridine N-oxide (hereinafter, referred to as “active compound 24”).
Reaction SMILES: [CH:1]([Si:4]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[O:15][CH3:16])([CH3:3])[CH3:2].[H][H]>CCO.[Pd]>[CH3:16][O:15][C:7]1[CH:8]=[C:9]([NH2:12])[CH:10]=[CH:11][C:6]=1[O:5][Si:4]([CH:17]([CH3:19])[CH3:18])([CH:20]([CH3:22])[CH3:21])[CH:1]([CH3:3])[CH3:2]
Reactant: COc1cc([N+](=O)[O-])ccc1O[Si](C(C)C)(C(C)C)C(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Yield: 77.6 %

Procedure:
Dissolve triisopropyl-(2-methoxy-4-nitro-phenoxy)-silane (95.7 g, 294.0 mmol) in EtOH (1800 mL) and add 5% Pd/C (10.0 g). Hydrogenate the slurry at room temperature under 50 psi hydrogen for 8 h. Filter the slurry through a pad of Celite® and rinse with EtOH. Concentrate the filtrate in vacuo to give a brown oil. Purify by flash chromatography, using a gradient from 100% hexanes to 20% EtOAc/hexanes, to give the title compound as a brown solid (67.4 g, 77.6% yield). MS (ES+) 296.2 (M+1)+.
Reaction SMILES: [C:1]([NH:9][CH:10]([C:14](=[O:16])[CH3:15])[CH2:11][C:12]#[CH:13])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(OC(=O)C(F)(F)F)=O.FC(F)(F)C(O)=O>[CH3:15][C:14]1[O:16][C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:9][C:10]=1[CH2:11][C:12]#[CH:13]
Reactant: C#CCC(NC(=O)c1ccccc1)C(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: C#CCc1nc(-c2ccccc2)oc1C
Yield: 101.4 %

Procedure:
A solution of 4-benzoylamino-1-hexyn-5-one (30 g, 0.14 mol) in trifluoroacetic anhydride (100 ml) and trifluoroacetic acid (200 ml) was heated to 35°-40° C. for 6 hours. The solution was concentrated and the residue taken up in ethyl acetate (400 ml). To this solution was added saturated sodium bicarbonate solution (400 ml) followed by solid sodium bicarbonate until the water layer became neutral. The layers were separated, the organic layer was washed with brine, dried over magnesium sulfate and concentrated to give a brown oil (28 g) which was used as such.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[C:5]([C:19]#[N:20])=[CH:4][N:3]=1.[CH:21]([C:24]1[C:29]([N:30]2[CH:34]=[N:33][N:32]=[N:31]2)=[CH:28][C:27]([NH2:35])=[C:26]([F:36])[CH:25]=1)([CH3:23])[CH3:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.FC1C(NC2CC(C)(C)NC(C)(C)C2)=NC(OC(C)C)=NC=1>CC(O)C>[CH3:15][C:13]1([CH3:16])[CH2:14][CH:9]([NH:8][C:6]2[C:5]([C:19]#[N:20])=[CH:4][N:3]=[C:2]([NH:35][C:27]3[CH:28]=[C:29]([N:30]4[CH:34]=[N:33][N:32]=[N:31]4)[C:24]([CH:21]([CH3:22])[CH3:23])=[CH:25][C:26]=3[F:36])[N:7]=2)[CH2:10][C:11]([CH3:18])([CH3:17])[NH:12]1
Reactant: CC1(C)CC(Nc2nc(Cl)ncc2C#N)CC(C)(C)N1
Reactant: CC(C)c1cc(F)c(N)cc1-n1cnnn1
Agent: CC(C)Oc1ncc(F)c(NC2CC(C)(C)NC(C)(C)C2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: CC(C)c1cc(F)c(Nc2ncc(C#N)c(NC3CC(C)(C)NC(C)(C)C3)n2)cc1-n1cnnn1
Temperature: 80 °C

Procedure:
A mixture of 2-chloro-5-cyano-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidin-4-amine (0.05 g, 0.17 mmol, 1 equiv), 4-isopropyl-2-fluoro-5-(1H-tetrazol-1-yl)benzenamine (0.045 g, 0.204 mmol, 1.2 equiv), and para-toluenesulfonic acid monohydrate (0.025 g, 0.136 mmol, 0.8 equiv) in IPA (5 mL) were heated to 80° C. overnight. LCMS indicated desired product plus approximately 10% of 5-fluoro-2-isopropoxy-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidin-4-amine byproduct. After cooling to ambient temperature, the crude mixture was quenched with 2M NH3/MeOH followed by concentrating to dryness and repeating once. The crude product was purified by flash chromatography and eluted with DCM:2M NH3/MeOH (100:0 to 95:5 using 1% 2M NH3/MeOH increments) to provide the desired product which was recrystallized with DCM/IPA to give the title compound (45 mg, 55%) as a solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@H:4]([N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[NH:26][C:27]([CH:29]2[CH2:31][CH2:30]2)=[O:28])[CH2:17]1)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH2:14][CH3:15])[CH:6]=1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH2:14]([O:13][C:7]1[CH:6]=[C:5]([C@H:4]([N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[NH:26][C:27]([CH:29]3[CH2:31][CH2:30]3)=[O:28])[CH2:17]2)[CH2:3][CH2:2][NH:1][S:40]([CH3:39])(=[O:42])=[O:41])[CH:10]=[CH:9][C:8]=1[O:11][CH3:12])[CH3:15]
Reactant: CCOc1cc([C@@H](CCN)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc([C@@H](CCNS(C)(=O)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reaction time: 3 h
Yield: 58 %

Procedure:
To a solution of (1R)-cyclopropanecarboxylic acid {2-[3-amino-1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (0.45 g, 1.1 mmol) and triethylamine (0.3 mL, 2 mmol) in methylene chloride (10 mL) was added methane sulfonyl chloride (0.10 mL, 1.3 mmol) at 0° C. After 3 hrs, the mixture was extracted with methylene chloride (20 mL) and water (20 mL). The organic layer was washed with HCl (1N, 20 mL), sodium hydrogen carbonate (sat 20 mL), brine (20 mL), and dried over MgSO4. The solvent was removed in vacuo to give a solid, which was purified with chromatography (Silca Gel) to give (1R)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-methanesulfonylamino-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (320 mg, 58% yield): mp, 93-95° C.; 1H NMR (CDCl3) δ 0.89-0.93 (m, 2H, CH2), 1.08-1.10 (m, 2H, CH2), 1.42 (t, J=7 Hz, 3H, CH3), 1.65-1.72 (m, 1H, CH), 2.27-2.32 (m, 2H, CH2), 2.94 (s, 3H, CH3), 2.97-3.06 (m, 1H, CHH), 3.85 (s, 3H, CH3), 3.50 (d, J=17 Hz, 1H, NCHH), 4.04 (q, J=7 Hz, 2H, CH2), 4.18 (d, J=17 Hz, 1H, NCHH), 5.51 (dd, J=6, 9 Hz, 1H, NCH), 5.60-5.62 (m, 1H, NH), 6.83-6.99 (m, 4H, Ar), 7.42 (t, J=8 Hz, 1H, Ar), 8.42 (d, J=8 Hz, 1H, Ar), 10.47 (s, 1H, NH); 13C NMR (CDCl3) δ 8.35, 14.76, 16.19, 32.26, 40.24, 40.65, 46.05, 51.12, 55.98, 64.63, 111.50, 112.83, 116.86, 116.94, 117.84, 119.64, 130.31, 133.43, 138.02, 141.44, 148.72, 149.41, 170.07, 172.72; Anal Calcd for C25H31N3O6S+0.35H2O: C, 59.12; H, 6.29; N, 8.27, H2O 1.26. Found: C, 59.42; H, 6.16; N, 8.05, H2O 1.24.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=1.CI>O1CCCC1>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]([CH3:1])[C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:16]=1
Reactant: COC(=O)Cc1ccc(OC)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1ccc(OC)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
A solution of lithium diisopropylamide (2.0M solution in tetrahydrofuran/ethylbenzene/heptane, 34.0 ml, 0.0667 mol) was added dropwise to a solution of methyl 4-methoxyphenylacetate (12.0 g, 0.0667 mol) in tetrahydrofuran (150 ml) at −70° C. under a nitrogen atmosphere and the mixture was stirred at −70° C. for 1 hour. A solution of methyl iodide (9.5 g, 0.0667 mol) in tetrahydrofuran (20 ml) was added dropwise and the mixture was stirred at −70° C. for a further 1 hour. The cooling bath was removed and the mixture was allowed to warm to room temperature overnight. The reaction was quenched with water, acidified with dilute aqueous hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate:hexane 1:9, to give methyl 2-(4-methoxyphenyl)propionate (8.8 g) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[O:9][CH2:10][C:11]#[CH:12])=[CH:4][CH:3]=1.[C-:14]#[N:15].[Na+].O.[OH-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:9][CH2:10][C:11]#[CH:12])[C:14]#[N:15])=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: C#CCOC(Cl)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOC(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
1-Chloro-4-(chloro-prop-2-ynyloxy-methyl)-benzene (13.0 g) is added to sodium cyanide (3.1 g) in N,N-dimethylformamide (40 ml) over 2 hours at room temperature. The reaction mixture is stirred at room temperature for 3 hours and then poured into water (200 ml), which contained sodium hydroxide (4 g). The aqueous phase is extracted with tert butyl methyl ether (2×200 ml). The organic phases are washed with water (2×50 ml), combined, dried (sodium sulfate) and evaporated. (4-Chloro-phenyl)-prop-2-ynyloxy-acetonitrile (9.2 g) is obtained which is purified by flash column chromatography on silica gel using ethyl acetate/hexane as eluant.
Reaction SMILES: [NH2:1]/[C:2](/[N:5]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1)[CH2:6][CH2:7][C:8]1[CH:24]=[CH:23][C:11]([O:12][C:13]([CH3:22])([CH3:21])[C:14]([O:16]C(C)(C)C)=[O:15])=[CH:10][CH:9]=1)=[N:3]\[OH:4].[F:36][C:37]([F:48])([F:47])[C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=O)=[CH:40][CH:39]=1.C(O)(C(F)(F)F)=O>>[CH3:21][C:13]([O:12][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][N:5]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=2)[C:2]2[N:1]=[C:42]([C:41]3[CH:40]=[CH:39][C:38]([C:37]([F:36])([F:47])[F:48])=[CH:46][CH:45]=3)[O:4][N:3]=2)=[CH:24][CH:23]=1)([CH3:22])[C:14]([OH:16])=[O:15]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)/C(N)=N/O)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2noc(-c3ccc(C(F)(F)F)cc3)n2)cc1)C(=O)O

Procedure:
Similarly prepared by condensation of tert-butyl 2-[4-(2-{[(E)-amino(hydroxyimino)methyl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate with 4-trifluoromethylbenzoyl chloride, followed by standard TFA hydrolysis.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:24])=[C:21]([CH:23]=1)[NH2:22]>>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:24])=[C:21]([CH:23]=1)[NH:22][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: COc1ccc(C)c(N)c1
Product: COc1ccc(C)c(Nc2cc(C)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and 5-methoxy-2-methylaniline (33 mg, 0.243 mmol) similar to Example 13 and isolated as a tan oil (45 mg, 60%). 1H NMR (CDCl3): 8.78–8.77 (m, 1H), 8.44 (d, J=8.1 Hz, 1H), 7.81–7.75 (m, 1H), 7.34–7.30 (m, 1H), 7.16 (d, J=8.4 Hz, 1H), 6.91 (d, J=2.7 Hz, 2H), 6.72 (dd, J=2.7, 8.7 Hz, 1H), 6.30 (s, 1H), 3.76 (s, 3H), 2.42 (s, 3H), 2.17 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:8]=1)=[O:5].[Cl:36][C:37]1[CH:38]=[CH:39][C:40]([CH2:44][C:45]#[N:46])=[N:41][C:42]=1Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([C:42]2[C:37]([Cl:36])=[CH:38][CH:39]=[C:40]([CH2:44][C:45]#[N:46])[N:41]=2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:8]=1)=[O:5]
Reactant: N#CCc1ccc(Cl)c(Cl)n1
Reactant: CCOC(=O)c1cc(NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)ccc2Cl)n(-c2ccccc2)n1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(NC(=O)c2cc(-c3nc(CC#N)ccc3Cl)ccc2Cl)n(-c2ccccc2)n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 51.6 %

Procedure:
To a degassed solution of ethyl 5-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylate (Preparation 5, 1.01 g, 1.34 mmol) and 2-(5,6-dichloropyridin-2-yl)acetonitrile (Preparation 59, 300 mg, 1.60 mmol) in dioxane (10 mL) was added Na2CO3 (213 mg, 2.01 mmol), water (1 drop) and Pd(PPh3)4 (144 mg, 0.134 mmol). The reaction was further degassed and heated to 80° C. for 1 hour. Further water (1 mL) was added and heating continued for 5 hours before cooling to room temperature. The reaction was filtered through Celite washing through with EtOAc, and concentrated in vacuo. The residue was purified using reverse phase column chromatography eluting with 0-100% MeCN in water with 0.1% formic acid to afford the title compound (360 mg, 49%).