Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(O)C.C([O-])([O-])=O.[K+].[K+].[C:20]([O:24][C:25](=[O:34])[N:26]([C:28]1[S:32][C:31](Br)=[N:30][CH:29]=1)[CH3:27])([CH3:23])([CH3:22])[CH3:21]>C1(C)C=CC=CC=1.C(OCC)(=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:20]([O:24][C:25](=[O:34])[N:26]([C:28]1[S:32][C:31]([C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:30][CH:29]=1)[CH3:27])([CH3:23])([CH3:21])[CH3:22]
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: CN(C(=O)OC(C)(C)C)c1cnc(Br)s1
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: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C(=O)OC(C)(C)C)c1cnc(-c2ccc(Cl)nc2)s1
Temperature: 100 °C
Yield: 82.9 %

Procedure:
To a suspension of 6-chloro-3-pyridine boronic acid (158 mg, 1.0 mmol) in toluene (4 mL) was added absolute ethanol (2 mL) followed by a 2.0 M solution of K2CO3 (1.0 mL). To this mixture was added (2-bromo-thiazol-5-yl)-methyl-carbamic acid tert-butyl ester (322 mg, 1.1 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol). The reaction mixture was heated to 100° C. for 16 h. The mixture was cooled and diluted with ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated. The organic layer was purified by silica gel chromatography (0-100% ethyl acetate/hexanes) to afford an off-white solid (270 mg, 83%): mp 167-170° C.; 1H NMR (300 MHz, CDCl3) δ 8.88 (br s, 1H), 8.16 (dd J=3.0, 8.0 Hz, 1H), 7.40 (d, J=7.0 Hz, 1H), 7.39 (s, 1H), 3.45 (s, 3H), 1.61 (s, 9H); ESIMS m/z 326 (M+1).
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:23])([CH2:17][CH2:18]1)[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.C(=O)(O)[O-].[Na+].[CH2:29]([OH:32])[CH2:30][CH3:31]>S(=O)(=O)(O)O>[CH2:29]([O:32][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:23])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:1])[CH2:30][CH3:31]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
2α,3α-Epoxy-5α-pregnan-20-one (360 mg) was dissolved in 80 mL of propanol and cooled to °C. and added to a cold 1.0 mL propanol solution containing 5-drops of concentrated sulfuric acid. This reaction mixture was stirred for 30 minutes at this temperature and additional 30 minutes at room temperature, poured into a 20% sodium bicarbonate solution and washed several times with chloroform. The combined organic phase was dried over potassium carbonate and concentrated. Purification of the crude product on a silica gel column eluting with hexane/ethyl acetate (70:30) gave the titled compound (206 mg, 50% yield) as white crystals.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3Cl)[CH:14]=2)=[N:11][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].[N+:29]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)([O-:31])=[O:30]>C1(OC2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:38][C:35]3[CH:36]=[CH:37][C:32]([N+:29]([O-:31])=[O:30])=[CH:33][C:34]=3[F:39])[CH:14]=2)=[N:11][CH:12]=1
Reactant: Clc1ccnc2cc(-c3ccc(C4OCCCO4)cn3)sc12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1
Temperature: 180 °C
Reaction time: 0.25 h
Yield: 82.4 %

Procedure:
To a suspension of 29 (22.48 g, 67.5 mmol) in phenyl ether (65 mL) was added sodium carbonate (14.32 g, 135 mmol) and 2-fluoro-4-nitrophenol (3) (15.92 g, 101 mmol). The reaction mixture was heated at 180° C. for 2 h, cooled down to 40° C., diluted with DCM (300 mL), stirred at r.t. for 15 min and filtered. The filtrate was collected and concentrated to a minimal volume; Et2O (200 mL) was added and the formed suspension was stirred for 30 min. The solid material was collected by filtration, to afford intermediate 30 (25.20 g, 55.6 mmol, 82% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d) δ (ppm): 8.63-8.62 (m, 2H), 8.48 (dd, J=10.6, 2.6 Hz, 1H), 8.43 (s, 1H), 8.31 (d, J=8.0 Hz, 1H), 8.21 (dt, J=8.8, 1.2 Hz, 1H), 7.94 (dd, J=8.4, 2.0 Hz, 1H), 7.71 (t, J=8.6 Hz, 1H), 6.98 (d, J=5.2 Hz, 1H), 5.67 (s, 1H), 4.19 (dd, J=10.8, 5.2 Hz, 2H), 3.98 (td, J=12.0, 2.0 Hz, 2H), 2.08-1.99 (m, 1H), 1.46 (d, J=13.6 Hz, 1H). MS (m/z): 454.2 (M+H).
Reaction SMILES: O.O.[Sn](Cl)Cl.[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[CH:17]=[CH:18][C:19]2[C:25](=[O:26])[C:24]3[CH:27]=[CH:28][C:29]([N+:31]([O-])=O)=[CH:30][C:23]=3[CH2:22][O:21][C:20]=2[CH:34]=1)([O-])=O>C(O)C>[NH2:6][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[CH:17]=[CH:18][C:19]2[C:25](=[O:26])[C:24]3[CH:27]=[CH:28][C:29]([NH2:31])=[CH:30][C:23]=3[CH2:22][O:21][C:20]=2[CH:34]=1
Reactant: O=C1c2ccc([N+](=O)[O-])cc2COc2cc(Nc3ccccc3[N+](=O)[O-])ccc21
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)COc1cc(Nc3ccccc3N)ccc1C2=O

Procedure:
In accordance with general method Y, 2.40 g (10.66 mmol) of tin(II) chloride dihydrate are dissolved in 15 ml of ethanol, and 0.35 g (0.89 mmol) of (9) is added. Yield: 0.20 g (67.9%);
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:19])([F:18])[C:5]1[CH:17]=[CH:16][C:8]([C:9]([CH:11]2[CH2:13][CH:12]2[C:14]#[N:15])=[O:10])=[CH:7][CH:6]=1.[Cl-].[NH4+]>C(O)C.C(OCC)(=O)C>[OH:10][CH:9]([C:8]1[CH:7]=[CH:6][C:5]([C:4]([F:3])([F:18])[F:19])=[CH:17][CH:16]=1)[CH:11]1[CH2:13][CH:12]1[C:14]#[N:15]
Reactant: N#CC1CC1C(=O)c1ccc(C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#CC1CC1C(O)c1ccc(C(F)(F)F)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
298 mg (7.88 mmol) of sodium borohydride were added to 1.71 g (7.17 mmol) of the compound from Example 122A in 30 ml of ethanol and 7 ml of ethyl acetate under argon, and the mixture was stirred at 40° C. for 1 h. The reaction mixture was added to saturated aqueous ammonium chloride solution and ethyl acetate, the phases were separated, the aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) to result in 1.64 g (95% of theory) of a mixture of the diastereomers of the title compound.
Reaction SMILES: C[O:2]C(=O)C1C=CC=CC=1N.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[O:21])=[CH:15][CH:14]=1.O=S(Cl)Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:21])=[O:2])=[CH:15][CH:14]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: COC(=O)c1ccccc1N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(O)Cc1ccc(F)cc1

Procedure:
First, 2-amino-benzoic acid methyl ester (1.00 g, 6.61 mmol) was dissolved in purified CH2Cl2, and DMAP (0.04 g, 0.33 mmol) was added thereto at 0° C. Then, the mixture was added to the reaction vessel containing (4-fluorophenyl)-acetyl chloride produced from reaction of (4-fluoro-phenyl)-acetic acid (1.53 g, 9.90 mmol) with SOCl2, and then reacted at normal temperature for 10 hours. After adding cold sodium bicarbonate solution containing ice, the reaction mixture was extracted with CH2Cl2, and then concentrated under reduced pressure to obtain 1.50 g (79%) of the compound 2-[2-(4-fluorophenyl)-acetylamino]-benzoic acid methyl ester as the solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1.O>CN(C)C=O>[C:13]([Si:10]([O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([CH3:12])[CH3:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: Oc1ccc(F)cc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2,4-difluoro-phenol (35, 5.00 g, 38.4 mmol) in N,N-dimethylformamide (100 mL) were added tert-butyldimethylsilyl chloride (7.00 g, 46.4 mmol) and imidazole (6.28 g, 92.2 mmol). The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane. The appropriate fractions were combined and concentrated to provide the compound (36, 7.50 g, 80.0%). MS(ESI) [M+H+]+=245.1.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].[NH2:16][C@H:17]([C:33]([O:35][CH3:36])=[O:34])[CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].Cl.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C>C(Cl)Cl>[NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([NH:16][C@H:17]([C:33]([O:35][CH3:36])=[O:34])[CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C

Procedure:
4.35 g of Boc-Val-OH and 6.6 g of H-Lys(Z)-OMe.HCl are subjected to a condensation reaction with 4.4 g of DCC in 50 ml of CH2Cl2, with the addition of 2.7 g of HOBt and 2.6 ml of N-ethylmorpholine (NEM). After filtering the mixture, the solvent is removed by distillation. The residue is taken up in ethyl acetate, washed successively with 2 N acetic acid, 1 M sodium bicarbonate and water and dried over sodium sulfate and, after removing the ethyl acetate by distillation, is recrystallized from diisopropyl ether. Yield 3.5 g, melting point 100°-102°, elementary analysis (C, H and N) correct.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.[CH3:15][NH:16][CH3:17].ClC(OCC1C=CC=CC=1)=O>C1(C)C=CC=CC=1.CN(C=O)C>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:16]([CH3:17])[CH3:15])=[O:5]
Reactant: CNC
Reactant: O=C(O)c1cccnc1Cl
Agent: O=C(Cl)OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cccnc1Cl
Temperature: 70 °C
Reaction time: 16 h
Yield: 78.9 %

Procedure:
A mixture of 2-chloronicotinic acid (1 kg, 6.35 mmol) and thionyl chloride (575 mL, 7.88 mmol) 30 mL of DMF and 3.2L of toluene was warmed slowly to 70° C. and heated at 70° C. for 30 minutes. The mixture was allowed to cool to approximately 40° C. and then added to a 40% solution of aqueous dimethylamine (3.2L, 25.5 mmol) at 10° C. such that the reaction mixture did not exceed 28° C. An additional 30 minutes was allowed and then the aqueous layer was separated and extracted with toluene (2×1L). Combined organic layers were dried (Na2 SO4), filtered and concentrated under reduced pressure. The residue was dissolved in 2L of ethyl acetate and 4L of hexanes were added slowly to give a precipitate. The mixture was aged for 16 hours and then an additional 1L of hexanes was added. The mixture was cooled in an ice bath for 2 hours and filtered. The filtered residue was washed with 20% ethyl acetate/hexanes (1×1L) and dried under a stream of air to give 2-chloro-N,N-dimethyl-nicotinamide (924.5 g, 5.01 mmol), m.p. 66°-67° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[CH:11]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)=O>[N+](C1C=CC=CC=1)([O-])=O.CCCCCC>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[N:9]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=3)[NH:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: COC(=O)c1ccc(C=O)cc1
Solvent: CCCCCC
Solvent: O=[N+]([O-])c1ccccc1
Product: COC(=O)c1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Temperature: 140 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
A mixture of 4,5-dichlorophenylendiamine (4 g, 22.6 mmol) and methyl 4-formylbenzoate (3.68, 22.6 mmol) in nitrobenzene (35 ml) was heated at 140° C. for 30 h. After cooling, the mixture was diluted with n-hexane (150 ml) and stirred for 1 h. The solid was filtered obtaining 5 g of the title compound (yield 68.9%) as a brown powder, mp=240–250° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=1.[CH2:9](Br)[CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[N:3]([CH2:9][CH2:10][CH3:11])[N:4]=[CH:5][C:6]=1[C:7]#[N:8]
Reactant: N#Cc1c[nH]nc1N
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1ncc(C#N)c1N
Temperature: 80 °C

Procedure:
3-Amino-4-pyrazolecarbonitrile 1 (Acros, 3.24 g, 30.0 mmol), propylbromide (Acros, 4.43 g, 36 mmol) and anhydrous potassium carbonate (Fisher, 5.0 g, 36 mmol) were suspended in 20 mL anhydrous DMF and heated at 80° C. in a sealed tube under argon overnight. The reaction was permitted to cool and the DMF was removed on a rotary evaporator. Water was added (100 mL) and the organics were extracted with dichloromethane (3×100 mL). The combined dichloromethane fractions were washed with water (50 mL) and brine (50 mL) and were dried (magnesium sulfate). Concentration of the organics afforded an oil which was subjected to flash chromatography on silica gel (1-3% methanol/dichloromethane). Two white crystals were obtained: compound 101 (1.88 g, 42%) elutes first and compound 102 (711 mg, 16%) elutes second. Compound 101: mp 85-90° C.; MS (ES+ calculated: 150.18; found: 151.15 M+H). HPLC (99%) purity, retention time 5.8 minutes—Method A); 1H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 5.52 (s, 2H), 3.82 (t, J=7, 2H), 1.70 (m, 2H), 0.79 (t, J=7, 3H). Compound 102: mp 162-164° C.; MS (ES+ calculated: 150.18; found: 151.18 M+H). HPLC (95%) purity, retention time 6.4 minutes—Method A); 1H1H NMR (400 MHz, DMSO-d6) δ 7.51 (s, 1H), 6.53 (s, 2H), 3.82 (t, J=7, 2H), 2.95 (m, 2H), 0.81 (t, J=7, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:33][C:34]1([C:39]#[N:40])[CH2:38][CH2:37][CH2:36][CH2:35]1>C1COCC1.O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10](=[O:12])[NH:33][C:34]1([C:39]#[N:40])[CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: N#CC1(N)CCCC1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)CC(NC(=O)OC(C)(C)C)C(=O)NC1(C#N)CCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
To a stirred solution of 2-tert-butoxycarbonylamino-4,4-dimethyl-pentanoic acid (5 g, 20.3 mmol) and N-methyl morpholine (4.46 mL, 40.6 mmol) in THF (40 mL) at 0° C. was added isobutyl chloroformate (2.64 mL, 20.3 mmol) and, after 10 min, the solution of 1-amino-cyclopentanecarbonitrile (3.35 g, 30.5 mmol) in THF (40 mL). The mixture was allowed to warm to room temperature and stirred overnight. It was diluted with water, extracted with dichloromethane, washed with brine, dried (sodium sulfate) and concentrated to give the crude product. Chromatography on silica gel (dichloromethane:MeOH=30:1) gave [1-(1-cyano-cyclopentylcarbamoyl)-3,3-dimethyl-butyl]-carbamic acid tert-butyl ester (6.15 g, 89.6%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]3[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:25]=[CH:24][CH:23]=3)=[N:14]2)=[C:9]([F:33])[CH:8]=1)(=O)=O.[F:36][CH:37]([F:52])[N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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:36][CH:37]([F:52])[N:38]1[CH:42]=[C:41]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]4[N:26]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:25]=[CH:24][CH:23]=4)=[N:14]3)=[C:9]([F:33])[CH:8]=2)[CH:40]=[N:39]1
Reactant: CC1(C)OB(c2cnn(C(F)F)c2)OC1(C)C
Reactant: COc1cn(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
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: COCCOC
Solvent: O
Product: COc1cn(-c2ccc(-c3cnn(C(F)F)c3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 85 %

Procedure:
A mixture of 3-fluoro-4-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]phenyl trifluoromethanesulfonate (230 mg, 0.45 mmol), 1-(difluoromethyl)-1H-pyrazole-4-boronic acid pinacol ester (122 mg, 0.50 mmol), Pd(PPh3)4 (17 mg, 0.015 mmol), Na2CO3 (106 mg, 1.0 mmol), DME (4 mL), and H2O (1 mL) was refluxed for 3 h under Ar atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt and recrystallized from MeOH/H2O to give the title compound (183 mg, 85% yield) as a white solid: mp 185-187° C.; NMR (300 MHz, CDCl3): δ ppm 3.92 (3H, s), 6.41 (1H, t, J=8.3 Hz), 7.03-7.48 (10H, m), 7.79 (1H, d, J=1.9 Hz), 7.83 (1H, d, J=2.3 Hz), 7.91 (1H, d, J=0.8 Hz). LC-MS (ESI) m/z 479 [M+H]+. Anal. Calcd for C24H17F3N6O2: C, 60.25; H, 3.58; N, 17.57. Found: C, 60.19; H, 3.48; N, 17.52.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[NH:8][C:9]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19]([O:21]C)=[O:20])=[CH:11][N:10]=1.CO.[OH-].[Na+].Cl>O1CCCC1>[C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[NH:8][C:9]1[N:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[C:12]([C:19]([OH:21])=[O:20])=[CH:11][N:10]=1
Reactant: COC(=O)c1cnc(N[C@@H]2C[C@H]3CC[C@@H]2C3)nc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cnc(N[C@@H]2C[C@H]3CC[C@@H]2C3)nc1C(F)(F)F
Temperature: 60 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a mixture of methyl rac-2-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]-4-(trifluoromethyl)pyrimidine-5-carboxylate (5.2 g), methanol (25 mL), and tetrahydrofuran (25 mL) was added a 1 M aqueous sodium hydroxide solution (33 mL) at room temperature, followed by stirring at 60° C. for 2 hours. To the reaction mixture was added 1 M hydrochloric acid, followed by stirring at room temperature for 30 minutes, and then the precipitate was collected by filtration and washed with water to obtain rac-2-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]-4-(trifluoromethyl)pyrimidine-5-carboxylic acid (4.9 g) as a white powder.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N12CCN(CC1)CC2.C([Li:21])CCC.CCCCCC>O1CCCC1>[C:1]1([S:7][CH2:8][Li:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1ccccc1
Reactant: [Li]CCCC
Agent: C1CN2CCN1CC2
Solvent: CCCCCC
Solvent: C1CCOC1
Product: [Li]CSc1ccccc1
Temperature: 0 °C

Procedure:
A solution of 5.4 g (44 mmol) of thioanisole and 4.89 g (43.6 mmol) of 1,4-diazabicyclo[2,2,2]-octane in 44 ml of tetrahydrofuran was placed in an oven-dried flask and cooled to 0° C. A 2.5M solution of butyl lithium in hexane (17.4 ml, 43.6 mmol) was added with stirring and the mixture allowed to warm to room temperature and react for about 1 hour to form phenylthiomethyl lithium. A solution of 3.14 g (8.71 mmol) of 1-(2-methoxymethoxyphenyl)-1-(3,4-dimethoxy-2-methoxymethoxyphenyl)ethene in tetrahydrofuran was added and the mixture heated to reflux with stirring under an argon atmosphere. After 10 hours another 21.8 mmol of phenylthiomethyl lithium was prepared and added to the mixture and refluxing was continued overnight. The mixture was then cooled and poured into 200 ml of 5 percent aqueous sodium hypochlorite solution and 200 g of ice and 150 ml of ether added. The organic phase was separated, dried over magnesium sulfate and concentrated by evaporation under reduced pressure to obtain 6.61 g of an oil. This was purified by silica gel chromatography (80 mm×3" filter funnel), eluting with hexane containing ever increasing amounts of ether to obtain 1.16 g of the title compound as an oil. The proton and carbon NMR and infrared spectra were consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16](=[O:30])[C:17]4[C:22]([C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.C[O:32][C:33]1[CH:38]=[N:37][CH:36]=[C:35]([Sn](CCCC)(CCCC)CCCC)[N:34]=1>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16](=[O:30])[C:17]4[C:22]([C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:13])[N:9]=[C:10]([C:35]3[CH:36]=[N:37][CH:38]=[C:33]([OH:32])[N:34]=3)[C:3]=12
Reactant: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(I)c2c(N)ncnc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(OC)n1
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cncc(O)n2)c2c(N)ncnc21
Yield: 22.2 %

Procedure:
The title compound was made in a similar way as that of the compound of example 89 from 3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-phenyl-1H-isochromen-1-one (intermediate D2a, 120 mg, 0.236 mmol) and 2-methoxy-6-(tributylstannyl)pyrazine (188 mg, 0.471 mmol) to give the title compound (25 mg, 36.8%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24](I)=[CH:23][C:22]=2[F:28])=[N:16]1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]#[CH:37])=[C:32]([F:38])[CH:31]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>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.CS(C)=O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:37]#[C:36][C:33]3[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][C:32]=3[F:38])=[CH:23][C:22]=2[F:28])=[N:16]1
Reactant: C#Cc1ccc(Cl)cc1F
Reactant: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(I)cc3F)[nH]c2=O)c1)C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(C#Cc4ccc(Cl)cc4F)cc3F)[nH]c2=O)c1)C1CC1
Yield: 47.8 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using N-(4-chloro-3-(3-(2-fluoro-4-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide (Intermediate-48, 0.050 g, 0.097 mmol), 4-chloro-1-ethynyl-2-fluorobenzene (Intermediate-49, 0.022 g, 0.14 mmol), TBAF (0.061 g, 0.19 mmol), bis(triphenylphosphine)palladium(II) chloride (catalytic) and DMSO (1.0 mL) at 80° C. to afford 0.025 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 0.65-0.68 (m, 4H), 1.60 (m, 1H), 4.32 (d, J=6.0 Hz, 2H), 7.33-7.52 (m, 3H), 7.55-7.74 (m, 5H), 7.90 (m, 1H), 8.68 (m, 1H), 12.0 (br s, 1H); MS (m/z): 539.0 (M+).