Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16](F)=[O:17])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O/[N:20]=[C:21](/[C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]2)=[CH:25][CH:24]=1)\[NH2:22].CCN(C(C)C)C(C)C>C(#N)C>[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:17][N:22]=[C:21]([C:23]4[CH:24]=[CH:25][C:26]([CH2:27][N:28]5[CH2:29][CH:30]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:31]5)=[CH:39][CH:40]=4)[N:20]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(F)c1onc(-c2ccccc2)c1C(F)(F)F
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Temperature: 25 °C
Yield: 78 %

Procedure:
A suspension of 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl fluoride (2.91 g, 11.2 mmol), (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (Int.1, 3.43 g, 11.2 mmol), and Hunig's Base (2.55 mL, 14.6 mmol) in acetonitrile (20 mL) was stirred at room temperature over the weekend. The reaction mixture had completely solidified (pinkish-tan in color), but was judged complete by HPLC and LCMS. The reaction mixture was partitioned between a saturated aqueous of sodium bicarbonate (150 mL) and dichloromethane (150 mL). The aqueous layer was extracted with dichloromethane (2×100 mL), and the combined organic layers were dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded a tan solid which was purified by flash silica gel chromatography using a mixture of ethyl acetate in hexane (0-50%) to afford tert-butyl 1-(4-(5-(3-phenyl-4-(trifluoromethyl) isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (4.60 g; 78%) as a white, crystalline solid. The material was suspended in methanol (−75 mL) and was sonicated for 5 minutes. The MeOH was removed under reduce pressure, and the residue was re-suspended in methanol (−50 mL) with sonication. Vacuum filtration and drying afforded tert-butyl 1-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (4.04 g, 7.67 mmol, 68% yield) as a white, crystalline solid. The methanol filtrate was concentrated to afford additional tert-butyl 1-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (570 mg; 10%) as a slightly off-white solid. The compound had an HPLC retention time=3.12 min.−Column. CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=527.1. 1H NMR (500 MHz, CDCl3) δ ppm 1.47 (s, 9H) 3.28-3.37 (m, 3H), 3.60 (br. s., 2H), 3.74 (br. s., 2H), 7.49 (d, J=7.70 Hz, 2H), 7.53-7.62 (m, 3H), 7.69 (d, J=7.15 Hz, 2H), and 8.16 (d, J=7.70 Hz, 2H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:26]3[C:34]4[C:29](=[CH:30][C:31](Br)=[CH:32][CH:33]=4)[N:28]([CH3:36])[CH:27]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[C:37]([O:41][CH2:42][CH3:43])(=[O:40])[CH:38]=[CH2:39].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:26]3[C:34]4[C:29](=[CH:30][C:31](/[CH:39]=[CH:38]/[C:37]([O:41][CH2:42][CH3:43])=[O:40])=[CH:32][CH:33]=4)[N:28]([CH3:36])[CH:27]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: C=CC(=O)OCC
Reactant: CC(C)c1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(Br)ccc23)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)/C=C/c1ccc2c(C(C(=O)NS(=O)(=O)c3ccc(C(C)C)cc3)c3ccc4c(c3)OCO4)cn(C)c2c1

Procedure:
Palladium acetate (9.5 mg, 0.042 mmol) was added to a stirred solution of 3-{1-(1,3-benzodioxol-5-yl)-2-[(4-isopropylphenyl)sulfonamido]-2-oxoethyl}-6-bromo-1-methyl-1H-indole (the product of Example 56, 200 mg, 0.35 mmol), ethyl acrylate (0.048 ml, 0.44 mmol), triethylamine (0.146 ml, 1 mmol) and tri-o-tolylphosphine (32 mg, 0.1 mmol) in acetonitrile (10 ml) at room temperature under a nitrogen atmosphere. The solution was heated at reflux for 2 h. After cooling the mixture was poured into brine (50 ml) and extracted with ethyl acetate (2×50 ml). The organic layers were washed with water (50 ml), dried (MgSO4) and concentrated to give a grey foam. Purification by flash column chromatography (elution with 95% dichloromethane/5% methanol) gave the product as a pale yellow foam.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:10].I[CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O.CN(C)P(N(C)C)(N(C)C)=O>[CH2:9]([O:11][C:12](=[O:20])[CH:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH3:10]
Reactant: CCOC(=O)Cc1ccccc1
Reactant: ICC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(CC1CCCC1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 106.5 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23 mL of a 0.31 M stock solution, 7.13 mmol) cooled to −78° C. was treated with phenyl-acetic acid ethyl ester (1.06 g, 6.48 mmol) in tetrahydrofuran/hexamethylphosphoramide (16.1 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (1.50 g, 7.14 mmol) in hexamethylphosphoramide (1.5 mL). The mixture was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 48 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (5 mL). The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (2×100 mL). The organics were washed with a saturated aqueous lithium chloride solution (2×50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 95/5 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-phenyl-propionic acid ethyl ester (1.70 g, quant.) as a pale yellow oil: EI-HRMS m/e calcd for C16H22O2 (M+) 247.1698, found 247.1704.
Reaction SMILES: COC[O:4][C@H:5]1[CH2:9][N:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C@@H:7]([CH2:20][N:21]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH2:25][O:24][C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]2=3)[CH2:6]1.Cl>CO>[OH:4][C@H:5]1[CH2:9][N:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C@@H:7]([CH2:20][N:21]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH2:25][O:24][C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]2=3)[CH2:6]1
Reactant: COCO[C@@H]1C[C@H](CN2c3ccccc3COc3ccccc32)N(CCc2ccc(OC)cc2)C1
Agent: Cl
Solvent: CO
Product: COc1ccc(CCN2C[C@H](O)C[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Yield: 79.3 %

Procedure:
4.20 g (8.85 mmol) of (+)-5,11-dihydro-5-[[(2R, 4R)-4-(methoxymethoxy)-1-(4-methoxyphenethyl)pyrrolidin-2-yl]methyl]dibenzo[b,e][1,4]oxazepine in 40 ml of methanol was treated with 20 ml of 10% HCl for 1 hour under reflux. Methanol was removed in vacuo and 1N NaOH was added to the residue. The products were extracted with ethyl acetate and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silicagel column chromatography (ethyl acetate ) to give 3.02 g (79.3%) of (+)-5,11-dihydro-5-[[(2R, 4R)-4-hydroxy-1-(4-methoxyphenethyl) pyrrolidin-2-yl]methyl]dibenzo[b,e][1,4]oxazepine as pale yellow amorphous.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[C:7]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])[N:6]=1)(=O)=O.[CH2:36]([NH:38][CH2:39][CH3:40])[CH3:37]>C1COCC1>[CH2:36]([N:38]([C:5]1[N:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[C:7]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])[N:6]=1)[CH2:39][CH3:40])[CH3:37]
Reactant: CS(=O)(=O)c1nc(OCc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)c1nc(OCc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
2-(Methylsulfonyl)-4-(3,4-difluorobenzyloxy)-5-[4-chlorophenyl]-6-[2,4-dichlorophenyl]pyrimidine (Reference Example 6, 55 mg, 0.10 mmol) was treated with excess diethylamine in THF according to the same general procedure described in Example 31, Step A. Workup (solvent removal under reduced pressure) and flash column chromatography on silica gel (eluted with 87/13 hexanes/ethyl acetate) afforded the title compound. HPLC/MS: m/e=550 (M++1); Rt=4.48 min. 1H-NMR 500 MHz (CDCl3): δ 1.23 (t, J=7 Hz, 3H), 3.65 (q, J=7 Hz, 2H), 5.39 (s, 2H), 7.04 (d, J=8 Hz, 2H), 7.08 (d, J=8 Hz, 2H), 7.13-7.22 (m, 5H), 7.34 (d, J=2 Hz, 1H).
Reaction SMILES: [F:1][CH:2]([F:31])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[CH:16]=2)[CH:4]=1.[S:32]([C:36]1[CH:37]=[C:38]([NH2:42])[CH:39]=[CH:40][CH:41]=1)(=[O:35])(=[O:34])[NH2:33]>>[S:32]([C:36]1[CH:37]=[C:38]([NH:42][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:31])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[C:17]([O:25][CH2:26][C:27]([F:28])([F:30])[F:29])[CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:39]=[CH:40][CH:41]=1)(=[O:34])(=[O:35])[NH2:33]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)c(OCC(F)(F)F)c3)nc12
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-[3-(2,2,2-trifluoroethoxy)-4-trifluoromethyl-phenyl]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.13) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Light yellow solid. MS (ISP) 607.9 [(M−H)−]; mp 241° C.
Reaction SMILES: C([O:3][C:4](=[O:40])[C@@H:5]([N:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36])[CH2:6][CH2:7][CH2:8][N:9]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([CH2:27][C:28]2[NH:29][CH:30]=[CH:31][N:32]=2)[CH2:20][C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[CH:14][CH:13]=1)[CH3:10])C>Cl>[CH2:34]([N:33]([C@@H:5]([CH2:6][CH2:7][CH2:8][N:9]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][N:19]([CH2:27][C:28]2[NH:29][CH:30]=[CH:31][N:32]=2)[CH2:20][C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[CH:16][CH:17]=1)[CH3:10])[C:4]([OH:40])=[O:3])[CH2:37][CH2:38][CH3:39])[CH2:35][CH3:36]
Reactant: CCCN(CCC)[C@@H](CCCN(C)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1)C(=O)OCC
Agent: Cl
Product: CCCN(CCC)[C@@H](CCCN(C)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1)C(=O)O
Temperature: 100 °C
Reaction time: 5 h
Yield: 104.7 %

Procedure:
The compound (33.0 mg) obtained in Example 94-2 was dissolved in concentrated hydrochloric acid (1.0 ml) and the whole was stirred at 100° C. for 5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was dried under vacuum, thereby obtaining a hydrochloride (32.8 mg) of the subject compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]([CH3:15])[C:12](Cl)=[O:13])(=[O:10])=[O:9].O1CCCC1.[CH3:21][NH:22][C:23]1[N:28]=[C:27]([O:29][CH2:30][C:31]([F:34])([F:33])[F:32])[CH:26]=[C:25]([CH3:35])[N:24]=1>C(N(CC)CC)C>[F:34][C:31]([F:32])([F:33])[CH2:30][O:29][C:27]1[CH:26]=[C:25]([CH3:35])[N:24]=[C:23]([N:22]([CH3:21])[C:12]([N:11]([CH3:15])[S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:10])=[O:9])=[O:13])[N:28]=1
Reactant: CN(C(=O)Cl)S(=O)(=O)c1ccccc1Cl
Reactant: CNc1nc(C)cc(OCC(F)(F)F)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(OCC(F)(F)F)nc(N(C)C(=O)N(C)S(=O)(=O)c2ccccc2Cl)n1

Procedure:
To 18 parts of N-[(2-chlorophenyl)sulfonyl]-N-methylcarbamyl chloride in 300 parts of tetrahydrofuran containing 10 parts of triethylamine is added 22 parts of 2-methylamino-4-(2,2,2-trifluoroethoxy)-6-methylpyrimidine. After stirring at reflux for 10 hours, the precipitated salts are filtered off and the filtrate is concentrated to yield N-[N-[4-(2,2,2,-trifluoroethoxy)-6-methylpyrimidin-2-yl]-N-methylaminocarbonyl]-2-chloro-N-methylbenzenesulfonamide.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][CH:6]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:19])[CH3:4].Br[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1>>[ClH:1].[CH3:4][N:3]([CH2:5][CH:6]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9][CH2:8][C:7]1([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[OH:19])[CH3:2]
Reactant: CN(C)CC1CC(Oc2ccccc2)CCC1=O
Reactant: COc1cccc(Br)c1
Agent: Cl
Product: COc1cccc(C2(O)CCC(Oc3ccccc3)CC2CN(C)C)c1
Yield: 47 %

Procedure:
The base of compound (27) was reacted with 1-bromo-3-methoxy-benzene corresponding to the conditions described in Example 1. The base obtained was purified with 6:1 ethyl acetate/methanol via a silica gel column and was taken up in 2-butanone. After adding trimethylchlorosilane/water, compound (24) was obtained in a yield of 47% theoretical.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:29])[CH:5]=[CH:6][C:7]=1[C:8]1[N:13]=[C:12]2[NH:14][N:15]=[C:16]([CH3:17])[C:11]2=[C:10]([CH2:18][N:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][CH2:21][C:20]2([CH3:28])[CH3:27])[CH:9]=1.[F:30][C:31]([F:36])([F:35])[CH2:32][CH:33]=O.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([OH:29])[CH:5]=[CH:6][C:7]=1[C:8]1[N:13]=[C:12]2[NH:14][N:15]=[C:16]([CH3:17])[C:11]2=[C:10]([CH2:18][N:19]2[CH2:24][C:23]([CH3:25])([CH3:26])[N:22]([CH2:33][CH2:32][C:31]([F:36])([F:35])[F:30])[CH2:21][C:20]2([CH3:28])[CH3:27])[CH:9]=1
Reactant: O=CCC(F)(F)F
Reactant: Cc1n[nH]c2nc(-c3ccc(O)cc3F)cc(CN3CC(C)(C)NCC3(C)C)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3F)cc(CN3CC(C)(C)N(CCC(F)(F)F)CC3(C)C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
To a solution of 300 mg of 3-fluoro-4-[3-methyl-4-(2,2,5,5-tetramethyl-piperazin-1-ylmethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-phenol, 387 mg 3,3,3-trifluoropropanal and 134 mg DIPEA in 6 ml dichloromethane and 6 ml THF was added 732 mg of sodium triacetoxyborohydride. The reaction was stirred at rt overnight. The solvents were removed in vacuo, and the residue was taken up in ethyl acetate and water. The pH was brought to neutral, and the phases were separated. The aqueous phase was extracted with ethyl acetate twice. The combined organic phases were dried over sodium sulphate, filtrated and concentrated in vacuo. The residue was purified by HPLC and 214 mg (63%) of the title compound were obtained.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][S:9][C:4]=2[CH:3]=1.[N+:13]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.C(O)C.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>[N+:13]([C:16]1[CH:21]=[C:20]([C:2]2[CH:12]=[CH:11][C:5]3[NH:6][C:7](=[O:10])[CH2:8][S:9][C:4]=3[CH:3]=2)[CH:19]=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: O=C1CSc2cc(Br)ccc2N1
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: COCCOC
Solvent: CCO
Solvent: O
Product: O=C1CSc2cc(-c3cccc([N+](=O)[O-])c3)ccc2N1
Temperature: 25 °C

Procedure:
A solution of 7-bromo-4H-benzo[1,4]thiazin-3-one (2 g, 8.2 mmol), 3-nitrophenyl boronic acid (2.72 g, 16.4 mmol), potassium carbonate (6.85 g, 49.2 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.95 g, 0.82 mmol) in dimethoxyethane (100 ml), ethanol (25 ml), and water (25 ml) was heated to reflux for 6 hours. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with water, then brine, dried (MgSO4) and evaporated to obtain crude 7-(3-nitro-phenyl)-4H-benzo[1,4]thiazin-3-one (0.15 g, 6%). Recrystallization of crude sample from EtOAc afforded the title compound: mp 290-292° C.; MS (EI) m/z 286 (M+).
Reaction SMILES: [OH:1][C:2]1([C:14]2[CH:18]=[CH:17][S:16][C:15]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2O)[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.B(F)(F)F.O>C(Cl)Cl>[S:16]1[C:15]2[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:1][C:2]3([CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]3)[C:14]=2[CH:18]=[CH:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccsc2-c2ccccc2O)C1
Agent: FB(F)F
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(C1)Oc1ccccc1-c1sccc12
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of tert-butyl 3-hydroxy-3-(2-(2-hydroxyphenyl)thiophen-3-yl)pyrrolidine-1-carboxylate (4.4 g, 12.1 mmol) in DCM (25 mL) at 0° C. was added BF3 (1.6 g, 24.2 mmol) dropwise. After stirring overnight, the reacton mixture was treated with water and extracted with EtOAc several times. The combined organic layer was washed with brine, and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (3.8 g, 92%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]3)[N:3]=1.Cl.[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH2:33])(=[O:28])=[O:27].C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH:33][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]3)[N:3]=1)(=[O:27])=[O:28]
Reactant: O=C1CCc2cc(Nc3ncc(C(F)(F)F)c(Cl)n3)ccc2N1
Reactant: CS(=O)(=O)c1cccc(CN)c1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1cccc(CNc2nc(Nc3ccc4c(c3)CCC(=O)N4)ncc2C(F)(F)F)c1
Temperature: 100 °C
Yield: 53.3 %

Procedure:
6-(4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-3,4-dihydro-1H-quinolin-2-one (50 mg, 0.145 mmol) was added to 0.5 ml NMP and 3-Methanesulfonyl-benzylamine mono hydrochloride salt (32 mg, 0.145 mmoles) and triethylamine (0.060 ml, 0.435 mmoles) were added the reaction was heated to 100° C. for one hour. The reaction was cooled to room temperature and 0.5 mL NMP was added. The reaction was then filtered and purify by preparative reverse phase HPLC 30×50 mm XTerra C18 prep column, fifteen minute gradient 15-60% (0.1% NH4OH in Acetonitrile) and (0.1% NH4OH in water)), flow rate 40 mL/min. The desired product eluted (retention time 8.41 minutes) and was concentrated to a solid (38 mg, 54% yield). 1H NMR (Methanol-d4, 400 MHz) δ 2.52 (m, 2H), 2.80 (m, 2H), 2.99 (s, 3H), 4.80 (s, 2H), 6.73 (d, J=9 Hz; 1H), 7.22 (d, J=9 Hz; 1H), 7.37 (s, 1H), 7.57 (t, J=8 Hz; 1H), 7.64 (d, J=8 Hz;1H), 7.80 (m, 1H), 7.90 (s, 1H), 8.12 (s, 1H). HPLC ret. time: 5.390, LRMS (M+) 492.12.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH2:19])[CH2:17][CH3:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+].N>C(O)C>[CH2:16]([NH:19][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1)[CH2:17][CH3:18]
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: CCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Agent: [BH4-]
Solvent: CCO
Solvent: O
Product: CCCNCc1cccc(Oc2ccccc2)c1
Temperature: 80 °C

Procedure:
3-Phenoxybenzaldehyde (2.00 mL, 2.29 g, 11.6 mmol), n-propylamine (0.95 mL, 0.68g, 11.5mmol), and p-toluenesulfonic acid monohydrate (15 mg, 0.08 mmol) were dissolved in absolute ethanol (15 mL), then heated to 80° C. in a sealed tube for 2.5 hours. The reaction was cooled to room temperature, transferred to a round-bottom flask, then sodium borohydride (440 mg, 11.6 mmol) was added, followed by heating under reflux for 2.5 hours. The reaction was concentrated, the residue was partitioned between water and EtOAc, and the EtOAc layer was washed with water and brine. After drying with Na2SO4, filtration, and concentration, the residue was purified by chromatography on silica gel using 4:6 followed by 3:7 hexane-EtOAc to give 1.59 g (57%) light yellow oil. 1H NMR (CDCl3) δ7.30 (m, 3H), 7.08 (m, 2H), 7.00 (m, 3H), 6.88 (dd, 1H), 3.77 (s, 2H), 2.60 (t, 2H), 1.53 (m, 2H), 0.92 (t, 3H). MS (DCl/NH3) m/e 242 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:21][CH2:20][C:15]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:14][CH2:13]2)[N:3]=1.[O:22]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC>[O:19]1[C:15]2([CH2:20][CH2:21][CH:12]([N:4]3[C:5]4=[N:6][CH:7]=[N:8][C:9]([NH2:11])=[C:10]4[C:2]([C:32]4[CH:33]=[CH:34][C:29]([O:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[CH:30][CH:31]=4)=[N:3]3)[CH2:13][CH2:14]2)[O:16][CH2:17][CH2:18]1
Reactant: Nc1ncnc2c1c(Br)nn2C1CCC2(CC1)OCCO2
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.8 %

Procedure:
3-bromo-1-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (Intermediate X) (4.0 g, 11.3 mmol), 4-phenoxyphenylboronic acid (Intermediate V) (2.66 g, 12 mmol), sodium carbonate (2.87 g, 27 mmol), palladium tetrakis(triphenyphosphine) (0.78 g, 0.6 mmol) in dimethoxyethane (120 mL)/water (60 mL) mixture was heated at 85° C. under nitrogen for 4 hrs. Cool to room temperature and stand for 72 hrs. The solid which precipitated was filtered and washed with water and diethylether (100 mL of each). Dry in vacuo for 3 hrs to furnish 4.2 g of 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine as a beige solid (87%). 1H NMR (400 MHz, d6-DMSO) 8.24 (1H, s), 7.67 (2H, m), 7.45 (2H, m), 7.19 (5H, m), 4.78 (1H, m), 3.90 (4H, m), 2.25 (2H, m), 1.71-1.84 (6H, m) Mass Spec.: MH+=444.2