Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[Cl:27])=[CH:14][CH:15]=1)=[O:5])C.[NH2:28][C:29]1[N:34]=[CH:33][C:32]([CH2:35][N:36]([CH3:41])[CH2:37][C:38]([NH2:40])=[O:39])=[CH:31][CH:30]=1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[C:38]([CH2:37][N:36]([CH2:35][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=3[Cl:27])=[CH:14][CH:15]=2)=[O:5])=[N:34][CH:33]=1)[CH3:41])(=[O:39])[NH2:40]
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2nccnc12
Reactant: CN(CC(N)=O)Cc1ccc(N)nc1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN(C)CC(N)=O)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 6 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 144.1), 2-[(6-amino-pyridin-3-ylmethyl)-methyl-amino]-acetamide (Step 118.1), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 6 h at 80° C. and pouring it onto a saturated aqueous solution of NaHCO3 and DCM. The title compound: ESI-MS: 539.0 [M+H]+; tR=3.61 min (System 1); TLC: Rf=0.49 (DCM/MeOH/NH3aq, 9:1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[CH:17][N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:23]=1.[F:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1.C([O-])(=O)C.[K+].CN(C=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.O>[F:24][C:25]1[C:30]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[CH:12]=[C:13]([C:15]5[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[CH:17][N:16]=5)[N:14]=[C:7]4[C:6]=3[CH:23]=2)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(-c3cccnc3F)ccc1OCC2
Temperature: 105 °C
Yield: 80.3 %

Procedure:
10-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 187 (0.057 g, 0.15 mmol), 2-fluoropyridin-3-ylboronic acid (0.026 g, 0.183 mmol), potassium acetate (0.059 g, 0.609 mmol), and tetrakis(triphenylphosphine)palladium(0) (8.8 mg, 0.007 mmol), DMF (6 mL) and water (0.6 mL) were mixed. Nitrogen was bubbled through the reaction mixture for 5 minutes. The reaction mixture was allowed to stir and heat at 105° C. for 24 hours before cooling, diluting with EtOAc, and filtering through a pad of celite. The filtrate was concentrated under reduced pressure and diluted with EtOAc. The solution was washed sequentially with water, and brine, before drying over MgSO4 and concentrating under reduced pressure. The crude material was dissolved in DMF and purified by reverse phase HPLC to provide 10-(2-fluoropyridin-3-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (47 mg, 80%). MS(ESI(+)): m/z 391.1 (M+H)
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[OH:14].[C:15](Cl)(=[O:17])[CH3:16]>CN(C=O)C.C(Cl)Cl>[C:15]([O:14][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH:1]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: Oc1ccc2c(c1)[nH]c1ccccc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)Oc1ccc2c(c1)[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To 9H-carbazol-2-ol (915 mg, 5 mmol) in 10 mL DMF and 20 mL DCM was added TEA (1.0 g, 10 mmol), followed by acetyl chloride (589 mg, 7.5 mmol) at 0° C. The reaction mixture was then stirred at rt for 1 h and poured onto ice (50 g). The mixture was extracted with EtOAc (2×60 mL) and combined organic phase was dried over MgSO4 and concentrated. The crude product was purified by silica chromatography to afford 9H-carbazol-2-yl acetate (WZ02013) as an off-white solid (800 mg, 71%). MS (ESI) m/z 348 (M+H+).
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[CH:50]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=1)=[CH2:51]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[N:53]1[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=1[CH:50]=[CH:51][C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1
Reactant: O=c1c(Br)cc(-c2ccccn2)cn1-c1ccccc1
Reactant: C=Cc1ccccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: O=c1c(C=Cc2ccccn2)cc(-c2ccccn2)cn1-c1ccccc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 8.1 %

Procedure:
23 mg of 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one was dissolved in 20 ml of acetonitrile. To the mixture were added 0.2 mg of palladium acetate, 4.3 mg of tri-o-tolylphosphine and 0.04 ml of triethylamine, followed by stirring at 110° C. in nitrogen atmosphere overnight. To the mixture was added 9.2 mg of 2-vinylpyridine, followed by stirring at 110° C. in nitrogen atmosphere for 5 hours. After cooling to room temperature, the reaction mixture was poured into water, followed by extracting with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate system), to give 2 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20]>C1COCC1>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)(=[O:21])=[O:20])=[CH:4][CH:3]=1
Reactant: Cc1ccc2cc[nH]c2c1
Reactant: O=S(=O)(Cl)c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc2ccn(S(=O)(=O)c3ccccn3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.7 %

Procedure:
6-Methylindole (42) (7.34 g, 56.0 mmol) was added in portions to a mixture of sodium hydride (3.36 g, 84.0 mmol) in THF (80 mL) at 0° C. After 15 min, pyridine-2-sulfonyl chloride (43) (10.0 g, 56.0 mmol) was added, and the reaction was allowed to warm to rt and stirred overnight under N2. The reaction mixture was then quenched with ice water and extracted with EtOAc. The organic layers were combined, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with a linear gradient ranging from 0 to 40% EtOAc-hexanes to provide 8.8 g (57%) of product 44 as a brown gum. 1H NMR (300 MHz, CDCl3) δ 2.44 (s, 3H), 6.62 (dd, J=1, 4 Hz, 1H), 7.03-7.06 (m, 1H), 7.41 (d, J=8 Hz, 1H), 7.41-7.45 (m, 1H), 7.59 (d, J=4 Hz, 1H), 7.79-7.81 (m, 1H), 7.84-7.90 (m, 1H), 8.10 (dt, J=1, 8 Hz, 1H), 8.58-8.60 (m, 1H). LC-MS (CI): m/z 273.0 [(M+H)+ C14H12N2O2S requires 272.06].
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:21]1(O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.P(=O)(O)(O)[OH:29]>>[OH:29][C:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:1]([OH:20])=[O:19]
Reactant: Oc1ccccc1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: O=P(O)(O)O
Product: CCCCCCCCCCCCCCCCC(O)(C(=O)O)c1ccccc1
Temperature: 200 °C

Procedure:
A 500-ml autoclave was charged with 166 g of commercial oleic acid (product of Nippon Oils & Fats Co., Ltd.), 169 g of phenol (product of Katayama Kagaku Kogyo K.K.), 6.6 g of activated clay (Nippon Kassei Hakudo K.K.), and 0.13 g of 85% aqueous phosphoric acid (product of Katayama Kagaku Kogyo K.K.). After purging the autoclave with nitrogen gas, the contents were allowed to react by heating at 200° C. for 4 hours. After completion of the reaction, the activated clay was filtered off and the unreacted phenol was distilled away at 80°-100° C., 3 mmHg to yield a yellow viscous reaction product in an amount of 224 g.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:4][CH2:3]1.[H][H]>CO.[Pd]>[CH3:1][CH:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:6][CH2:7]1
Reactant: CC1CCN(CCOc2ccc([N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1CCN(CCOc2ccc(N)cc2)CC1

Procedure:
A reaction mixture of 680 mg (2.57 mmol) of 4-methyl-1-[2-(4-nitrophenoxy)ethyl]piperidine and 80 mg palladium (10% on charcoal) in 10 mL of methanol is hydrogenated at ambient temperature and 3 bar hydrogen for 4.5 hours. The catalyst is suction filtered and the filtrate is evaporated down. Yield: 540 mg (90% of theory); C14H22N2O (M=234.34); calc.: molecular ion peak (M+H)+: 235; found: molecular ion peak (M+H)+: 235; Rf value: 0.33 (silica gel, dichloromethane/methanol/ammonia (90:10:0.1)).
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=CC=C[CH:2]=1.C[O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([Cl:30])[CH:24]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.C(O)(C)C>C1COCC1>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[O:29][CH:1]([CH3:6])[CH3:2])[C:22]([OH:21])=[O:31]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(C(=O)O)cc1Cl
Yield: 73.1 %

Procedure:
Into a round bottom flask was added triphenylphosphine (62 g, 0.263 mol), 3-chloro-4-hydroxy-benzoic acid methyl ester (10 g, 0.0535 mol) and anhydrous THF (500 mL). The mixture was briefly stirred under nitrogen, then DBAD (19.75 g, 0.0858 mol) was added. The mixture was stirred for a few minutes before adding anhydrous isopropanol (5.125 mL, 0.067 mol). After the reaction mixture was stirred at room temperature under an atmosphere of nitrogen for about 3 hours, DBAD (19.75 g, 0.0858 mol) and anhydrous isopropanol (5.125 mL, 0.067 mol) were added and the mixture was left to stir at room temperature overnight. The solvent was removed under reduced pressure. The residue was dissolved in minimum amount of ethyl acetate. Heptane was added and the precipitate was removed by filtration. The filtrate was brought up in methanol. Water was added until cloudy. Precipitate was filtered off. The methanol/water precipitation procedure was repeated two more times. The filtrate was taken up in THF (200 mL) and 5 M NaOH (200 mL). The mixture was stirred at room temperature overnight. The organic solvent was removed under reduced pressure. The aqueous layer was extracted three times with ethyl acetate. The aqueous layer was further acidified to pH 1-2 with 2 M HCl. The cloudy suspension was then extracted with ethyl acetate three times. The organic layers were combined, dried over magnesium sulfate, and concentrated to dryness to give 3-chloro-4-isopropoxy-benzoic acid (8.4 g, 71.4%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[C:10]([F:11])=[CH:9][C:8](F)=[C:7]([F:13])[C:6]=1[F:14])[CH3:2].C(N(CC)CC)C.[C:23]([O:27][C:28](=[O:35])[NH:29][C@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)([CH3:26])([CH3:25])[CH3:24]>C(#N)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[C:10]([F:11])=[CH:9][C:8]([N:32]2[CH2:33][CH2:34][C@H:30]([NH:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:35])[CH2:31]2)=[C:7]([F:13])[C:6]=1[F:14])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: CCOC(=O)c1c(F)cc(F)c(F)c1F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(F)cc(N2CC[C@H](NC(=O)OC(C)(C)C)C2)c(F)c1F
Yield: 69.8 %

Procedure:
A solution of 2,3,4,6-tetrafluorobenzoic acid ethyl ester (Example 1b, 5.1 g, 22.9 mmol), triethylamine (22 mL, 157 mmol), and (S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester (5.2 g, 27.9 mmol) in acetonitrile (60 mL) is stirred at room temperature for 64 hours. The mixture is concentrated in vacuo and the residue dissolved in chloroform, washed with NaHCO3 and then brine, dried over Na2SO4, filtered, and concentrated under vacuum to afford a solid. The solid is purified by column chromatography (1:1:7 ethyl acetate/chloroform/hexanes) to afford the title compound (6.21 g). 1H NMR (CDCl3): δ 6.07 (ddd, 1H), 4.78-4.63 (bd, 1H), 4.49-4.22 (m, 3H), 3.80-3.68 (m, 1H), 3.66-3.28 (m, 3H), 2.33-2.13 (m, 1H), 2.04-1.83 (m, 1H), 1.45 (s, 9H), 1.36 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:33])=[C:19]([NH:23][S:24]([C:27]3[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=3)(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:35]>>[ClH:1].[NH2:35][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:33])=[C:19]([NH:23][S:24]([C:27]3[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=3)(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: Cn1ccnc1S(=O)(=O)Nc1cccc(-c2nc(C(C)(C)C)sc2-c2ccnc(Cl)n2)c1F
Agent: [OH-]
Product: Cl
Product: Cn1ccnc1S(=O)(=O)Nc1cccc(-c2nc(C(C)(C)C)sc2-c2ccnc(N)n2)c1F

Procedure:
Following a procedure analogous to the procedure described in Example 282 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1-methyl-1H-imidazole-2-sulfonamide (560 mg, 1.10 mmol) and ammonium hydroxide (15 ml), the title compound was obtained as a white solid (156 mg, 27%). 1HNMR (MEOD-d4): δ ppm 8.06 (br s, 1H), 7.66 (s, 1H), 7.53-7.58 (m, 2H), 7.44 (s, 1H), 7.36-7.40 (t, J=8.0 Hz, 1H), 6.47-6.51 (m, 1H), 4.06 (s, 3H), 1.50 (s, 9H). MS: 488 [M+H]+.
Reaction SMILES: C1(=O)OC(=O)C=C1.[C:8]([OH:13])(=[O:12])[C:9]([CH3:11])=[CH2:10].C(OOC(C)(C)C)(C)(C)C.[C:24]([O:37]CC)(=[O:36])[C:25]1[C:26](=CC=CC=1)[C:27]([O:29]CC)=[O:28]>O>[C:8]([O-:13])(=[O:12])[C:9]([CH3:11])=[CH2:10].[C:24]([O-:37])(=[O:36])/[CH:25]=[CH:26]\[C:27]([O-:29])=[O:28]
Reactant: C=C(C)C(=O)O
Reactant: CCOC(=O)c1ccccc1C(=O)OCC
Agent: CC(C)(C)OOC(C)(C)C
Agent: O=C1C=CC(=O)O1
Solvent: O
Product: C=C(C)C(=O)[O-]
Product: O=C([O-])/C=C\C(=O)[O-]
Reaction time: 0.17 h

Procedure:
The preparation of Example 4 is repeated with the exception that 39 g (0.40) mole maleic anhydride is copolymerized with 52 g (0.60 mole) methacrylic acid in the presence of 14 g di-t-butyl peroxide initiator and 945 g diethyl phthalate in a 2000 ml flask, the methacrylic acid is added over a 20-minute period at a polymerization temperature of 150° C., the reaction solution is held at the polymerization temperature for 10 minutes following the methacrylic acid addition, and the copolymer is hydrolyzed by the addition of 420 g water added at a temperature of 120° C. A substantially homogeneous hydrolyzed methacrylate/maleate copolymer is obtained.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.O[C@@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:17]3[CH2:18][CH2:13][CH2:14][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H](n2nc(I)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2 g, 0.0077 mol), (R)-tert-butyl 3-hydroxy-1-piperidinecarboxylate (2.3 g, 0.012 mol), and triphenylphosphine (3 g, 0.012 mol) in tetrahydrofuran (70 mL), diethyl azodicarboxylate (2 g, 0.012 mol) was added at 0° C. The mixture was stirred at room temperature under an atmosphere of nitrogen for 2 days. In order to complete the reaction, additional (R)-tert-butyl 3-hydroxy-1-piperidinecarboxylate (0.62 g, 0.003 mol), and triphenylphosphine (0.81 g, 0.012 mol), and diethyl azodicarboxylate (0.6 g, 0.003 mol) were added to the mixture. The mixture was stirred at room temperature under an atmosphere of nitrogen for additional 18 hours. The solvent was removed under the reduced pressure to yield crude (S)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate, which was used crude for the next reaction.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].S(Cl)([Cl:16])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].Cl>C1(C)C=CC=CC=1.O>[Cl:16][C:8]1[CH:7]=[CH:6][C:5]([OH:10])=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:9]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Oc1ccccc1OC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Oc1ccc(Cl)cc1OC(F)(F)F
Temperature: 30 °C
Reaction time: 0.33 h

Procedure:
1.78 g of o-trifluoromethoxyphenol was dissolved in 5 mL of toluene, and the mixture was stirred in an ice water bath for 20 min. 1.485 g of sulfonyl chloride was added dropwise to the reaction system within 10 min, which was then stirred for 20 min. The solution was moved to a water bath maintained at 30° C., and allowed to stir at this temperature for 1 h. 200 mL of 5% sodium carbonate aqueous solution and 50 mL of toluene were added to the system, which was then violently vibrated and isolated (pH of water layer was 10 upon determination). The pH of water layer was adjusted to 2 with 2 N of hydrochloric acid aqueous solution. The solution was extracted with 50 mL of toluene once again. The toluene layers were combined, successively washed with 100 mL of water and 100 mL of saturated sodium chloride aqueous solution, dried over 5 g of anh. MgSO4 for 30 min, and concentrated via a rotary evaporator to obtain a white granular solid. MS anion peak (M-H: 213).
Reaction SMILES: [C:1]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:13])[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[H-].[Na+].Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([P:35](=[O:46])([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])([F:34])[F:33])=[CH:28][CH:27]=1>CN(C=O)C>[C:42]([O:41][P:35]([C:32]([F:34])([F:33])[C:29]1[CH:30]=[CH:31][C:26]([CH2:25][C:2]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([P:35]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:46])([F:34])[F:33])=[CH:28][CH:27]=2)([C:1]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[C:3]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])=[CH:27][CH:28]=1)([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:46])([CH3:43])([CH3:44])[CH3:45]
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)(F)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)(F)c1ccc(CC(Cc2ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc2)(C(=O)OCc2ccccc2)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
To a solution of dibenzyl malonate (0.5 g) in DMF (4 mL), was added sequentially NaH (0.12 g, 80% in mineral oil), di(tert-butyl) [[4-(bromomethyl)phenyl](difluoro)methyl]phosphonate (1.60 g). The reaction mixture was stirred at room temperature for 1 h, then quenched with 20 mL of saturated aqueous NH4Cl solution and extracted with 50 mL EtOAc. The extract was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 1:1 hexane/EtOAc to give the title compound (0.3 g).
Reaction SMILES: [CH:1]([N:4]([CH:11]([CH3:13])[CH3:12])[C:5](=[O:10])[CH2:6][C:7](=[O:9])[CH3:8])([CH3:3])[CH3:2].[OH-].[Na+].[Cl-].[C:17]1([N+:23]#[N:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH:11]([N:4]([CH:1]([CH3:2])[CH3:3])[C:5](=[O:10])[C:6](=[N:24][NH:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:7](=[O:9])[CH3:8])([CH3:13])[CH3:12]
Reactant: N#[N+]c1ccccc1
Reactant: CC(=O)CC(=O)N(C(C)C)C(C)C
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C(=NNc1ccccc1)C(=O)N(C(C)C)C(C)C
Yield: 68.2 %

Procedure:
7.0 g (0.038 mol) of N,N-diisopropyl-3-oxobutyramide, a solution of 5.3 g (0.133 mol) of NaOH in 58 ml of water and 0.04 mol of phenyldiazonium chloride were treated as described in preparation 8. The crude reaction mixture was purified by chromatography on silica gel (hexane/Et2O 95:5) obtaining 7.5 g of the title compound which was used as such in the subsequent step. M.p.=143°-145° C.
Reaction SMILES: [C:1]([N:4]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)[C:5](=[O:31])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:10][CH:9]=1)(=[O:3])[CH3:2].[CH3:39][I:40]>>[I-:40].[C:1]([N:4]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N+:34]=1[CH3:39])[C:5](=[O:31])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)N(Cc2ccccn2)C(C)=O)cc1
Reactant: CI
Product: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)N(Cc2cccc[n+]2C)C(C)=O)cc1
Product: [I-]
Yield: 88.1 %

Procedure:
The title compound is prepared by the procedure of Example 28, using 0.268 g of product from Example 90 and 3.63 g of methyl iodide. The residue is crystallized from hot methyl alcohol/chloroform to give 0.30 g of the desired product as colorless needles.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC.[NH2:30][C:31]1[C:32]([C:49]([OH:51])=O)=[N:33][C:34]([C:37]2[CH:42]=[CH:41][C:40]([S:43]([CH:46]([CH3:48])[CH3:47])(=[O:45])=[O:44])=[CH:39][CH:38]=2)=[CH:35][N:36]=1.[NH2:52][NH:53][C:54]([NH2:56])=[S:55]>CN(C=O)C.O>[NH2:30][C:31]1[C:32]([C:49]([NH:52][NH:53][C:54](=[S:55])[NH2:56])=[O:51])=[N:33][C:34]([C:37]2[CH:42]=[CH:41][C:40]([S:43]([CH:46]([CH3:47])[CH3:48])(=[O:45])=[O:44])=[CH:39][CH:38]=2)=[CH:35][N:36]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C(=O)O)n2)cc1
Reactant: NNC(N)=S
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C(=O)NNC(N)=S)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TBTU (749.4 mg, 2.334 mmol) and Et3N (157.5 mg, 216.9 μL, 1.556 mmol) were added to a suspension of 3-amino-6-(4-isopropylsulfonylphenyl)pyrazine-2-carboxylic acid (500 mg, 1.556 mmol) and aminothiourea (141.8 mg, 1.556 mmol) in DMF (10 mL). The reaction was allowed to stir at ambient temperature for 1 h. The reaction mixture was added to rapidly stirring water and the resultant precipitate isolated by filtration to give the product as a khaki solid (587 mg, 96%) 1H NMR (400 MHz, DMSO) d 1.18 (d, 6H), 3.40-3.56 (m, 1H), 7.64 (s, 2H), 7.79 (s, 2H), 7.88 (d, 2H), 8.56 (d, 1H), 9.03 (s, 1H), 9.41 (s, 1H) and 10.75 (s, 1H) ppm; MS (ES+) 395.2