Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[O-][C:3]#[N:4].[Na+].[CH:6]([N:19]1[CH2:22][CH:21](OS(C)(=O)=O)[CH2:20]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH:6]([N:19]1[CH2:22][CH:21]([C:3]#[N:4])[CH2:20]1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: N#C[O-]
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 65 °C
Reaction time: 9 h
Yield: 92.3 %

Procedure:
Water (7.2 ml) and sodium cyanate (3.48 g) were added to a solution of 1-benzhydryl-3-(methanesulfonyloxy)azetidine (7.52 g) in N,N-dimethylformamide (60 ml), followed by stirring at 65° C. for 9 hours. Water, sodium carbonate and ethyl acetate were added to the reaction mixture, which was partitioned. The aqueous layer was extracted with ethyl acetate. The organic layer was collected, washed with brine, and dried over anhydrous sodium sulfate. This was concentrated under reduced pressure, and the resultant crystals were suspended by addition of diethyl ether (10 ml). The crystals were collected by filtration, and washed with diethyl ether. This was dried under aeration to give the title compound (5.43 g, 92.3%) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].Cl.[NH2:11][OH:12].Cl[C:14](Cl)(Cl)[CH:15]([OH:17])O.S([O-])([O-])(=O)=O.[Na+].[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:15](=[O:17])[CH:14]=[N:11][OH:12])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(F)c1
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: NO
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: O=C(C=NO)Nc1ccc(F)c(F)c1

Procedure:
A process for producing 2-chloro-4,5-difluorobenzoic acid which comprises reacting 3,4-difluoroaniline and hydroxylamine hydrochloride in an aqueous acidic solution with an aqueous solution of chloral hydrate and sodium sulfate at reflux, filtering while hot, giving N-(3,4-difluorophenyl)-2-(hydroxyimino)acetamide, which is reacted with concentrated sulfuric acid and heat, giving 5,6-difluoro-1H-indole-2,3-dione, which is dissolved in an aqueous base, treated with hydrogen peroxide and heat, then cooled and acidified, giving 2-amino-4,5-difluorobenzoic acid, which is reacted with anhydrous copper(II) chloride, t-butyl nitrite and anhydrous acetonitrile at 0°-5° C., then added to a dilute mineral acid, giving the desired compound.
Reaction SMILES: [Br-].[CH2:2]([O:9][C:10]([CH2:12][N+:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])[C:20]#[CH:21].C(N(CC)CC)C.O>CN(C=O)C>[C:24]([O:23][C:19]([C:20]1[CH:21]=[C:12]([C:10]([O:9][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:11])[N:13]2[C:18]=1[CH:17]=[CH:16][CH:15]=[CH:14]2)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: C#CC(=O)OC(C)(C)C
Reactant: O=C(C[n+]1ccccc1)OCc1ccccc1
Agent: [Br-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1cc(C(=O)OCc2ccccc2)n2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 1-benzyloxycarbonylmethyl-pyridinium bromide (1.50 g, 9.74 mmol) and tert-butyl propiolate (1.34 mL, 9.74 mmol) in DMF (80 mL) was added a solution of triethylamine (4.1 mL, 29.2 mmol) in DMF (10 mL). The mixture was vigourously stirred 4 h at 60° C. under air atmosphere. The solution was allowed to cool to RT, poured into water and extracted with EtOAc (2×). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 8:2) to give the desired material. TLC, Rf (c-hexane/EtOAc 8:2)=0.6; MS (LC/MS): 725.3 [2M+Na]+; tR (HPLC conditions a): 4.84 min.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([SH:12])=[N:6][C:5]=2[NH:4][CH:3]=1.[OH-].[Na+].[F:15][C:16]1[CH:31]=[CH:30][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=2)=[O:21])=[CH:18][CH:17]=1>CO.COCCOC>[F:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH2:26][S:12][C:7]3[NH:8][C:9](=[O:11])[C:10]4[C:2]([CH3:1])=[CH:3][NH:4][C:5]=4[N:6]=3)=[CH:24][CH:23]=2)=[O:21])=[CH:30][CH:31]=1
Reactant: Cc1c[nH]c2nc(S)[nH]c(=O)c12
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: COCCOC
Product: Cc1c[nH]c2nc(SCc3ccc(C(=O)c4ccc(F)cc4)cc3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.6 %

Procedure:
In methanol (25 ml) was suspended 5-methyl-2-mercapto-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (1.82 g) followed by addition of 1N-sodium hydroxide (10.5 ml) for dissolution. Then, under ice-cooling, a solution of 4-(4-fluorobenzoyl)benzyl bromide (3.51 g) in DME (10 ml) was added dropwise. The mixture was stirred at room temperature for 4 hours and the resulting crystalline precipitate was collected by filtration and rinsed with water. The crystals were further rinsed with 50% ethanol/water, methanol and ether serially, dried, and recrystallized from DME (1,2-dimethoxyethane) to provide the title compound (2.71 g). 1H-NMR (DMSO-d6) δ: 2.24(3H,s), 4.51(2H,s), 6.65(1H,s), 7.37(2H,t,J=8.8Hz), 7.64(2H,d,J=8.8Hz), 7.70(2H,d,J=8.8Hz), 7.81(2H,dd,J=5.6,8.8Hz), 11.43(1H,s), 11.97(1H,s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:11]=[C:10]3[NH:27][N:28]=[CH:29][C:9]=23)=[CH:4][CH:3]=1.[OH-].[K+].O.[CH3:33][CH2:34]OC(C)=O>C1(C)C=CC=CC=1>[CH2:33]([N:28]1[CH:29]=[C:9]2[C:10]([N:11]=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:13]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:27]1)[CH3:34].[CH2:33]([N:27]1[C:10]2=[N:11][C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[C:13]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:9]2[CH:29]=[N:28]1)[CH3:34]
Reactant: Fc1ccc(-c2nc3[nH]ncc3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Reactant: CCOC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Product: CCn1ncc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc21
Temperature: 100 °C
Reaction time: 48 h
Yield: 61 %
Yield: 9 %

Procedure:
A suspension of 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (0.39 g, 0.8 mmol, obtained in example 1), KOH (0.05 g, 0.8 mmol) and crown ether 18-C-6 (0.01 g, 0.03 mmol) in toluene (3 mL) was heated to 100° C. for 2 h. A solution of lodoethane (0.18 g, 1.2 mmol) in toluene (1 mL) was added and stirred at 100° C. for 2 days. It was allowed to cool, water and EtOAc were added and the phases were separated. The aqueous phase was extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 0.20 g of 2-ethyl-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (yield: 61%) and 28 mg of 1-ethyl-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (yield: 9%).
Reaction SMILES: [NH2:1][C:2]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16](=[O:31])[C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Cl[C:42]([O:44][CH2:45][CH3:46])=[O:43]>C(Cl)Cl.C(OCC)(=O)C>[F:30][C:27]([F:28])([F:29])[C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=1)[C:16]([NH:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:2]2([NH:1][C:42](=[O:43])[O:44][CH2:45][CH3:46])[CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:9][CH2:10]1)=[O:31]
Reactant: NC1(CN2CCC(CNC(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)CCCC1
Reactant: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)NC1(CN2CCC(CNC(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-((1-((1-aminocyclopentyl)methyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide (100 mg, 0.28 mmol) and i-Pr2NEt (0.2 mL, 1.1 mmol) in CH2Cl2 (5 mL) was added ethyl chloroformate (0.05 mL, 0.53 mmol). The reaction mixture was allowed to stir at room temperature for 18 hours and then diluted with ethyl acetate. The organic fraction was washed with sat. NaHCO3, and then brine and dried over Na2SO4. The solvent was removed and the crude was purified by HiTOPs to provide ethyl 1-((4-((3,5-bis(trifluoromethyl)benzamido)methyl)piperidin-1-yl)methyl)cyclopentylcarbamate.
Reaction SMILES: ClC(O[C:6](=[O:12])OC(Cl)(Cl)Cl)(Cl)Cl.C(N(CC)CC)C.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([O:36][CH:37]([CH3:39])[CH3:38])[CH:29]=2)=[N:25][CH:26]=1.[Cl-].[CH3:41][C@@:42]([NH3+:49])([CH2:47][CH3:48])[C:43](OC)=[O:44].C[O-].[Na+]>C(Cl)Cl.CO>[CH2:47]([C@:42]1([CH3:41])[C:43](=[O:44])[N:20]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([O:36][CH:37]([CH3:39])[CH3:38])[CH:29]=3)=[N:25][CH:26]=2)[C:6](=[O:12])[NH:49]1)[CH3:48]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)Oc1cc(Oc2ccc(N)cn2)ccc1C#N
Reactant: CC[C@@](C)([NH3+])C(=O)OC
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CC[C@@]1(C)NC(=O)N(c2ccc(Oc3ccc(C#N)c(OC(C)C)c3)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 54.7 %

Procedure:
In a 2-necked round bottomed flask, bis(trichloromethyl)carbonate (174.5 mg, 0.59 mmol) was dissolved in DCM (10 mL). N,N-diethylethanamine (0.651 mL, 3.74 mmol) was added therein. The obtained solution was cooled to 0° C. In a separate vial, 4-[(5-amino-2-pyridinyl)oxy]-2-[(1-methylethyl)oxy]benzonitrile (Intermediate 156, 145.4 mg) was dissolved in DCM (10 mL). The obtained solution was added dropwise in 5 min to the chilled bis(trichloromethyl)carbonate solution. At the end of addition, at 0° C., having checked that 4-[(5-amino-2-pyridinyl)oxy]-2-[(1-methylethyl)oxy]benzonitrile completely disappeared, a solution in DCM (5 mL) of N,N-diethylethanamine (0.280 mL, 1.60 mmol) and (2R)-2-methyl-1-(methyloxy)-1-oxo-2-butanaminium chloride (Tetrahedron 1988, 44(15), 4793-6, 179.2 mg, 1.07 mmol) was added to the reaction mixture and it was stirred for 25 min. The reaction mixture was quenched with 10 mL of water, diluted with 50 mL of DCM, and acidified to pH ˜5-6 using an aqueous pH 3 buffer solution. Phases were separated. The organic layer was washed with 15 mL of brine, dried over dry sodium sulphate, filtered and evaporated in vacuo to obtain a white foam. This foam was dissolved in 8 mL of methanol and Sodium methoxide (17.3 mg, 0.32 mmol) was added to the reaction mixture. The vial was sealed and shaken on PLS at 60° C. After 15 min, further sodium methoxide (17.3 mg, 0.32 mmol) was added portionwise to the reaction mixture and it was shaken up to 1.5 hr. The reaction mixture was then evaporated in vacuo using a biotage V10 apparatus to obtain a pale yellow solid. This crude was purified by Biotage SP1 (Silica; from 100:0 to 50:50 Cyclohexane/EtOAc in 10 CV) to give the title compound (116.5 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C@@H:12]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][CH2:14][CH:15]=[CH2:16].C([C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([CH3:40])[CH:31]=1)=C>CC1C=C(C)C=C(C)C=1N1CCN(C2C(C)=CC(C)=CC=2C)C1=[Ru-4](Cl)(Cl)=CC1C=C(S(N(C)C)(=O)=O)C=CC=1OC(C)C.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C@H:12]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:13][CH2:14]/[CH:15]=[CH:16]/[C:30]1[CH:35]=[C:34]([C:36]([F:37])([F:39])[F:38])[CH:33]=[C:32]([CH3:40])[CH:31]=1
Reactant: C=CCC[C@H](NC(=O)OCc1ccccc1)c1cc(C(F)(F)F)ccc1Br
Reactant: C=Cc1cc(C)cc(C(F)(F)F)c1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru-4](Cl)(Cl)=Cc2cc(S(=O)(=O)N(C)C)ccc2OC(C)C)c(C)c1
Solvent: ClCCl
Product: Cc1cc(/C=C/CC[C@@H](NC(=O)OCc2ccccc2)c2cc(C(F)(F)F)ccc2Br)cc(C(F)(F)F)c1
Temperature: 60 °C
Yield: 73.7 %

Procedure:
To a 100 mL RBF equipped with a reflux condenser was added benzyl {(1S)-1-[2-bromo-5-(trifluoromethyl)phenyl]pent-4-en-1-yl}carbamate (0.5 g, 1.13 mmol), 1-ethenyl-3-methyl-5-(trifluoromethyl)benzene (421 mg, 2.26 mmol) and dichloromethane (10 mL). The system was flushed with nitrogen and 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene[2-(i-propoxy)-5-(N,N-dimethylaminosulfonyl)phenyl]methyleneruthenium(II) dichloride (41 mg, 0.57 mmol) (Zhan catalyst-1B) was added before heating at 60° C. for 20 min. The reaction was cooled to room temperature and was directly purified by column chromatography to yield benzyl {(1R,4E)-1-[2-bromo-5-(trifluoromethyl)phenyl]-5-[3-methyl-5-(trifluoromethyl)phenyl]pent-4-en-1-yl}carbamate (500 mg, 0.833 mmol). 1H NMR (500 MHz, CDCl3) δ7.72 (m, 1H), 7.58 (s, 1H), 7.39 (b, 5H), 6.4 (d, J=8.2 Hz, 1H), 6.25 (m, 1H), 5.35 (m, 1H), 5.20 (m, 1H), 5.10 (s, 2H), 2.40 (s, 3H), 2.19 (m, 1H), 2.05 (m, 1H), 1.95 (m, 1H), 1.78 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[S:9](=O)(=[O:12])([OH:11])[OH:10]>O>[NH2:5][C:4]1[CH:6]=[CH:7][C:8]([S:9]([OH:12])(=[O:11])=[O:10])=[C:2]([Cl:1])[CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1cccc(Cl)c1
Solvent: O
Product: Nc1ccc(S(=O)(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.4 mL of 3-chloroaniline was slowly added to 4 mL of a fuming sulfuric acid and stirred at room temperature overnight. Cooling it down to 0° C., the reaction solution was poured in water, and a precipitated solid substance was taken by filtration. The solid substance was dissolved in an aqueous solution of 2N sodium hydroxide. Then, a concentrated hydrochloric acid wad added thereto to make the liquid acidic. The precipitated solid substance was filtered out to obtain a crude product of 4-amino-2-chlorobenzenesulfonic acid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:2]1.C(N(CC)CC)C.Cl[Si](C)(C)C.[Cl:27][CH2:28][CH2:29][CH2:30][C:31](Cl)=[O:32]>ClCCl>[Cl:27][CH2:28][CH2:29][CH2:30][C:31]([N:10]([C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH:2]=1)[CH2:11][C:12]([OH:14])=[O:13])=[O:32]
Reactant: O=C(O)CNc1csc2ccccc12
Reactant: O=C(Cl)CCCCl
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CN(C(=O)CCCCl)c1csc2ccccc12
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of 621 mg (3 mM) of 3-benzothienylglycine in 15 ml of dichloromethane containing 0.92 ml (6.6 mM) of triethylamine and 717 mg of chlorotrimethylsilane was heated at 50° C. and stirred for thirty minutes and then cooled to 5° C. A solution of 0.336 ml (3 mM) of 4-chlorobutyryl chloride in 5 ml of dichloromethane was added dropwise to the reaction mixture and stirring was continued at 5° C. for one hour following the addition. The reaction mixture was warmed to 25° C. and stirred for an additional hour. The reaction mixture was next washed twice with 10 ml portions of water, dried, and the solvent was removed by evaporation to give an oil. The oil was crystallized from 0.7 ml of acetone and 2.7 ml of water, and recrystallized from ethyl acetate to afford 150 mg of N-(3-chloropropylcarbonyl)-3-benzothienylglycine. m.p. 167°-168° C.
Reaction SMILES: [C:1]1([CH2:11][CH2:12][OH:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClCCl.[C:24](Cl)(=[O:28])[C:25]([CH3:27])=[CH2:26]>CN(C)C1C=CN=CC=1.C(OCC)C>[C:24]([O:13][CH2:12][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:28])[C:25]([CH3:27])=[CH2:26]
Reactant: OCCc1cccc2ccccc12
Reactant: C=C(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OCCc1cccc2ccccc12

Procedure:
A solution of 2-(1-naphthy)ethanol (30.0 g, 174 mmol), triethylamine (24.2 g, 239 mmol), 4-(dimethylamino)pyridine (1.1 g, 9.1 mmol), and dichloromethane (500 mL) was treated dropwise under nitrogen with methacryloyl chloride (18.9 g, 181 mmol), and then heated at refluxed for 4 h. The reaction mixture was cooled to ambient and diluted with diethyl ether. The solution was filtered and the filtrate was washed twice with water, once with NaHCO3, and once with brine. The solution was dried (Na2SO4) and concentrated to deposit a yellow oil. The product was purified by distillation at reduced pressure, collecting the fraction bp 120-125° C./0.08 mm to provide a colorless oil, mass: 36.0 g (86% theory). 1H (CDCl3): δ 2.00 (s, 3H), 3.50 (t, 2H), 4.55 (t, 2H), 5.60 (s, 1H), 6.15 (s, 1H), 7.50 (m, 4H), 7.8 (d, 1H), 7.9 (d, 1H), 8.2 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][C:13](Cl)=[N:14][CH:15]=3)[N:10]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:37][C:38]([O:41][C:42]([NH:44][CH:45]1[CH2:50][CH2:49][CH:48]([NH2:51])[CH2:47][CH2:46]1)=[O:43])([CH3:40])[CH3:39].CCN(CC)CC>CC(O)C>[C:38]([O:41][C:42](=[O:43])[NH:44][CH:45]1[CH2:46][CH2:47][CH:48]([NH:51][C:13]2[N:12]=[C:11]3[N:10]([C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:9]=[C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=4)[C:16]3=[CH:15][N:14]=2)[CH2:49][CH2:50]1)([CH3:40])([CH3:37])[CH3:39]
Reactant: Clc1ncc2c(-c3cccc(Br)n3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2n1
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4cccc(Br)n4)nn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c3n2)CC1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
The mixture of 3-(6-bromo-pyridin-2-yl)-6-chloro-1-trityl-1H-pyrazolo[3,4-d]pyrimidine (from Example 34 supra) (3.8 g, 6.89 mmol), tert-butyl (1r,4r)-4-aminocyclohexylcarbamate (1.8 g, 8.40 mmol) and Et3N (1.2 mL, 8.3 mmo,) in IPA (80 mL) was stirred at 90° C. for 15 hours. The reaction was cooled to room temperature and the precipitate was collected by filtration to give {-4-[3-(6-bromo-pyridin-2-yl)-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester as white powder. (Yield 1.5 g, 30%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[CH2:17])[C:11]2=[O:18])=[C:6](/[CH:19]=[CH:20]/[CH3:21])[CH:5]=1)([O-:3])=[O:2].C12BC(CCC1)CCC2.[OH-:31].[Na+].OO>O1CCCC1>[OH:31][CH2:17][CH2:16][C:12]1[C:11](=[O:18])[N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2/[CH:19]=[CH:20]/[CH3:21])[CH:15]=[CH:14][CH:13]=1
Reactant: C=Cc1cccn(-c2ccc([N+](=O)[O-])cc2/C=C/C)c1=O
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: C/C=C/c1cc([N+](=O)[O-])ccc1-n1cccc(CCO)c1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
452 g (1.60 mmol) of the compound from Example 45A are dissolved in 1.7 ml of anhydrous tetrahydrofuran and cooled to 0° C. 488 mg (176 mmol) of 9-bora-bicyclo[3.3.1]nonane (0.5 M solution in tetrahydrofuran) are added slowly, and the mixture is stirred at room temperature for 2 h. The mixture is then again cooled to 0° C., and 8 ml of 1N aqueous sodium hydroxide solution are added slowly. After the addition has ended, 1.6 ml of 30% strength hydrogen peroxide solution are added dropwise at this temperature. The mixture is stirred at 0° C. for 30 min and then washed with 1.3 ml of 40% strength sodium bisulphite solution to destroy the peroxides and diluted with 500 ml of ethyl acetate. The organic phase is removed and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and, after filtration, concentrated to dryness under reduced pressure. The product is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate=2:1). This gives 514 mg (100% of theory) of the desired product.
Reaction SMILES: [C:1]([Sn](CCCC)(CCCC)CCCC)#[CH:2].Br[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:24][C:25]([CH3:28])=[N:26][N:27]=2)=[C:19]([O:29][CH3:30])[CH:18]=1>C1COCC1.[Cl-].[Na+].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>[C:1]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:24][C:25]([CH3:28])=[N:26][N:27]=2)=[C:19]([O:29][CH3:30])[CH:18]=1)#[CH:2]
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Reactant: COc1cc(Br)ccc1-c1nnc(C)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(-c2nnc(C)o2)c(OC)c1
Temperature: 120 °C
Yield: 50 %

Procedure:
Pd(Ph3P)4 (100 mg, 0.087 mmol) and ethynyltributylstannane (600 mg, 1.904 mmol) was treated with a solution of 2-(4-bromo-2-methoxyphenyl)-5-methyl-1,3,4-oxadiazole (457.7 mg, 1.701 mmol) in 10 ml of THF and heated to 120° C. for 15 minutes in a microwave. The reaction was dissolved in brine and extracted three times with EtOAc. Organics were combined, dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel (100% hexanes followed by 0-25% EtOAc/DCM) gave a cream-colored solid (180 mg, 0.850 mmol, 49%).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].[CH2:20]([NH2:23])[CH2:21][CH3:22].Cl>C(O)C.C(O)(=O)C.O>[N+:11]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[NH:23][CH2:20][CH2:21][CH3:22])[C:6]([OH:8])=[O:7])([O-:13])=[O:12]
Reactant: CCCN
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCCNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 80.1 %

Procedure:
To a suspension of 4-fluoro-3-nitrobenzoic acid (2.0 g, 10.8 mmol) in ethanol (20 mL) was added potassium carbonate (2.34 mg, 16.2 mmol) and propylamine (1.27 g, 21.6 mmol), and this was heated to reflux for 4 hours. After the reaction was complete, this was cooled to room temperature, and water was added, this was adjusted to pH 5 with 10% hydrochloric acid and acetic acid, and after the precipitated crystals were filtered and washed with water, they were dried to yield the title compound (1.94 g, 80% yield).
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1.[Cl-].[Al+3].[Cl-].[Cl-]>[N+](CC)([O-])=O>[O:3]=[S:2]1(=[O:4])[C:10]2[CH:11]=[C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:14][C:9]=2[NH:8][C:6](=[O:7])[NH:5]1
Reactant: CS(=O)(=O)Nc1ccc(N)cc1
Reactant: O=C=NS(=O)(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC[N+](=O)[O-]
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)NC(=O)N2
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 77.4 %

Procedure:
Chloro-sulfonyl-isocyanate (1.7 mL, 19.6 mmol) was dissolved in nitroethane (10 mL) and chilled to −40° C. under nitrogen. N-(4-Amino-phenyl)-methanesulfonamide (Example 3b, 3g, 16.1 mmol) was added dropwise as a pre-dissolved solution in nitroethane (25 mL). The mixture was stirred at −40° C. for 15 min. Aluminum chloride (8 g, 60 mmol) was added and the mixture was heated at 110° C. for 30 min while stirring. The mixture was poured onto ice (150 g). Upon melting, the product was extracted into ethyl acetate (5×250 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford the desired product, N-(1,1,3-trioxo-1,2,3,4-tetrahydro-1λ6-benzo[1,2,4]thiadiazin-7-yl)-methanesulfonamide (3.63 g, 12.46 mmol, 77% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 3.00 (3H, s), 7.22 (1H, d, J=8.5 Hz), 7.46 (1H, dd, J1=8.8 Hz, J2=2.7 Hz), 7.51 (1H, d, J=2.4 Hz), 9.92 (1H, s), 11.20 (1H, s).