Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:23]CCI.[NH4+].[Cl-]>CCCCC.C(OCC)C.COCCOC>[C:1]([O:5][C:6]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([I:23])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2cccc(NC(=O)OC(C)(C)C)c2cc1OC
Reactant: ICCI
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCC
Solvent: CCOCC
Solvent: COCCOC
Product: COc1cc2c(I)ccc(NC(=O)OC(C)(C)C)c2cc1OC
Temperature: -20 °C
Reaction time: 5 h

Procedure:
t-Buthyllithium (2.7 mL of a 1.7 M solution in pentane, 4.61 mmol) was added to a solution of 1-(N-tert-Butoxycarbonylamino)-6,7-dimethoxynaphthalene (0.50 g, 1.65 mmol) in dry diethyl ether (5.0 mL) and dry DME (2.5 mL) at −40° C. under nitrogen. The resulting mixture was stirred at −20° C. for 5 h and then cooled to −78° C. A solution of 1,2-diiodoethane (1.30 g, 4.61 mmol) in dry DME was added and the resulting solution was allowed to warm to ambient temperature over several hours. Aq. NH4Cl was added, and the mixture was extracted twice with DCM. The combined organic extracts were washed with water, dried, filtered and evaporated to leave a dark glass. The compound was purified by column chromatography to give the pure product 1-(N-tert-Butoxycarbonylamino)-6,7-dimethoxy-4-iodonaphthalene. 1H NMR (200 MHz) (DMSO-d6) δ 1.51 (s, 9H), 3.82 (s, 3H), 3.97 (s, 3H), 7.42 (t, J=8.5 Hz, 1H), 7.48 (s, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.79 (d, J=8.5 Hz, 1H), 9.28 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([C:19]#[C:20][CH2:21][OH:22])=[CH:13][CH:12]=3)=[O:5])[CH3:2].CC(C)=O>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([C:19]#[C:20][CH:21]=[O:22])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(C#CCO)cc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(C#CC=O)cc12
Reaction time: 4 h
Yield: 50.3 %

Procedure:
300 mg of 6-(3-hydroxy-1-propinyl)-beta-carboline-3-carboxylic-acid-ethylester is suspended in 25 ml of chloroform and 25 ml of acetone and mixed with 1.4 g of manganese dioxide. After stirring for 4 h, manganese dioxide is added again in an amount of 0.4 g. After standing overnight, 0.4 g of manganese dioxide is added again and the mixture is stirred for 8 h. Then it is filtered and the manganese dioxide is extracted in an Soxhlet extractor under acetone. After consolidating the filtrates, 150 mg of 6-(3-oxo-1-propinyl)-beta-carboline-3-carboxylic-acid-ethylester is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.Br.[CH3:12][N:13]([CH2:15][C:16]1[C:17]([S:23][CH2:24][CH3:25])=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1)[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][N:13]([CH3:12])[CH3:14])[C:17]=2[S:23][CH2:24][CH3:25])[CH:3]=1
Reactant: CCSc1c(O)cccc1CN(C)C
Reactant: N#Cc1ccc(Cl)cc1F
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1c(CN(C)C)cccc1Oc1cc(Cl)ccc1C#N
Reaction time: 1 h
Yield: 73.4 %

Procedure:
4-Chloro-2-fluorobenzonitrile (0.567 g, 3.6 mmol), 3-dimethylaminomethyl-2-ethylsulfanyl-phenol hydrobromide (0.77 g, 2.6 mmol) and cesium carbonate (1.19 g, 3.6 mmol) were heated with stirring in dry DMF (4 mL) at 50° C. for 17 h. More cesium carbonate (1.19 g, 3.6 mmol) was added. After 1 h, the reaction was complete by LC/MS analysis. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water (1×), 10% sodium carbonate solution (2×), water (2×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-(3-dimethylaminomethyl-2-ethylsulfanyl-phenoxy)-benzonitrile (662 mg, 52%) as a clear oil. Fumaric acid (30 mg, 0.26 mmol) in methanol (5 mL) was added to 4-chloro-2-(3-dimethylaminomethyl-2-ethylsulfanyl-phenoxy)-benzonitrile (91 mg, 0.26 mmol). The solvent was removed in vacuo and diethyl ether (20 mL) was added with stirring. After 17 h, 4-chloro-2-(3-dimethylaminomethyl-2-ethylsulfanyl-phenoxy)-benzonitrile fumarate (41.4 mg, 34%) was filtered off as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:49]([O:53][C:54]([NH:56][CH2:57][CH:58]([NH2:69])[C:59]1[NH:63][C:62]2[CH:64]=[CH:65][C:66]([Cl:68])=[CH:67][C:61]=2[N:60]=1)=[O:55])([CH3:52])([CH3:51])[CH3:50].ClCl>O1CCCC1.C1CCCCC1.C(O)C>[C:49]([O:53][C:54]([NH:56][CH2:57][CH:58]([NH:69][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[C:2]([CH3:1])[CH:3]=1)[C:59]1[NH:63][C:62]2[CH:64]=[CH:65][C:66]([Cl:68])=[CH:67][C:61]=2[N:60]=1)=[O:55])([CH3:52])([CH3:50])[CH3:51]
Reactant: CC(C)(C)OC(=O)NCC(N)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCCCC1
Solvent: CCO
Product: Cc1cc(C(=O)NC(CNC(=O)OC(C)(C)C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 64 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and 2-tert-butoxycarbonylamino-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: 64%; Rf value: 0.67 (silica gel; cyclohexane/ethanol=7:3); C27H32ClN5O4 (526.03); mass spectrum: (M+H)+=526/528 (chlorine isotope) and (M−H)−=524/526 (chlorine isotope).
Reaction SMILES: [Cu](C#N)[C:2]#[N:3].[F:6][C:7]1[CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[C:10](I)=[C:11]([CH3:13])[CH:12]=1>CN(C)C=O>[F:6][C:7]1[CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[C:10]([C:2]#[N:3])=[C:11]([CH3:13])[CH:12]=1
Reactant: Cc1cc(F)cc([N+](=O)[O-])c1I
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: Cc1cc(F)cc([N+](=O)[O-])c1C#N
Temperature: 130 °C

Procedure:
Copper cyanide (11.9 g, 133 mmol) was added to an N,N-dimethylformamide (240 ml) solution of 5-fluoro-2-iodo-1-methyl-3-nitrobenzene (I-262) (34.0 g, crude product), followed by heating at 130° C. for 3.5 hours. After cooling, the insoluble matter was removed by filtration under suction, water was added to the filtrate, and the precipitated insoluble matter was removed by filtration through Celite under suction. The filtrate was extracted with ethyl acetate, the organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, then the residue was subjected to column chromatography, and eluted with a mixed solvent of n-hexane/ethyl acetate (3:1, v/v) to obtain the entitled compound (17.6 g, 81% from I-235) as a red brown solid.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[Br-:12].[NH2:13][N+:14]1[CH:18]=[CH:17][N:16]([CH2:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=1[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1.CCOCC>C(O)(=O)C>[Br-:12].[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:13][N+:14]2[CH:18]=[CH:17][N:16]([CH2:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=2[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2n(CC(=O)C(C)(C)C)cc[n+]2N)cc1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [Br-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1ccc(-c2n(CC(=O)C(C)(C)C)cc[n+]2N=Cc2ccc(N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1.50 g of p-(dimethylamino)benzaldehyde are added to a solution of 3.7 g of 1-amino-2-(p-methoxyphenyl)-3-(pivaloylmethyl)imidazolium bromide in 25 ml of glacial acetic acid. The mixture is stirred at room temperature for 15 hours. Then, 20 ml of ether are added thereto and, after an additional 3 hours, the product is removed by filtration. After recrystallization from ethanol/ether, there is obtained 1-[[p-(dimethylamino)benzylidene]amino]-2-(p-methoxyphenyl)-3-(pivaloylmethyl)imidazolium bromide of melting point 241°.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH:28]=O.[BH3-]C#N.[Na+]>CO.CN1C(=O)N(C)CC1>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][CH2:28][C:27]4[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:25]([O:24][CH3:23])[CH:26]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(C=O)cc1OC
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CN1CCN(C)C1=O
Product: COc1ccc(CNc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1OC

Procedure:
Analogously to Example 21, 1.00 mmol of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine in 26 ml of methanol, 13 ml of DMEU and 3.0 mmol of acetic acid are first reacted with 3,4-dimethoxy-benzaldehyde and then reduced with 7.00 mmol of NaCNBH3 (5-7 days). 4-(3-Chloro-phenylamino)-3-(3,4-dimethoxybenzylamino)-1H-pyrazolo[3,4-d]pyrimidine is obtained; m.p. 228-232° C.; TRet (Grad5-40)=19.0.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:14][C:15]1[CH:16]=[C:17]([NH3+:21])[CH:18]=[CH:19][CH:20]=1>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([F:14])[CH:16]=1)=[O:6]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: [NH3+]c1cccc(F)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1cccc(F)c1)c1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-Fluoro-5-nitro benzoic acid (1.48 g, 8 mmol) and 3-Fluoro-phenyl-ammonium (920 μl, 8.5 mmol) in methylene chloride/DMF (10:1) 20 ml was added 10 g PS-resin (1.54 mmol/g). The reaction mixture was stirred at room temperature for overnight and then PS-resin was moved by filtration. The filtrate was evaporated to yield the title compound as a yellow solid. (1.11 g, 50%). MS (ESI) m/z=279 [M+H]+. 1H NMR (400 MHz, d6-DMSO) δ 10.89(s, 1H), 8.58-8.47(m, 1H), 7.72-7.67 (m, 1H), 7.45-7.42 (m, 1H), 7.00-6.98 (m, 1H), 6.37-6.28 (m, 2H)
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH:18]=[CH:17][C:7]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])=[C:6]([F:19])[CH:5]=1)[CH3:3].Cl[C:21]1[N:26]=[C:25]([N:27]2[C@@H:31]([CH:32]([CH3:34])[CH3:33])[CH2:30][O:29][C:28]2=[O:35])[C:24]([F:36])=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH:11]1([NH:10][C:8](=[O:9])[C:7]2[CH:17]=[CH:18][C:4]([C@@H:2]([NH:1][C:21]3[N:26]=[C:25]([N:27]4[C@@H:31]([CH:32]([CH3:33])[CH3:34])[CH2:30][O:29][C:28]4=[O:35])[C:24]([F:36])=[CH:23][N:22]=3)[CH3:3])=[CH:5][C:6]=2[F:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)[C@H]1COC(=O)N1c1nc(Cl)ncc1F
Reactant: C[C@H](N)c1ccc(C(=O)NC2CCCCC2)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)[C@H]1COC(=O)N1c1nc(N[C@@H](C)c2ccc(C(=O)NC3CCCCC3)c(F)c2)ncc1F
Temperature: 125 °C
Yield: 8.4 %

Procedure:
To (S)-4-(1-aminoethyl)-N-cyclohexyl-2-fluorobenzamide (16 mg, 0.061 mmol) was added (S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (31.4 mg, 0.121 mmol), NMP (0.5 ml) and Hunig's Base (0.032 ml, 0.182 mmol). The reaction was heated at 125° C. for 4 hours or until done by LCMS. The reaction was let cool, 0.5 ml of NMP added, filtered, purified by prep LC and lyophilized to give 2.5 mg of N-cyclohexyl-2-fluoro-4-((S)-1-(5-fluoro-4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzamide as the TFA Salt. LCMS m/z 488.2 (M+H)+, Rt 0.99 min.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[SH:34].CCN(C(C)C)C(C)C>CN(C=O)C>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[S:34][CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Reactant: Fc1ccc(S)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc2c(ccn2CCSc2ccc(F)cc2F)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), 2,4-difluorobenzenethiol (0.33 mmol) and 0.06 mL of DIEA are added, and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. To the residue, acetonitrile is added and the solution is stirred at 60° C. for 0.5 h. The solution is then cooled to RT, and the resulting solids are collected by filtration to give 7-(2-(2,4-difluorophenylthio)ethyl)-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=412.91). 1H NMR (DMSO-d6, 400 MHz) δ 3.40 (m, 2H), 4.32 (m, 2H), 6.56 (m, 1H), 6.72 (m, 1H), 7.05 (m, 1H), 7.12 (m, 1H), 7.22 (m, 2H), 7.53 (m, 3H), 7.92 (s, 1H). Anal. calculated for (C19H14F2N6OS): C, 55.33; H, 3.42; F, 9 21; N, 20 38; O, 3.88; S, 7.77. Found C, 55.01; H, 3 75; N, 21.95; S, 6.89.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31].C(=O)(O)[O-].[Na+]>CN(C=O)C.C1COCC1>[Cl:21][C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:29](=[O:32])[CH:30]=[CH2:31])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]#[N:13])[CH:20]=[CH:19][CH:18]=1
Reactant: C=CC(=O)Cl
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Cl)c3)c2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 39.3 %

Procedure:
Dissolved 430 mg (1.46 mmol) 6-amino-4-[(3-chlorophenyl)amino]-3-quinolinecarbonitrile in 4 ml DMF, added 10 ml THF and chilled to 0° C. under N2. Added 224 μl (1.60 mmol) triethylamine and 133 μl (1.60 mmol) acryloyl chloride. Removed ice bath at 15 minutes, reaction complete at this time, but stirred overnight at 25° C. Stripped solvent, added a dilute sodium bicarbonate to the residue and collected solids. Washed with water and dried in vacuo. Boiled in ethyl acetate, collected solids and dried in vacuo, giving 200 mg of orange solid: mass spectrum (electrospray m/e): M+H=349.0, 351.0.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:10][S:11](O)(=[O:13])=[O:12].S(=O)(=O)(O)N>>[N+:1]([C:4]1[CH:9]=[C:8]([S:11]([Cl:10])(=[O:13])=[O:12])[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(O)Cl
Reactant: O=[N+]([O-])c1ccccc1
Agent: NS(=O)(=O)O
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Yield: 79 %

Procedure:
123.1 g (1.0 mol) of nitrobenzene and 582.5 g (5.0 mol) of chlorosulfonic acid are reacted as described in Example 20, but without addition of sulfamic acid. 175.1 g of dry 3-nitrobenzenesulfonyl chloride, corresponding to a yield of 79.0% of theory, are obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([O:14][CH2:15][CH3:16])[CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:22].C(OCC)(=O)C>C(Cl)Cl>[CH2:15]([O:14][C:5]1[CH:4]=[C:3]([S:2]([CH3:1])=[O:22])[CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:16]
Reactant: CCOC(=O)c1ccc(SC)cc1OCC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(S(C)=O)cc1OCC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 60.7 %

Procedure:
To a cooled solution of ethyl 4-methylthio-2-ethoxybenzoate (1.1 g, 4.6 mmol) in methylene chloride (40 mL) was added 3-chloroperoxybenzoic acid (1.1 g, 4.5 mmol, 77%) in several portions. The reaction mixture was stirred at 0° C. for 15 min, after which TLC (50% ethyl acetate in hexanes) showed consumption of starting material. The reaction mixture was quenched with a solution of sodium thiosulfate and neutralize with a solution of sodium bicarbonate. The product was extracted three times with methylene chloride. The organic layer was washed with sodium bicarbonate, dried over magnesium sulfate, and concentrated. Purification of the crude residue by flash column chromatography (silica gel, eluting with 50% ethyl acetate in hexanes) gave ethyl 2-ethoxy-4-methanesulfinylbenzoate as a yellow oil (0.70 g, 58%). LC-MS: 257.2 [(M+H)+].
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.[CH3:9][N:10]1[CH2:15][CH2:14][C:13](=[CH2:16])[CH2:12][CH2:11]1.[Br:17][C:18](Br)=[N:19][OH:20].C(=O)([O-])[O-].[Na+].[Na+]>C(=O)(O)[O-].[Na+]>[Br:17][C:18]1[CH2:16][C:13]2([CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)[O:20][N:19]=1
Reactant: ON=C(Br)Br
Reactant: C=C1CCN(C)CC1
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Product: CN1CCC2(CC1)CC(Br)=NO2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35.5 %

Procedure:
To a solution of 1-methyl-4-methlenepiperidine maleate (1.8 g, 0.0081 mol) in saturated sodium bicarbonate (50 mL) was added dibromoformaldoxime (4.94 g, 0.0244 mol) portionwise. The reaction was stirred at room temperature for 1.5 hours. Additional sodium carbonate was added and then the reaction mixture was extracted with chloroform. The extract was dried(MgSO4) and the solvent was evaporated. The residue was purified by flash chromatography on silica gel and elution with ammoniated CHCl3 /EtOAc/MeOH (2/2/1) to give an oil (0.67 g) which solidified. The solid was dissolved in ether and filtered from the insolubles. The filtrate was acidified with maleic acid and the precipitated solid was recrystallized from EtoAc/Et2O to give the bromo derivative as the maleate salt, mp. 159°-160.5° C.
Reaction SMILES: [O:1]1[CH2:4][C:3](=O)[CH2:2]1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])C=CC=CC=1>C(Cl)Cl>[O:1]1[CH2:2][C:3](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4]1
Reactant: O=C1COC1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C=C1COC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.6 %

Procedure:
To a solution of oxetan-3-one (500 mg, 6.938 mmol) in DCM (15.00 mL) at 0° C. was added ethyl 2-triphenylphosphoranylideneacetate (2.659 g, 7.632 mmol). The solution was allowed to warm to room temperature and stirred for 15 minutes. The reaction mixture was then filtered through a pad of silica (washing with 30% EtOAc:Petrol ether). and the solvent removed under reduced pressure to give ethyl 2-(oxetan-3-ylidene)acetate as a colourless viscous oil (815 mg, 79%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH:8]([C:3]1=[CH:2][C:1]([O:6][C:4]1=[O:5])=[O:7])=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=Cc1ccccc1
Reactant: O=C1C=CC(=O)O1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1C
Product: O=C1C=C(C=Cc2ccccc2)C(=O)O1

Procedure:
A styrene-maleic anhydride interpolymer is prepared by the following procedure. 176 parts of maleic anhydride are dissolved in 2641 parts of xylene. To this mixture at 105° C. is added first 188 parts of styrene. Then 1.83 parts benzoyl peroxide dissolved in 32 parts xylene are added over a 1.5 hour period. The mixture is maintained at 104°-106° C. for 4 hours, then is stripped to 150° C. at 200 torr. The resulting interpolymer has RSV of 0.25.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[CH:21]=[C:22]([S:27]([CH2:30][CH2:31][OH:32])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:20]2[CH:21]=[C:22]([S:27]([CH2:30][CH2:31][OH:32])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=2[CH3:26])[CH:11]=1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)CCO)cc1Br
Product: Cc1ccc(S(=O)(=O)CCO)cc1C#Cc1cc(Cl)ccc1OCC(=O)O

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-chloro-2-ethynyl phenoxy)acetate (Intermediate 3) and 2-[(3-bromo-4-methylphenyl)sulfonyl]ethanol (Intermediate 67), the title compound was obtained as a yellow solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]1[CH:8]=[C:9]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]=[CH:11][CH:12]=1.[Br:18]N1C(=O)CCC1=O>C1COCC1.CCCCCC>[Br:18][C:5]1[S:1][C:2]([NH:6][C:7]2[CH:8]=[C:9]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[N:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CS(=O)(=O)Nc1cccc(Nc2nccs2)c1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CS(=O)(=O)Nc1cccc(Nc2ncc(Br)s2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 85.4 %

Procedure:
To a stirred solution of N-(3-(thiazol-2-ylamino)phenyl)methanesulfonamide 55 (1.17 g, 1.85 mmol) in anhydrous THF (25 mL) was added N-bromosuccinimide (0.363 g, 2.03 mmol) at room temperature. Reaction mixture was stirred for 14 hours at ambient temperature. After completion of the reaction (as judged by TLC), it was concentrated and the crude product was MPLC (Biotage) silica column chromatographed using Acetone:Hexane as an eluent to obtain N-(3-((5-bromothiazol-2-yl)amino)phenyl)methanesulfonamide 56 (0.55 g, 86% yield). MS (ES) m/z 348 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[CH:13][N:14]([CH3:16])[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:17]([O:20][CH2:21][C:22]1[C:23]([N:37]2[N:46]=[CH:45][C:44]3[C:39](=[C:40]([F:51])[CH:41]=[C:42]([C:47]([CH3:50])([CH3:49])[CH3:48])[CH:43]=3)[C:38]2=[O:52])=[N:24][CH:25]=[CH:26][C:27]=1B1OC(C)(C)C(C)(C)O1)(=[O:19])[CH3:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:17]([O:20][CH2:21][C:22]1[C:23]([N:37]2[N:46]=[CH:45][C:44]3[C:39](=[C:40]([F:51])[CH:41]=[C:42]([C:47]([CH3:49])([CH3:48])[CH3:50])[CH:43]=3)[C:38]2=[O:52])=[N:24][CH:25]=[CH:26][C:27]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[CH:13][N:14]([CH3:16])[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reactant: Cn1cnc(Nc2cc(Br)cn(C)c2=O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cn(C)cn3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 90 °C
Yield: 39.6 %

Procedure:
A 50-mL round-bottomed flask equipped with a magnetic stirrer was charged with 130a (150 mg, 0.53 mmol), 3-(acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridin-4-ylboronic acid 116c (438 mg, 1.06 mmol), PdCl2(dppf) (43 mg, 0.053 mmol), K3PO4 (225 mg, 1.06 mmol), sodium acetate (87 mg, 1.06 mmol), acetonitrile (10 mL), and water (0.2 mL). After bubbling nitrogen into the mixture for 10 minutes, a reflux condenser was attached to the flask and the reaction mixture was heated at 90° C. for 2.5 h. It was then cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (50:1 to 20:1) to afford 130b as a yellow solid (120 mg, 40%). MS-ESI: [M+H]+ 572.3.