Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([O:8][C:9]1[C:16]([O:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:25](=[O:32])C1C=CC=CC=1.[C:33]1(C)C=CC=CC=1>CO.C(OC)(OC)OC>[CH3:33][O:12][CH:11]([O:32][CH3:25])[C:10]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9]=1[O:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)Oc1cccc(C=O)c1OC(=O)OC(C)(C)C
Reactant: Cc1ccccc1
Reactant: O=Cc1ccccc1
Solvent: CO
Solvent: COC(OC)OC
Product: COC(OC)c1cccc(OC(=O)OC(C)(C)C)c1OC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Three g (9 mmol) of 2,3-bis-tert.-butoxycarbonyloxy-benzaldehyde were dissolved at room temperature in 10 ml of methanol and 1.2 ml of trimethyl orthoformate. For complete dissolution of the benzaldehyde derivative, 1.5 ml of toluene were added. This was followed by the addition of 3.75 mg of RhCl3 [CH3C(CH2PPh2)3 ] as catalyst. The mixture was then stirred overnight at room temperature. The solvents were separated off by steam distillation and the oily residue was taken up in a little toluene. The undissolved rhodium catalyst was filtered off over a G-4 frit. After the toluene had been stripped off under reduced pressure, the product was dried in an oil pump vacuum.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH3:5].C([Li])CCC.[C:11]([C:15]1([C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:17][O:16]1)([CH3:14])([CH3:13])[CH3:12].C(OCC)C>CCCCC.CN(P(N(C)C)(N(C)C)=O)C>[C:11]([C:15]([OH:16])([CH2:17][C:1]#[C:2][CH2:3][CH2:4][CH3:5])[C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:14])([CH3:13])[CH3:12]
Reactant: C#CCCC
Reactant: CC(C)(C)C1(C(C)(C)C)CO1
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCC#CCC(O)(C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.3 %

Procedure:
1.26 ml (12.8 mmol) 1-pentyne were added dropwise at 0° C. under argon for 5 minutes to 8.0 ml (12.8 mmol) of a 1.6-molar n-butyllithium solution in pentane. The solution obtained was cooled for another 15 minutes, and then the solvent was withdrawn under reduced pressure. 5 ml HMPA and a solution of 1.0 g (6.4 mmol) 2,2-di-tert-butyloxirane in 2 ml HMPA were added. The reaction solution was stirred for 20 hours at room temperature. Subsequently, it was processed analogous to Example 1. The raw product obtained was cleaned by means of a silica column with 2% diethyl ether/light gasoline. There were obtained 1.21 g (84%) 3-tert-butyl-2,2-dimethylnon-5-in-3-ol
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:21]1[CH:25]=[CH:24]N=C1)=O.Cl.C[O:33]C(=O)CN.C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][C:13](=[O:15])[N:21]2[CH2:25][CH2:24][CH2:16][C@H:17]2[C:18]1=[O:33])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: COC(=O)CN
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC(=O)N2CCC[C@H]2C1=O
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
In 150 ml of tetrahydrofuran, 12.5 g of N-benzyloxycarbonyl-L-proline and 8.9 g of carbonyldiimidazole were dissolved and stirred for 30 minutes. Then 6.9 g of glycine methyl ester hydrochloride and 5.6 g of triethylamine were added to the solution and stirred for an overnight at room temperature. The solution was concentrated, and ethyl acetate was added, followed by washing with saturated aqueous sodium hydrogencarbonate solution, 10% aqueous citric acid and saturated brine, drying over anhydrous magnesium sulfate and concentration. The residue was dissolved in 100 ml of methanol, to which solution 2.0 g of 10% palladium-on-carbon was added and stirred for an overnight in gaseous hydrogen current. Filtering the catalyst off, the filtrate was concentrated. This residue was dissolved in 100 ml of methanol and following addition of triethylamine, the solution was heated under reflux for 14 hours. After concentration, a suitable amount of 2-propanol was added to the residue and the precipitated crystals were recovered by filtration and dried to provide 6.48 g (84%) of (8aS)-2-benzyloxycarbonylhexahydropyrrolo[1,2-a]pyrazin-1,4-dione. In 40 ml of tetrahydrofuran, 4.0 g of this product was dissolved and the solution was dropped into a suspension of 5.9 g of lithium aluminium hydride in 60 ml of tetrahydrofuran, followed by 14 hours' heating under reflux. The solution was cooled with ice, and excessive lithium aluminium hydride therein was decomposed by addition of saturated aqueous sodium hydrogencarbonate solution. After addition of benzyloxycarbonyl chloride, the solution was stirred for an hour under cooling with ice and for further 2 hours at room temperature, followed by extraction with chloroform, washing with saturated brine, drying over anhydrous magnesium sulfate and concentration. The residue was purified on silica gel column chromatography (chloroform:methanol=25:1) to provide 2.77 g (41%) of (8aS)-2-benzyloxycarbonyloctahydropyrrolo[1,2-a]pyrazine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH3:22])[N:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:28]>ClCCl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH3:22])[N:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:28])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CNc1nccc(-c2cccnc2Sc2ccc(N)cc2)n1
Solvent: ClCCl
Product: CNc1nccc(-c2cccnc2S(=O)c2ccc(N)cc2)n1
Temperature: 0 °C
Reaction time: 7 h

Procedure:
To a cold (0° C.) suspension of 4-(2-(4-aminophenylthio)pyridin-3-yl)-N-methylpyrimidin-2-amine (400 mg, 1.28 mmol) in 20 mL of dichloromethane was added dropwise a solution of 3-chloroperoxybenzoic acid (330 mg, 1.28 mmol, 77% maximum purity) in dichloromethane. The reaction was stirred for 7 hours at 0° C. Then the reaction flask was stored in the freezer overnight without stirring. After 17 hours, the reaction was removed from the freezer and was stirred for another 6 hours in an ice-water bath. The solid was filtered off and collected. The product, 4-(2-(4-aminophenylsulfinyl)pyridin-3-yl)-N-methylpyrimidin-2-amine was obtained as an off-white solid. 1H NMR (Varian, 300 MHz, CDCl3): 8.76 (s, 1H), 8.35 (s, 1H), 8.00 (d, J=7.7 Hz, 1H), 7.60 (m, 1H), 7.46 (m, 3H), 6.78 (d, J=4.9 Hz, 1H), 6.46 (d, J=8.0 Hz, 2H), 5.63 (br s, 2H), 2.81 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH2:31]=O>>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH3:31])[CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: O=C(NC(COCC1CCNCC1)c1ccc(F)cc1)c1ccc2c(Cl)c[nH]c2c1
Reactant: C=O
Product: CN1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccc(F)cc2)CC1

Procedure:
Using alkylation method B, 3-chloro-N-[1-(4-fluoro-phenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (373 mg, 0.87 mmol) and paraformaldehyde (520 mg, 17 mmol) afforded, after purification (SiO2: 8:2:1 hexane:EtOAc:isopropylamine), 115 mg (30%) of the title compound.
Reaction SMILES: C([NH:8][CH:9]([C:13]1[C:14]([CH:22]([CH3:24])[CH3:23])=[N:15][N:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=12)[CH:10]([CH3:12])[CH3:11])C1C=CC=CC=1>C(O)(=O)C.O=[Pt]=O>[CH:22]([C:14]1[C:13]([CH:9]([NH2:8])[CH:10]([CH3:12])[CH3:11])=[C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][N:16]2[N:15]=1)([CH3:24])[CH3:23]
Reactant: CC(C)c1nn2ccccc2c1C(NCc1ccccc1)C(C)C
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC(C)c1nn2c(c1C(N)C(C)C)CCCC2
Reaction time: 4 h
Yield: 36.9 %

Procedure:
To a solution of 600 mg (4.6 mmol) of N-benzyl-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-amine in 10 ml of acetic acid was added 100 mg of PtO2 in hydrogenation bottle. H2 was applied at 50 psi for 4 hours. The reaction was worked up by filtration and dilution with 0.1N HCl to provide 503 mg of crude product. Purification by C18 preparative HPLC furnished 400 mg of purified 1-(2-isopropyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-amine after lyophilization. Compound 1011.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[CH:16][C:17]4[S:22][CH:21]=[C:20]([C:23]5[CH:34]=[CH:33][C:26]([CH2:27]CS([O-])(=O)=O)=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:41]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH3:42]>CN(C)C=O.C(OCC)(=O)C>[CH2:41]([N:43]1[CH2:48][CH2:47][N:46]([CH2:27][C:26]2[CH:25]=[CH:24][C:23]([C:20]3[C:18]4[N:19]=[C:14]([NH:13][C:10]5[CH:11]=[N:12][C:7]([N:4]6[CH2:5][CH2:6][O:1][CH2:2][CH2:3]6)=[CH:8][CH:9]=5)[N:15]=[CH:16][C:17]=4[S:22][CH:21]=3)=[CH:34][CH:33]=2)[CH2:45][CH2:44]1)[CH3:42]
Reactant: O=S(=O)([O-])CCc1ccc(-c2csc3cnc(Nc4ccc(N5CCOCC5)nc4)nc23)cc1
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN1CCN(Cc2ccc(-c3csc4cnc(Nc5ccc(N6CCOCC6)nc5)nc34)cc2)CC1
Temperature: 80 °C
Yield: 71.1 %

Procedure:
4-(2-(6-Morpholinopyridin-3-ylamino)thieno[3,2-d]pyrimidin-7-yl)benzylmethanesulfonate (30 mg, 0.06 mmol) was dissolved in N,N-dimethylformamide (1 mL) and potassium carbonate (17 mg, 0.12 mmol) and 1-ethylpiperazine (38 μL, 0.30 mmol) were added. The reaction mixture was stirred at 80° C. for a day, diluted with ethyl acetate, and washed with brine. The organic layer was dried with magnesium sulfate, filtered with celite, and then concentrated. Purification by chromatography (5% methanol/dichloromethane) yielded the target compound (22 mg, 70% yield).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:13]1([CH2:19][C:20](Cl)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClC(Cl)C>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[CH:19]([C:20]([CH:19]([C:7]1[CH:8]=[C:1]([OH:2])[CH:3]=[CH:4][C:5]=1[OH:6])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Oc1ccc(O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: O=C(C(c1ccccc1)c1cc(O)ccc1O)C(c1ccccc1)c1cc(O)ccc1O
Yield: 23.7 %

Procedure:
22 g (0.2 mole) of hydroquinone were dissolved in 60 ml of dichloroethane and 26.8 g (0.2 mole) of anhydrous aluminum chloride were added to the solution. To the obtained complex 30.8 g (0.2 mole) of phenyl-acetyl chloride in 30 ml of dichloroethane were added. Further the procedure of Example 1 was followed. 10.1 g of 2,5-dihydroxy-phenyl-benzyl-ketone were obtained, m.p.: 118°-120° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[C:16]([O:20][C:21]([NH:23][C:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=S)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl>[C:30]([O:29][C:27]([NH:26][C:24]([NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])=[N:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH:10]=1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: N#Cc1cccnc1-c1cccc(N)c1
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(=Nc1cccc(-c2ncccc2C#N)c1)NC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 87.6 %

Procedure:
To a suspension of 3-(3-cyanopyridin-2-yl)aniline (195 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (332 mg) and diisopropylethylamine (0.401 ml) in dichloromethane (10 ml) was added 1-methyl-2-chloropyridinium iodide (332 mg), and the mixture was stirred for 18 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was crystallized from methanol. The precipitate was collected by filtration, washed with methanol and dried to give N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-cyanopyridin-2-yl)phenyl)guanidine (383 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[O:5][N:4]=1.C[O:19][C:20](=[O:31])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[CH:25][C:24]=1[CH3:30]>>[CH3:30][C:24]1[CH:25]=[C:26]([S:29][CH2:2][C:3]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[O:5][N:4]=2)[CH:27]=[CH:28][C:23]=1[O:22][CH2:21][C:20]([OH:31])=[O:19]
Reactant: FC(F)(F)c1ccc(-c2cc(CCl)no2)cc1
Reactant: COC(=O)COc1ccc(S)cc1C
Product: Cc1cc(SCc2cc(-c3ccc(C(F)(F)F)cc3)on2)ccc1OCC(=O)O

Procedure:
The title compound was prepared in a manner analogous to Example 1F using 42C and 2C. MS m/z 438 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=[O:5].O1CCCC1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: Cc1ccc(F)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(F)c(CO)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.4 %

Procedure:
A solution of 2-fluoro-5-methylbenzaldeyde (1.80 g, 12.3 mmol) in 3:1 tetrahydrofuran:methanol (82 ml total) at 0° C. was treated with sodium borohydride (0.93 g, 24.6 mmol). The reaction was slowly warmed to ambient temperature and stirred for about three hours. The reaction was quenched with water, transferred to a separatory funnel, and extracted with methylene chloride. The organic fraction was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was further purified by high performance liquid chromatography to yield 1.3 grams (76%) of a clear oil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:15])[CH2:12][N:11]([CH2:13][CH3:14])[CH2:10]1.ClC1C=C(C=CC=1)C(OO)=[O:21]>ClCCl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:15])[CH2:12][N+:11]([O-:21])([CH2:13][CH3:14])[CH2:10]1
Reactant: CCN1CC(O)(c2cccc(F)c2F)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC[N+]1([O-])CC(O)(c2cccc(F)c2F)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 23.9 %

Procedure:
To a stirred solution of 3-(2,3-difluorophenyl)-1-ethylazetidin-3-ol (0.622 g, 2.91 mmol) in dichloromethane (30 mL) was added 3-chloroperoxybenzoic acid in portions (77%, 0.98 g, 4.37 mmol). The resulting mixture was stirred at ambient temperature for 5 h. The reaction mixture was poured onto a column of basic alumina, the column was washed with dichloromethane and eluated with methanol. Purification by HPLC on waters OBD C18, 5 μm (MeOH/33 mM NH3, 10:90 to 30:70) gave the title compound (0.160 g, 23.9%). The N-oxide was converted to the hydrochloric acid salt and recrystallized from methanol/acetonitrile. The product was analyzed by LCMS (Qtrap, Applied Biosystems, Q1 MS): MS (m+1)/z; 231 (M+1, bp).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][O:6][CH:7]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH2:17][CH3:18])[CH3:2].Cl>CO>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][O:6][CH:7]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][NH:20]1)[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH2:17][CH3:18])[CH3:2]
Reactant: CCOC(=O)COC(COc1ccccc1OCC)c1ccccn1
Agent: Cl
Solvent: CO
Product: CCOC(=O)COC(COc1ccccc1OCC)C1CCCCN1
Reaction time: 1 h
Yield: 60 %

Procedure:
This pyridine compound (5.18 g, 0.015 mole) was dissolved in the minimal amount of methanol and converted to the hydrochloride salt via ethereal hydrogen chloride. All solvents were removed and the volume was adjusted to 100 ml using methanol. To this methanol solution was added 1.4 g of platinum oxide and the reaction mixture was hydrogenated for 1 hr at room temperature. The methanol was removed by rotary evaporator and the residue was partitioned between dilute base and methylene chloride. Removal of methylene chloride gave 3.15 g (60% of the title compound as a red oil.
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Na+:5].[Na+].[CH2:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OCC)(=O)C=C.C(OCCO)(=O)C(C)=C>O>[CH2:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([S:1]([O-:4])(=[O:3])=[O:2])=[CH:11][CH:10]=1.[Na+:5]
Reactant: C=Cc1ccccc1
Reactant: O=S([O-])[O-]
Agent: C=C(C)C(=O)OCCO
Agent: C=CC(=O)OCC
Agent: [Na+]
Solvent: O
Product: C=Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 509.4 %

Procedure:
A polymerization flask, the inner atmosphere of which was substituted with nitrogen, was charged with 0.2 g of Emulgen 935 (polyoxyethylene nonylphenol ether supplied by Kao-Atlas), 0.2 g of Emulgen 920 (polyoxyethylene nonylphenol ether supplied by Kao-Atlas), 0.3 g of acidic sodium sulfite (NaHSO3) and 46.5 g of water, and the temperature was elevated to 40° C. in a nitrogen current. A liquid monomer mixture comprising 30 g of styrene, 67 g of ethyl acrylate and 3 g of 2-hydroxyethyl methacrylate, an aqueous solution of 2.5 g of sodium p-styrene-sulfonate having a purity of 82.0% (Spinomar NaSS supplied by Toyo Soda) in 47.5 g of water and an aqueous solution of a polymerization initiator formed by dissolving 0.5 g of ammonium persulfate in 49.5 g of water were added into the polymerization flask over a period of 3 hours and polymerization was carried out at 40° C. After completion of the addition, the polymerization was further conducted at 40° C. for 3 hours.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH2:12][CH2:13][N:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.B(O)(O)[C:22]1[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:11][N:9]1[C:10]2[C:2]([NH:1][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)=[CH:3][CH:4]=[CH:5][C:6]=2[C:7]2[CH2:15][N:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:13][CH2:12][C:8]1=2
Reactant: CCOC(=O)N1CCc2c(c3cccc(N)c3n2C)C1
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCc2c(c3cccc(Nc4ccc(C)cc4)c3n2C)C1
Reaction time: 36 h
Yield: 54.3 %

Procedure:
Ethyl 6-amino-5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (103 mg, 0.37 mmol) was combined with p-tolylboronic acid (100 mg, 0.74 mmol), triethylamine (75 mg, 0.74 mmol), and copper (II) acetate (68 mg, 0.37 mmol) in CH2Cl2 (2 mL) and allowed to stir for 36 h. The solvent was evaporated and the residue purified by silica gel column chromatography (20% EtOAc-Hex) affording ethyl 5-methyl-6-(4-toluidino)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate as a green semi-solid (73 mg, 73%) yield. 1H NMR (CDCl3, 300 MHz) δ 7.32 (d, 1H, J=7.7 Hz), 7.03 (t, 1H, J=7.7 Hz), 6.97 (d, 2H, J=8.0 Hz), 6.92 (d, 1H, J=6.9 Hz), 6.54 (d, 2H, J=8.4 Hz), 5.37 (s, 1H), 4.70 (s, 2H), 4.21 (q, 2H, J=7.0 Hz), 3.88 (br. s, 2H), 3.71 (s, 3H), 2.76 (t, 2H, J=5.5 Hz), 2.24 (s, 3H), 1.30 (t, 3H, J=7.3 Hz) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])([CH3:9])[CH3:8].[S:21](Cl)(=[O:24])(=[O:23])[NH2:22]>>[S:21]([NH:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])([CH3:8])[CH3:9])(=[O:24])(=[O:23])[NH2:22]
Reactant: NS(=O)(=O)Cl
Reactant: CCNC(=O)NC(C)(C)COc1cccc(N)c1C#N
Product: CCNC(=O)NC(C)(C)COc1cccc(NS(N)(=O)=O)c1C#N
Yield: 100 %

Procedure:
Prepared as in Example 215a from 1-(1-(3-amino-2-cyanophenoxy)-2-methylpropan-2-yl)-3-ethylurea (Example 230b) and sulfamoyl chloride in 100% yield. MS 356 (MH+).
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:23][CH2:24][C:25]([NH:27][C@H:28]([C:33]([OH:35])=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:26].C(N(CC)CC)C.O>O1CCOCC1>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([NH:23][CH2:24][C:25]([NH:27][C@H:28]([C:33]([OH:35])=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:26])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)CN)C(=O)O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 8 h
Yield: 73.6 %

Procedure:
The N-hydroxysuccinimide ester of Z-Phe-OH (19.15 g, 48.3 mmol) was dissolved in 50 mL of dioxane and the resulting solution was filtered into a solution consisting of H-Gly-Leu-OH (10.0 g, 53.1 mmol), triethylamine (10.1 mL, 72.4 mmol), and water (50 mL). This reaction mixture was stirred overnight at about 23°, and then concentrated approximately 60% by evaporation. The resulting concentrated solution was diluted with 1.0N hydrochloric acid until acidic. Product Z-Phe-Gly-Leu-OH was extracted into ethyl acetate, and the resulting extract was washed with 0.2N hydrochloric acid, followed by saturated aqueous sodium chloride adjusted to 0.10N hydrochloric acid. After washing, the ethyl acetate solution was dried over anhydrous sodium sulfate and filtered. The ethyl acetate was then evaporated to yield 22.5 g of a white, foamy product, which was subsequently crystallized from ethyl acetate to yield 16.7 g of Z-Phe-Gly-Leu-OH (m.p. 147°-148°).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCC2C(=C(OS(C(F)(F)F)(=O)=O)N(C3C=CC=C(C(F)(F)F)C=3)N=2)CC1)=O)(C)(C)C.C1(B(O)O)C=CC=CC=1>>[C:28]1([C:12]2[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=3)[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(-c3cccc(C(F)(F)F)c3)c(-c3ccccc3)c2CC1
Agent: CC(C)(C)OC(=O)N1CCc2nn(-c3cccc(C(F)(F)F)c3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Agent: OB(O)c1ccccc1
Product: FC(F)(F)c1cccc(-n2nc3c(c2-c2ccccc2)CCNCC3)c1

Procedure:
3-Phenyl-2-(3-trifluoromethyl-phenyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester. The desired compound (172.0 mg) was prepared from 279.1 of mg of 3-trifluoromethanesulfonyloxy-2-(3-trifluoromethyl-phenyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (made from (3-trifluoromethyl-phenyl)-hydrazine as in Example 176, Steps A and B) and 0.21 g of phenylboronic acid, as described in Example 177, Step C. MS (ESI): exact mass calculated for C25H26F3N3O2, 457.20; found, m/z 458.1 [M+H]+.