Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:21])=[C:6]([C:18]([NH2:20])=[S:19])[C:7](=[O:17])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:9]=1)(=[O:3])[CH3:2].Cl[CH2:23][CH:24]=O>C(O)C>[C:1]([C:4]1[C:5]([CH3:21])=[C:6]([C:18]2[S:19][CH:23]=[CH:24][N:20]=2)[C:7](=[O:17])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1nn(-c2cccc(Cl)c2)c(=O)c(C(N)=S)c1C
Reactant: O=CCCl
Solvent: CCO
Product: CC(=O)c1nn(-c2cccc(Cl)c2)c(=O)c(-c2nccs2)c1C

Procedure:
To a suspension (5 ml) of 6-acetyl-4-(aminothioxomethyl)-2-(3-chlorophenyl)-5-methyl-3(2H)-pyridazinone (200 mg) in ethanol (5 ml) was added a 50% aqueous solution of chloroacetoaldehyde, followed by heating under reflux for 10 hours. After cooling on standing, the reaction mixture was extracted with ethyl acetate. After washing with a saturated sodium hydrogen carbonate aqueous solution and a brine, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2), and the resulting crude crystals was washed with hexane to obtain 6-acetyl-2-(3-chlorophenyl)-5-methyl-4-(1,3-thiazol-2-yl)-3(2H)-pyridazinone (90 mg) (Compound No. 1-155).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][O:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[N:9][N:10]=2)[N:7]=1.[Cl:25][C:26]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[CH:37][C:27]=1[CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[Cl:25][C:26]1[CH:40]=[C:39]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][O:12][C:13]4[C:22]5[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=5)[N:16]=[CH:15][CH:14]=4)=[N:9][N:10]=3)[N:7]=2)[CH:38]=[CH:37][C:27]=1[CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Reactant: COc1ccc2c(OCc3nnc4ccc(Cl)nn34)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(CNC(=O)OC(C)(C)C)c(Cl)c5)nn34)ccnc2c1
Temperature: 100 °C

Procedure:
A suspension of 4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline (200 mg, 585 μmol), tert-butyl 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (323 mg, 878 μmol), dichloro[1,1 bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethane adduct (86 mg, 117 μmol), cesium carbonate (763 mg, 2341 μmol) in dioxane (3 mL) and water (0.3 mL) was sparged with argon for 10 min then heated to 100° C. for 18 h. Reaction then partitioned between 9:1 CHCl3/IPA (50 mL) and 5% NaHCO3 (25 mL). Aqueous further extracted with 9:1 CHCl3/IPA (2×10 mL). Combined organics then dried over MgSO4, concentrated, and purified on silica (40 g) eluting with 0>6% 2M NH3 in MeOH/DCM. Product isolated as an off white solid. 84024-19-2 MS (ESI pos. ion) m/z: 547 (MH+). Calc'd exact mass for C28H27ClN6O4: 546.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:17]2[CH:21]=[C:20]([C:22]3[C:23]4[CH:30]=[CH:29][N:28](COCC[Si](C)(C)C)[C:24]=4[N:25]=[CH:26][N:27]=3)[CH:19]=[N:18]2)[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1)#[N:2].C(O)(C(F)(F)F)=O>>[N:25]1[C:24]2[NH:28][CH:29]=[CH:30][C:23]=2[C:22]([C:20]2[CH:19]=[N:18][N:17]([C:4]3([CH2:3][C:1]#[N:2])[CH2:5][CH2:6][NH:7][CH2:8][CH2:9]3)[CH:21]=2)=[N:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CCNCC1
Reaction time: 1.3 h
Yield: 3.6 %

Procedure:
tert-Butyl 4-(cyanomethyl)-4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (0.670 g, 1.24 mmol) was dissolved in TFA (5.0 mL, 65 mmol) and was stirred for 1.3 h. LCMS showed conversion to the hydroxymethyl intermediate, M+H 338. The solution was concentrated to remove the TFA. Methanol was added to the resulting residue, and the resulting mixture was concentrated. The resulting residue was dissolved in methanol (10 mL) and 15.0 M ammonium hydroxide in water (1.66 mL) was added. The resulting solution was stirred for 2 h. LCMS and HPLC analyses showed complete deprotection. The mixture was concentrated. Toluene was added to the resulting residue and the resulting mixture was concentrated to provide a white semisolid. Most of this intermediate product was used for the next step. The rest was purified by prep HPLC using a 30 mm×100 mm C18 column; 8% ACN—H2O (0.1% NH4OH), 1.0 min, to 27% at 6 min; 60 mL/min; detector set at m/z 308; retention time, 5.4 min. Tubes containing pure product were combined and freeze dried to give 13.6 mg of the product.
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.[CH3:8][N:9]([CH3:17])[C:10](=[O:16])[C@H:11]([CH2:13][O:14][CH3:15])[NH2:12]>C(O)C>[CH3:8][N:9]([CH3:17])[C:10](=[O:16])[C@H:11]([CH2:13][O:14][CH3:15])[NH:12][C:2]1[CH2:6][S:5][C:4](=[O:7])[N:3]=1
Reactant: COC[C@H](N)C(=O)N(C)C
Reactant: O=C1NC(=S)CS1
Solvent: CCO
Product: COC[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
To a solution of 4-thioxothiazolidin-2-one (1.00 g) in ethanol (20 mL) was added N,N,O-trimethyl-L-serinamide (1.82 g) at room temperature. The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (434 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:10]([CH2:21][OH:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:25][C:26]([F:40])([F:39])[C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:30]Br>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:10]([CH2:21][O:22][CH2:30][C:29]2[CH:32]=[C:33]([C:35]([F:37])([F:38])[F:36])[CH:34]=[C:27]([C:26]([F:25])([F:39])[F:40])[CH:28]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(F)cc2)[C@H](CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(F)cc2)[C@H](COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 124.3 %

Procedure:
To a solution of (3S,4R)-4-(4-fluoro-phenyl)-3-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (1.58 g, 5.11 mmol) in 30 ml DMF were added 0.29 g (6.0 mmol) sodium hydride (50% in mineral oil) at 0° C. The reaction mixture was allowed to warm to room temperature. After 20 min. 3,5-bis(trifluoromethyl)benzyl bromide (3.14 g, 10.2 mmol) was added. Stirring at room temperature for 2 h was followed by quenching with water and extraction with three portions of tert-butyl methyl ether. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, heptane/ethyl acetate) to give 3.4 g (>100%) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:48][CH2:49][C:50]1[CH:54]=[N:53][N:52]([CH2:55][C@@H:56]2[C@H:59]([NH:60][C:61](=[O:97])/[C:62](=[N:76]\[O:77][C:78]3([C:81]([O:83][CH:84]([C:91]4[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=4)[C:85]4[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=4)=[O:82])[CH2:80][CH2:79]3)/[C:63]3[N:64]=[C:65]([NH:68][C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[S:66][CH:67]=3)[C:58](=[O:98])[NH:57]2)[N:51]=1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([NH:48][CH2:49][C:50]1[CH:54]=[N:53][N:52]([CH2:55][C@@H:56]2[C@H:59]([NH:60][C:61](=[O:97])/[C:62](=[N:76]\[O:77][C:78]3([C:81]([O:83][CH:84]([C:91]4[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=4)[C:85]4[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=4)=[O:82])[CH2:80][CH2:79]3)/[C:63]3[N:64]=[C:65]([NH:68][C:69]([O:71][C:72]([CH3:73])([CH3:75])[CH3:74])=[O:70])[S:66][CH:67]=3)[C:58](=[O:98])[NH:57]2)[N:51]=1)=[O:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2ncc(CN)n2)cs1
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCC(=O)NCc1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)/C(=N\OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)c2csc(NC(=O)OC(C)(C)C)n2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46.6 %

Procedure:
To a solution of 4-((tert-butoxycarbonyl)amino)butanoic acid (30.7 mg, 0.15 mmol) in DCM (2 mL) at 0° C. was added DIPEA (35 μL, 0.20 mmol) and HATU (65 mg, 0.17 mmol). After 10 min, benzhydryl 1-(((Z)-(2-(((2R,3S)-2-((4-(aminomethyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidin-3-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylate (90 mg, 0.10 mmol) was added. After stirring at 0° C. for 1 h, the reaction mixture was diluted with DCM (40 mL), washed with 2M aq. Na2CO3 (20 mL), brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography (MeOH-DCM, 5-10%) to afford the title compound (42 mg, 46%). LCMS: Rt=1.07 min, m/z=901.5 (M+1) Method 2m_acidic.
Reaction SMILES: [CH3:1][S-:2].[Na+].FC(F)(F)CO[C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[C:15]([S:17]([NH:20][C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:28])(=[O:19])=[O:18])[N:16]=[C:10]2[N:9]=1>CS(C)=O.Cl>[CH3:1][S:2][C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[C:15]([S:17]([NH:20][C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:28])(=[O:19])=[O:18])[N:16]=[C:10]2[N:9]=1
Reactant: C[S-]
Reactant: O=S(=O)(Nc1c(Cl)cccc1Cl)c1nc2nc(OCC(F)(F)F)ccn2n1
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: CSc1ccn2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2n1
Temperature: 25 °C
Reaction time: 25 h
Yield: 66 %

Procedure:
To 25 ml (13 mmol) of a 0.52M solution of sodium methyl mercaptide in DMSO prepared by bubbling methyl mercaptan into a suspension of sodium hydride in DMSO, was added 2.6 g (5.9 mmol) of 5-(2,2,2-trifluoroethoxy)N-(2,6-dichlorophenyl)-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide. The solution was stirred at room temperature for 25 hours, diluted with 100 ml of ice water and neutralized with 3N aqueous HCl. The gummy solid which separated was collected and taken up in 0.5N aqueous NaOH. The mixture was filtered to remove insoluble material, and the filtrate was acidified with 6N aqueous HCl. The solid which separated was collected by filtration and dried to yield 1.5 g (66%) of the desired product as a pale yellow solid, mp 239°-243° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: Br[C:2]1[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:4][C:5]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[N:6][CH:7]=1.C([Li])CCC.[CH:23]1[C:33]2[CH:32]=[CH:31][C:30]3[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=3[C:28](=[O:38])[C:27]=2[CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:10][C:9]([CH3:12])([O:8][C:5]1[N:4]=[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:2]([C:28]2([OH:38])[C:29]3[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=3[CH:31]=[CH:32][C:33]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]2=3)=[CH:7][N:6]=1)[CH3:11]
Reactant: O=c1c2ccccc2ccc2ccccc12
Reactant: CC(C)(C)Oc1ncc(Br)c(OC(C)(C)C)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)Oc1ncc(C2(O)c3ccccc3C=Cc3ccccc32)c(OC(C)(C)C)n1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of the product of step (i) (50 g) in dry tetrahydrofuran (11) at -78° C. was added n-butyllithium (69 ml of a 2.5M solution in hexane) dropwise such that the internal temperature of the reaction did not rise above -65° C. After 0.5 hours a solution of 5H-dibenzo[a,d]cyclohepten-5-one (44 g) in tetrahydrofuran (100 ml) was added. The reaction mixture was stirred at -78° C. for three hours and then allowed to warm to room temperature overnight. Saturated aqueous ammonium chloride solution (400 ml) was added and the mixture extracted with ethyl acetate. The organic solution was dried (MgSO4) and evaporated under reduced pressure to give the crude 5-{2,4-bis(1,1-dimethylethoxy)pyrimidin-5-yl)-5H-dibenzo[a,d]cyclohepten-5-ol which was used directly. To a stirred solution of this product and triethylsilane (64 ml) in dry dichloromethane (400 ml) cooled in an ice-bath was added trifluoroacetic acid (150 ml) dropwise over ten minutes. The cooling bath was removed and the solution was stirred at room temperature overnight. Toluene (300 ml) was added and solution was evaporated under reduced pressure. The residue was azeotroped with toluene (3 times). The oil was treated with diethyl ether and the precipitated product collected as a white powder. Yield 44 g.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]2[O:14][CH2:15][C@H:16]([CH3:17])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:20])[C:5]([C:18]#[N:19])=[CH:6]3.[N-:21]=[N+:22]=[N-:23].[Na+]>C(O)(C)C.O.[Cl-].[Zn+2].[Cl-]>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]2[O:14][CH2:15][C@H:16]([CH3:17])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:20])[C:5]([C:18]1[NH:23][N:22]=[N:21][N:19]=1)=[CH:6]3
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C#N)cn1c23
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: O
Solvent: CC(C)O
Product: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(-c4nnn[nH]4)cn1c23
Temperature: 110 °C
Yield: 60.2 %

Procedure:
To a mixture of nitrile 5 (40 mg, 0.14 mmol) in isopropanol and water (1:1 v/v, 15 ml) were added 20 mg of sodium azide (0.29 mmole) and 22 mg of zinc chloride (0.29 mmole). The mixture was heated to 110° C. for 18 h. The precipitates were collected by filtration and washed with water. The solid was dried under vacuum to give 27 mg (60% yield) of 13. This title compound was used without further purification in the next step.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[S:12])=[CH:6][CH:5]=1)([O-])=O.[NH:13]1[C:21]2C(=CC=CC=2)C(CN[C@@H](CCC2NC=C(C3C=CC=CC=3)N=2)C(OCC2C=CC=CC=2)=O)=[CH:14]1.C(N(CC)CC)C>C1COCC1>[N:10]([CH2:7][CH2:8][CH2:9][CH2:4][CH2:5][CH2:6][N:13]([CH3:21])[CH3:14])=[C:11]=[S:12]
Reactant: O=[N+]([O-])c1ccc(N=C=S)cc1
Reactant: O=C(OCc1ccccc1)[C@H](CCc1nc(-c2ccccc2)c[nH]1)NCc1c[nH]c2ccccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)CCCCCCN=C=S
Temperature: 20 °C
Reaction time: 2 h
Yield: 241.3 %

Procedure:
4-nitro-phenylisothiocyanate (43 mg; 1.2 eq.) is added to a solution of benzyl (2S)-2-[(1H-indol-3-ylmethyl)amino]-4-(4-phenyl-1H-imidazol-2-yl)butanoate (93 mg; 1 eq.) in THF (2 ml). The mixture is stirred for 2 hours at approximately 20° C. then diluted with 4 ml of THF. Aminomethylpolystyrene resin (acquired from Novabiochem, load 3.2 mmol/g, 125 mg, 2 eq.) is added, then triethylamine (200 μl). The mixture is stirred for 15 hours at approximately 20° C. then filtered on frit. The filtrate is concentrated to dryness under reduced pressure at 40° C. (a co-evaporation with dichloromethane is necessary to eliminate the excess triethylamine). Purification of the residue by flash chromatography on silica gel (eluent: ethyl acetate/heptane 9:1) yields the expected compound (90 mg; 84% yield).
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]([OH:11])=O)=[CH:3][CH:2]=1.[NH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][N:22]=1)[C:17]([NH2:19])=[O:18].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]1([CH3:12])[CH:2]=[CH:3][C:4]([O:7][CH2:8][C:9]([NH:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][N:22]=2)[C:17]([NH2:19])=[O:18])=[O:11])=[CH:5][CH:6]=1
Reactant: NC(=O)c1ccnc(N)c1
Reactant: Cc1ccc(OCC(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(OCC(=O)Nc2cc(C(N)=O)ccn2)cc1
Yield: 66.7 %

Procedure:
A solution of 4 p-tolyloxy-acetic acid (60.1 mg, 0.36 mmol), 2-amino-isonicotinamide (74.1 mg, 0.54 mmol), DIPEA (0.12 ml, 0.72 mmol) and PyBOP (374.4 mg, 0.72 mmol) in DMF 5.0 mL was stirred, then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous MgSO4, and concentrated. The residue was purified by Prep-TLC(CH2Cl2:MeOH=10:1) to give 2-(2-p-tolyloxy-acetylamino)-isonicotinamide as a white solid (68.5 mg, 66.8% yield).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH2:47][C:48]([NH:50][CH3:51])=[O:49])[CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:52]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:61])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH2:47][C:48]([NH:50][CH3:51])=[O:49])[CH:42]=[CH:43][N:44]=5)=[O:61])=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:52]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CCCC(=O)NC)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CCCC(=O)NC)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 83.8 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-[4-(methylamino)-4-oxobutyl]-1H-imidazol-2-yl]methyl]thio]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (400 mg) in dichloromethane (10 ml) was added a solution of 3-chloroperbenzoic acid (70%, 0.2 g) in dichloromethane (15 ml) at −78° C. The mixture was stirred for 1.5 hours at −78° C., an aqueous solution of sodium thiosulfate was added to the mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate, washed with an aqueous solution of sodium bicarbonate and saturated brine, and dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethanol:ethyl acetatel:19), and was further recrystallized from ethyl acetate-diisopropyl ether to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-[4-(methylamino)-4-oxobutyl]-1H-imidazol-2-yl]methyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 424) (342.8 mg) as yellow crystals.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:13]([CH2:27][CH2:28][CH3:29])=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:30]Br.O>C(O)(=O)C>[Br:30][C:10]1[C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[C:13]([CH2:27][CH2:28][CH3:29])[N:14]2[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: BrBr
Reactant: CCCc1cc2cc(OCc3ccccc3)ccc2n1S(=O)(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CCCc1cc2c(Br)c(OCc3ccccc3)ccc2n1S(=O)(=O)c1ccccc1
Reaction time: 0.17 h

Procedure:
To a rt solution of 5-[(phenylmethyl)oxy]-1-(phenylsulfonyl)-2-propyl-1H-indole (1.16 g, 0.0024) in acetic acid (20 mL, glacial) was added Br2 (1.2 g, 0.008 mol in acetic acid) dropwise. The mixture was stirred for an additional 10 min and water (10 mL) was added. The mixture was extracted with EtOAc (100 mL). The organic layer was separated and dried (MgSO4) and concentrated. Purification via ISCO normal phase chromatography (SiO2, 5-15% ethyl acetate/hexanes) to provide 4-bromo-5-[(phenylmethyl)oxy]-1-(phenylsulfonyl)-2-propyl-1H-indole as the regioselective bromination product: MS (ES) m/z 485 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16]=[O:17])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[Mn]([O-])(=O)(=O)=[O:19].[K+].CO>CC(C)=O>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([OH:19])=[O:17])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Product: CCn1c2ccccc2c2cc(C(=O)O)ccc21
Reaction time: 3 h
Yield: 61.6 %

Procedure:
50 g of N-ethylcarbazole-3-carboxaldehyde was dissolved in 1 L of acetone, and the solution was added with 70.6 g of potassium permanganate under ice cooling, stirred for 3 hours, then added with 100 mL of methanol and filtered. The filtrate was evaporated under reduced pressure, and the residue was dissolved in aqueous sodium hydrogencarbonate. Then, the solution was made acidic by adding concentrated hydrochloric acid, and the deposited precipitates were collected to obtain 33 g of N-ethylcarbazole-3-carboxylic acid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([CH3:15])=[CH2:14])=[CH:11][CH:10]=1>>[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([C:2]2[CH:3]=[C:4]([C:13]([C:12]3[CH:16]=[CH:17][C:9]([Cl:8])=[CH:10][CH:11]=3)([CH3:15])[CH3:14])[CH:5]=[CH:6][C:1]=2[OH:7])([CH3:15])[CH3:14])=[CH:11][CH:10]=1
Reactant: Oc1ccccc1
Reactant: C=C(C)c1ccc(Cl)cc1
Product: CC(C)(c1ccc(Cl)cc1)c1ccc(O)c(C(C)(C)c2ccc(Cl)cc2)c1
Yield: 66.2 %

Procedure:
The title compound is prepared according to the procedure of Example 3 by reacting 19 g of phenol with 80 g of 4-chloro-α-methylstyrene to give 53.4 g of the title compound as a white solid. The structure is confirmed by 1Hnmr and mass spectroscopy.
Reaction SMILES: [CH:1]1([C:7]2[N:11]3[CH:12]=[CH:13][N:14]=[CH:15][C:10]3=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)C.O=[Pt]=O>[CH:1]1([C:7]2[N:11]3[CH2:12][CH2:13][NH:14][CH2:15][C:10]3=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: c1cn2c(C3CCCCC3)ncc2cn1
Agent: O=[Pt]=O
Solvent: CCO
Product: c1nc(C2CCCCC2)n2c1CNCC2
Yield: 87.5 %

Procedure:
A solution of 3-cyclohexyl-imidazo[1,5-a]pyrazine 8a (960 mg, 4.4 mmol) in 25 ml ethanol was treated with 100 mg Adam's catalyst and stirred vigorously under one atmosphere of hydrogen for 18 hr. The mixture was filtered through a pad of Celite®. The filtrate was concentrated in vacuo to yield 790 mg of 3-cyclohexyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine 9a as a greenish-yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:19]O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([O:11][CH3:19])=[O:10])=[CH:6][CH:7]=1
Reactant: CO
Reactant: Cc1ccc(C(C)(C)C(=O)O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)(C)c1ccc(C)cc1

Procedure:
A solution of 2-(4-methylphenyl)-2-methylpropionic acid (60.0 g), sulfuric acid (0.6 ml) and methanol (300 ml) was refluxed for 19 hr. The solvent was evaporated, and water (200 ml) was added and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound (61.52 g) as a pale-brown oil. 1H-NMR(CDCl3)δ:1.56(6H, s), 2.32(3H, s), 3.64(3H, s), 7.13(2H, d, J=8.6 Hz), 7.22(2H, d, J=8.6 Hz). MS(EI): 192(M+).