Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][Si](C)(C)C)[N:4]=1.C1C=CC(O[C:23](Cl)=[S:24])=CC=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([N:11]=[C:23]=[S:24])[N:4]=1
Reactant: S=C(Cl)Oc1ccccc1
Reactant: COc1cc(OC)nc(N[Si](C)(C)C)n1
Solvent: CC#N
Product: COc1cc(OC)nc(N=C=S)n1
Yield: 43.5 %

Procedure:
A solution of 45.0 g of 4,6-dimethoxy-2-trimethylsilylaminopyrimidine and 35.0 g of phenyl chlorothionocarbonate in 300 ml of acetonitrile is refluxed for 10 hours. The reaction solution is concentrated under reduced pressure to remove acetonitrile. Toluene (300 ml) is added to the residue and filtered to remove insoluble substance. The filtrate is concentrated under reduced pressure and purified by silica gel column-chromatography (eluent: ethyl acetate:hexane =1:1). 4,6-Dimethoxy-2-isothiocyanatopyrimidine (17.0 g) is obtained from the first eluate. mp 85°~86° C.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].I[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1.C(N(CC)CC)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[Cl:12][C:9]1[CH:10]=[C:11]([C:3]#[C:2][CH2:1][OH:4])[CH:6]=[CH:7][C:8]=1[Cl:13]
Reactant: C#CCO
Reactant: Clc1ccc(I)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OCC#Cc1ccc(Cl)c(Cl)c1
Temperature: 35 °C
Reaction time: 12 h
Yield: 93 %

Procedure:
Bis(triphenylphosphine)palladium(II) chloride (120 mg; 0.171 mmol) was added to a stirred solution of propargyl alcohol (5.24 g; 93.4 mmol; 1.02 eq), 1-iodo-3,4-dichlorobenzene (25.0 g; 91.6 mmol, 1 eq), triethylamine (18.5 g; 183.2 mmol, 2 eq), and copper iodide (60 mg; 0.32 mmol) in THF (50 mL). The mixture was stirred at 35° C. for 12 h under a nitrogen atmosphere. The mixture was then filtered through a bed of celite and the filtrate was washed with ethyl acetate. The filtrate was then concentrated at 35° C. (vac.=28 in Hg) using a rotary evaporator. The residue was purified using a silica gel column (4:1 heptane/ethyl acetate→2:1 heptane/ethyl acetate) to give the desired product as a light yellow solid (17.10 g; 85.2 mmol; 93%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.53 (s, 2H) 7.19 (d, 1H) 7.29 (d, 1H) 7.49 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Cl[C:27]1[CH:36]=[CH:35][C:30]([C:31]([NH:33][CH3:34])=[O:32])=[CH:29][N:28]=1>C(O)(C)(C)C>[CH3:34][NH:33][C:31]([C:30]1[CH:35]=[CH:36][C:27]([O:19][C:16]2[CH:17]=[CH:18][C:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:14][CH2:13][C:12]=3[CH:15]=2)=[N:28][CH:29]=1)=[O:32]
Reactant: CNC(=O)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
7-Hydroxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester (PCT Int. Appl. (2002), WO 02/40471) (8.7 g, 33 mmol) was dissolved in tert-butanol and treated with potassium-tert-butoxide (4 g, 36 mmol). After stirring for 30 minutes at room temperature, 6-chloro-N-methyl-nicotinamide (D10) (5.1 g, 30 mmol) was added and the reaction mixture was stirred at reflux for 20 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. Ice/water was added to the crude residue resulting in a precipitate which was collected by filtration. The solid precipitate was dissolved in ethyl acetate, washed with brine and dried (magnesium sulfate). The organic layer was filtered, concentrated in vacuo and the resulting residue was purified by column chromatography eluting with a mixture of ethyl acetate:hexane (1:1) to afford the title compound (D39). NMR (CDCl3) 8.52 (1H, d, J=2.4), 8.12 (1H, dd, J=8.8), 7.16 (1H, m), 6.95-6.81 (3H, m), 6.02 (1H, br), 3.57 (4H, br), 3.02 (3H, d, J=2.4), 2.89 (4H, br), 1.49 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](I)=[CH:4][CH:3]=1.C1N2CCN(CC2)C1.[C:18]([OH:23])(=[O:22])[C:19]([CH3:21])=O>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[N:7]=[C:6]2[NH:8][C:19]([C:18]([OH:23])=[O:22])=[CH:21][C:5]2=[CH:4][CH:3]=1
Reactant: Nc1nc(Cl)ccc1I
Reactant: CC(=O)C(=O)O
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(O)c1cc2ccc(Cl)nc2[nH]1
Temperature: 110 °C
Yield: 194.8 %

Procedure:
To a solution of 6-chloro-3-iodopyridin-2-amine (24 g, 94 mmol) in DMF is added DABCO (32 g, 283 mmol) and pyruvic acid (20 mL, 283 mmol). The mixture is degassed by bubbling argon gas through the mixture for 20 min. Pd(OAc)2 (1 g, 4.7 mmol) is added and the mixture is again degassed. The reaction mixture is heated at 110° C. for 3 h, and the solvent is evaporated to afford the title compound as a viscous liquid (36 g, >99%) which is used in the next step without purification.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([CH:25]=[O:26])=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]3)[N:13]=2)=[CH:5][CH:4]=1.[CH2:29]([Mg]Br)[CH3:30].OP([O-])(O)=O.[K+]>O1CCCC1.COC(C)(C)C>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([CH:25]([OH:26])[CH2:29][CH3:30])=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21]([F:22])([F:24])[F:23])[CH2:17][CH2:16]3)[N:13]=2)=[CH:5][CH:4]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1CN1CCC(C(F)(F)F)CC1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCC(O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CN1CCC(C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 530 mg of 2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazole-5-carbaldehyde in 43 ml tetrahydrofuran at 0° C. was slowly added 2.2 ml of a molar solution of ethylmagnesium bromide in tert-butyl methyl ether. The reaction mixture was stirred at 0° C. for one hour then poured onto an aqueous solution of KH2PO4 and extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 545 mg 1-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-yl]-propan-1-ol which was used without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[SH:18][C:19]1[N:23]=[CH:22][NH:21][N:20]=1>>[NH:21]1[CH:22]=[N:23][C:19]([S:18][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]3)=[N:20]1
Reactant: Sc1nc[nH]n1
Reactant: O=c1ccc2cc(OCCCCBr)ccc2[nH]1
Product: O=c1ccc2cc(OCCCCSc3nc[nH]n3)ccc2[nH]1

Procedure:
Prepared analogous to Example 122 from 6-(4-bromobutoxy)-carbostyril and 3-mercapto-1,2,4-triazole.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[C:11]([OH:14])(=[O:13])[CH3:12]>>[C:11]([O:14][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)O
Reactant: Ic1c[nH]c2ccccc12
Product: CC(=O)Oc1c[nH]c2ccccc12
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Into a 500 mL round bottom flask was placed a solution of 3-iodo-1H-indole (23 g, 94.65 mmol) in acetic acid (300 mL). To the mixture was added CH3COOAg (31.6 g, 189.22 mmol). The resulting solution was allowed to react, with stirring, for 1 hour while the temperature was maintained at 90° C. in a bath of oil. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:1). A filtration was performed. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. The resulting solution was dissolved with 100 mL of ethyl acetate. The resulting mixture was washed 2 times with 100 mL of NaCl(aq.). The final product was purified by recrystallization from MeOH/H2O in the ratio 2:3. This resulted in 8.5 g (41%) of 1H-indol-3-yl acetate as a dark purple solid.
Reaction SMILES: O(C)[Na].[NH2:4][OH:5].[Cl:6][C:7]1[CH:12]=[C:11]([N:13]2[C:18](=[O:19])[NH:17][C:16](=[O:20])[CH:15]=[N:14]2)[CH:10]=[CH:9][C:8]=1[CH:21]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:22]#[N:23]>C(O)C>[Cl:6][C:7]1[CH:12]=[C:11]([N:13]2[C:18](=[O:19])[NH:17][C:16](=[O:20])[CH:15]=[N:14]2)[CH:10]=[CH:9][C:8]=1[CH:21]([C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1)[C:22](=[N:4][OH:5])[NH2:23]
Reactant: N#CC(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Reactant: NO
Agent: CO[Na]
Solvent: CCO
Product: NC(=NO)C(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.5 %

Procedure:
NaOCH3 (0.189 mol; 30% in CH3OH) was added to a solution of hydroxylamine (0.189 mol) in ethanol (105 ml) The mixture was stirred at RT for 15 minutes and then filtered. The filtrate was added to a mixture of 2-chloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2-(3H)-yl)benzeneacetonitrile (0.054 mol) in ethanol (55 ml). The mixture was stirred at 60° C. for 1 hour, stirred and refluxed for 2 hours and stirred at RT overnight. The solvent was evaporated. The residue was taken up in water and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 20.3 g of (±)-2-chloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-N′-hydroxybenzeneethanimidamide (interm. 66).
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[C:13]([CH:17]=[CH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:25])[C:7]=2[N:6]=[CH:5]1>C(O)C.[Pd]>[CH3:1][CH:2]([CH3:26])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[C:13]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:25])[C:7]=2[N:6]=[CH:5]1
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(C=Cc4ccccc4)cc3c21
Agent: [Pd]
Solvent: CCO
Product: CC(C)Cn1cnc2c(N)nc3ccc(CCc4ccccc4)cc3c21
Yield: 21.8 %

Procedure:
A solution of 1-(2-methylpropyl)-8-styryl-1H-imidazo[4,5-c]quinolin-4-amine (1.37 g, 4.00 mmol) in ethanol (40 mL) was added to a Parr vessel charged with 10% palladium on carbon (137 mg). The reaction was placed under hydrogen pressure (40 psi, 2.8×105 Pa) for six days. The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with ethanol. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from methanol to provide 0.300 g of 1-(2-methylpropyl)-8-phenethyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 175–178° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([O:21]C4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=O)=[CH:15][CH:16]=3)[N:11]=[CH:10][N:9]=2)[C:5]([O:33][CH3:34])=[CH:4][C:3]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1.[S:42]1[C:46]([NH2:47])=[N:45][CH:44]=[N:43]1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:47][C:46]4[S:42][N:43]=[CH:44][N:45]=4)(=[O:20])=[O:21])=[CH:15][CH:16]=3)[N:11]=[CH:10][N:9]=2)[C:5]([O:33][CH3:34])=[CH:4][C:3]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1
Reactant: Nc1ncns1
Reactant: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1ncnc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1ncnc2cc(S(=O)(=O)Nc3ncns3)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A vial was charged with perfluorophenyl 4-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)quinazoline-7-sulfonate (0.060 g, 0.098 mmol), 1,2,4-thiadiazol-5-amine (10.93 mg, 0.108 mmol), and cesium carbonate (0.096 g, 0.295 mmol). The vial was flushed with Ar (g), then acetonitrile (0.491 ml) was added. The reaction was stirred overnight at room temperature. The mixture was diluted with EtOAc and 1 N aq. HCl. The layers were separated, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-10% MeOH/DCM) to give 4-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(1,2,4-thiadiazol-5-yl)quinazoline-7-sulfonamide as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=9.55-9.42 (m, 1H), 8.44-8.35 (m, 2H), 8.01 (td, J=2.0, 8.8 Hz, 1H), 7.96-7.89 (m, 1H), 7.67 (dd, J=1.5, 2.3 Hz, 1H), 7.63-7.54 (m, 1H), 7.49-7.41 (m, 2H), 7.38-7.28 (m, 2H), 3.75 (d, J=2.2 Hz, 3H). m/z (ESI) 529.8 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH:4]([C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21](=[O:37])[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:15][CH:14]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1.[Li+].[OH-].Cl>CO.O>[C:33]([O:32][C:30]([NH:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:22][C:21](/[CH:20]=[CH:19]/[C:16]1[CH:15]=[CH:14][C:13]([CH:4]([CH2:5][CH:6]2[CH2:7][CH2:8][N:9]([CH3:12])[CH2:10][CH2:11]2)[C:3]([OH:38])=[O:2])=[CH:18][CH:17]=1)=[O:37])=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: COC(=O)C(CC1CCN(C)CC1)c1ccc(/C=C/C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN1CCC(CC(C(=O)O)c2ccc(/C=C/C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (E)-2-{4-[2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-3-(1-methyl-piperidin-4-yl)-propionic acid methyl ester (52.1 mg, 10 mmol) in MeOH/H2O (4:1) (2 mL), LiOH (24 mg, 100 mmol.) was added. After the solution was stirred at room temperature for 5 h, the solution was neutralized with 2N HCl to pH 5-6. The mixture was evaporated to dryness under reduced pressure, then EtOAc (10 mL) was added. The organic layer was washed with brine, dried with Na2SO4, filtered, and evaporated to obtain a yellow solid product without further purification. MS: calc'd 508 (MH+), exp 508 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([N:29]1[C:33]([CH3:34])=[N:32][N:31]=[N:30]1)[CH2:11][S:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:7])=[O:6].C(SCC(OC)CNS(CCC[I:62])(=O)=O)CCCCCCCCCCCCCCC>>[CH2:13]([S:12][CH2:11][CH:10]([N:29]1[C:33]([CH3:34])=[N:32][N:31]=[N:30]1)[CH2:9][NH:8][S:5]([CH2:4][CH2:3][CH2:2][I:62])(=[O:7])=[O:6])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)n1nnnc1C
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)n1nnnc1C

Procedure:
3-(3-Chloropropylsulfonylamino)-1-hexadecylthio-2-(5-methyl-1H-tetrazol-1-yl)propane IIIi1 is allowed to react and worked up by the same procedure as described in (5). m.p. 63.5°-65.5° C. The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[CH2:11][CH2:12][C:13]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:3]1=2.C(N(CC)CC)C.Cl[CH2:27][C:28]1[CH:29]=[C:30]([O:34][CH3:35])[CH:31]=[CH:32][CH:33]=1.[Cl-].[Na+]>ClCCl>[CH3:35][O:34][C:30]1[CH:29]=[C:28]([CH2:27][N:16]2[CH2:17][CH2:18][C:13]3([C:3]4[N:2]([CH3:1])[C:10]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[C:4]=4[CH2:11][CH2:12]3)[CH2:14][CH2:15]2)[CH:33]=[CH:32][CH:31]=1
Reactant: COc1cccc(CCl)c1
Reactant: Cn1c2c(c3ccccc31)CCC21CCNCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(CN2CCC3(CCc4c3n(C)c3ccccc43)CC2)c1
Yield: 34.7 %

Procedure:
A solution of 1,4-dihydro-4-methylspiro[cyclopent[b]indole-3(2H), 4'-piperidine] (2.5 g) and triethylamine (2.9 ml) in dichloromethane (100 ml) and 3-(chloromethyl)anisole (1.95 g) was stirred overnight at ambient temperature, under nitrogen. Saturated sodium chloride solution was added and the mixture was extracted with dichloromethane. The extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was flashed chromatographed (silica gel), eluting with 10% anhydrous acetone/dichloromethane. The appropriate fractions were collected and concentrated to give 1.3 g (35%) of product, mp 100-101° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]1[NH:15][C@H:14]([C:16]([OH:18])=[O:17])[CH2:13][S:12]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:25][C:26]1[CH:39]=[CH:38][C:29]([C:30]([S:32][CH2:33][CH2:34][C:35](Cl)=[O:36])=[O:31])=[CH:28][CH:27]=1>O>[C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]1[N:15]([C:35](=[O:36])[CH2:34][CH2:33][S:32][C:30](=[O:31])[C:29]2[CH:38]=[CH:39][C:26]([CH3:25])=[CH:27][CH:28]=2)[C@H:14]([C:16]([OH:18])=[O:17])[CH2:13][S:12]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C1N[C@H](C(=O)O)CS1
Reactant: Cc1ccc(C(=O)SCCC(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=O)Oc1ccccc1C1SC[C@@H](C(=O)O)N1C(=O)CCSC(=O)c1ccc(C)cc1
Reaction time: 1 h

Procedure:
2.7 g of (4R)-2-(2-acetoxyphenyl)-4-thiazolidinecarboxylic acid and 2.8 g of potassium carbonate are dissolved in 60 ml of water. To this solution, 2.6 g of S-(4-methylbenzoyl)-3-mercaptopropanoyl chloride is added dropwise with stirring under icecooling. After the addition, the mixture is stirred under icecooling for 1 hour and at room temperature for additional 1 hour. This reaction solution is washed with ethyl acetate, acidified with conc. hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give oil, yield 3.6 g. The oil is purified by silica gel column chromatography to give the titled compound, yield 2.7 g (57%), mp. 93°-96° C. (benzene). [α]D24 +80.4° (c=1.0, methanol).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([OH:13])=O.S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[OH:26]>>[Br:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[OH:26])=[O:13]
Reactant: O=C(O)c1c(Br)sc2c1CCCC2
Reactant: Nc1ccc(F)cc1O
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccc(F)cc1O)c1c(Br)sc2c1CCCC2

Procedure:
In the same manner as in Starting Material Synthesis Example 60 and using 2-bromo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid, thionyl chloride and 2-amino-5-fluorophenol, 2-bromo-4,5,6,7-tetrahydro-N-(4-fluoro-2-hydroxyphenyl)-benzo[b]thiophene-3-carboxamide is obtained.
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1(=O)O[CH2:11][CH2:10]1>>[CH2:11]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:1]1=[O:8])[CH:10]=[CH2:9]
Reactant: O=C1CCO1
Reactant: O=C1CCCCCO1
Product: C=CCC1CCCCOC1=O

Procedure:
10.02 g of 3-(2-propenyl)-2-oxepanone of interest were prepared in the same manner as in Preparation Example 2Z-5 except that 11.41 g (100.0 mmol) of ε-caprolactone were used instead of β-propiolactone described in Preparation Example 2Z-5.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][NH2:9])[CH:3]=1.ClC1C=C(N2[C:22]([C:23]3[CH:28]=[C:27]([O:29][C:30]([F:33])([F:32])[F:31])[CH:26]=[C:25]([F:34])[CH:24]=3)=[CH:21][C:20]([C:35]([OH:37])=[O:36])=N2)C=CC=1F>>[F:34][C:25]1[CH:24]=[C:23]([C:22]2[N:8]([C:4]3[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=3)[N:9]=[C:20]([C:35]([OH:37])=[O:36])[CH:21]=2)[CH:28]=[C:27]([O:29][C:30]([F:33])([F:32])[F:31])[CH:26]=1
Reactant: O=C(O)c1cc(-c2cc(F)cc(OC(F)(F)F)c2)n(-c2ccc(F)c(Cl)c2)n1
Reactant: NNc1cccnc1
Agent: Cl
Product: O=C(O)c1cc(-c2cc(F)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1

Procedure:
1.82 g (4.71 mmol) of the compound from example 1A is reacted with 1.03 g (7.07 mmol) 3-pyridylhydrazine hydrochloride in a manner analogous to the synthesis of the compound from example 8A. Following hydrolysis, 1.12 g (65% of theoretical yield) of the title compound is produced.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:6]([O:5][CH3:1])=[O:7])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 70 °C
Reaction time: 8 h

Procedure:
In methanol (50 ml), 2-tert-butoxycarbonyl-6-trifluoromethanesulfonyloxy-1,2,3,4-tetrahydroisoquinoline (1.34 g) was dissolved, followed by the addition of triethylamine (0.73 ml), palladium (II) acetate (40 mg) and 1,3-(diphenylphosphino)propane (145 mg). The resulting mixture was stirred overnight at 70° C. under a carbon monoxide gas stream. After the reaction mixture was concentrated under reduced pressure, the residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=15:1), whereby the title compound (665 mg, 65%) was obtained.
Reaction SMILES: [CH:1]([NH:3][CH:4]1[C:15](=[O:16])[N:6]2[CH:7]([C:12]([OH:14])=[O:13])[C:8](=[CH2:11])[CH2:9][S:10][C@H:5]12)=[O:2].[C:17]1([C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N+]=[N-])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)(=O)C>[CH:1]([NH:3][CH:4]1[C:15](=[O:16])[N:6]2[CH:7]([C:12]([O:14][CH:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:13])[C:8](=[CH2:11])[CH2:9][S:10][C@H:5]12)=[O:2]
Reactant: C=C1CS[C@@H]2C(NC=O)C(=O)N2C1C(=O)O
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: C=C1CS[C@@H]2C(NC=O)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
7-Formamido-3-methylenecepham-4-carboxylic acid (1.570 g) was added to a solution (0.93M, 8.36 l) of diphenyldiazomethane in ethyl acetate by portions. The mixture was stirred at 45° C. for 1 hour and evaporated in vacuo. The residue was triturated with diisopropyl ether to give benzhydryl 7-formamido-3-methylenecepham-4-carboxylate (2.337 g).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH3:25])=[O:23].Cl.[NH:27]1[CH2:32][CH2:31][O:30][CH:29]([C:33]([OH:35])=[O:34])[CH2:28]1>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:27]2[CH2:32][CH2:31][O:30][CH:29]([C:33]([OH:35])=[O:34])[CH2:28]2)=[C:4]1[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Reactant: O=C(O)C1CNCCO1
Agent: Cl
Product: COC(=O)C1=C(CN2CCOC(C(=O)O)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 40.4 %

Procedure:
Methyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.11 g, 2.5 mmol) was reacted with morpholine-2-carboxylic acid hydrochloride (0.5 g, 3 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (0.5 g, 40%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:8][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1.O.O>[CH2:16]([O:23][C:24](=[O:25])[NH:1][C:2]1[C:3]([O:8][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ncccc1N
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ncccc1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3-amino-2-methoxypyridine (3.93 g, 31.7 mmol) in THF/H2O (1:1) (120 mL) was added Cs2CO3 (12.4 g, 38.0 mmol) and benzylchloroformate (5.33 mL, 37.9 mmol) and the reaction stirred at room temperature for 5 hours. The mixture was diluted with water, extracted with EtOAc, dried over MgSO4, filtered, and the solvent was removed. The crude product was purified by chromatography (silica gel, 25% EtOAc/hexanes). MS 259 (M+H)+.