Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][C:23]([F:31])([F:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.C(=O)(O)[O-].[Na+].[OH-].[Na+]>C(Cl)Cl.O.[Cl-].[Na+].O.CCOCC>[F:31][C:23]([F:30])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:22][CH2:21][CH:18]1[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(F)(F)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: FC(F)(CCC1CCNCC1)c1ccccc1
Reaction time: 1.33 h

Procedure:
Trifluoroacetic acid (2.5 mL, 3.7 g, 32 mmol) was added dropwise to a solution of 1-(t-butoxycarbonyl)4-(3,3-difluoro-3-phenylprop-1-yl)piperidine from Step C (42 mg, 0.12 mmol) in methylene chloride (2.5 mL) at 0° C. After 80 min., the solution was transferred using a double-ended needle to a rapidly stirred solution of sodium bicarbonate (5.0 g, 60 mmol) in water (50 mL). Ether (50 mL) and 2.5 N aq. NaOH (20 mL) were added, followed by solid brine to saturate the aqueous layer. The aqueous layer was separated and extracted with ether (50 mL). The organic layers were washed in succession with saturated aq. brine (20 mL), combined, dried (sodium sulfate), decanted, and evaporated to give the title compound as 27 mg of colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]([N:18]([CH3:27])[C:19](=[O:26])/[CH:20]=[CH:21]/[CH2:22][N:23]([CH3:25])[CH3:24])=[CH:14][CH:13]=3)[N:9]=[C:10](I)[C:3]=12.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(Cl)Cl>COCCOC.O.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]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]([N:18]([CH3:27])[C:19](=[O:26])/[CH:20]=[CH:21]/[CH2:22][N:23]([CH3:25])[CH3:24])=[CH:14][CH:13]=3)[N:9]=[C:10]([C:32]3[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=3)[C:3]=12
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CN(C)C/C=C/C(=O)N(C)c1ccc(-n2nc(I)c3c(N)ncnc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: CN(C)C/C=C/C(=O)N(C)c1ccc(-n2nc(-c3ccc(Cl)cc3)c3c(N)ncnc32)cc1
Temperature: 80 °C
Yield: 24.7 %

Procedure:
To a suspension of (E)-N-(4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-4-(dimethylamino)-N-methylbut-2-enamide (32) (174 mg, 0.36 mmol), 4-chlorophenylboronic acid (68 mg. 0.44 mmol) and K3PO4.3H2O (292 mg, 1.1 mmol) in DME (3 mL) and water (0.5 mL) was added Pd(dppf)Cl2.DCM (15 mg, 0.02 mmol). The resulting mixture was purged with N2 (3×) before heated to 80° C. overnight under N2 atmosphere. The mixture was cooled down to room temperature. The solvents were evaporated and the residue was pre-purified by column chromatography (silica gel, methanol in methylene chloride (1% Et3N)) followed by preparative HPLC (RP, C18, 10 to 95% acetonitrile in water (0.2% NH3)) to give (E)-N-(4-(4-amino-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-4-(dimethylamino)-N-methylbut-2-enamide (33) (41 mg, yield 25%) as a white solid. LC-MS (ESI): m/z (M/M+2) 463/465. 1H NMR (400 MHz, DMSO) δ 8.38 (s, 1H), 8.29 (d, J=8.8 Hz, 2H), 7.77 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.5 Hz, 2H), 7.47 (d, J=8.8 Hz, 2H), 6.69-6.60 (m, 1H), 5.94 (s, 1H), 3.27 (s, 2H), 2.88 (d, J=5.8 Hz, 1H), 2.03 (s, 3H).
Reaction SMILES: [CH2:1]([C:7]1[C:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:27][C:26]2[C:9](=[CH:10][C:11]3[C:12](=[O:36])[C:13]4[C:22]([C:23](=[O:35])[C:24]=3[CH:25]=2)=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=4)[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([BH-](CC)CC)C.[Li+].Cl>C1COCC1>[CH2:29]([C:28]1[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:8][C:9]2[C:26](=[CH:25][C:24]3[CH:23]([OH:35])[C:22]4[C:13]([CH:12]([OH:36])[C:11]=3[CH:10]=2)=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=4)[CH:27]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCc1cc2cc3c(cc2cc1CCCCCC)C(=O)c1cc2ccccc2cc1C3=O
Agent: CC[BH-](CC)CC
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCc1cc2cc3c(cc2cc1CCCCCC)C(O)c1cc2ccccc2cc1C3O

Procedure:
A solution of 334 mg of 2,3-dihexyl-6,13-pentacenequinone dissolved in 50 mL of THF was added to 11 mL of a 1 mol/1000 mL THF solution of lithium triethylborohydride, and the mixture was heated for 20 hours under reflux in a nitrogen atmosphere. The resulting solution was neutralized with diluted aqueous hydrochloric acid, and the organic phase was separated, concentrated and dried under a vacuum to produce 2,3-dihexyl-6,13-dihydro-6,13-dihydroxypentacene almost stoichiometrically.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH3:13])[CH3:12])=[O:4].Cl[C:22]([CH:24]1[CH2:29][CH2:28][CH:27]([CH3:30])[CH2:26][CH:25]1[O:31][C:32](=[O:34])[CH3:33])=[O:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCCl.C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[CH:8][C:9]=1[N:10]([C:22]([CH:24]1[CH2:29][CH2:28][CH:27]([CH3:30])[CH2:26][CH:25]1[O:31][C:32](=[O:34])[CH3:33])=[O:23])[CH:11]([CH3:13])[CH3:12])=[O:4]
Reactant: COC(=O)c1sc(-c2cccc(F)c2)cc1NC(C)C
Reactant: CC(=O)OC1CC(C)CCC1C(=O)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1sc(-c2cccc(F)c2)cc1N(C(=O)C1CCC(C)CC1OC(C)=O)C(C)C
Yield: 12.4 %

Procedure:
To a solution of 5-(3-Fluoro-phenyl)-3-isopropylamino-thiophene-2-carboxylic acid methyl ester (200 mg, 0.683 mmol) in 1,2-dichloroethane (5 mL), acetic acid 2-chlorocarbonyl-5-methyl-cyclohexyl ester (148 mg, 0.679 mmol) and triphenylphosphine (197 mg, 0.751 mmol) were added under an atmosphere of N2. The reaction mixture was refluxed for 12 h and then diluted with chloroform and water. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by preparative TLC plate using 15% ethyl acetate in hexane to obtain 3[(2-Acetoxy-4-methyl-cyclohexanecarbonyl)-isopropyl-amino]-5-(3-fluoro-phenyl)-thiophene-2-carboxylic acid methyl ester as a white solid (40 mg, 12%). 1H NMR (CDCl3, 400 MHz): δ7.45-7.25 (m, 4H), 7.13-6.95 (m, 1H), 5.13 (m, 1H), 4.87-4.75 (m, 1H), 3.80 (s, 3H), 2.37-0.62 (m, 20H).
Reaction SMILES: O.Cl.[N+:3]([O-:6])([O-])=[O:4].[Na+].[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1>ClCCl.C(OCC)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][C:14]=1[N+:3]([O-:6])=[O:4]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)Oc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(Cc1ccc(O)c([N+](=O)[O-])c1)Oc1ccccc1
Reaction time: 2.5 h
Yield: 80.8 %

Procedure:
Water (2.5 ml), concentrated aqueous hydrogen chloride solution (1.17 ml) and sodium nitrate (297 mg) were added to a solution of ethyl 3-(4-hydroxyphenyl)-2-phenoxypropionate (1.00 g), which is the product of Reference example 4(c), in a mixture of dichloromethane (4.0 ml) and diethyl ether (8.0 ml) at ambient temperature. The mixture was stirred for 2.5 hours at the same temperature and allowed to stand for 14 hours. The reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified via chromatography on a silica gel column using hexane/ethyl acetate=4/1 as the eluant to afford the desired compound (935 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH:28]=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH:30]1[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][N:30]3[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][CH2:31]3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CC=O)cn(C)c34)no2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C1CCN(CCc2cn(C)c3c(-c4noc(-c5ccc(OC(C)C)c(Cl)c5)n4)cccc23)CC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
To a stirred solution of [7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]acetaldehyde (D88) (50 mg), ethyl 4-piperidinecarboxylate (38 mg) and acetic acid (0.1 mL) in DCM (10 mL) was added sodium triacetoxyborohydride (52 mg). The reaction was stirred at 20° C. for 3 h. The mixture was quenched with water, partitioned between DCM (25 mL) and water (25 mL). The organic phase was washed with brine, dried over sodium sulphate and evaporated to afford the crude product ethyl 1-{2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethyl}-4-piperidinecarboxylate (D91) (60 mg). MS (ES): C30H35ClN4O4 requires 550; found 551.3 (M+H+).
Reaction SMILES: [N+]([O-])([O-])=O.[K+].Cl[C:7]1SC2C=CC=CC=2[N:11]=1.Cl[C:17]1[S:18][C:19]2[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[CH:22][C:20]=2[N:21]=1.[Sn].ClC1SC2C=C(N)C=CC=2N=1.[C-]#N.[K+]>S(=O)(=O)(O)O.Cl.CS(C)=O>[C:7]([C:17]1[S:18][C:19]2[CH:25]=[C:24]([NH2:26])[CH:23]=[CH:22][C:20]=2[N:21]=1)#[N:11]
Reactant: Clc1nc2ccccc2s1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Agent: Cl
Agent: Nc1ccc2nc(Cl)sc2c1
Agent: O=S(=O)(O)O
Solvent: CS(C)=O
Product: N#Cc1nc2ccc(N)cc2s1

Procedure:
By adding potassium nitrate under ice cooling in concentrated sulfuric acid to commercially available 2-chlorobenzothiazole and nitrating, and then reacting the generated 2-chloro-6-nitrobenzothiazole with tin in hydrochloric acid, the nitro group is reduced to an amino group, thus deriving 2-chloro-6-aminobenzothiazole. Adding potassium cyanide thereto in an argon atmosphere in DMSO solvent and heating to reflux overnight yields 2-cyano-6-aminobenzothiazole. Allyl bromide and potassium carbonate are reacted in DMF solvent to allylate the amino group, and by aza-Claisen rearrangement, an allyl group is introduced into the 7-position. Potassium carbonate in methanol and cysteine are added and stirred, and by neutralizing with hydrochloric acid, a 7-allyl-aminoluciferin-type compound can be obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[N:19]([CH2:20][CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:25][CH2:24]3)[C:18](=[O:37])[C:17]3[C:12](=[C:13]([O:38]C)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:4][CH:3]=1>Br.CC(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[N:19]([CH2:20][CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:25][CH2:24]3)[C:18](=[O:37])[C:17]3[C:12](=[C:13]([OH:38])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc2c(=O)n(CCCC3CCN(CCc4ccccc4)CC3)c(C=Cc3ccc(Cl)cc3)nc12
Agent: Br
Solvent: CC(=O)O
Product: O=c1c2cccc(O)c2nc(C=Cc2ccc(Cl)cc2)n1CCCC1CCN(CCc2ccccc2)CC1
Temperature: 25 °C

Procedure:
A solution of 2-[2-(4-chloro-phenyl)-vinyl]-8-methoxy-3-[3-(1-phenethyl-piperidin-4-yl)-propyl]-3H-quinazolin-4-one (530 mg, 0.98 mmol) in conc HBr/HOAc (1:1 mixture, 60 mL) was heated at 120° C. for 48 h. After cooling to room temperature, the reaction mixture was concentrated under vacuum to yield the desired product. API-MS: 529 (M+1)
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1.[CH3:12][C:13]1([CH3:21])[C:17](=[O:18])[CH:16]([CH3:19])[NH:15][C:14]1=[O:20].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:10][C:8]1[CH:9]=[C:2]([N:15]2[CH:16]([CH3:19])[C:17](=[O:18])[C:13]([CH3:21])([CH3:12])[C:14]2=[O:20])[CH:3]=[C:4]([F:11])[C:5]=1[C:6]#[N:7]
Reactant: CC1NC(=O)C(C)(C)C1=O
Reactant: N#Cc1c(F)cc(Br)cc1F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC1C(=O)C(C)(C)C(=O)N1c1cc(F)c(C#N)c(F)c1

Procedure:
Using 4-bromo-2,6-difluorobenzonitrile (502 mg), 3,3,5-trimethylpyrrolidine-2,4-dione (250 mg), cesium carbonate (866 mg), tris(dibenzylideneacetone)dipalladium(0) (162 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (205 mg), and in the same manner as in Reference Example 3, the title compound was obtained as a colorless solid (yield: 305 mg, 62%).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[O:7].[C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br)(=[O:16])[CH3:15]>>[CH3:9][O:8][C:6](=[O:7])/[CH:5]=[CH:4]/[C:3]1[CH:10]=[CH:11][CH:12]=[CH:13][C:2]=1[O:1][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:14](=[O:16])[CH3:15]
Reactant: COC(=O)C=Cc1ccccc1O
Reactant: CC(=O)OCCCCCBr
Product: COC(=O)/C=C/c1ccccc1OCCCCCOC(C)=O

Procedure:
Using the procedure of example 63, 1.78 g (10 mmol) of methyl 2-hydroxycinnamate was alkylated with 2.3 g (11 mmol) of 5-bromopentyl acetate giving (E)-3-[2-[[5-(acetyloxy)pentyl]oxy]phenyl]-2-propenoic acid methyl ester, as a pale-yellow oil, in quantitative yield. The crude product was used without further purification.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:13]2[C:12](=[O:14])[CH2:11][CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:9][C:8]=2[NH:7][CH:6]=1)[CH3:4].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>CN(C)C=O>[CH2:3]([C:5]1[C:13]2[C:12](=[O:14])[CH2:11][CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:9][C:8]=2[N:7]([S:22]([CH3:21])(=[O:24])=[O:23])[CH:6]=1)[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1c[nH]c2c1C(=O)CC(c1ccccc1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cn(S(C)(=O)=O)c2c1C(=O)CC(c1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.6 %

Procedure:
To a suspension of 60% sodium hydride (0.13 g, washed with hexane thrice) in dimethylformamide (10 ml) was added 3-ethyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.64 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added a solution of methanesulfonylchloride (0.34 g) in dimethylformamide (1 ml), and the mixture was stirred at the same temperature for 24 hours and then at 40° C. for 5 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from diisopropylether and hexane to give colorless crystals of 3-ethyl-1-methanesulfonyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.26 g).
Reaction SMILES: C([O:9][C@H:10]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1)(=O)C1C=CC=CC=1.C[O-].[Na+].C(O)(=O)C>CO>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][C@H:10]([OH:9])[CH2:11]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OC(=O)c2ccccc2)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 140.8 %

Procedure:
To a solution of (S)-3-benzoyloxy-1-t-butoxycarbonylpyrrolidine (21 g) in methanol (210 ml) was added 28% sodium methoxide in methanol solution (18 ml) under nitrogen at -10° C. After stirring at 0° C. for 2 hours, acetic acid (4.95 ml) was added thereto and the mixture was evaporated. The residue was extracted with ethyl acetate and the extract was washed with water and brine successively. The dried organic solvent was evaporated to give (S)-1-t-butoxycarbonyl-3-hydroxypyrrolidine (19.0 g).
Reaction SMILES: C(C1C=CC=CC=1[CH:6]=[C:7]1[C:19]2[N:18]3[CH:20]=[CH:21][N:22]=[C:17]3[C:16](=[O:23])[NH:15][C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2)(O)=O.C1N2C3CC4C=CC=CC=4C=3NC(=O)C2=NC=1.C[O:46][C:47]([C:49]1[CH:50]=[C:51]([CH:54]=[CH:55][CH:56]=1)C=O)=[O:48].[H-].[Na+].[OH-].[Na+]>O.C(O)(=O)C.CS(C)=O>[C:47]([C:49]1[CH:56]=[C:55]([CH:54]=[CH:51][CH:50]=1)[CH:6]=[C:7]1[C:19]2[N:18]3[CH:20]=[CH:21][N:22]=[C:17]3[C:16](=[O:23])[NH:15][C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2)([OH:48])=[O:46]
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: O=C(O)c1ccccc1C=c1c2ccccc2c2[nH]c(=O)c3nccn3c12
Agent: O=c1[nH]c2c(n3ccnc13)Cc1ccccc1-2
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cccc(C=c2c3ccccc3c3[nH]c(=O)c4nccn4c23)c1

Procedure:
The process is performed as in Example 3 for the preparation of 10-(2-carboxybenzylidene)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one but starting with 5 g of 5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 100 ml of dimethyl sulphoxide, 4.04 g of 3-methoxycarbonylbenzaldehyde and 1.6 g of 80% sodium hydride. After treatment of the reaction mixture with 100 ml of water and 10 ml of acetic acid, the suspension obtained is filtered; the insoluble product is washed with water, air-dried and then triturated with 80 ml of dimethylformamide, filtered off and dried. The yellow solid obtained (1 g) is suspended in 100 ml of water and, after addition of 25 ml of 0.1N sodium hydroxide, the solution is filtered and acidified with 2.5 ml of 1N hydrochloric acid. The precipitate formed is washed with water, triturated with 50 ml of methanol and dried at 60° C. under vacuum (1 mmHg; 0.13 kPa). 0.8 g of 10-(3-carboxybenzylidene)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is obtained in the form of a yellow solid melting above 260° C., which product is converted into the disodium salt of formula C21 H11N3O3Na2 (Analysis, % calculated C 63.17, H: 2.78, N: 10.52, O: 12.02, Na : 11.51, % found C: 62.9, H: 2.6, N: 10.2).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].C[Si]([N:13]=[N+:14]=[N-:15])(C)C.CCOCC>O>[N:13]1[NH:14][N:15]=[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:2]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1ccccn1
Solvent: CCOCC
Solvent: O
Product: c1ccc(-c2cn[nH]n2)nc1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
2-Ethynylpyridine (3.1 g, 30 mmol) and trimethylsilylazide (7.9 mL, 60 mmol) were combined under Ar (g) and heated at 95° C. for 18 h. After cooling to ambient temperature, Et2O (50 mL) and H2O (2 mL) were added and the resulting reaction mixture was stirred for 2 h. The reaction mixture was then extracted with H2O (3×50 mL) and the organic layer extracted with 1M KOH (3×30 mL). The two aqueous layers were combined and the pH adjusted to 7 with HCl (2M), extracted with EtOAc (3×50 mL), dried over Na2SO4 and concentrated in vacuo to afford 2-(2H-1,2,3-triazol-4-yl)pyridine as a brown solid that was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[C:5](=[C:10]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>C(O)C>[CH:21]([C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:24])=[O:2])[C:5]=2[C:6]([OH:8])=[O:7])=[CH:20][CH:19]=1)([CH3:23])[CH3:22]
Reactant: COC(=O)c1cccc(Nc2ccc(C(C)C)cc2)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1ccc(Nc2cccc(C(=O)O)c2C(=O)O)cc1

Procedure:
A mixture of 3-(4-isopropylphenylamino)phthalic acid dimethyl ester (0.70 g, 2.1 mmol) and 3N NaOH (50 mL) in ethanol (100 mL) was heated to reflux for 90 minutes. The mixture was cooled, and the solvent was removed under vacuum. The residue was dissolved in water (100 mL), washed with ethyl acetate (3×75 mL), acidified (HCl) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were washed with water (3×75 mL), dried (MgSO4), and evaporated, providing 0.64 g in quantitative yield: 1H NMR (DMSO-d6) δ 1.18 (d, J=6.9 Hz, 6H), 2.84 (m, 1H), 7.02-7.06 (m, 2H), 7.08-7.18 (m, 3H), 7.26-7.37 (m, 2H), 7.99 (br, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[O:5][CH2:6][C:7]([O:9]CC)=[O:8].[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[O:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)COc1ccc(OC)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(OCC(=O)O)cc1Cl

Procedure:
The above ethyl 3-chloro-4-methoxyphenoxyacetate (700 mg) was hydrolysed with 1M aq. NaOH in THF-MeOH (30 mL, 2:1) to provide the title compound as a white powder.
Reaction SMILES: C[N+](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O.[CH3:12][O:13][N:14]=[C:15]([C:19]1[N:20]=[C:21]([NH:24][CH:25]=[O:26])[S:22][CH:23]=1)[C:16]([OH:18])=O.Cl.[NH2:28][CH:29]1[C:56](=[O:57])[N:31]2[C:32]([C:40]([O:42][CH:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])=[C:33]([CH:36]=[C:37]([Cl:39])[Cl:38])[CH2:34][S:35][C@H:30]12>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[CH3:12][O:13][N:14]=[C:15]([C:19]1[N:20]=[C:21]([NH:24][CH:25]=[O:26])[S:22][CH:23]=1)[C:16]([NH:28][CH:29]1[C:56](=[O:57])[N:31]2[C:32]([C:40]([O:42][CH:43]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])=[C:33]([CH:36]=[C:37]([Cl:39])[Cl:38])[CH2:34][S:35][C@H:30]12)=[O:18]
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=C(Cl)Cl)CS[C@H]12
Reactant: CON=C(C(=O)O)c1csc(NC=O)n1
Agent: C[N+](C)=CCl
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=C(Cl)Cl)CS[C@H]12)c1csc(NC=O)n1
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
To a stirred suspension of Vilsmeier reagent prepared from N,N-dimethylformamide (0.56 ml) and phosphorus oxychloride (0.664 ml) in tetrahydrofuran (11 ml) in a usual manner was added 2-methoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (1.38 g) under ice-cooling and the mixture was stirred for 30 minutes at the same temperature. To a solution of benzhydryl 7-amino-3-(2,2-dichlorovinyl)-3-cephem-4-carboxylate hydrochloride (2.5 g) and monotrimethylsilylacetamide (3.95 g) in ethyl acetate (25 ml) was added the activated acid solution obtained above at -20° C. and mixture was stirred at -20° to -10° C. for 30 minutes. After water and ethyl acetate were added to the resultant mixture, the separated organic layer was washed in turn with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate. The solution was evaporated in vacuo to give benzhydryl 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(2,2-dichlorovinyl)-3-cephem-4-carboxylate (syn isomer) (2.28 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:17]1([C:23]2[O:27][CH:26]=[N:25][C:24]=2[C:28](O)=[O:29])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][S:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:28]([C:24]3[N:25]=[CH:26][O:27][C:23]=3[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:29])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Cn2ncc(N)n2)o1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CS(=O)(=O)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)o1

Procedure:
Following general procedure A, starting from 2-(5-methanesulfonyl-furan-2-ylmethyl)-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.