Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 70 °C
Reaction time: 28 h
Yield: 15 %

Procedure:
To a solution of 1.03 mmol 3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester in 15 ml tetrahydrofuran were added successively 1.23 mmol 4-hydroxybenzotrifluoride, 1.43 mmol triphenylphosphine and 1.43 mmol di-tert-butyl azodicarboxylate. The reaction mixture was stirred at 70° C. for 28 h and was then cooled to room temperature and concentrated in vacuo. The crude material was purified by chromatography (ethyl acetate/heptane) to afford the title compound as a white crystalline solid (yield 15%). MS (m/e): 276.1 ([M+H-Me2C═CH2]+, 100%).
Reaction SMILES: S1C=CC(CC2C3NCNC(=O)C=3NC=2)=C1.[NH2:17][C:18]1[NH:19][C:20](=[O:36])[C:21]([N+:33]([O-])=O)=[C:22]([CH:24]([CH2:27][C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)[C:25]#[N:26])[N:23]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[ClH:45].[OH-].[NH4+]>[OH-].[Na+]>[NH2:17][C:18]1[NH:19][C:20](=[O:36])[C:21]2[NH:33][C:25]([NH2:26])=[C:24]([CH2:27][C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[C:22]=2[N:23]=1.[ClH:45]
Reactant: N#CC(Cc1ccsc1)c1nc(N)[nH]c(=O)c1[N+](=O)[O-]
Agent: Cl
Agent: O=C1NCNc2c(Cc3ccsc3)c[nH]c21
Agent: O=S([O-])S(=O)[O-]
Product: Nc1nc2c(Cc3ccsc3)c(N)[nH]c2c(=O)[nH]1
Temperature: 90 °C

Procedure:
2,6-Diamino-3,5™dihydro-7-(3-thienylmethyl)-4H-pyrrolo-[3,2-d]pyrimidin-4-one. To a solution of 2-Amino-1,6-dihydro-5-nitro-6-oxo-α-(3-thienylmethyl)-4-pyrimidineacetonitrile prepared above (5.0 g) in 1N NaOH (300 mL) is added sodium dithionite (20 g). The reaction mixture is heated for 30 min at 90° C. and then is acidified (pH 1) with conc HCl while still hot. The reaction mixture is cooled and neutralized with ammonium hydroxide. The resulting precipitate is collected by filtration, washed with cold water and dried under vacuum. The crude product is added to 100 mL conc HCl in small portions with stirring and the hydrochloride salt is collected by filtration. The product is recrystallized from 1N HCl to give 2,6-Diamino-3,5-dihydro-7-(3-thienylmethyl)-4H-pyrrolo [3,2-d]pyrimidin4-one as the monohydro-chloride salt (2.35 g), mp>185° C. (dec). ##STR19##
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:13][CH3:14])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[C:15]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:14][O:13][C:10]1[C:11]2[O:12][CH2:15][O:1][C:2]=2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)c(O)c(OC)c1
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(OC)c2c(c1)OCO2
Temperature: 25 °C
Yield: 76.9 %

Procedure:
To a solution of methyl 3,4-dihydroxy-5-methoxybenzoate (15.3 g, 0.078 mol) in acetone (500 mL) was added CH2BrCl (34.4 g, 0.27 mol) and K2CO3 (75 g, 0.54 mol) at 80° C. The resulting mixture was heated at reflux for 4 h. The mixture was cooled to room temperature and solid K2CO3 was filtered off. The filtrate was concentrated under reduced pressure, and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with water, dried over anhydrous Na2SO4, and evaporated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (Petroleum Ether/Ethyl Acetate=10:1) to afford methyl 7-methoxybenzo[d][1,3]dioxole-5-carboxylate (12.6 g, 80%). 1H NMR (400 MHz, CDCl3) δ 7.32 (s, 1H), 7.21 (s, 1H), 6.05 (s, 2H), 3.93 (s, 3H), 3.88 (s, 3H).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]3[CH2:24][C@:14]4([C:22]5[C:17](=[N:18][CH:19]=[CH:20][CH:21]=5)[NH:16][C:15]4=[O:23])[CH2:13][C:8]=3[CH:9]=2)[N:4]=1.S(Cl)([Cl:27])=O>ClCl>[Cl:27][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]3[CH2:24][C@:14]4([C:22]5[C:17](=[N:18][CH:19]=[CH:20][CH:21]=5)[NH:16][C:15]4=[O:23])[CH2:13][C:8]=3[CH:9]=2)[N:4]=1
Reactant: O=C1Nc2ncccc2[C@@]12Cc1cc3ccc(CO)nc3cc1C2
Reactant: O=S(Cl)Cl
Agent: ClCl
Product: O=C1Nc2ncccc2[C@@]12Cc1cc3ccc(CCl)nc3cc1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (S)-2-(hydroxymethyl)-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step A (203 mg, 0.64 mmol) in CH2 Cl2 (20 mL) was added thionyl chloride (761 mg, 6.40 mmol) and the resulting mixture was stirred at ambient temperature for 1 h, then concentrated in vacuo. The residue was partitioned between saturated aqueous NaHCO3 (20 mL) and CH2 Cl2 (30 mL). The aqueous layer was extracted further with CH2 Cl2 (2×30 mL). The combined organic extracts were dried over Na2 SO4, filtered, and concentrated in vacuo to give the title compound in sufficient purity for use in the next step. MS: m/z=336 (M+1).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=2)[CH2:3][CH2:2]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 120 °C
Yield: 14.3 %

Procedure:
A stirred mixture of tert-butyl 1-piperazinecarboxylate (1.00 g, 5.37 mmol), ethyl 4-fluorobenzoate (903 mg, 5.37 mmol), and K2CO3 (1.11 g, 8.06 mmol) in DMF (10 mL) was heated at 120° C. overnight. After cooling, the mixture was diluted with EtOAc (300 mL), followed by washing with brine (2×200 mL), drying over MgSO4, and evaporation. The residue was chromatographed on silica-gel with CHCl3-EtOAc (20:1 to 4:1, v/v) as eluent to give 257 mg (14%) ethyl 4-[4-(tert-butyloxycarbonyl)-1-piperazinyl]benzoate as a pale yellow amorphous solid. IR (KBr) 1701, 1612 cm−1; 1H-NMR (CDCl3) d 1.37 (3 H, t, J=7.3 Hz), 1.49 (9 H, s), 3.30 (4 H, t, J=5.4 Hz), 3.58 (4 H, t, J=5.4 Hz), 4.33(2 H, q, J=7.3 Hz), 6.87(2 H, d, J=8.8 Hz), 7.94 (2 H, dt, J=8.8, 2.4 Hz); MS (FAB) m/z 335 (M++1); Anal. Calcd for C18H26N2O4: C, 64.54; H, 7.84; N, 8.38. Found: C, 64.39; H, 7.89; N, 8.38.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[CH3:9][O:10][C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19](O)=[O:20])[CH2:15][CH2:14]1)=[O:12]>C1COCC1>[O:8]=[C:3]1[CH2:4][CH2:5][C:6](=[O:7])[N:2]1[O:1][C:19]([C@H:16]1[CH2:15][CH2:14][C@H:13]([C:11]([O:10][CH3:9])=[O:12])[CH2:18][CH2:17]1)=[O:20]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](C(=O)ON2C(=O)CCC2=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of N-hydroxysuccinimide (6.18 g, 0.0537 mol) and trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (10.00 g, 0.05370 mol) in THF (100.00 mL) was charged with (N,N-dicyclohexylcarbodiimide (11.08 g, 0.0537 mol) in THF (16 mL). This reaction was stirred at rt for an additional 16 h then stirred at 45° C. for 1 h. The reaction mixture was filtered while still warm through a fritted funnel. The cake was washed with 3 more portions of THF and the filtrate was concentrated in vacuo and was crystallized from i-PrOH (300 mL) and filtered through a fritted funnel resulting in 11.8 g, (78% yield) of the title compound as a white crystals. 1H NMR (400 MHz, CDCl3) δ ppm 1.45-1.69 (m, 4H), 2.07-2.16 (m, 2H), 2.18-2.28 (m, 2H), 2.29-2.39 (m, 1H), 2.59-2.71 (m, 1H) 2.84 (br. 4H) and 3.68 (s, 3H); MS (ES+): m/z 284.09 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:16](Cl)(=[O:18])[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(=S)=S>[C:16]([C:13]1[CH:12]=[CH:11][C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)=[CH:15][CH:14]=1)(=[O:18])[CH3:17]
Reactant: COc1ccc(-c2ccccc2)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COc1ccc(-c2ccc(C(C)=O)cc2)cc1F
Yield: 29.3 %

Procedure:
Into a flask were charged 150 g (0.74 mol) of the above 3-fluoro-4-methoxy biphenyl, 1 l of carbon disulfide and 58 g (0.74 mol) of acetyl chloride, to which was added 120 g (0.90 mol) of anhydrous aluminum chloride over about 2.5 hours with stirring under ice cooling. The resulting mixture was further stirred for 2 hours and refluxed for 3 hours. After the air cooling, the reaction mixture was poured into 3 l of 1 normal hydrochloric acid. The precipitated solid was filtered and recrystallized with 2-propanol two times and with methanol to obtain 53 g (yield: 29%) of 4-acetyl-3'-fluoro-4'-methoxy biphenyl.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH2:11][CH3:12])[CH:3]=1.O=S(Cl)Cl.[CH3:17]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[C:4]([CH2:11][CH3:12])[CH:3]=1
Reactant: CCc1cc(Br)ccc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CCc1cc(Br)ccc1C(=O)OC
Temperature: 70 °C
Yield: 87 %

Procedure:
Charged compound 4-bromo-2-ethylbenzoic acid (2.05 g, 9.58 mmol) and methanol (20 mL) to a flask, SOCl2 (3.42 g, 28.74 mmol) was added slowly at 0° C. The reaction mixture was heated to 70° C. for three hour. Solvent was removed and the residue was dissolved in CH2Cl2, filtered, the filtrate was concentrated to a residue which was purified by flash column chromatograph to give 1.9 g of the title compound (87%).
Reaction SMILES: [OH:1][C:2]([C:14]1[S:15][CH:16]=[CH:17][N:18]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[C:3]([F:6])([F:5])[F:4].Cl.Cl[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.C(=O)([O-])[O-].[K+].[K+]>>[OH:1][C:2]([C:14]1[S:15][CH:16]=[CH:17][N:18]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)[CH:8]=1)[C:3]([F:5])([F:4])[F:6]
Reactant: Oc1cccc(C(O)(c2nccs2)C(F)(F)F)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OC(c1cccc(OCc2ccc3ccccc3n2)c1)(c1nccs1)C(F)(F)F
Temperature: 25 °C
Yield: 35.1 %

Procedure:
A mixture of 2-[1-hydroxy-1-(3-hydroxyphenyl)-2,2,2-trifluoroethyl]thiazole (0.33 g), 2-chloromethylquinoline hydrochloride (0.22 g), potassium carbonate (0.5 g) and dimethylformamlde (5 ml) was stirred at ambient temperature for Z4 hours. The mixture was partitioned between ethyl aceiate and water and the organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with chloroform/ethyl acetate (9/1 v/v) to give 2-[1-hydroxy-1-[3-(quinol-2-ylmethoxy)phenyl]-2,2,2-trifluoroethyl]thiazole (0.15 g, 30%), m.p. 177° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:57][C:58]1[CH:59]=[C:60]([N:64]2[CH2:68][CH2:67][CH:66]([C:69](O)=[O:70])[C:65]2=[O:72])[CH:61]=[CH:62][CH:63]=1>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:69]([CH:66]1[CH2:67][CH2:68][N:64]([C:60]2[CH:61]=[CH:62][CH:63]=[C:58]([F:57])[CH:59]=2)[C:65]1=[O:72])=[O:70]
Reactant: O=C(O)C1CCN(c2cccc(F)c2)C1=O
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2cccc(F)c2)C1=O
Yield: 41.3 %

Procedure:
A mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.104 g; 0.448 mmol), PyBOP (0.350 g; 0.672 mmol), N,N-diisopropylethylamine (0.232 mL; 1.34 mmol) and 1-(3-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (0.100 g; 0.448 mmol) was stirred in DMF (3 mL) overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.074 g (41%) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[C:10]([C:11]#[N:12])=[C:6]2[N:5]=[C:4]([CH3:14])[C:3]=1[CH2:15][CH2:16]Cl.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(Cl)(Cl)Cl>[C:18]([N:22]1[C:2]2[N:7]3[N:8]=[CH:9][C:10]([C:11]#[N:12])=[C:6]3[N:5]=[C:4]([CH3:14])[C:3]=2[CH2:15][CH2:16]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1nc2c(C#N)c(C)nn2c(Cl)c1CCCl
Reactant: CC(C)(C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1nc2c(C#N)cnn2c2c1CCN2C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
A mixture of 88.9 g of Compound (VI) [R2 =H, R3 =CN], 33.0 g of tert-butylamine, 89 g of anhydrous potassium carbonate, and 700 ml of anhydrous dimethylformamide were stirred at room temperature overnight. To the reaction solution was added 500 ml of chloroform to remove insoluble substances by filtration. The filtrate was condensed under reduced pressure to dryness. The residue was dissolved in chloroform, washed with water, and dried over anhydrous sodium sulfate. The residue from which the solvent was evaporated was recrystallized in benzene to produce 73.6 g of 8-tert-butyl-3-cyano-6,7-dihydro-5-methyl-8H-pyrrolo [3,2-e]pyrazolo[1,5-a]pyrimidine [R1 =C(CH3)3, R2 =H, R3 =CN in formula (I)] having a melting point of 220°-224° C. at a yield of 82.8%.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[C:10]([C:11]#[N:12])=[C:6]2[N:5]=[C:4]([CH3:14])[C:3]=1[CH2:15][CH2:16]Cl.C(N(CC)CC)C.[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26].C(O)C>C(C(C)=O)C>[C:25]([N:29]1[C:2]2[N:7]3[N:8]=[CH:9][C:10]([C:11]#[N:12])=[C:6]3[N:5]=[C:4]([CH3:14])[C:3]=2[CH2:15][CH2:16]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)N
Reactant: Cc1nc2c(C#N)c(C)nn2c(Cl)c1CCCl
Solvent: CCC(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc2c(C#N)cnn2c2c1CCN2C(C)(C)C
Temperature: 85 °C
Yield: 80 %

Procedure:
(ii-1) 2.7 g (0.01 mol) of Compound (VI) [R2 =CH3, R3 =CN], 2 ml of triethylamine, 3.2 ml of tert-butylamine, and 15 ml of anhydrous ethanol were placed in a closed tube and heated at 85° C. in a water bath for 8 hours. Then the tube was opened, and 100 ml of methyl ethyl ketone was added to the reaction solution. The mixed solution was warmed and subjected to filtration. The filtrate was purified over a chromatographic column packed with 10 g of silica gel (pH=7, 200 mesh) using methyl ethyl ketone in advance. The eluant was then evaporated to obtain 2.4 g of 8-tert-butyl-3-cyano-6,7-dihydro-2,5-dimethyl-8H-pyrrolo[3,2-e]pyrazolo[1,5-a]pyrimidine [R1 =C(CH3)3, R2 =CH3, R3 =CN in formula (I)] (Compound 2 of this invention) as yellowish orange plate crystals having a melting point of 229°-230° C. at a yield of 80.0%.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C:24]2=[O:29])=[CH:19][CH:18]=1>C(O)C.O>[OH:1][C@H:2]([CH2:3][NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C:24]2=[O:29])=[CH:21][CH:22]=1)[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15]
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Solvent: CCO
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C[C@H](O)CNc1ccc(N2CCOCC2=O)cc1

Procedure:
A suspension of 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)-dione (A. Gutcait et al. Tetrahedron Asym. 1996, 7, 1641) (5.68 g, 27.9 mmol) and 4-(4-aminophenyl)-3-morpholinone (5.37 g, 27.9 mmol) in ethanol/water (9:1, 140 ml) is heated under reflux for 14 hours (the precipitate dissolves; after some time, another precipitate is formed). The precipitate (desired product) is filtered off, washed three times with diethyl ether and dried. The combined mother liquors are concentrated under reduced pressure and, after addition of a second portion of 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3-(2H)-dione (2.84 g, 14.0 mmol), suspended in ethanol/water (9:1, 70 ml) and heated under reflux for 13 hours (the precipitate dissolves; after some time, another precipitate is formed). The precipitate (desired product) is filtered off, washed three times with diethyl ether and dried. Total yield: 10.14 g, 92% of theory.
Reaction SMILES: [CH3:1][Sn:2]([CH3:15])([CH3:14])[C:3]1[CH:12]=[N:11][C:10]2[NH:9][C:8](=[O:13])[CH2:7][O:6][C:5]=2[CH:4]=1.[Li]N([Si](C)(C)C)[Si](C)(C)[CH3:19].COS(OC)(=O)=O>C1COCC1>[CH3:19][N:9]1[C:8](=[O:13])[CH2:7][O:6][C:5]2[CH:4]=[C:3]([Sn:2]([CH3:15])([CH3:14])[CH3:1])[CH:12]=[N:11][C:10]1=2
Reactant: [Li]N([Si](C)(C)C)[Si](C)(C)C
Reactant: C[Sn](C)(C)c1cnc2c(c1)OCC(=O)N2
Solvent: C1CCOC1
Solvent: COS(=O)(=O)OC
Product: CN1C(=O)COc2cc([Sn](C)(C)C)cnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 680 mg of 7-trimethylstannyl-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (0.0022 mole) in 10 ml of THF is added 2.4 ml of LiN(TMS)2 (0.0024 mole) in THF. The homogenous solution is maintained under nitrogen at room temperature for 20 min., 300 mg (0.0024 mole) of dimethylsulfate is added and the reaction mixture allowed to stir overnight. The reaction mixture is then quenched with 10 ml of sat. ammonium chloride and extracted with 3×50 ml ethyl acetate. The ethyl acetate is then washed with 3×10 ml sat. ammonium chloride, dried over sodium sulfate and concentrated to obtain off white product which is used directly in the next step.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH2:6][C:7]([C:9](=[N:25][O:26][CH3:27])[C:10]([NH:12][CH:13]1[C:23](=[O:24])[N:15]2[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]12)=[O:11])=O>C(O)C>[NH2:1][C:2]1[S:3][CH:6]=[C:7]([C:9](=[N:25][O:26][CH3:27])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:4]=1
Reactant: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reactant: NC(N)=S
Solvent: CCO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1

Procedure:
Thiourea (11 mg.) and a solution of 7-[2-(2-bromoacetyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 30 mg.) in ethanol (2 ml.) were treated in a similar manner to that of Example 36-(4) to give 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer). The product was identified with an authentic sample by thin layer chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:8][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a solution of 3-bromophenol (50 g, 289 mmol) in 340 mL DMF was added Et3N (35 g, 347 mmol) and tert-butyldimethylsilyl chloride (52 g, 347 mmol). The mixture was stirred for 0.5 h, and then diluted with ET2O (2 L). The organic phase was washed with 5% aqueous HCl and brine, and dried over MgSO4. Flash chromatography using hexane:EtOAc (95:5) gave 80.1 g (96%) of product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([Si:13](Cl)([CH3:15])[CH3:14])([CH3:12])([CH3:11])[CH3:10].N1C=CN=C1.O>CN(C)C=O>[Si:13]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:15])[CH3:14]
Reactant: Oc1cccc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 133.1 %

Procedure:
A mixture of 300.0 g (1.7 mol) of 3-bromophenol, 392.1 g (2.6 mol) of tert-butylchlorodimethylsilane and 295.1 g (4.3 mol) of imidazole in 1 L of N,N-dimethylformamide was stirred at room temperature under nitrogen for 18 hours. The reaction mixture was poured into cold water and extracted with diethyl ether. The ether extracts were washed with water and brine, dried over sodium sulfate, and the solvent was evaporated under vacuum to give 650 g of crude 3-bromophenyl tert-butyldimethylsilyl ether as an orange oil. NMR (CDCl3, 200 MHz) δ: 0.2 (s, 6H); 0.95 (s, 9H); 6.8 (m, 1H); 7.0-7.1 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10]C(=O)[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])[C:7](=[O:24])[C:6]=2[CH:25]=1.C(O)C.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:25]=[C:6]([C:7]([NH:8][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:24])[C:5]([OH:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCCCCCn1c(=O)oc2ccc(Cl)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCCCCCNC(=O)c1cc(Cl)ccc1O
Temperature: 40 °C

Procedure:
Ethyl 8-(6-chloro-2H-1,3-benzoxazine-2,4(3H)-dionyl)octanoate (641 g, 1.7 mol) and ethyl alcohol (3200 ml) were added to a 22 liter, five neck flask. In a separate 5 liter flask, sodium hydroxide (NaOH) (288.5 g, 7.2 mol) was dissolved in deionized water (3850 ml). This mixture was added to the reaction mixture contained in the 22 liter flask. A temperature increase to 40° C. was noted. Heating of the reaction mixture was started and when the reaction temperature had increased to 50° C. it was noted that all of the solids in the reaction mixture had dissolved. A temperature of 50° C. was maintained in the reaction mixture for a period of 1.5 hours. The reaction flask was then set up for vacuum distillation. 2200 ml of distillate were collected at a vapor temperature of 55° C. (10 mm Hg) before the distillation was discontinued. The reaction flask was then placed in an ice/water bath and concentrated hydrochloric acid (HCl) (752 ml) was added over a period of 45 minutes. During this addition the reaction mixture was noted to have thickened somewhat and an additional 4 liters of deionized water was added to aid the stirring of the reaction mixture. The reaction mixture was then vacuum filtered and the filter cake was washed with 3 liters of deionized water. After drying in vacuo at room temperature 456.7 g (83.5%) of N-(5-chlorosalicyloyl)-8-aminocaprylic acid was isolated.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH:6]=[CH:7][C:8]([OH:10])=[O:9]>[Pd].CO>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)C=Cc1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: O=C(O)CCc1cccc(C(F)(F)F)c1
Reaction time: 10 h
Yield: 99 %

Procedure:
3-trifluoromethyl cinnamic acid (0.463 moles, 100 gms) was dissolved in 1.0 lt. of methanol and charged to a hydrogenating vessel. 5% Pd/C (3 gms) was added. The reaction mass was hydrogenated at H2 pressure of 1 kg/cm2 at a temperature of 25° C. for about 10 hours. After completion of the reaction, the contents of the vessel was filtered, washed with methanol (100 ml). Methanol was evaporated from the filtered material to get a residue of 3-(3-trifluoromethylphenyl)propanoic acid (100 gms, Yield 100%).