Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.[C:15]([O:27]C)(=[O:26])[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1.C(O)CO.O=[Sb]O[Sb]=O>O.O.C([O-])(=O)C.C([O-])(=O)C.[Zn+2].O.CO>[CH:4]12[C:7](=[O:8])[O:9][CH2:10][CH2:14][O:13][C:11](=[O:12])[CH:1]([CH2:2][CH2:3]1)[CH2:6][CH2:5]2.[C:15]([O-:27])(=[O:26])[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O-:22])=[O:21])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Reactant: COC(=O)C1CCC(C(=O)OC)CC1
Agent: CC(=O)[O-]
Agent: O=[Sb]O[Sb]=O
Agent: [Zn+2]
Solvent: O
Solvent: CO
Solvent: OCCO
Product: O=C([O-])c1ccc(C(=O)[O-])cc1
Product: O=C1OCCOC(=O)C2CCC1CC2
Temperature: 240 °C
Reaction time: 3 h

Procedure:
A mixture of dimethyl 1,4-cyclohexanedicarboxylate (88.1 g, 0.40 mole), dimethyl terephthalate (194.0 g, 1.0 mole), and ethylene glycol (147.7 g, 1.7 mole) in the presence of zinc diacetate dihydrate (0.0629 g) and antimony trioxide (0.158 g) was heated at 200° C. under a slow stream of nitrogen overnight until the evolution of methanol ceased. The temperature was increased to 240° C., and the mixture was stirred under reduced pressure (0.025 mm Hg) for 3 hours until the stirring was difficult. The reaction mixture on cooling under nitrogen afforded a water white, amorphous polymer Tg 59° C., I.V. 0.58 dl/g).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C1(C)C=CC=CC=1.[CH3:12][C:13]([C:16]1[CH:17]=[C:18]([CH2:27][CH2:28][C:29]([NH:31][NH2:32])=[O:30])[CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])([CH3:15])[CH3:14].C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:26][C:23]([C:20]1[CH:19]=[C:18]([CH2:27][CH2:28][C:29]2[O:30][C:1](=[O:2])[NH:32][N:31]=2)[CH:17]=[C:16]([C:13]([CH3:12])([CH3:14])[CH3:15])[C:21]=1[OH:22])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Reactant: O=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CCc2n[nH]c(=O)o2)cc(C(C)(C)C)c1O
Reaction time: 0.17 h
Yield: 74 %

Procedure:
A 12.5% solution of phosgene in toluene (10.7 mL, 12.0 mmol) is added dropwise to a -78° C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoic acid hydrazide in tetrahydrofuran (200 mL). The reaction mixture is stirred for 10 minutes then poured into a separatory funnel containing ethyl acetate and aqueous sodium bicarbonate. The organic phase is washed three times with water and once with brine. Drying the organic phase over magnesium sulfate and evaporation gives a crude product which is crystallized from hexane to afford 1.6 g (74%) of 5-[2-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethyl]-1,3,4-oxadiazol-2(3H)-one, mp 120.0°-123.0° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:21]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)=[CH:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]C)=[O:27])[CH:18]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:21]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)=[CH:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH:18]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CCCC=C(c1cccnc1)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Br)cc1)C2
Solvent: CCO
Product: O=C(O)CCCC=C(c1cccnc1)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Br)cc1)C2

Procedure:
3.7 g of methyl 6-(2-(4-bromobenzenesulphonylamino)indan-5-yl)-6-(3-pyridyl)hex-5-enoate are refluxed for 15 minutes in 30 ml of ethanol and with 1N of 15N sodium hydroxide solution. After cooling the solution is rotary evaporated and the residue is taken up in water and washed with 30 ml of methylene chloride. Then the aqueous phase is adjusted to pH 4 using hydrochloric acid. The precipitate formed is washed and dried.
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].C([Li])CCC.COCN[C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:21]>O1CCCC1>[CH3:4][O:3][C:2]1[C:1]([O:9][CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:21]
Reactant: COc1ccccc1OC
Reactant: COCNC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1OC
Temperature: -15 °C
Reaction time: 1 h
Yield: 125.2 %

Procedure:
A 1 L flask equipped with mechanical stirrer, thermometer well, and pressure equalizing addition funnel was charged with 500 mL of tetrahydrofuran and 49 ml (0.38 mol) veratrole under a nitrogen atmosphere. The solution was cooled to −15° C. and 160 mL (2.5M, 0.42 mol) of n-butyllithium was placed in the addition funnel. The n-butyllithium solution was added to the reaction mixture over a 25 minute period while maintaining the reaction temperature below −10° C. After complete addition, the pale green solution was held at 0° C. for one hour and then room temperature for 2 hours resulting in a very thick slurry. A 3 L Morton flask containing 82.3 g (0.32 mol) 4-[(methoxymethylamino)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15) in 300 mL of tetrahydrofuran under nitrogen atmosphere was cooled to −15° C. while the lithiated veratrole slurry was cooled to 0° C. The lithiated veratrole slurry was added to the 4-[(methoxymethylamino)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester solution over a 15 minute period while keeping the temperature below −10° C. The resulting pale green slurry was stirred an additional 15 minutes at −15° C. and then allowed to warm to room temperature, causing the reaction mixture to become clear. The reaction mixture was stirred for 20 hours at room temperature then quenched with 500 mL of saturated ammonium chloride solution. The aqueous phase was extracted with toluene (2×250 mL) which was then combined with the tetrahydrofuran solution. The organic solution was washed with brine (2×25 mL) and dried over sodium sulfate. The solution was filtered and then concentrated by rotary evaporator to give 140 g of an orange oil. The crude oil was quickly run through 350 g of silica gel using 20% ethyl acetate in toluene as eluant. Solvent evaporation then gave 88.9 g of an orange oil. The orange oil was then placed in a kugelrohr for three hours (80° C., 1 mm Hg) to remove most of the veratrole, giving the title compound (7) remaining in the pot as an orange syrup (55.9 g, 50%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][CH:8]=[C:9]([CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=2[O:21][CH3:22])[N:10]=1.C(O)C.[BH4-].[Na+].O>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][CH:8]=[C:9]([CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][C:14]=2[O:21][CH3:22])[N:10]=1
Reactant: COc1cc(C=O)ccc1OCc1coc(-c2ccco2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CO)ccc1OCc1coc(-c2ccco2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of 4-{[2-(2-furyl)-1,3-oxazol-4-yl]methoxy}-3-methoxybenzaldehyde (9.70 g) in tetrahydrofuran (100 mL)-ethanol (50 mL) was gradually added sodium borohydride (1.23 g) at room temperature. After stirring at room temperature for 30 min., water was added to the reaction mixture and the precipitated crystals were collected by filtration to give (4-{[2-(2-furyl)-1,3-oxazol-4-yl]methoxy}-3-methoxyphenyl)methanol as pale-brown crystals (8.40 g, yield 86%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 117-118° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:10][CH2:11][C:12](OC)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[Al]CC(C)C)C>ClCCl>[C:1]([O:5][C:6]([NH:8][CH:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:10][CH2:11][CH2:12][OH:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCC(NC(=O)OC(C)(C)C)c1ccccc1
Agent: CC(C)C[Al]CC(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CCCO)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution of methyl 4-[(t-butoxycarbonyl)-amino]-4-phenylbutanoate (293 mg, 1.0 mmol) in dichloromethane (25 mL) was added Dibal-H (3 mL of a 1.0 M solution in dichloromethane, 3.0 mmol). The mixture was then stirred at 0° C. for 2 hours before being quenched with a saturated aqueous sodium potassium tartrate solution (10 mL). The biphasic mixture was then rapidly stirred for approximately 45 minutes, until the aqueous and organic layers clarified. The aqueous and organic layers were then separated and the aqueous layer was extracted twice with dichloromethane. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a pale yellow residue, which was purified by silica gel flash chromatography (1:1 hexanes:ethyl acetate) to afford 4-[(t-butoxycarbonyl)-amino]-4-phenylbutanol as a colourless oil in a yield of 138 mg (52%). 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.45 (m, 2H), 1.56 (m 2H), 2.71 (br s, 1H(OH)), 3.54 (t, 2H, J=6.9 Hz), 4.56 (m, 1H), 5.22 (br s, 1H (NH)), 7.16-7.26 (m, 5H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:24][C:14]3=[N:15][C:16](Cl)=[C:17]([N+:20]([O-:22])=[O:21])[C:18](=[O:19])[N:13]3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH3:25]>C(O)C.CN(C)C=O>[NH2:25][C:16]1[N:15]=[C:14]2[S:24][C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)=[N:12][N:13]2[C:18](=[O:19])[C:17]=1[N+:20]([O-:22])=[O:21]
Reactant: N
Reactant: CC(C)(C)c1ccc(-c2nn3c(=O)c([N+](=O)[O-])c(Cl)nc3s2)cc1
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(-c2nn3c(=O)c([N+](=O)[O-])c(N)nc3s2)cc1

Procedure:
1.9 g of 2-(4-tert-butylphenyl)-7-chloro-6-nitro-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one was suspended in a mixture of 20 ml of ethanol and 10 ml of dimethylformamide, and 5 ml of concentrated aqueous ammonia was added dropwise to the suspension while maintaining at a temperature of 60° C. to 70° C. After heating at that temperature for 2 hours, the mixture was cooled and the precipitate formed was separated by filtration to obtain 1.3 g of 7-amino-2-(4-tert-butylphenyl)-6-nitro-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one as pale yellow prisms having a melting point higher than 300° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([C:11](N)=[O:12])=[N:9][S:10][C:6]=2[CH:5]=[C:4]([CH3:14])[CH:3]=1.[OH-:15].[K+].Cl>CCO.O>[CH3:1][C:2]1[C:7]2[C:8]([C:11]([OH:15])=[O:12])=[N:9][S:10][C:6]=2[CH:5]=[C:4]([CH3:14])[CH:3]=1
Reactant: Cc1cc(C)c2c(C(N)=O)nsc2c1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c2c(C(=O)O)nsc2c1
Temperature: 85 °C

Procedure:
To a solution of 4,6-dimethyl-benzo[d]isothiazole-3-carboxylic acid amide (20 mg, 0.097 mmol) in EtOH (10 mL) and H2O (2 mL) was added KOH (11 mg, 0.19 mmol). The solution was heated to 85° C. for 48 hours. The solution was cooled and was placed in an ice bath. Conc. HCl was added to adjust the pH of the solution to 2. The solid that precipitated out from the solution was collected by filtration. The white solid was dried and was confirmed to be the title compound (15 mg, 75%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C:11](O)=O)=[CH:5][CH:4]=1)#[N:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:26][N:27]([CH:40]1[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]1)[S:28]([C:31]1[CH:36]=[CH:35][C:34]([NH:37][CH3:38])=[C:33]([NH2:39])[CH:32]=1)(=[O:30])=[O:29].ClCCl.C(O)C>O1CCCC1>[CH3:26][N:27]([CH:40]1[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]1)[S:28]([C:31]1[CH:36]=[CH:35][C:34]2[N:37]([CH3:38])[C:11]([CH2:10][O:9][C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[N:39][C:33]=2[CH:32]=1)(=[O:30])=[O:29]
Reactant: CNc1ccc(S(=O)(=O)N(C)C2CCN(C)CC2)cc1N
Reactant: N#Cc1ccc(OCC(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CCC(N(C)S(=O)(=O)c2ccc3c(c2)nc(COc2ccc(C#N)cc2)n3C)CC1
Reaction time: 8 h

Procedure:
532 mg (3.0 mMol) of 4-cyanophenyloxyacetic acid and 486 mg (3.0 mMol) of 1,1'-carbonyldiimidazole were dissolved in 40 ml of tetrahydrofuran and refluxed for 15 minutes. Then 700 mg (2.24 mMol) of 3-amino-4-methylaminobenzenesulphonic acid-N-methyl-N-(1-methyl-piperidin-4-yl)-amide were added and boiling was continued for a further eight hours. Then the mixture was evaporated down and the resulting oily residue was refluxed in 30 ml of glacial acetic acid for one hour. The glacial acetic acid was distilled off, the residue was mixed with about 30 ml of water and made alkaline with concentrated ammonia, and the solution was extracted three times with about 20 ml of dichloromethane. The organic phases were dried and evaporated down. The resulting product was further reacted without any purification. Yield: 400 mg (39% of theory), C23H27N5O3S (453.6) Rf value: 0.37 (silica gel; dichloromethane/ethanol=4:1)
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:4]1=[O:32].C(N(CC)CC)C.[CH3:40][C:41]([CH3:46])=[CH:42][C:43](Cl)=[O:44]>C(Cl)Cl>[CH3:40][C:41]([CH3:46])=[CH:42][C:43]([NH:2][C@@H:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:4]1=[O:32])=[O:44]
Reactant: N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)C1=O
Reactant: CC(C)=CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)=CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)C1=O
Temperature: -15 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a suspension of 1.18 g (2.64 mmol) of 3(R)-amino-1,3,4,5-tetrahydro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-2H-1-benzazepin-2-one, hydrochloride (Example 4, Step C) in 30 mL of methylene chloride under nitrogen at -15° C. was added 0.923 mL (2.64 mmol) of triethylamine followed by 0.294 mL (2.64 mmol) of 3,3-dimethylacryloyl chloride. The reaction mixture was stirred at -15° C. for 2 hours then quenched by the addition of 1N hydrochloric acid. The mixture was diluted with 50 mL of methylene chloride and washed with 50 mL of 1N hydrochloric acid and brine. The organic layer was removed and concentrated to dryness under vacuum. The residue was redissolved in 30 mL of methanol and treated with 1.5 mL of 9N hydrochloric acid. After stirring for 30 minutes, the mixture was concentrated to dryness under vacuum to give 1.3 g (2.63 mmol, 99%) of the product as a white solid.
Reaction SMILES: C(C1[C:8]([C:9]([O:11]CC)=[O:10])=[CH:7][N:6]=[C:5]2[N:14]([CH2:17][CH3:18])[N:15]=[CH:16][C:4]=12)#N.[OH-:19].[Na+].[CH2:21]([OH:23])[CH3:22]>O>[CH2:17]([N:14]1[C:5]2=[N:6][CH:7]=[C:8]([C:9]([OH:11])=[O:10])[C:22]([C:21]([OH:19])=[O:23])=[C:4]2[CH:16]=[N:15]1)[CH3:18]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1C#N
Reactant: CCO
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CCn1ncc2c(C(=O)O)c(C(=O)O)cnc21
Yield: 50 %

Procedure:
4-Cyano-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester (2.0 g, 8.2 mmol) was suspended in ethanol (20 mL), and an aqueous solution of NaOH (6 N, 3 eq) was added. The reaction mixture was heated at reflux for 2 h and then diluted with water (100 mL). This aqueous solution was extracted with diethyl ether (50 mL×2) and the organic extracts were discarded. The aqueous layer was then acidified with phosphoric acid and extracted with EtOAc (50 mL×3). The extracts were concentrated via evaporation under reduced pressure to afford the title compound (>90% purity, 50-90% yield). This material was used directly without further purification.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][NH:35]C(OC(C)(C)C)=O)=[CH:30][CH:29]=2)[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:8]=1)=O.[ClH:43]>CO>[ClH:43].[ClH:43].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([CH2:34][NH2:35])=[CH:32][CH:33]=2)[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:8]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CON=C(C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)c2csc(NC=O)n2)cc1
Agent: Cl
Solvent: CO
Product: NCc1ccc(CON=C(C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)c2csc(N)n2)cc1
Yield: 70.6 %

Procedure:
7-[2-(2-Formamidothiazol-4-yl)-2-(4-tertbutoxycarbonylaminomethylbenzyloxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.4 g.), conc. hydrochloric acid (0.95 g.) and methanol (15 ml.) were treated in a similar manner to that of Example 4-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-(4-aminomethyl benzyloxyimino)acetamido]-3-cephem-4-carboxylic acid dihydrochloride (syn isomer, 0.9 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:4]=1[CH:5]=[CH:6][C:7]([OH:9])=O.C(OP(Cl)(=O)OCC)C.[NH2:25][C:26]1[CH:31]=[C:30]([CH3:32])[C:29]([OH:33])=[C:28]([CH3:34])[CH:27]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:4]=1[CH:5]=[CH:6][C:7]([NH:25][C:26]1[CH:31]=[C:30]([CH3:32])[C:29]([OH:33])=[C:28]([CH3:34])[CH:27]=1)=[O:9]
Reactant: Cc1cc(N)cc(C)c1O
Reactant: COc1ccc(OC)c(C=CC(=O)O)c1
Agent: CCOP(=O)(Cl)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(OC)c(C=CC(=O)Nc2cc(C)c(O)c(C)c2)c1
Reaction time: 1 h
Yield: 71 %

Procedure:
Under ice-cooling, 4.16 g of 2,5-dimethoxycinnamic acid is dissolved in 50 ml of acetonitrile, and to the resultant solution are added 3.03 g of triethylamine, then 4.13 g of diethylphosphorochloridate. After the mixture is stirred for one hour, 2.74 g of 4-amino-2,6-dimethylphenol is added and the reaction mixture is stirred at room temperature. After completion of the reaction, ice chips are added, and then 5 % aqueous sodium hydrogen carbonate solution is added. The crystals precipitated are collected by filtration, and washed with isopropyl ether. The crystals obtained are recrystallized form ethyl acetate to give 4.64 g of 4-(2,5-dimethoxycinnamoylamino)-2,6-dimethylphenol as white crystals.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]([OH:9])=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][CH:43]=1)[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([N:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[CH:31]=1>CN(C)C=O.CN(C)C(=O)C>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:23]=[C:22]([NH:21][C:7]([C:6]5[O:5][CH:4]=[N:3][C:2]=5[CH3:1])=[O:9])[CH:43]=[CH:42][CH:41]=4)=[CH:31][N:30]3[N:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Cc1ncoc1C(=O)O
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Cc1ncoc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Yield: 37.7 %

Procedure:
In the same manner as in Example 18-4 and using 4-methyl-1,3-oxazole-5-carboxylic acid (410 mg, 3.22 mmol), tetrahydrofuran (10 mL), oxalyl chloride (420 μL, 4.84 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.647 mmol), N,N-dimethylformamide (2 drops) and N,N-dimethylacetamide (10 mL) as starting materials, the title compound (102 mg, 38%) was obtained as a white solid.
Reaction SMILES: C1(O)C=CC=CC=1.[C:8]1([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCC.[Br:27]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[C:8]1([CH:14]([Br:27])[CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(CCCOc2ccccc2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCC
Solvent: Oc1ccccc1
Product: BrC(CCOc1ccccc1)c1ccccc1

Procedure:
Following the above procedure but using phenol in place of m-methoxyphenol, there was prepared 1-phenyl-3-phenoxypropane distilling at 146°-9° C. at 6 torr. This propane derivative was brominated α to the phenyl group with N-bromosuccinimide and benzoyl peroxide to yield 1-phenyl-3-phenoxypropylbromide which compound was in turn reacted with dimethylamine in a sealed reaction vessel to yield N,N-dimethyl 1-phenyl-3-phenoxypropylamine boiling in the range 116°-118° C. at 0.3 torr. The hydrochloride salt was prepared by the above procedure to yield N,N-dimethyl 1-phenyl-3-phenoxy-propylamine hydrochloride melting at 165°-167° C. after recrystallization from an ethyl acetate/acetone solvent mixture.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:21][C:22]([NH:24][C@@H:25]([C:33](=[O:40])[NH:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:23])[C:14]([O:16]C(C)(C)C)=[O:15])=O)(C)(C)C.[Cl:41]CCl.C(O)(C(F)(F)F)=O>>[ClH:41].[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:21][C:22]([NH:24][C@@H:25]([C:33](=[O:40])[NH:34][CH2:35][CH2:36][CH:37]([CH3:38])[CH3:39])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:23])[C:14]([OH:16])=[O:15]
Reactant: CC(C)CCNC(=O)[C@@H](Cc1ccccc1)NC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CCNC(=O)[C@@H](Cc1ccccc1)NC(=O)N[C@@H](CCCCN)C(=O)O
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product from Example 1c) (0.500 g, 0.889 mmol) was dissolved in dichloromethane/TFA (10 ml, 1:1, v/v) and stirred at RT for 2 h. The solution was concentrated and purified by preparative HPLC. The combined product fractions were mixed with 2N HCl, concentrated and freeze dried.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[C:41](Cl)=[O:42].C(=O)(O)[O-].[Na+]>ClCCl>[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[C:41]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:8]2)=[CH:22][CH:23]=1)=[O:42]
Reactant: CCOC(=O)Cc1nn(Cc2ccc(N)cc2)c2ccccc12
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccccc12
Yield: 46.9 %

Procedure:
The crude ethyl 2-[1-(4-aminobenzyl)-1H-indazol-3-yl]acetate (about 1.04 mmol) obtained in the last step and triethylamine (1.4 mL) were dissolved in dichloromethane (15 mL). In an ice bath, a dichloromethane solution (10 mL) of 2-naphthoyl chloride (210 mg, 1.1 mmol) was added dropwise slowly. Upon completion of the dropwise addition, it was reacted at room temperature for 16 hours. An aqueous solution of sodium bicarbonate was added to quench. It was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and filtered. The filtrate was removed under reduced pressure, and the resulting residue was chromatographed on a silica gel column (petroleum ether:ethyl acetate=2:1) to obtain a white solid 226 mg, at a total yield over two steps of reactions of 46.9%.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]([CH3:28])[C:14](=[O:27])[C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)[C:3]1=[O:29].[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:21]1([C:18]2[CH:19]=[CH:20][C:15]([C:14]([N:13]([CH3:28])[C:10]3[CH:11]=[CH:12][C:7]([N:4]4[CH2:5][CH2:6][CH:2]([N:30]5[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)[C:3]4=[O:29])=[CH:8][CH:9]=3)=[O:27])=[CH:16][CH:17]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N2CCC(Br)C2=O)cc1
Reactant: C1CCNCC1
Product: CN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N2CCC(N3CCCCC3)C2=O)cc1

Procedure:
N-[4-(3-Bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide was reacted with piperidine by method L. This resulted in the product with the molecular weight of 459.64 (C29H37N3O2); MS (ESI): 460 (M+H+).