Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([OH:14])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[C:20]([N+]([O-])=O)[CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C>[Cl:15][C:16]1[CH:21]=[C:20]([O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][CH:8]([C:12]([OH:14])=[O:13])[CH2:9]3)=[CH:4][CH:3]=2)[CH:19]=[CH:18][N:17]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: O=C(O)C1CCc2ccc(O)cc2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(O)C1CCc2ccc(Oc3ccnc(Cl)c3)cc2C1
Temperature: 25 °C
Yield: 52.1 %

Procedure:
A mixture of 7-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (5.62 g, 29.2 mmol); 2-chloro-4-nitropyridine (5.10 g, 32.2 mmol) and cesium carbonate (28.6 g, 87.7 mmol) in DMF (150 mL) was heated at 50° C. for 5 hr. The reaction mixture was allowed to cool to rt and acidified to pH 3 by addition of 1N HCl. The mixture was extracted with EtOAc and the organic solutions were combined, washed with water, dried over Na2SO4 and evaporated. The residue was adsorbed onto silica and purified by filtration through a pad of silica. The product was then triturated with EtOAc to give 7-[(2-chloropyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (4.62 g, 52.0%). LCMS: (FA) ES+ 304.1, ES− 302.1.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:27])=[O:26])[C:15]([C:17]4[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=4)[CH:20]=O)=[CH:16][C:9]=23)[C:5]([C:34]2[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=2)=[N:4]1)[CH3:2].[NH:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:25]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)(=[O:27])=[O:26])[C:15]([C:17]4[CH:24]=[CH:23][CH:22]=[C:19]([CH2:20][N:43]5[CH2:47][CH2:46][CH2:45][CH2:44]5)[CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:34]2[CH:35]=[CH:36][C:37]([N+:40]([O-:42])=[O:41])=[CH:38][CH:39]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3c2cc(-c2cccc(C=O)c2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: C1CCNC1
Product: CCn1cc(-c2ccnc3c2cc(-c2cccc(CN4CCCC4)c2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described for Intermediate 101 using 3-[4-[1-ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]benzaldehyde and pyrrolidine provided the title compound. ESMS [M+H]+: 633.0.
Reaction SMILES: O[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:12]1([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[CH2:16]1[CH2:17][CH:12]([O:18][C:5]2[N:4]=[CH:3][CH:2]=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])[CH2:13][CH2:14][CH2:15]1
Reactant: OC1CCCCC1
Reactant: COC(=O)c1cncc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cccnc1OC1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.2 %

Procedure:
To a stirred solution of methyl 5-hydroxynicotinate (2.40 g, 15.7 mmol) in methylene chloride (40 mL) was added cyclohexanol (1.73 g, 1.80 mL, 17.2 mmol) and triphenylphosphine (5.75 g, 21.9 mmol). The solution was treated with diethyl azodicarboxylate (3.20 mL, 20.4 mmol), resulting in a mild exotherm and development of an orange colored solution. The reaction mixture was allowed to stir at room temperature. After 16 hours, the cloudy yellow suspension was filtered, and the filtrate was washed with saturated sodium bicarbonate solution and brine, dried (magnesium sulfate), filtered, and concentrated to provide a yellow oil. Flash chromatography over silica (hexanes/ethyl acetate) afforded 1.08 g (29%) of the desired product as a colorless oil: 1H NMR (CDCl3) δ 8.77 (d, J=1.7 Hz, 1H), 8.43 (d, J=2.9 Hz, 1H), 7.74 (dd, J=1.7, 2.9 Hz, 1H), 4.37-4.31 (m, 1H), 3.94 (s, 3H), 2.01-1.93 (m, 2H), 1.85-1.75 (m, 2H), 1.62-1.49 (m, 3H), 1.46-1.31 (m, 3H) ppm. 13C NMR (CDCl3) δ 166.2, 154.0, 144.2, 142.9, 126.6, 122.3, 76.3, 52.7, 31.6, 25.6, 23.7 ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[O:10])=[CH:4][CH:3]=1.[CH2:11](O)[CH2:12][OH:13].O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[O:13][CH2:12][CH2:11][O:10]2)=[CH:4][CH:3]=1
Reactant: O=CCc1ccc(Br)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1ccc(CC2OCCO2)cc1
Yield: 55.1 %

Procedure:
A solution of 4-bromophenylacetaldehyde from Step 1 (44.5 g, 224 mmol), ethylene glycol (13.7 mL, 246 mmol) and p-toluenesulfonic acid monohydrate (85 mg, 0.45 mmol) in toluene (300 mL) was refluxed for 3 h with concomitant Dean-Stark water trapping. The reaction mixture was then washed successively with 5% aqueous NaHCO3 (2×), water and brine, dried (MgSO4) and concentrated. The residue was distilled under reduced pressure (bp 110°-115° C./0.5 mmHg) to afford the title compound as a colorless liquid (30.0 g, 55%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2([OH:27])[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][N:22]=3)[CH2:17][CH2:16]2)[C:10](=[O:28])[CH2:9]1)=O)(C)(C)C.[ClH:29]>O1CCCC1.C(OCC)(=O)C>[ClH:29].[OH:27][C:15]1([CH2:14][N:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]2=[O:28])[CH2:16][CH2:17][N:18]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][N:22]=2)[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC2(O)CCN(c3ccncn3)CC2)C(=O)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1CNCCN1CC1(O)CCN(c2ccncn2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(tert-butoxycarbonyl)-1-[4-hydroxy-1-(4-pyrimidinyl)piperidin-4-ylmethyl]piperazin-2-one (516 mg) in tetrahydrofuran (4 ml) was added a solution of 4N hydrochloric acid in ethyl acetate (4 ml), and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated, and the residue was crystallized from tetrahydrofuran to give colorless crystals of 1-[4-hydroxy-1-(4-pyrimidinyl)piperidin-4-ylmethyl]piperazin-2-one hydrochloride (435 mg).
Reaction SMILES: [CH2:1]([C:5]([NH:16]C(OC(C)(C)C)=O)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH:3]=[CH2:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:16][C:5]([CH2:1][CH2:2][CH:3]=[CH2:4])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: C=CCCC(NC(=O)OC(C)(C)C)(C(=O)OCC)C(=O)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCCC(N)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of diethyl 2-but-3-enyl-2-(tert-butoxycarbonylamino)propanedioate 81b (14.5 g, 4.4 mmol) in DCM (30 mL) was added TFA (10 mL), The mixture was stirred at room temperature for 16 h, quenched with saturated NaHCO3 (50 mL) and then extracted with DCM (150 mL) two times, washed with saturated NaHCO3 (100 mL) three times, dried over anhydrous sodium sulfate and concentrated in vacuo to afford diethyl 2-amino-2-but-3-enyl-propanedioate as a crude product (9.5 g, 94%), which was used for next step without further purification. MS: calc'd (MH+) 230, measured (MH+) 230.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=[CH:21][O:22][CH3:23])[C:17]([O:19][CH3:20])=[O:18].[Na+].[Cl-]>CN(C)C=O.C1COCC1>[CH2:1]([O:5][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=[CH:21][O:22][CH3:23])[C:17]([O:19][CH3:20])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Reactant: CCCCO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCOCc1ccccc1C(=COC)C(=O)OC
Temperature: 0 °C

Procedure:
7.4 g of n-butanol are dissolved in 50 ml of dimethylformamide, and 2.4 g of sodium hydride are added. The solution is slightly heated until everything has reacted. This solution is gradually added dropwise at -20° C. to 28.4 g of methyl α-(2-bromomethylphenyl)-β-methoxyacrylate in 150 ml of THF. Once the bromomethyl compound is no longer detectable by thin layer chromatography, 100 g of ice and 100 ml of saturated NaCl solution are added. Extraction with methylene chloride gives 23 g of an oil which is chromatographed. 10 g of a resin are obtained after elution with ethyl acetate/hexane.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[CH:7][NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[CH:7][N:8]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Fc1ccc(CBr)cc1
Reactant: CCCCc1nc[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1ncn(Cc2ccc(F)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
A mixture of 4′-[(4-butyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.5 g), sodium hydride (0.07 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 1-(bromomethyl)-4-fluorobenzene (0.22 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.54 g, 82%).
Reaction SMILES: [ClH:1].[C:2]1([C:8]2([C:12]([OH:14])=[O:13])[CH2:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]=[C:16]1[CH:21]2[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]2)[CH:17]1O>C(Cl)Cl>[ClH:1].[C:2]1([C:8]2([C:12]([O:14][CH:17]3[C:16](=[CH2:15])[CH:21]4[CH2:22][CH2:23][N:18]3[CH2:19][CH2:20]4)=[O:13])[CH2:9][CH2:10][CH2:11]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C1C2CCN(CC2)C1O
Reactant: O=C(O)C1(c2ccccc2)CCC1
Agent: Cl
Solvent: ClCCl
Product: C=C1C2CCN(CC2)C1OC(=O)C1(c2ccccc2)CCC1

Procedure:
The title compound was prepared in an analogous manner to that in Example 36 by reacting 1-phenylcyclobutanecarboxylate hydrochloride with 3-methylidenequinuclidinol. The esterification was carried out in CH2Cl2. The crude was chromatographed on silica gel using toluene-Et3N 88:12 as eluent. The yield was 0.07 g (9%); mp 155-157° C.; 1H NMR (CDCl3) δ 1.80-2.10 (m, 7H), 2.25 (m, 1H), 2.52 (m, 2H), 2.76 (m, 3H), 3.18 (m, 5H), 4.09 (m, 2H), 7.29 (m, 5H), 12.2 (br, 1H). Anal. (C19H25NO2.HCl) H, N; C: calcd, 67.94; found, 67.25.
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([SH:7])[CH3:6].Cl[C:9]1[C:10]([C:15](=[O:18])[CH2:16][CH3:17])=[N:11][CH:12]=[CH:13][N:14]=1.O>C(O)C>[CH2:5]([S:7][C:9]1[C:10]([C:15](=[O:18])[CH2:16][CH3:17])=[N:11][CH:12]=[CH:13][N:14]=1)[CH3:6]
Reactant: CCC(=O)c1nccnc1Cl
Reactant: CCS
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCSc1nccnc1C(=O)CC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
A mixture of sodium ethoxide (100 mg, 1.47 mmoles) and ethanethiol (110 mg, 1.77 mmoles) in 7 ml of absolute ethanol is stirred under nitrogen at room temperature for 10 minutes. 1-(3-Chloro-2-pyrazinyl)-1-propanone (250 mg, 1.47 moles) in 5 ml absolute ethanol is added to the above mixture, and the reaction mixture is stirred for 4 hours at which time thin layer chromatography indicates that all of the starting materials have reacted. The mixture is poured into water (100 ml) and extracted with methylene chloride (3×10 ml), and the extracts are combined and washed with water (1×50 ml) and saturated NaCl solution (1×50 ml). After drying (MgSO4), the solvent is removed under reduced pressure to give an 87% yield of 1-(3-ethylthio-2-pyrazinyl)-1-propanone (m.p. 45°-48° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[CH2:17][CH2:18][C:19]([O:21]C)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCn1ccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCn1ccnc1

Procedure:
A solution of 0.117 g of methyl 8-(p-chlorophenylsul- fonamido)-4-[2-(1-imidazolyl)ethyl]-octanoate in 3 mL methanol is mixed with 0.55 mL 1N sodium hydroxide. The mixture is heated at 50° for 4 hours. The reaction mixture is neutralized with 0.55 mL 1N hydrochloric acid and the solvent is evaporated. The residue is triturated with methylene chloride and the organic layer evaporated to dryness. The yellow oil is triturated with ether to obtain 8-(p-chlorophenylsulfonamido)-4-[2-(1-imidazolyl)ethyl]-octanoic acid as a crystalline solid, NMR (CDCl3): delta 7.82 (d,2H), 7.45 (d,2H), 4.15 (m,2H), 2.35 (t,2H).
Reaction SMILES: O.Cl.[Cl:3][C:4]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:5]=1[NH:6][C:7]([CH3:20])([CH3:19])[CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1>C1COCC1.[Fe]>[Cl:3][C:4]1[CH:24]=[C:23]([NH2:25])[CH:22]=[CH:21][C:5]=1[NH:6][C:7]([CH3:20])([CH3:19])[CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: CC(C)(Cc1ccc2ccccc2c1)Nc1ccc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(Cc1ccc2ccccc2c1)Nc1ccc(N)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.7 %

Procedure:
To a mixture of water (50 mL) and iron powder (3.78 g, 67.7 mmol) at 65° C. was added concentrated hydrochloric acid (1.0 mL) dropwise and the mixture was stirred for 15 min. The aqueous layer of the mixture was poured out and a solution of 2-chloro-N-(2-methyl-1-(naphthalen-2-yl)propan-2-yl)-4-nitroaniline (2.4 g, 6.76 mmol) in THF (50 mL) was added to the above processed iron powder. The mixture was stirred further at 65° C. for 30 min. The mixture was then cooled to rt and filtered, and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=8:1) to give the title compound as a white solid (1.86 g, 84%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](SC)[C:6]([F:11])=[CH:5][N:4]=1.O.[NH2:13][NH2:14]>C(O)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:13][NH2:14])[C:6]([F:11])=[CH:5][N:4]=1
Reactant: NN
Reactant: CSc1ncc(F)c(SC)n1
Solvent: O
Solvent: CCO
Product: CSc1ncc(F)c(NN)n1
Temperature: 0 °C
Yield: 86 %

Procedure:
A 1 liter (L) flask equipped with a condensor and thermometer was charged with 80g (0.42 moles) of 2,4-bis(methylthio)-5-fluoropyrimidine, 200 mL of ethanol and 105g (2.1 moles) of hydrazine hydrate. The reaction mixture was poured onto 350 mL of ice-water. The solid product was isolated by filtration. After washing with water, the product was dried under vacuum at 60° C. to give 62.8g (86 percent yield) of 2-methylthio-4-hydrazino-5-fluoropyrimidine having a melt point of 146°-147° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:23]([F:34])([F:33])[F:22])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(CN2CCN[C@@H](Cc3ccccc3)C2)cc1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccccc1-c1ccc(CN2CCN[C@@H](Cc3ccccc3)C2)cc1
Temperature: 120 °C

Procedure:
0.13 g of 3-(S)-benzyl-1-(4-bromo-benzyl)-piperazine were combined with 1.5 equiv. of 2-trifluoromethylphenyl boronic acid, 0.05 equiv. of tetrakis(triphenylphosphine)palladium(0), 2M aqueous sodium carbonate solution, toluene and ethanol. The reaction mixture was heated in a sealed tube at 120° C. overnight. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography to afford 0.18 g of the title compound. ES MS (+) m/z 411.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:22]([CH:24]1[O:26][CH2:25]1)Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:26]1[CH2:25][CH:24]1[CH2:22][N:17]1[CH2:16][CH2:15][N:14]([CH:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[C:5]2[CH:20]=[CH:21][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:19][CH2:18]1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc(C(c2ccc(F)cc2)N2CCN(CC3CO3)CC2)cc1
Temperature: 25 °C
Reaction time: 100 h

Procedure:
A solution of 4,4'-difluorobenzhydrylpiperazine (28.83 g, 100 mmol) in acetonitrile (250 mL) was added to an ice cold mixture of epibromohydrin (9.1 mL, 110 mmol) and anhydrous potassium carbonate (15.2 g, 110 mmol) in acetonitrile (150 mL) over a period of 40 min. The mixture was stirred at room temperature for 100 h, filtered and the solids were washed with methylene chloride. The combined filtrates were concentrated to dryness to give an oil which was eluted through a flash chromatographic silica gel column using 2-3% methanol/methylene chloride to give the title compound as glass, 23.98 (69.6%); 300 MHz 1H NMR (CDCl3): δ 7.4-6.9 (m, 8H). 4.22 (s. 1H). 3.09 (br m, 1H), 2.8-2.25 (m, 12H); MS 345 (MH+).
Reaction SMILES: O.[C:2]([N:5]([CH2:10][C:11]([OH:13])=[O:12])[CH2:6][C:7]([OH:9])=[O:8])(=O)C.[P:14]([OH:17])([OH:16])[OH:15].S(=O)(=O)(O)O.C=O>O>[P:14]([CH2:2][N:5]([CH2:10][C:11]([OH:13])=[O:12])[CH2:6][C:7]([OH:9])=[O:8])([OH:17])([OH:16])=[O:15]
Reactant: CC(=O)N(CC(=O)O)CC(=O)O
Reactant: OP(O)O
Agent: C=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CN(CC(=O)O)CP(=O)(O)O
Temperature: 110 °C
Yield: 151.4 %

Procedure:
Cycle 1: A reactor was charged with N-acetyliminodiacetic acid monohydrate (1 7.0 g), water (5 g), phosphorous acid (11.39 g) and 98% sulfuric acid (15 g). The mixture was heated to 110° C. and 42.2% formaldehyde (5.6 mL) was added drop wise over a one hour period. After another 13/4 hour at 110° C. the mixture was cooled to 25° C. The mixture was filtered and the solid was washed with water to give 12.46 g of N-(phosphonomethyl)iminodiacetic acid.
Reaction SMILES: [C:1]1([CH:7]([C:11]([OH:13])=[O:12])[C:8]([O-:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[NH2:15][CH:16]1[C:27](=[O:28])[N:18]2[C:19]([C:24]([OH:26])=[O:25])=[C:20]([CH3:23])[CH2:21][S:22][C@H:17]12>>[C:11]([CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([NH:15][CH:16]1[C:27](=[O:28])[N:18]2[C:19]([C:24]([OH:26])=[O:25])=[C:20]([CH3:23])[CH2:21][S:22][C@H:17]12)=[O:10])([OH:13])=[O:12]
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C([O-])C(C(=O)O)c1ccccc1
Agent: [Na+]
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(C(=O)O)c3ccccc3)[C@H]2SC1

Procedure:
The process was carried out in the same manner as in Example 21 using 2.2 g of mono-sodium phenylmalonate and 2.14 g of 7-amino-3-methyl-3-cephem4-carboxylic acid. 7-(α-Carboxyphenylacetamido)-3-methyl-3-cephem-4-carboxylic acid was afforded in a yield of 2.1 g (56%).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH:6]1[CH:11]=[C:10]([CH:12]([OH:21])[C:13]([C:15]2[N:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[N:9]=[CH:8][CH:7]=1>C(#N)C>[Cl:1][CH2:2][C:3]([O:14][CH:13]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][N:20]=1)[C:12]([C:10]1[CH:11]=[CH:6][CH:7]=[CH:8][N:9]=1)=[O:21])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: O=C(c1ccccn1)C(O)c1ccccn1
Solvent: CC#N
Product: O=C(CCl)OC(C(=O)c1ccccn1)c1ccccn1
Reaction time: 1 h

Procedure:
Chloroacetyl chloride (1.4 g, 0.0123 mole) in an equal amount of dry acetonitrile was added dropwise with stirring to 5.4 g (0.0252 mole) of α-pyridoin in 50 ml of dry acetonitrile. The reaction mixture was stirred one hour. The orange solid was filtered off and washed with acetonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:11]=2[C:12]([O:27]C(C2C=CC=CC=2)C2C=CC=CC=2)=[C:13]2[C:17](=[O:18])[N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:15][C:14]=12)=[O:4].C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>ClCCl>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:11]=2[C:12]([OH:27])=[C:13]2[C:17](=[O:18])[N:16]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH2:15][C:14]=12)=[O:4]
Reactant: COC(=O)c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a solution of 9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid methyl ester 212 (3 mg, 0056 mmol) in dichloromethane (1 mL) were added TFA (0.1 mL) and triethylsilane (0.2 mL). Stirring was continued at the room temperature for 1 hour and the volatiles were evaporated in vacuo. The residue was triturated in Et2O/hexane to afford 7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid methyl ester 316 (2.0 mg, 100%) as a yellow solid: 1H NMR (CDCl3) δ 9.5 (d, 1H), 9.0 (m, 1H), 7.66 (dd, 1H), 7.35 (dd, 2H), 7.0 (t, 2H), 4.8 (s, 2H), 4.7 (s, 2H), 4.0 (s, 3H); MS: 365 (M−1).
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[N+:8]([O-])[CH:9]=[CH:10][C:5]=2[N:4]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH:3]=1.[CH3:22][C:23]([NH2:30])([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH3:24].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.ClCCl>[Cl:1][C:2]1[C:6]2[C:7]([NH:30][C:23]([CH3:24])([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH3:22])=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH:3]=1
Reactant: CC(C)(C)CC(C)(C)N
Reactant: O=C(OCc1ccccc1)n1cc(Cl)c2c[n+]([O-])ccc21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)CC(C)(C)Nc1nccc2c1c(Cl)cn2C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 17.3 %

Procedure:
A solution of benzyl 3-chloro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate 5-oxide (2.6 g, 8.53 mmol) in chloroform was treated dropwise with 2,4,4-trimethylpentan-2-amine (6.026 mL, 37.54 mmol) and stirred for about 15 minutes. The mixture was cooled to 0° C. followed by the portion wise addition of p-toluenesulphonyl chloride (3.578 g, 18.77 mmol). The reaction mixture was then stirred at room temperature for about 1 hour, diluted with dichloromethane and washed with saturated aq. sodium bicarbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under vacuum to get viscous oil. The crude product was purified by silica gel column chromatography using ethyl acetate and hexane (1%) to yield benzyl 3-chloro-4-[(2,4,4-trimethylpentan-2-yl)amino]-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (610.8 mg, 43%) as a pale yellow solid.