Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:11]=1.[BH4-].[Na+].O>CC#N.CCOC(C)=O>[CH2:1]([N:19]1[CH2:18][CH:17]=[C:16]([C:12]2[N:11]=[C:10]([Cl:9])[CH:15]=[CH:14][N:13]=2)[CH2:21][CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: Clc1ccnc(-c2ccncc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1ccnc(C2=CCN(Cc3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
Benzyl chloride (460 μl, 4.0 mmol) was added to a stirred suspension of 4-chloro-2-(pyridin-4-yl)pyrimidine (prepared according to J. Med. Chem., 1982, 25(7), 837-842) (383 mg, 2.00 mmol) in MeCN (10 ml) and the mixture was heated at reflux for 30 h and then concentrated under reduced pressure. EtOH (5 ml) was then added, followed by NaBH4 (151 mg, 4.0 mmol), and the mixture stirred at room temperature for 30 min. Water (10 ml) and EtOAc (70 ml) were added, separated and the organics washed with H2O (20 ml), brine (20 ml) and concentrated under reduced pressure. The residue was purified by column chromatography on silica using 3% MeOH/CH2Cl2 as eluent to yield 2-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-4-chloropyrimidine (325 mg, 57%): 1H NMR (360 MHz, CDCl3) δ 8.52 (1H, d, J 5.3), 7.40-7.23 (6H, m), 7.11 (1H, d, J 5.3), 3.66 (2H, s), 3.30-3.20 (2H, m), 2.80-2.63 (4H, m); m/z (ES+) 286, 288 (1:1, M+H+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11][C:12]2[S:13][C:14]([C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:15]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[O:10])[CH:6]=[CH:5][N:4]=1.O.[CH3:31][NH:32][CH3:33]>CO>[C:22]([C:14]1[S:13][C:12]([NH:11][C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][N:32]([CH3:33])[CH3:31])[CH:8]=2)=[O:10])=[N:16][C:15]=1[C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CNC
Reactant: O=C(Nc1nc(-c2ccco2)c(C(=O)c2ccccc2)s1)c1ccnc(CCl)c1
Solvent: O
Solvent: CO
Product: CN(C)Cc1cc(C(=O)Nc2nc(-c3ccco3)c(C(=O)c3ccccc3)s2)ccn1
Reaction time: 8 h
Yield: 41 %

Procedure:
Compound 140 (100 mg, 0.236 mmol) was dissolved in a methanol solution (2 mL) of 2.0 mol/L dimethylamine, followed by stirring overnight. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate) to afford the entitled Compound 141 (42.0 mg, 41%).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]=O)[N:3]=[CH:2]1.[NH2:8][CH:9]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>>[S:1]1[CH:5]=[C:4]([CH:6]=[N:8][CH:9]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)C(N)Cc1ccccn1
Reactant: O=Cc1cscn1
Product: CC(C)(C)OC(=O)C(Cc1ccccn1)N=Cc1cscn1

Procedure:
Prepared in a similar manner to that described for Intermediate 1, replacing 2-amino-4-methyl-pentanoic acid tert-butyl ester, hydrochloride with 2-amino-3-(2-pyridyl) propionic acid, tert-butyl ester.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][C:14]1[CH:15]=[C:16]([O:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH3:34])(=[O:33])=[O:32])(=[O:24])=[O:23])[CH:17]=[C:18]([OH:20])[CH:19]=1.[CH2:35](O)[CH2:36][CH2:37][OH:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CCCCCC>[CH3:13][C:14]1[CH:15]=[C:16]([O:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH3:34])(=[O:33])=[O:32])(=[O:24])=[O:23])[CH:17]=[C:18]([CH:19]=1)[O:20][CH2:35][CH2:36][CH2:37][OH:38]
Reactant: OCCCO
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2S(C)(=O)=O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2ccccc2S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Diethyl azodicarboxylate (0.46 mL, 2.9 mmol) was added slowly to a solution of 1.0 g (2.9 mmol) of 5-methyl-3-[2-(methylsulfonyl)phenylsulfonyloxy]phenol, as prepared in the preceding step, 0.21 mL (2.9 mmol) of 1,3-propanediol, and 760 mg (2.9 mmol) of triphenylphosphine in tetrahydrofuran (25 mL). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was evaporated to dryness. The residue was triturated with hexane under sonication and decanted (4 times). The residue was dissolved in dichloromethane and diluted with hexane to produce a crystalline material, which was discarded. The filtrate was diluted with hexane to give an oil and the solvent was decanted. The oil was dissolved in a minimum of methanol and diluted with water to initiate crystallization. The solid was collected by filtration to afford the title compound 1.16 g (quantitative yield). 1H-NMR (300 MHz, CDCl3) δ8.45 (dd, 1H, J=7.8, 1.3 Hz), 8.12 (dd, 1H, J=7.8, 1.2 Hz), 7.88 (td, 1H, J=7.7, 1.3 Hz), 7.74 (td, 1H, J=7.7, 1.3 Hz), 6.61-6.56 (m, 3H), 4.00 (t, 2H, J=6Hz), 3.81 (t, 3H, J=5.9 Hz), 3.45 (s, 3H), 2.24 (s, 3H), and 1.97 (pentet, 2H, J=6.2 Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C17H20O7S2: 423.1 (M+Na). Found: 423.1.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21](=[O:33])[CH2:22][N:23]([C:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])[CH3:24])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:34]1[CH2:36][C@@H:35]1[CH2:37][O:38][C:39]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:40]=1[CH:41]=[CH:42][CH:43]=[N:44]2>C(O)C>[C:14]1([CH2:13][CH2:12][CH2:11][CH:10]([NH:20][C:21](=[O:33])[CH2:22][N:23]([C:25]([CH:27]2[CH2:28][CH2:29][N:30]([CH2:36][C@@H:35]([OH:34])[CH2:37][O:38][C:39]3[CH:48]=[CH:47][CH:46]=[C:45]4[C:40]=3[CH:41]=[CH:42][CH:43]=[N:44]4)[CH2:31][CH2:32]2)=[O:26])[CH3:24])[CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Reactant: CN(CC(=O)NC(CCCc1ccccc1)CCCc1ccccc1)C(=O)C1CCNCC1
Solvent: CCO
Product: CN(CC(=O)NC(CCCc1ccccc1)CCCc1ccccc1)C(=O)C1CCN(C[C@@H](O)COc2cccc3ncccc23)CC1
Temperature: 25 °C
Yield: 34 %

Procedure:
N-(Piperidine-4-carbonyl)-(N-methyl)-2-aminoacetic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (68) (223.5 mg; 0.497 mmol) is dissolved in ethanol (12 mL) at ambient temperature. (R)-5-Oxiranylmethoxy-quinoline (2) (100.0 mg; 0.497 mmol) is added, then the mixture is refluxed for 15.5 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (50%→100% acetone in hexanes, then 5%→20% ethanol in acetone) affording the desired product (110 mg) as a white solid. ESMS: MH+ 651.6
Reaction SMILES: [CH3:1][Li].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][CH2:11][C:10]([C:14]([O:16][CH3:17])=[O:15])=[C:9](OS(C(F)(F)F)(=O)=O)[C:8]=2[CH:26]=1>C(OCC)C.[Cu]I>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][CH2:11][C:10]([C:14]([O:16][CH3:17])=[O:15])=[C:9]([CH3:1])[C:8]=2[CH:26]=1
Reactant: [Li]C
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)c2cc(Br)ccc2CCC1
Agent: [Cu]I
Solvent: CCOCC
Product: COC(=O)C1=C(C)c2cc(Br)ccc2CCC1
Reaction time: 0.33 h
Yield: 106.6 %

Procedure:
To a suspension of CuI (760 mg, 4.0 mmol) in anhydrous diethyl ether (5 mL) was dropwise added a 1.6 M solution of methyllithium (8 mmol, 5 mL) in an ice-salt bath (−10° C.). After stirring for 20 min, a homogeneous 0.4 M (Me)2CuLi solution was ready for use. To a solution of (Z)-methyl 2-bromo-9-(trifluoromethylsulfonyloxy)-6,7-dihydro-5H-benzo[7]annulene-8-carboxylate from step B1 (52 mg, 0.121 mmol) in diethyl ether (0.5 mL) was dropwise added the above Me2CuLi solution (0.727 mmol, 1.82 mL) at −78° C. The mixture was stirred from −78° C. to −40° C. over 2 h. The reaction mixture was then quenched with 10 mL of water, and the mixture was extracted with diethyl ether (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give (E)-methyl 2-bromo-9-methyl-6,7-dihydro-5H-benzo[7]annulene-8-carboxylate (38 mg, 0.129 mmol, 106% yield). The material was used for the next step without purification. LCMS (M+H)+=297.0. 1H NMR (500 MHz, chloroform-d) δ 7.43 (d, J=1.8 Hz, 1H), 7.35 (dd, J=8.1, 2.0 Hz, 1H), 7.07 (d, J=8.2 Hz, 1H), 3.82 (s, 3H), 2.56-2.49 (m, 2H), 2.38 (s, 3H), 2.17-2.07 (m, 4H).
Reaction SMILES: C[S-:2].[Na+].[CH:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>CN(C)C=O>[O:10]([C:11]1[CH:16]=[CH:15][C:14]([SH:2])=[CH:13][CH:12]=1)[C:7]1[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1ccc(Oc2ccccc2)cc1
Reactant: C[S-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Sc1ccc(Oc2ccccc2)cc1

Procedure:
A solution of sodium thiomethoxide (25 g) and 4-bromodiphenyl ether (25 g) in N,N-dimethylformamide (DMF) (150 ml) was refluxed overnight. The mixture was cooled and added to dilute aqueous sodium hydroxide. The water layer was washed with ether to remove by-products and acidified with hydrochloric acid. The product, 4-(phenoxy)thiophenol, was extracted with ether, and the ether layer dried and evaporated to give 4-(phenoxy)thiophenol (19-20 g) as a red oil. This material can be used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[C@H:5]([OH:36])[C@H:6]([C:8]1[C:9]([O:34][CH3:35])=[CH:10][C:11]2[CH2:12][CH2:13][N:14]3[C:20]4[C:21](=[O:33])[N:22]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH2:26][C:19]=4[CH:18]=[C:15]3[C:16]=2[CH:17]=1)[OH:7])[CH3:2].[C:38]1(C)[CH:43]=CC(S(O)(=O)=O)=C[CH:39]=1.C(N(CC)CC)C>CC(C)=O.COC(OC)(C)C>[C:29]([N:22]1[CH2:23][CH2:24][C:25]([CH3:27])([CH3:28])[CH2:26][C:19]2[CH:18]=[C:15]3[C:16]4[CH:17]=[C:8]([C@@H:6]5[O:7][C:38]([CH3:43])([CH3:39])[O:36][C@H:5]5[C:4]([O:3][CH2:1][CH3:2])=[O:37])[C:9]([O:34][CH3:35])=[CH:10][C:11]=4[CH2:12][CH2:13][N:14]3[C:20]=2[C:21]1=[O:33])([CH3:30])([CH3:31])[CH3:32]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(=O)[C@H](O)[C@@H](O)c1cc2c(cc1OC)CCn1c-2cc2c1C(=O)N(C(C)(C)C)CCC(C)(C)C2
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: COC(C)(C)OC
Product: CCOC(=O)[C@@H]1OC(C)(C)O[C@H]1c1cc2c(cc1OC)CCn1c-2cc2c1C(=O)N(C(C)(C)C)CCC(C)(C)C2
Reaction time: 0.08 h
Yield: 1722.8 %

Procedure:
A solution of 868 mg of 21c in 10 ml of acetone, 2.2 ml of 2,2-dimethoxypropane, and 17 mg of p-toluenesulfonic acid was stirred for 2 hr. The reaction was treated with 0.8 ml of triethylamine, stirred for 5 min, and then concentrated to a small volume and diluted with 30 ml of 5% NaHCO3 solution. The product was extracted with ethyl acetate and the extracts were washed with water, dried and concentrated, to provide 940 mg of product 21d, which was used as is in the next step; Rf (heptane/ethyl acetate 1/1) 0.57.
Reaction SMILES: [I:1][C:2]1[C:3]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:4][NH:5][CH:6]=1.[H-].[Na+].[CH:14](I)([CH3:16])[CH3:15].IC1C(C2SC=CC=2)=NN(C(C)C)C=1>CN(C)C=O.CC(OC)(C)C.O>[I:1][C:2]1[CH:6]=[N:5][N:4]([CH:14]([CH3:16])[CH3:15])[C:3]=1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1
Reactant: Ic1c[nH]nc1-c1cccs1
Reactant: CC(C)I
Agent: CC(C)n1cc(I)c(-c2cccs2)n1
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1ncc(I)c1-c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 4-iodo-3-(2-thienyl)-1H-pyrazole (1.1 mmol) in 3 mL dry N,N-dimethylformamide under argon atmosphere was added sodium hydride (1.3 mmol, 60% dispersion in mineral oil) in portions. The reaction mixture was stirred at room temperature, then isopropyl iodide (1.7 mmol) was added dropwise. After 2 h at room temperature, water and MTBE were added to the reaction mixture. The phases were separated and the aqueous phase was extracted with MTBE. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated to afford 350 mg of a mixture of 4-iodo-1-isopropyl-3-(2-thienyl)-1H-pyrazole and 4-iodo-1-isopropyl-5-(2-thienyl)-1H-pyrazole (75:25; 99% yield). The mixture was purified by chromatography on silica gel (cyclohexane:ethyl acetate 100:0 to 0:100) to afford 151 mg 4-iodo-1-isopropyl-3-(2-thienyl)-1H-pyrazole (42% yield) and 42 mg of 4-iodo-1-isopropyl-5-(2-thienyl)-1H-pyrazole (11% yield).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:19]2[O:18][CH2:17][CH2:16][O:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[C:20]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=O)[CH:21]=1>>[C:20]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:1]2[CH:2]([C:10]3[C:19]4[O:18][CH2:17][CH2:16][O:15][C:14]=4[CH:13]=[CH:12][CH:11]=3)[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])[CH:21]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Reactant: COC(=O)CCCC(N)c1cccc2c1OCCO2
Product: O=C1CCCC(c2cccc3c2OCCO3)N1Cc1cccc(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pentanoate with commercially available [1,1′-biphenyl]-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.91 min.; [M+H]+: 400.01 g/mol.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[O:10][C:3]=12.[CH3:19][C:20]1[C:28]([NH2:29])=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[CH:23][NH:24]2>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([C:9]2[O:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[NH:29][C:28]3[C:20]([CH3:19])=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[CH:22]4)[CH:8]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1c(N)ccc2[nH]ccc12
Reactant: COc1cccc(-c2cc3nccc(Cl)c3o2)c1
Product: COc1cccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4C)c3o2)c1

Procedure:
The title compound was prepared by procedure E using 7-chloro-2-(3-methoxyphenyl)furo[3,2-b]pyridine (29.70 mg; 0.11 mmol; 1.00 eq.) instead of 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine, and 4-methyl-1H-indol-5-ylamine (17.56 mg; 0.12 mmol; 1.05 eq.) instead of 6-amino-2,2-difluoro-4H-benzo[1,4]oxazin-3-one, and was obtained as a beige solid (25 mg, 59%). (HPLC (method F): 98%, RT: 3.96 min); 1H NMR (500 MHz, DMSO-d6) δ[ppm] 11.15 (s, 1H), 8.58 (s, 1H), 7.96 (d, J=5.4, 1H), 7.55 (d, J=7.6, 1H), 7.49 (s, 1H), 7.47 (s, 1H), 7.42-7.35 (m, 2H), 7.31 (d, J=8.4, 1H), 7.01 (d, J=8.5, 1H), 6.98 (d, J=8.0, 1H), 6.52 (s, 1H), 6.12 (d, J=5.4, 1H), 3.79 (s, 3H), 2.36 (s, 3H); MS (m/z) 370 [M+H]+, RT: 3.8 min.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]([OH:12])=O)[N:8]=1)=[O:2].CN(C)C=O.P(Cl)(Cl)(Cl)=O.[NH2:29][CH:30]1[C:50](=[O:51])[N:32]2[C:33]([C:37]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=3)=[O:38])=[CH:34][CH2:35][S:36][C@H:31]12>O.CC(C)=O.O1CCCC1>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]([NH:29][CH:30]2[C:50](=[O:51])[N:32]3[C:33]([C:37]([O:39][CH2:40][C:41]4[CH:42]=[CH:43][C:44]([N+:47]([O-:49])=[O:48])=[CH:45][CH:46]=4)=[O:38])=[CH:34][CH2:35][S:36][C@H:31]23)=[O:12])[N:8]=1)=[O:2]
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Reactant: CC(C)CON=C(C(=O)O)c1csc(NC=O)n1
Solvent: O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(NC=O)n1
Yield: 91 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-iso-butoxyiminoacetic acid (syn isomer, 6.48 g.), N,N-dimethylformamide (2.10 g.), phosphoryl chloride (4.40 g.), tetrahydrofuran (110 ml.), 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (8.23 g.), acetone (16 ml.) and water (16 ml.) were treated in a similar manner to that of Example 15-(1) to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-iso-butoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 12.8 g.).
Reaction SMILES: C([O:5][C:6](=[O:53])[CH:7]([N:11]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:52])[NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][NH:43][C:44](=[O:51])[CH2:45][CH2:46][CH2:47][C:48]([OH:50])=[O:49])=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.Cl>ClCCl>[C:48]([CH2:47][CH2:46][CH2:45][C:44]([NH:43][CH2:42][CH2:41][O:40][CH2:39][CH2:38][O:37][CH2:36][CH2:35][O:34][CH2:33][CH2:32][NH:31][C:30]([C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:11]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)(=[O:13])=[O:14])[CH:7]([CH:8]([CH3:10])[CH3:9])[C:6]([OH:53])=[O:5])=[CH:25][CH:26]=1)=[O:52])=[O:51])([OH:50])=[O:49]
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccc(C(=O)NCCOCCOCCOCCNC(=O)CCCC(=O)O)cc2)C(C(=O)OC(C)(C)C)C(C)C)cc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(Cc2ccc(C(=O)NCCOCCOCCOCCNC(=O)CCCC(=O)O)cc2)C(C(=O)O)C(C)C)cc1

Procedure:
Dichloromethane (5 ml) was added to the tert-butyl ester (Compound 14*; 50 mg, 0.046 mmol) and to the milky coloured solution which was obtained at ambient temperature was bobbled hydrochloric acid gas for 10 minutes. The mixture was evaporated to dryness and the residue was co-evaporated with dichloromethane (5×5 ml) to afford the product as white solid. Yield 47 mg (99%). M+1=1035.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[C:18]([Cl:26])[C:17]=1[N+:27]([O-])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(=O)([O-])O.[Na+]>CO.[Fe]>[NH2:27][C:17]1[C:18]([Cl:26])=[N:19][C:20]2[C:25]([C:16]=1[NH:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])=[CH:24][CH:23]=[CH:22][CH:21]=2
Reactant: O=C(NCCCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12)OCc1ccccc1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Product: Nc1c(Cl)nc2ccccc2c1NCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
0.27 g (0.651 mmol) of 4-[3-(benzyloxycarbonylamino)propylamino]-2-chloro-3-nitroquinoline was dissolved in 10 ml of methanol. One ml of concentrated hydrochloric acid and 0.22 g (0.390 mmol) of iron powder were added thereto and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into a saturated sodium hydrogencarbonate aqueous solution. After the resulting mixed solution was extracted with ethyl acetate, the extract was washed with brine and dried (Na2SO4). The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=300:1 (v/v)) to obtain 0.12 g (0.312 mmol) of 3-amino-4-[3-(benzyloxycarbonylamino)propylamino]-2-chloroquinoline shown below as faint yellow powder. ##STR30## Its spectroscopic data are as follows: 1H-NMR (CDCl3) δ (ppm) :1.76 (2H, m), 3.30 (2H, m), 3.42 (2H, q, J=6.3 Hz), 4.21 (2H, b r), 4.44 (1H, br), 4.92 (1H, br), 5.16 (2H, s), 7.30~7.39 (5H, m), 7.46 (2H, m), 7.89 (2H, m).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1CCCC1.[Cl:16][C:17]1[CH:25]=[C:24]([C:26]#[C:27][CH:28]([O:30][CH3:31])[CH3:29])[C:20]2[O:21][CH2:22][O:23][C:19]=2[C:18]=1[NH2:32].Cl[C:34]1[C:43]2[C:38](=[CH:39][C:40]([O:46][CH2:47][CH2:48][CH2:49][N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)=[C:41]([O:44][CH3:45])[CH:42]=2)[N:37]=[CH:36][N:35]=1>CN(C=O)C.[Cl-].[NH4+]>[Cl:16][C:17]1[CH:25]=[C:24]([C:26]#[C:27][CH:28]([O:30][CH3:31])[CH3:29])[C:20]2[O:21][CH2:22][O:23][C:19]=2[C:18]=1[NH:32][C:34]1[C:43]2[C:38](=[CH:39][C:40]([O:46][CH2:47][CH2:48][CH2:49][N:50]3[CH2:51][CH2:52][O:53][CH2:54][CH2:55]3)=[C:41]([O:44][CH3:45])[CH:42]=2)[N:37]=[CH:36][N:35]=1
Reactant: COC(C)C#Cc1cc(Cl)c(N)c2c1OCO2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(Cl)cc(C#CC(C)OC)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Temperature: 0 °C

Procedure:
A solution of sodium bis(trimethylsilyl)amide (1.5 ml) in tetrahydrofuran (1.0M, 1.5 mmol) was added over 5 min. to a stirred mixture of 5-chloro-7-(3-methoxybut-1-yn-1-yl)-1,3-benzodioxol-4-yl-amine (0.190 g) and 4-chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazoline (0.230 g) in DMF (6.5 ml) cooled to 0° C. under a nitrogen atmosphere; the resultant mixture was stirred for 1 hr at ambient temperature. The reaction mixture was diluted with saturated aqueous ammonium chloride (70 ml) and extracted with ethyl acetate (3×25 ml). The organic extracts were washed with brine (25 ml), dried over sodium sulphate and then evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methanol in dichloromethane as eluent. There was thus obtained the title compound as a racemate and in the form of a solid (0.314 g). NMR Spectrum: (DMSOd6) 1.42 (d, 3H), 1.95 (m, 2H), 2.37 (m, 4H), 2.45 (t, 2H), 3.35 (s, 3H), 3.57 (m, 4H), 3.92 (s, 3H), 4.18 (t, 2H), 4.39 (q, 1H), 6.15 (s, 2H), 7.13 (s, 1H), 7.18 (s, 1H), 7.82 (s, 1H), 8.32 (s, 1H), 9.50 (s, 1H); Mass Spectrum: M+H+ 555 and 557.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:15])[NH:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH:23]([OH:26])[CH2:24][CH3:25]>C(#N)C>[CH2:1]([O:8][C:9]1[C:10](=[O:15])[N:11]([CH2:25][CH2:24][CH2:23][OH:26])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(O)I
Reactant: O=c1[nH]cccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=c1c(OCc2ccccc2)cccn1CCCO
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To the solution of Compound 6 (0.202 g, 1 mmol) in acetonitrile was added K2CO3 (2 equiv.) followed by iodopropanol (0.186 g, 1 mmol). The reaction mixture was stirred at 65° C. overnight. On completion of the reaction, the reaction mixture was filtered and solvent was evaporated under vacuum. The residue was dissolved in water and extracted three times with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuum. The resulting compound 12 was purified by column chromatography (2:100, CH3OH/CH2Cl2). Yield: (85%)
Reaction SMILES: C[O:2][C:3]([CH:5]1[C:14]2[N:13]=[CH:12][N:11]([C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]=2[CH2:9][CH2:8][CH2:7][CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[C:28]1([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:11]2[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH2:3][OH:2])[C:14]=3[N:13]=[CH:12]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)C1CCCCc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCC1CCCCc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
To a solution of 1-triphenylmethyl-1,4,5,6,7,8-hexahydrocycloheptaimidazole-4-carboxylic acid methyl ester (5.5 g, 12.6 mmol) in THF (140 ml) was added lithium aluminum hydride (9.5 ml, 1 mol/L in THF, 9.5 mmol). The mixture was stirred at 20° C. for 2 hours, and water (1.4 ml) and NaOH (1.4 ml, 4 mol/l in water) were carefully added. After stirring at room temperature for 0.5 hours, water (5 ml) was added, and after stirring for 0.5 hours the mixture was dried by addition of magnesium sulfate. Filtration, concentration, and precipitation from methanol yielded 4.4 g (86%) of the title alcohol as a solid.