Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH3:10])[CH:6]=[CH:7][CH:8]=1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[NH:15][NH2:16].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:19]([O:18][C:14]([NH:15][N:16]=[C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=1)[CH3:10])=[O:17])[CH3:20]
Reactant: CCOC(=O)NN
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)NN=C(C)c1cccc(C(F)(F)F)c1
Yield: 99 %

Procedure:
m-Trifluoromethylacetophenone (74 g, 0.394 mole), ethyl carbazate (43 g, 0.413 mole), and catalytic p-toluenesulfonic acid (20 mg) were refluxed under N2 over a Dean-Stark trap in toluene (1.2 L) until the theoretical amount of water of reaction was removed (7.1 mL, 6 h). The solvent was then removed in vacuo and 2-(1-(3-(trifluoromethyl)phenyl)ethylidene)hydrazinecarboxylic acid ethyl ester (107 g, 100% yield) was obtained as a white solid which was recrystallized from cyclohexane, mp=94°-96° C.
Reaction SMILES: [CH3:1][CH:2]1[NH:6][CH2:5][C:4]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[O:3]1.C(N(CC)CC)C.[C:20](Cl)(=[O:28])[CH:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24]>ClCCl>[CH3:1][CH:2]1[N:6]([C:20](=[O:28])[CH:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[CH2:5][C:4]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[O:3]1
Reactant: CCCC(CCC)C(=O)Cl
Reactant: CC1NCC2(CCN(C)CC2)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(CCC)C(=O)N1CC2(CCN(C)CC2)OC1C
Temperature: 0 °C

Procedure:
2,8-Dimethyl-1-oxa-3,8-diaza-spiro[4.5]decane (1.52 g, 8.95 mmol) was dissolved in dry dichloromethane (5 ml) under an argon atmosphere. Distilled triethylamine (1.87 ml, 13.42 mmol) was added and the resulting solution was cooled to 0° C. Valproyl chloride (1.46 g, 8.95 mmol) was added dropwise with a syringe. The reaction flask was allowed to warm to room temperature with stirring, and a white solid started to precipitate. After 4 h of stirring, dichloromethane (100 ml) was added and the resulting solution was washed with water (10 ml). The two phases were separated and the aqueous phase was extracted with dichloromethane (2×50 ml). The combined organic phase was dried with anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (silica, CH2Cl2/EtOH/NH4OH 130/10/1) to give AF712 (389 mg, 98.7% chemical purity) as a yellow powder. 1H NMR. (CDCl3, 300 MHz) δ 5.43 (q, J=5.2 Hz, 1H, CHCH3), 4.13, 3.63 (2d, J=11.35 and J=9.6 Hz, 1H, CHHNCO), 3.22, 3.00 (2d, J=9.6 and J=11.35 Hz, 1H, CHHNCO), 2.56-2.38 (m, 5H), 2.30, 2.29 (2s, 3H, NCH3), 1.84-1.53 (3m, 6H), 1.44, 1.43 (2d, J=5.2 Hz, 3H, CH3CH), 1.4-1.19 (m, 6H), 0.90 (app t, J=7.11 Hz, 6H, CH3CH2) ppm; 13C NMR. (CDCl3, 300 MHz) δ 173.92, 173.68 (C), 84.75, 84.20 (CH), 78.32, 78.09 (C), 54.24 (CH2), 52.34 (CH2), 52.02 (CH2), 46.03 (CH3), 44.34, 43.64 (CH), 35.63 (CH2), 35.05 (CH2), 34.92 (CH2), 32.83 (CH2), 23.52, 20.91 (CH3), 20.59 (CH2), 20.43 (CH2), 14.30 (CH3), 14.16 (CH3) ppm.
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][C:6]([OH:8])=[O:7])[CH3:3].O.F[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20].C(=O)([O-])O.[Na+]>C(O)C>[CH2:2]([N:4]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20])[CH2:5][C:6]([OH:8])=[O:7])[CH3:3]
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: CCNCC(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCN(CC(=O)O)c1ccc(C=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 79 %

Procedure:
(a-1) To a stirred solution of 1.4 parts of ethyl glycine hydrochloride in 10 parts of water was added a solution of 1.7 parts of 4-fluoro-3-nitrobenzaldehyde in 8 parts of ethanol. Then there were added 1.76 parts of sodium hydrogen carbonate and stirring at room temperature was continued for 48 hours. The precipitated product was filtered off, washed successively with water, ethanol and 2,2'-oxybispropane, and dried, yielding 2 parts (79%) of ethyl N-(4-formyl-2-nitrophenyl)-glycine; mp. 90° C. (int. 29).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][C:3]=1[CH3:13].CN([CH:17]=[O:18])C>CCCCCC.C1COCC1>[Cl:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH:17]=[O:18])=[C:3]([CH3:13])[N:4]=1
Reactant: Cc1nc(Cl)c2ccccc2c1Br
Reactant: CN(C)C=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1nc(Cl)c2ccccc2c1C=O
Reaction time: 0.67 h
Yield: 81 %

Procedure:
n-BiLi (12.3 ml of 1.6 M in hexane, 20 mmol) is added dropwise to a solution of 4-bromo-1-chloro-3-methyl-isoquinoline (4.6 g, 18 mmol) in THF (80 ml) at −78° C. and the mixture is stirred for 40 min. DMF (4.2 ml, 54 mmol) is then added slowly. The cold bath is removed, and stirring is continued for 15 min. The mixture is acidified with 1N—HCl to pH 2 and extracted with ether. The combined extracts are dried over Na2SO4 and concentrated in vacuo. The residue is chromatographed on silica gel to give 3.0 g of 1-chloro-3-methyl-isoquinoline-4-carbaldehyde. 1H NMR (CDCl3) 10.9 (s, 1H), 9.06 (d, 1H), 8.40 (d, 1H), 7.88 (t, 1H), 7.70 (t, 1H), 2.99 (s, 3H).
Reaction SMILES: [N:1]1([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:42][CH2:41][CH2:40][C@H:2]1[C:3]([NH:5][C@H:6]([C:24]([NH:26][C@H:27]([C:35]([O:37]CC)=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:23])[NH:12][S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:4].Cl>CO>[N:1]1([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:42][CH2:41][CH2:40][C@H:2]1[C:3]([NH:5][C@H:6]([C:24]([NH:26][C@H:27]([C:35]([OH:37])=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:23])[NH:12][S:13]([C:16]1[CH:17]=[CH:18][C:19]([CH3:20])=[CH:21][CH:22]=1)(=[O:15])=[O:14])=[O:4]
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.9 %

Procedure:
The substance [38] (35.04 g, 50 mM) was dissolved in methanol (200 ml). Ln-HCl (60 ml, 60 mM) was added dropwise during 20 minutes at 0° C. and the mixture was stirred at room temperature for 90 minutes. 1 N HCl (10 ml) was added to the reaction mixture at 0° C., methanol was removed in vacuo, and 1 N HCl (55 ml) was added thereto at 0° C. (pH 2). The precipitate was filtered and dried in vacuo (27.95 g). The filtration was extracted with chloroform. The chloroform layer was washed three times with saturated sodium chloride and water and dehydrated with anhydrous sodium sulfate, then concentrated in vacuo. The residue was combined with the above, and twice recrystallized to obtain the substance [39] (29.22 g, yield: 86.9%).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O>[CH2:11]([N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccn(Cc2ccccc2)n1
Yield: 84.2 %

Procedure:
To a solution of 3-nitro-1H-pyrazole (prepared in example 3, 200 mg, 1.77 mmol) in anhydrous N,N-dimethylformamide (2 mL), a 60% dispersion of sodium hydride in mineral oil (92 mg, 2.30 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture was stirred for additional 10 min, benzylbromide (273 μL, 2.33 mmol) was added. The mixture was continued to stir under nitrogen for an additional 2 h. The solvent was removed in vacuo and purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 2% methanol/methylene chloride to 5% methanol/methylene chloride) afforded 1-benzyl-3-nitro-1H-pyrazole (303 mg, 84%) as a white solid: H1-NMR (400 MHz, CDCl3) δ: 5.33 (2H, s), 6.84 (1H, d, J=2.7 Hz), 7.26 (2H, m), 7.32 (3H, m), 7.40 (1H, d, J=1.5 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](Cl)=[N:11][OH:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:16]=1[CH:17]=[CH2:18].C(N(CC)CC)C>C1COCC1>[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:16]=1[CH:17]1[O:12][N:11]=[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:18]1
Reactant: O=[N+]([O-])c1cccc(C(Cl)=NO)c1
Reactant: C=Cc1c(Cl)cccc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(C2=NOC(c3c(Cl)cccc3Cl)C2)c1

Procedure:
3-Nitro-N-hydroxybenzenecarboximidoyl chloride (1.16 g, 5.78 mmol) and 2,6-dichlorostyrene (1.0 g, 5.78 mmol) were dissolved in anhydrous THF (20 mL) and triethylamine (1.21 mL, 8.67 mmol). Upon addition of triethylamine a while solid formed. After 3 h this solid was collected by filtration under reduced pressure to provide the title compound as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:14][CH:13]=[CH:12][C@@H:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]([CH3:21])[C:9]1=[O:22])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>C(Cl)Cl.C([O-])(O)=O.[Na+]>[NH2:7][C@H:8]1[CH2:14][CH:13]=[CH:12][C@@H:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]([CH3:21])[C:9]1=[O:22]
Reactant: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CC=C[C@H]1c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)[C@@H](N)CC=C[C@H]1c1ccccc1
Reaction time: 1 h
Yield: 93.6 %

Procedure:
To the tert-butyl[(3S,7S)-1-methyl-2-oxo-7-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-yl]carbamate (1d) (200 mg) was added a 1:3 mixture of TFA/DCM (2 ml). The reaction mixture was stirred for 1 h, then diluted with DCM and saturated aq. NaHCO3. The organic layer was isolated and washed with saturated aq. NaHCO3, brine, dried (Na2SO4) and concentrated to yield an oil (128 mg, 93%). MS APCI, m/z=217 (M+1). LC/MS 1.55 min., Method A.
Reaction SMILES: [Cl-].[C:2]([NH+:6]1[CH2:11][CH:10]=[C:9]([C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[CH:17][C:18](=[O:30])[N:19]3[C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])=[C:14]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[N:13]=2)[CH2:8][CH2:7]1)([CH3:5])([CH3:4])[CH3:3]>CO.CCOC(C)=O.O=[Pt]=O>[C:2]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[CH:17][C:18](=[O:30])[N:19]3[C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])=[C:14]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[N:13]=2)[CH2:10][CH2:11]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[NH+]1CC=C(c2cc3c(ccc(=O)n3-c3c(Cl)cccc3Cl)c(-c3ccccc3Cl)n2)CC1
Agent: O=[Pt]=O
Agent: [Cl-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)N1CCC(c2cc3c(ccc(=O)n3-c3c(Cl)cccc3Cl)c(-c3ccccc3Cl)n2)CC1
Reaction time: 1 h

Procedure:
To a solution of 75 mg of 1-tert-butyl-4-[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl]-1,2,3,6-tetrahydropyridinium chloride in 3 mL of MeOH and 1 mL of EtOAc was added 35 mg of PtO2 (Adam's catalyst). The mixture was evacuated and purged with N2, then evacuated and purged with H2, then stirred under an H2 balloon for 1 h. The mixture was filtered through Celite, washing with MeOH, and concentrated. The residue was purified by preparative thin-layer chromatography, eluting with 95:5 CH2Cl2-2M NH3 in MeOH, followed by preparative HPLC (YMC C8 19×50 mm column; 10:90 to 90:10 v/v acetonitrile/water+0.05% TFA over 12 min; 20 mL/minute) to yield the title compound. Mass spectrum (ESI) 542 (M+1). 1H NMR (500 MHz, CD3OD): δ 1.40 (s, 9H); 2.04-2.20 (m, 4H); 3.00-3.12 (m, 3H); 3.68 (br d, J=12.5 Hz, 2H); □6.46 (s, 1H); 6.75 (d, J=10 Hz, 1H); 7.48-7.75 (m, 8H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1([CH3:31])[C:11](=[O:12])[N:10]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=2)[C:9](=[O:25])[N:8]1[CH2:26][CH2:27][CH2:28][CH2:29][OH:30]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:1][S:2]([O:30][CH2:29][CH2:28][CH2:27][CH2:26][N:8]1[C:7]([CH3:31])([CH3:6])[C:11](=[O:12])[N:10]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:22])([F:23])[F:24])[CH:14]=2)[C:9]1=[O:25])(=[O:4])=[O:3]
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1CCCCO
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1CCCCOS(C)(=O)=O

Procedure:
0.17 ml of methanesulfonyl chloride were added to 740 mg of the product of Example 58 in solution in 7.4 ml of pyridine and 24 mg of 4-dimethylamino-pyridine and the mixture was stirred for one hour. The mixture was poured into ice-cooled water and extraction was carried out with methylene chloride. The extracts were washed with water and the residual pyridine was eliminated by distillation. The residue was chromatographed on silica (eluant: methylene chloride-ethyl acetate 8-2) to obtain 771 mg of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].[C:36]([O:40][C:41]([NH:43][C:44]([CH3:51])([CH3:50])[C:45]([O:47][CH2:48]Cl)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C>[C:36]([O:40][C:41]([NH:43][C:44]([CH3:51])([CH3:50])[C:45]([O:47][CH2:48][N:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]2[C:16]([C:17](=[O:18])[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=2[F:33])=[CH:15]1)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)OCCl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(COC(=O)C(C)(C)NC(=O)OC(C)(C)C)c3ncc(-c4ccc(Cl)cc4)cc23)c1F

Procedure:
The title compound was prepared according to the procedure as described in Example 14 Step 2 using N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.3 g, 0.61 mmol) in DMF (2.5 mL), KOH (69 mg, 0.4 mmol), and a solution of chloromethyl 2-((tert-butoxycarbonyl)amino)-2-methylpropanoate (158 mg, 0.61 mmol) in DMF (0.5 mL). The title compound was purified by a silica gel columnchromatography (PE/EtOAc (v/v)=4/1 to 3/1) and was obtained as a white solid (339 mg, 78.7%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=2)[C:8]2[S:16][C:15]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=2)[C:8]2[S:16][C:15]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2sc3ccncc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)sc2ccncc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.2 %

Procedure:
To a mixture of ethyl 3-{[(4-{[cyclohexyl(3-methylthieno[3,2-c]pyridin-2-yl)methyl]amino}phenyl)carbonyl]amino}propanoate (186 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (186 mg, 93%) as a white solid.
Reaction SMILES: Cl.[C:2]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]([C:18]([NH:20][C@H:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:22][OH:23])=[O:19])[NH2:17])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C(N([CH2:35][CH3:36])CC)C>C(Cl)Cl>[C:2]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]([C:18]([NH:20][C@H:21]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:22][OH:23])=[O:19])[NH:17][C:22](=[O:23])[CH:21]([C:36]1[CH:35]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:3]
Reactant: CCN(CC)CC
Reactant: N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: O=C(NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)N[C@@H](CO)c1ccccc1)OCc1ccccc1
Yield: 140 %

Procedure:
Prepared according to the method described in Example 1(d) above from (R)-N5 -(Cbz)-(R)-N-(2-hydroxy-1-phenylethyl)ornithine amide hydrochloride (2.6 g; 6.16 mmol; from step (b) above), 2-nitrophenyl diphenyl acetate (2.37 g; 7.39 mmol; see Example 1(c) above) and triethylamine (1.28 mL; 9.24 mmol) in 150 mL of CH2Cl2, yielding 2.5 g of the sub-title compound as a white, crystalline material.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.S(Cl)(Cl)=O.[NH3:19]>C1C=CC=CC=1>[CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:19])=[O:8])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: CSc1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: N
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CSc1ccc(C(N)=O)c([N+](=O)[O-])c1

Procedure:
A stirred solution of 4-methylthio-2-nitrobenzoic acid (4.56 g) and thionyl chloride (2.77 g) in benzene (65 ml) was heated under reflux for 1.5 hours. Aqueous ammonia (10 ml) was added dropwise to the stirred cooled (5° C.) reaction mixture, which was then stirred with cooling for 45 minutes. Benzene was removed under reduced pressure and the residual solid was washed with water and recrystallized to yield 4-methylthio-2-nitrobenzamide, (2.35 g), m.p. 176°-8° C.
Reaction SMILES: [CH2:1]([O:8][CH:9]([C:11]1[C:16]([C:17]#[N:18])=[CH:15][N:14]=[CH:13][C:12]=1Br)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]3[C:35](=[N:36][CH:37]=2)[NH:34][CH2:33][CH2:32][CH2:31]3)O1>>[CH2:1]([O:8][CH:9]([C:11]1[C:16]([C:17]#[N:18])=[CH:15][N:14]=[CH:13][C:12]=1[C:32]1[CH:33]=[N:34][C:35]2[NH:36][CH2:37][CH2:28][CH2:29][C:30]=2[CH:31]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(OCc1ccccc1)c1c(Br)cncc1C#N
Reactant: CC1(C)OB(c2cnc3c(c2)CCCN3)OC1(C)C
Product: CC(OCc1ccccc1)c1c(C#N)cncc1-c1cnc2c(c1)CCCN2

Procedure:
4-(1-Benzyloxy-ethyl)-5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-nicotinonitrile is synthesized according to the procedure of Suzuki Coupling Method VI using 4-(1-benzyloxy-ethyl)-5-bromo-nicotinonitrile and crude 6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine (which is prepared according to Step 4 of Example 105).
Reaction SMILES: [CH:1](=[N:8][CH:9]1[C:36](=[O:37])[N:11]2[C:12]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[C:13]([CH:16]=[CH:17][CH2:18]Cl)[CH2:14][S:15][C@H:10]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:38].[Na+].[C:40]([NH2:48])(=[O:47])[C:41]1[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=1>CC(C)=O.CN(C)C=O>[I-:38].[CH:1](=[N:8][CH:9]1[C:36](=[O:37])[N:11]2[C:12]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[C:13]([CH:16]=[CH:17][CH2:18][N+:44]3[CH:45]=[CH:46][C:41]([C:40](=[O:47])[NH2:48])=[CH:42][CH:43]=3)[CH2:14][S:15][C@H:10]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccncc1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(C=CCCl)CS[C@@H]2C(N=Cc3ccccc3)C(=O)N12
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: NC(=O)c1cc[n+](CC=CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N=Cc4ccccc4)[C@H]3SC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.8 %

Procedure:
To a chilled mixture of the 3-chloropropenylcephem XVII (Z isomer) (16.4 g) in acetone (5 ml), was added dropwise a solution of sodium iodide (6.3 g, 42 mmole) in acetone (30 ml) over 10 minutes under nitrogen atmosphere, and the mixture was stirred at room temperature. The reaction was monitored by the ratio of uv absorption [E1 cm1% (255 nm)/E1 cm1% (320 nm)]. When the ratio reached below 1.30 (after 45 minutes), the mixture was diluted with carbon tetrachloride (400 ml), and allowed to stand at room temperature. When the ratio came to below 1.10 (after 3 hours), the mixture was concentrated to a half its volume. The concentrate was treated with a small amount of charcoal and diatomaceous earth, and filtered. The filter cake was washed with a 1:1 mixture (100 ml) of methylene chloride and carbon tetrachloride. To the combined solution of the filtrate and washings, was added a solution of isonicotinamide (3.5 g, 28.7 mmole) in dimethylformamide (20 ml) and the mixture was concentrated under reduced pressure. The concentration was allowed to stand at room temperature for 1.5 hours and washed with isopropyl ether (100 ml×3). The residual brown semi-solid was dissolved in methylene chloride (50 ml) and the solution was added dropwise, with stirring, to ethyl acetate (1.5 L). The resulting precipitate was collected by filtration and washed with ethyl acetate (200 ml). After drying over phosphorous pentoxide in vacuo, 17 g of the title compound XXI-H (E isomer) was obtained. Yellow amorphous powder. M.p. 150°-155° C. (dec.). Estimated purity 80% by nmr.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:26][S:27]([N:23]1[CH2:24][CH2:25][CH:20]([C:11]2[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)[NH:13][N:12]=2)[CH2:21][CH2:22]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Yield: 13.3 %

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 3. Thus, 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (0.057 g, 0.17 mmol) was reacted with methanesulfonyl chloride (0.013 mL, 0.17 mmol) in the presence of triethylamine (0.1 mL, 0.71 mmol) and DMAP (0.0021 g, 0.017 mmol) in DMF (3 mL) to give 0.009 g of white solid.