Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[N:20]=[C:21](/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=3[F:36])[O:22][CH:23]=2)[CH:14]=[CH:13][C:3]=1[CH2:4][S:5][CH2:6][CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[N:9]1.ClC1C=C(C(OO)=[O:45])C=CC=1>ClCCl.C(OCC)(=O)C>[F:36][C:27]1[CH:28]=[C:29]([C:32]([F:34])([F:33])[F:35])[CH:30]=[CH:31][C:26]=1/[CH:25]=[CH:24]/[C:21]1[O:22][CH:23]=[C:19]([CH2:18][O:17][C:15]2[CH:14]=[CH:13][C:3]([CH2:4][S:5]([CH2:6][CH2:7][N:8]3[CH:12]=[CH:11][N:10]=[N:9]3)=[O:45])=[C:2]([CH3:1])[CH:16]=2)[N:20]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3F)n2)ccc1CSCCn1ccnn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3F)n2)ccc1CS(=O)CCn1ccnn1
Temperature: -30 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
To a solution of 650 mg (1.25 mmol) 1-[2-(2-methyl-4-{2-[2-(E)-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-benzylsulfanyl)-ethyl]-1H[1,2,3]triazole in 35 ml dichloromethane at −30° C. were added dropwise during 20 min. 493 mg (2.20 mmol) 3-chloro-benzenecarboperoxoic acid (77% peracid) dissolved in 20 ml ethyl acetate. After 1 hour stirring at −30° C. the mixture was allowed to warm up over night, stirred another 48 hours at room temperature, diluted with dichloromethane, washed with sodium bicarbonate solution, then with water, dried and evaporated. Elution from silica with ethyl acetate (1–10% methanol gradient) furnished as the second fraction 310 mg (46%) title compound as white solid.
Reaction SMILES: C([O:8][C:9](=[O:23])/[C:10](/[O:21][CH3:22])=[CH:11]/[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2)C1C=CC=CC=1.Cl[CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31]>>[CH3:22][O:21]/[C:10](=[CH:11]\[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:25][C:26]1[N:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29][C:30]=1[CH3:31])[CH:16]=[CH:15]2)/[C:9]([OH:8])=[O:23]
Reactant: CO/C(=C\c1ccc2[nH]ccc2c1)C(=O)OCc1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Product: CO/C(=C\c1ccc2c(ccn2Cc2nc(-c3ccccc3)oc2C)c1)C(=O)O
Yield: 75 %

Procedure:
Starting from (Z)-3-(1H-indol-5-yl)-2-methoxy-acrylic acid benzyl ester and 4-chloromethyl-2-phenyl-5-methyl-oxazole, the title compound was obtained in 75% yield as an off-white solid. MS: (M+H)+ 389.2.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[CH:9][N:8]2[CH:19]=[CH:20][N:21]=[C:7]2[CH:6]=1)=O.CO.[Li+].[BH4-]>C1COCC1>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:10]1[C:5]([CH2:3][OH:2])=[CH:6][C:7]2[N:8]([CH:19]=[CH:20][N:21]=2)[CH:9]=1
Reactant: COC(=O)c1cc2nccn2cc1-c1ccc(Cl)cc1Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cc2nccn2cc1-c1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 4 h
Yield: 43.1 %

Procedure:
A solution of 6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (394 mg, 1.23 mmol) and MeOH (0.15 mL, 3.68 mmol) in THF (8 mL) was cooled to 0° C. (ice bath) then LiBH4 (2 M solution in THF, 1.8 mL, 3.6 mmol) was added dropwise and the resulting mixture was heated at 50° C. and stirred for 4 h. The reaction mixture was cooled to RT, quenched by the addition of a saturated NH4Cl solution in water, diluted in water and extracted with AcOEt (2×). The combined organic fractions were dried over Na2SO4, filtered and evaporated to dryness. The remaining residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, DCM/MeOH 99:1→8.2) to yield the title compound (156 mg, 0.53 mmol, 43%). MS: 293 [M+1]+; HPLC: AtRet=1.20, TLC: RF 0.20 (DCM/MeOH 95:5).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:14]I>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[CH:7][N:8]2[CH3:14])=[CH:4][CH:3]=1
Reactant: Cc1c[nH]c2cc(Br)ccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(C)c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6-bromo-3-methyl-1H-indole (200 mg, 0.95 mmol) in DMF (8 mL) was added NaH (114 mg, 2.85 mmol, m %/60%). The mixture was stirred at room temperature for 1 h before the addition of MeI (162 mg, 1.14 mmol). The system was stirred at room temperature for 4 h then the mixture was quenched with water and extracted with EtOAc. The organic layer was concentrated to give crude product which was used in next step without further purification. LCMS (m/z): 224.1 [M+H]+.
Reaction SMILES: [CH2:1]([SH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1)([O-:22])=[O:21].N1C=CC=CC=1>C(#N)C>[N+:20]([C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30](=[O:31])[S:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:27][CH:28]=1)([O-:22])=[O:21]
Reactant: CCCCCCCCCCCCCCCCCCS
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCSC(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.1 %

Procedure:
In a three necked flask equipped with a dropping funnel, a thermometer and reflux condenser, n-octadecanethiol (183 g) was dissolved in acetonitrile (1000 ml) in a nitrogen atmosphere. To the solution, p-nitrophenyl isocyanate (100 g) was gradually added and then pyridine (4 ml) was added dropwise, the mixture was stirred at room temperature for 10 minutes and then refluxed for 30 minutes. The reaction mixture was cooled to room temperature to allow crystals to precipitate. The crystals were collected by filtering and washed with acetonitrile, to obtain S-n-octadecyl p-nitrophenylthiocarbamate (272 g) at a yield of 99%.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8](=[O:19])[CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=1[CH3:18].[CH3:20][O:21][N:22]1[CH2:27][CH2:26][C:25]([S:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)([C:28](Cl)=[O:29])[CH2:24][CH2:23]1>C(NC(C)C)(C)C.O1CCCC1>[CH3:6][O:7][C:8](=[O:19])[CH:9]([C:10]1[C:11]([CH3:18])=[CH:12][C:13]([CH3:17])=[CH:14][C:15]=1[CH3:16])[C:28]([C:25]1([S:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)[CH2:24][CH2:23][N:22]([O:21][CH3:20])[CH2:27][CH2:26]1)=[O:29]
Reactant: COC(=O)Cc1c(C)cc(C)cc1C
Reactant: COc1ccc(CSC2(C(=O)Cl)CCN(OC)CC2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(C(=O)C1(SCc2ccc(OC)cc2)CCN(OC)CC1)c1c(C)cc(C)cc1C
Temperature: -5 °C
Reaction time: 1 h

Procedure:
In a separate flask, 512 mg diisopropylamine was dissolved in 15 ml tetrahydrofuran, cooled to −5° C., and 2.86 ml n-butyllithium (1.6M in hexane) was added, then stirred at 0° C. for 1 hour. Then 864 mg (2,4,6-trimethyl-phenyl)-acetic acid methyl ester was added, and the mixture stirred for additional 30 minutes at 0° C. The crude 1-methoxy-4-(4-methoxybenzylsulfanyl)-piperidine-4-carbonyl chloride was dissolved in 5 ml tetrahydrofuran and added to the reaction mixture, which was then allowed to warm to room temperature and stirred for 18 hours. The solvent was evaporated, the residue partitioned between half saturated aqueous ammonium chloride and t-butylmethyl ether, the organic layer washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel with ethyl acetate/cyclohexane (1:9, then 1:5, then 1:2) as a solvent. Thus, 508 mg 3-[1-methoxy-4-(4-methoxy-benzylsulfanyl)-piperidin-4-yl]-3-oxo-2-(2,4,6-trimethylphenyl)-propionic acid methyl ester was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[Cl:14][C:15]1[CH:16]=[C:17]([CH2:22][CH2:23][O:24][CH2:25][C:26]([NH2:28])=[NH:27])[CH:18]=[CH:19][C:20]=1[F:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][C:3]=1[C:4]([NH:28][C:26](=[NH:27])[CH2:25][O:24][CH2:23][CH2:22][C:17]1[CH:18]=[CH:19][C:20]([F:21])=[C:15]([Cl:14])[CH:16]=1)=[O:6]
Reactant: CCc1cnc(Cl)c(C(=O)O)c1
Reactant: N=C(N)COCCc1ccc(F)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(Cl)c(C(=O)NC(=N)COCCc2ccc(F)c(Cl)c2)c1

Procedure:
In analogy to the procedure described in example 78.3, 2-chloro-5-ethyl-nicotinic acid (example 124.1) was reacted with 2-[2-(3-chloro-4-fluoro-phenyl)-ethoxy]-acetamidine hydrochloride (example 82.2) in the presence of TBTU and DIPEA to give 2-chloro-N-{2-[2-(3-chloro-4-fluoro-phenyl)-ethoxy]-1-imino-ethyl}-5-ethyl-nicotinamide as yellow oil. MS: m/e=398.1 [M+H+].
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]([F:25])([F:24])[C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[NH2:16]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:16][C:15]1[CH:17]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:19]=[C:13]([C:12]([F:11])([F:24])[F:25])[CH:14]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Clc1nc2ccccc2[nH]1
Product: FC(F)(F)c1cc(Nc2nc3ccccc3[nH]2)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 3,5-bis(trifluoromethyl)aniline by Procedure A. The product was isolated by filtration to give the title compound as a hydrochloride salt (white solid, mp 245-246° C.). MS(ES+) m/z 346 ([M+1]+, 100).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11](S(C)(=O)=O)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2].[NH2:30][C:31]1[CH:32]=[C:33]([CH:39]=[CH:40][CH:41]=1)[C:34]([N:36]([CH3:38])[CH3:37])=[O:35]>CC(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11]([NH:30][C:31]3[CH:41]=[CH:40][CH:39]=[C:33]([C:34](=[O:35])[N:36]([CH3:37])[CH3:38])[CH:32]=3)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2]
Reactant: CN(C)C(=O)c1cccc(N)c1
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Solvent: CC(C)O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3cccc(C(=O)N(C)C)c3)ncc2c1=O
Temperature: 90 °C
Reaction time: 15 h
Yield: 65.3 %

Procedure:
8-Indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (20 mg, 0.048 mmol) and 3-amino-N,N-dimethyl-benzamide (8 mg, 0.05 mmol) were combined in i-PrOH (2 mL) and heated to 90° C. After 15 h, the reaction mixture was concentrated and purified by preparative HPLC (C-18 column, 32 mL/min 5-100% MeCN/H2O gradient over 15 min) and lyophilized to provide 15.6 mg of 2-(3-dimethylcarbamoyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.31 (s, 1H), 1.13 (s, 1H), 7.46 (br s, 1H), 7.33 (d, 1H, J=7.9 Hz), 7.16-7.21 (m, 2H), 7.10 (d, 1H, J=7.6 Hz), 6.96 (br s, 2H), 4.29 (q, 2H, J=7.1 Hz), 2.97-3.04 (m, 5H), 2.85-2.93 (m, 5H), 2.14 (p, 2H, J=7.4 Hz), 1.29 (t, 3H, J=7.1 Hz)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH2:11]([N:13]([CH2:27][CH2:28][CH3:29])[C:14]([C:16]1[CH:17]=[C:18]([CH:23]=[C:24](I)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])=[O:15])[CH3:12]>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH2:11]([N:13]([CH2:27][CH2:28][CH3:29])[C:14]([C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])=[O:15])[CH3:12]
Reactant: CCCN(CC)C(=O)c1cc(I)cc(C(=O)OC)c1
Reactant: c1cocn1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCN(CC)C(=O)c1cc(C(=O)OC)cc(-c2ncco2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a −70° C. stirred solution of oxazole (106 mg, 1.5 mmol) in tetrahydrofuran (4 mL) is added n-butyllithium (1.6 M in hexanes, 1.0 mL, 1.7 mmol). After 30 min, zinc chloride (1 M in diethyl ether, 4.6 mL, 4.6 mmol) is added and the reaction mixture is warmed to 0° C. for 1 h. To this mixture is added a solution of methyl 3-{[ethyl(propyl)amino]carbonyl}-5-iodobenzoate (535 mg, 1.45 mmol) in anhydrous tetrahydrofuran (1.8 mL) followed by palladium(0) tetrakis(triphenylphosphine) (120 mg, 0.10 mmol). The reaction mixture is heated at reflux for 2 h. The reaction mixture is cooled, diluted with ethyl acetate, washed with water, and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 60% ethyl acetate/hexane) provides the title compound. ESI MS m/z 317.1 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:25]=[CH:24][C:8]([C:9]([NH:11][C:12]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C)C=O>[N+:21]([C:18]1[CH:19]=[CH:20][C:12]2[N:11]=[C:9]([C:8]3[CH:24]=[CH:25][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][CH:7]=3)[O:16][C:14](=[O:15])[C:13]=2[CH:17]=1)([O-:23])=[O:22]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])cc2C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(-c2nc3ccc([N+](=O)[O-])cc3c(=O)o2)cc1
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a suspension of 2-(4-tert-butylbenzoylamino)-5-nitrobenzoic acid (37.1 g, 108 mmol) and N,N-dimethylformamide (0.4 mL, 5.4 mmol) in methylene chloride (200 mL) was added oxalyl chloride (10.4 mL, 119 mmol) in a dropwise manner. After stirring for 2 h, the mixture was filtered and the small amount of black solid was discarded. The filtrate was concentrated in vacuo to give 32.9 g (94%) of the title compound as a light brown solid; mp 159-61° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[H-].[Na+].CI.[C:17]([O-])(O)=O.[Na+]>CN(C=O)C.[Cl-].[Na+].O>[CH3:17][NH:7][C:6]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CNc1ccc(OC)cc1[N+](=O)[O-]

Procedure:
To 4-methoxy-2-nitroaniline (10 mmol, 1.68 g) in 20 mL of DMF was added NaH (12 mmol, 480 mg of a 60% dispersion in mineral oil) (exothermic, H2 evolution), affording a deep red slurry. After 15 min MeI (20 mmol, 1.2 mL) was added (exothermic). After 30 min the reaction was poured into a solution of brine and NaHCO3, resulting in formation of a bright orange precipitate. The slurry was filtered and the filter cake was washed with H2O. The solid was dried under reduced pressure, affording a bright orange solid. HPLC A: 1.77 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Fc1ccc([C@H]2CCCN2)cc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)N2CCC[C@@H]2c2ccc(F)cc2)cc1

Procedure:
The title compound, white solid, m.p. 136° C., [a]D20=174° (c=0.1 in CHCl3) and MS: m/e=319 (M+) was prepared in accordance with the general method of example 1e from (R)-2-(4-fluoro-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: C([NH:3][C:4]1[S:5][C:6]([CH3:35])=[C:7]([C:9](=[N:32][O:33][CH3:34])[C:10]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]4[S:23][CH:24]=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:36]>>[ClH:36].[NH2:3][C:4]1[S:5][C:6]([CH3:35])=[C:7]([C:9](=[N:32][O:33][CH3:34])[C:10]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]4[S:23][CH:24]=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1nc(NC=O)sc1C
Agent: Cl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1nc(N)sc1C

Procedure:
7-[2-(2-Formamido-5-methylthiazol-4-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer, 2.4 g.) was treated with conc. hydrochloric acid (1.3 ml.) in a similar manner to that of Example 1-(2) to give 7-[2-(2-amino-5-methylthiazol-4-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid hydrochloride (syn isomer, 2.3 g.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[C:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(Br)n1
Product: CC(=O)Nc1cccc(Br)n1
Yield: 68 %

Procedure:
20 g (0.116 mole) of 2-amino-6-bromopyridine was dissolved in 140 ml. acetic anhydride and heated at 70° C. for 45 minutes. 2-Acetamido-6-bromopyridine was isolated by filtration as white flakes, m.p=159.2°-160.0° C., in 68% yield. The excess acetic anhydride present in the reaction mixture was hydrolyzed by the addition of 300 ml. water to the filtrate; the reaction mixture was agitated and an additional 27% yield of 2-acetamido-6-bromopyridine was collected by filtration, giving a 95% yield of reaction product, 2-acetamido-6-bromopyridine which was recrystallized from benzene. Elemental Analysis:
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([O:23][CH2:24][CH3:25])=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[C@H:36]1[CH2:40][CH2:39][C@H:38]([NH2:41])[CH2:37]1>>[CH2:24]([O:23][C:19]1[C:17]2[O:18][C@@H:13]([CH2:12][NH:41][C@H:38]3[CH2:39][CH2:40][C@H:36]([C:30]4[C:29]5[C:33](=[CH:34][CH:35]=[C:27]([F:26])[CH:28]=5)[NH:32][CH:31]=4)[CH2:37]3)[CH2:14][O:15][C:16]=2[CH:22]=[CH:21][CH:20]=1)[CH3:25]
Reactant: CCOc1cccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Reactant: N[C@H]1CC[C@H](c2c[nH]c3ccc(F)cc23)C1
Product: CCOc1cccc2c1O[C@@H](CN[C@H]1CC[C@H](c3c[nH]c4ccc(F)cc34)C1)CO2
Yield: 57.3 %

Procedure:
This compound was prepared in the same manner as for Example 1, using [(2R)-8-ethoxy-2,3-dihydro-benzo[1,4]dioxin-2-yl]methyl 4-methylbenzenesulfonate (0.25 g, 0.68 mmol) and trans-3-(5-fluoro-1H-indol-3-yl)-cyclopentylamine (0.3 g, 1.38 mmol) to afford 0.16 g (64%) of the title compound as its hydrochloride salt: MS (ESI) m/z 411 [M+H]+.
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([C:10]([C:12]2[O:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][N:16]=2)=[O:11])[CH2:7]1)(=O)=O.O[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][C:25]=1[CH3:32]>>[CH3:32][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:24]=1[O:5][CH:6]1[CH2:9][N:8]([C:10]([C:12]2[O:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][N:16]=2)=[O:11])[CH2:7]1)[CH:28]=[O:29]
Reactant: CS(=O)(=O)OC1CN(C(=O)c2nnc(-c3ccccc3)o2)C1
Reactant: Cc1cc(C=O)ccc1O
Product: Cc1cc(C=O)ccc1OC1CN(C(=O)c2nnc(-c3ccccc3)o2)C1
Yield: 28 %

Procedure:
Using a similar protocol as described in Example 71A employing 53B and 4-hydroxy-3-methylbenzaldehyde as starting materials afforded 0.8 g (28%) of 74A as a solid. 1H NMR (500 MHz, CDCl3): δ 2.33 (s, 3H), 4.40 (m, 1H), 4.71 (m, 1H), 4.82 (m, 1H), 5.19 (m, 2H), 6.61 (s, 1H), 7.54 (t, 2H), 7.60 (t, 1H), 7.73 (d, 1H), 7.75 (s, 1H), 8.18 (d, 2H), 9.89 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[C:19]1(B(O)O)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:27]2[C:28]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:24]=[CH:25][CH:26]=2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: OB(O)c1cccc2ccccc12
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(CC1CCCC1)c1ccc(-c2cccc3ccccc23)cc1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (3.87 g, 10.81 mmol), 1-naphthaleneboronic acid (2.79 g, 16.22 mmol), triethylamine (4.5 mL, 32.44 mmol), palladium (II) acetate (72.8 mg, 0.324 mmol), and tri-o-tolylphosphine (204.1 mg, 0.670 mmol) in dry N,N-dimethylformamide (43 mL) was heated at 100° C. under nitrogen for 1 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove N,N-dimethylformamide. The residue was diluted with ethyl acetate (200 mL). The organic phase was washed with a saturated aqueous sodium bicarbonate solution (1×100 mL) and water (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 19/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propionic acid methyl ester (3.51 g, 90%) as a yellow oil: EI-HRMS m/e calcd for C25H26O2 (M+) 358.1933, found 358.1930.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.S(Cl)(Cl)=O.Cl.[CH3:20][NH:21][O:22][CH3:23].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[OH:1][C:2]1[C:3]([C:12]([N:21]([O:22][CH3:23])[CH3:20])=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=C(O)c1ccc2cccnc2c1O
Reactant: CNOC
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc2cccnc2c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To a mixture of 8-hydroxyquinoline-7-carboxylic acid (5.0 g, 26 mmol, TCI America) in methylene chloride (50 mL) was added thionyl chloride (4.24 mL, 58.1 mmol). After stirred at room temperature overnight, the mixture was concentrated to dryness under reduced pressure. The residue was exposed to high vacuum then mixed with tetrahydrofuran (50 mL). To the resultant mixture was added N,O-dimethylhydroxylamine hydrochloride (3.09 g, 31.7 mmol) followed by N,N-diisopropylethylamine (13.8 mL, 79.3 mmol). The reaction was heated at 50° C. overnight, then cooled and quenched with water, and extracted with dichloromethane. The combined organic layers were washed with water, brine and dried over sodium sulfate. After evaporated to dryness, the residue was purified on silica gel, eluting with 0 to 10% methanol in dichloromethane, to give the desired product (4.09 g, 66%). LCMS calculated for C12H13N2O3(M+H)+: m/z=233.1; found: 233.0.