Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][C:6]([CH3:16])=[C:7]([C:14]#[CH:15])[CH:8]=2)[O:3]1.Cl[C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][N:20]=1.[Cl-]>C(N(CC)CC)C.[Pd].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>[CH2:26]([O:25][C:23](=[O:24])[C:22]1[CH:28]=[CH:29][C:19]([C:15]#[C:14][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][C:6]=2[CH3:16])[O:3][C:2]([CH3:17])([CH3:1])[CH2:11][C:10]3([CH3:12])[CH3:13])=[N:20][CH:21]=1)[CH3:27]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: C#Cc1cc2c(cc1C)OC(C)(C)CC2(C)C
Agent: [Pd]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2cc3c(cc2C)OC(C)(C)CC3(C)C)nc1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
A solution of 300 mg (1.316 mmol) of 2,2,4,4,7-pentamethyl-6-ethynyl-chroman (Compound 9) and 245.6 mg (1.3276 mmol) of ethyl 6-chloro-nicotinate (Compound 98) in 2 ml of triethylamine was placed in a pressure tube and a stream of nitrogen was bubbled through the solution for 15 min. The tube was then flushed with argon and a finely ground mixture 100 mg (0.1425 mmol) of bis (triphenylphosphine) palladium II) chloride and 50 mg (0.2625 mmol) of cuprous iodide was added to the solution. The pressure tube was then sealed and the reaction mixture heated at 60 degrees C. for 72 h. The mixture was cooled to room temperature and the triethylamine removed under vacuum. The residue was purified by flash chromatography (silica; 10% ethyl acetate in hexane) to give the title compound as a yellow solid. PMR (CDCl3): & 1.37 (6H, s), 1.38 (6H, s), 1.44 (3H, t, J~7.2 Hz), 1.85 (2H, s), 2.49 (3H, s), 4.43 (2H, q, J~7.2 Hz), 6.70 (1H, s), 7.55-7.61 (2H, m), 8.28 (1H, dd, J~8.2 Hz, 2.1 Hz), 9.22 (1H, d, J~2.1 Hz). MS exact mass, m/e 377.1982 (calcd. for C24H27O3N, 377.1991).
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[CH3:21][O:22][C:23]1[C:24]([NH2:29])=[CH:25][CH:26]=[CH:27][CH:28]=1>ClCCl.N1C=CC=CC=1>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:1](=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[O:22][CH3:21])=[O:13]
Reactant: COc1ccccc1N
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccccc1NC(=O)c1ccccc1SSc1ccccc1C(=O)Nc1ccccc1OC
Yield: 21.3 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and o-anisidine (1.42 g, 11.5 mmol) in 10 mL of pyridine. The crude product was recrystallized from ethanol-ethyl acetate, then again from acetonitrile-DMF to yield 0.634 g of the title compound, mp 154°-155° C.
Reaction SMILES: [CH3:1][N:2]([CH3:44])[C:3]1[CH:8]=[CH:7][C:6]([P:9]([C:35]2[CH:40]=[CH:39][C:38]([N:41]([CH3:43])[CH3:42])=[CH:37][CH:36]=2)([CH2:11][CH2:12][CH2:13][CH2:14][P:15]([C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)([C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=2)=O)=O)=[CH:5][CH:4]=1.C(N(CCCC)CCCC)CCC.C[SiH](Cl)Cl>CC1C=CC=CC=1C>[CH3:34][N:32]([CH3:33])[C:29]1[CH:30]=[CH:31][C:26]([P:15]([C:17]2[CH:18]=[CH:19][C:20]([N:23]([CH3:24])[CH3:25])=[CH:21][CH:22]=2)[CH2:14][CH2:13][CH2:12][CH2:11][P:9]([C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:1])[CH3:44])=[CH:4][CH:5]=2)[C:35]2[CH:40]=[CH:39][C:38]([N:41]([CH3:42])[CH3:43])=[CH:37][CH:36]=2)=[CH:27][CH:28]=1
Reactant: CN(C)c1ccc(P(=O)(CCCCP(=O)(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2)cc1
Agent: C[SiH](Cl)Cl
Solvent: Cc1ccccc1C
Solvent: CCCCN(CCCC)CCCC
Product: CN(C)c1ccc(P(CCCCP(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 91.9 %

Procedure:
6.1 g (10 mmol) of 1,4-bis[bis(4-dimethylaminophenyl)phosphinyl]butane and 9.3 g (50 mmol) of tri-n-butylamine are initially charged in 30 ml of o-xylene in an argon atmosphere. 5.75 g (50 mmol) of methyldichlorosilane are slowly added dropwise with the reaction mixture warming up to 50° C. It is subsequently heated to 100° C. and stirred for 4 hours, then heated to 145° C. and stirred for 16 hours. Cooling the clear solution results in formation of colorless crystals which are filtered off and washed with 10 ml of degassed o-xylene. Drying in a high vacuum gives 5.5 g of colorless crystals, corresponding to a yield of 95%.
Reaction SMILES: O[CH2:2][C:3]1[C:4]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])(=[O:24])=[O:23])=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH:12]([O:11][C:9]([C:4]1[C:3]([CH2:2][N:25]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[S:22]([C:19]2[CH:18]=[CH:17][C:16]([CH3:15])=[CH:21][CH:20]=2)(=[O:24])=[O:23])=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:10])([CH3:14])[CH3:13]
Reactant: CC(C)OC(=O)c1ncccc1CO
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CN(Cc1cccnc1C(=O)OC(C)C)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Isopropyl 3-(hydroxymethyl)pyridine-2-carboxylate (prepared in accordance with P. Ornstein et. al. J. Med. Chem. 1989, 32, 827) (200 g, 1.02 mol), methyl N-[(4-methylphenyl)sulfonyl]glycinate (249 g, 1.02 mol), and triphenylphosphine (403 g, 1.5 mol) were dissolved in dry THF (3000 mls) and cooled to zero degrees under N2. The diethylazodicarboxylate (DEAD) (267.6 g, 1.5 mol) was dissolved in dry THF (250 mls) and placed in a 500 ml addition funnel. The DEAD was added dropwise over 1 hour. The ice bath was removed and the reaction was allowed to warm slowly to RT. After 2 hours, the reaction was checked by HPLC (above conditions) and some glycinate remained. More starting reagents were added and the reaction was left to stir at RT. After 30 min, the reaction was checked again and saw a very small amount of the glycinate remaining. Concentrated reaction down to a reddish-orange oil that was carried onto the next step.
Reaction SMILES: C(=O)([S:3][CH2:4][CH2:5][N:6]1[CH2:10][C:9]([CH3:12])([CH3:11])[NH:8][C:7]1=[O:13])C.[OH-].[Na+]>CO.O>[SH:3][CH2:4][CH2:5][N:6]1[CH2:10][C:9]([CH3:11])([CH3:12])[NH:8][C:7]1=[O:13]
Reactant: CC(=O)SCCN1CC(C)(C)NC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)CN(CCS)C(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
To a cold (0° C.) solution of S-(2-(4,4-dimethyl-2-oxoimidazolidin-1-yl)ethyl) ethanethioate (1.5 g, 6.9 mmol) in 14 mL of methanol and 7.2 mL of water was added 2.1 mL of 5 N NaOH. The external ice bath was removed and the mixture was allowed to warm to room temperature and stirred for 18 hours. Concentrated HCl (11 mL) was added and the resultant solution was concentrated to about ½ its original volume and extracted with ethyl acetate. The organic layer was washed with a brine solution, dried over sodium sulfate, and concentrated to give 1.2 g of a tan liquid. 1H NMR (CDCl3, 400 MHz) δ 1.32 (s, 6H), 1.39-1.43 (t, J=8.1 Hz, 1H) 2.66-2.27 (q, J=6.8 Hz, 2H), 3.24 (s, 2H), 3.36-3.340 (t, J=7.2 Hz, 2H), 4.94 (br s, 1H); LRMS (ESI/APCI) m/z 175 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[O:12][C:11]([NH:14][CH:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([O:29][CH2:30][CH3:31])[CH:23]=4)[CH2:17][CH2:16]3)=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-].O.Cl>C1COCC1.CO>[CH2:30]([O:29][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[CH3:28])[CH2:21][N:18]1[CH2:17][CH2:16][CH:15]([NH:14][C:11]2[O:12][C:13]3[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=[CH:8][C:9]=3[N:10]=2)[CH2:20][CH2:19]1)[CH3:31]
Reactant: CCOc1cc(CN2CCC(Nc3nc4cccc(C(=O)OC)c4o3)CC2)ccc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCOc1cc(CN2CCC(Nc3nc4cccc(C(=O)O)c4o3)CC2)ccc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 0.1 %

Procedure:
To a solution of 2-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-benzooxazole-7-carboxylic acid methyl ester (22.0 mg, 52.0 mmol, 1.0 equiv; example 308/step 3) in a 1:1 mixture of THF/methanol (0.26 mL) was added a 1 M solution of LiOH in water (0.13 mL, 130.0 mmol, 2.5 equiv). After stirring for 18 h at rt, the pH of the reaction mixture was adjusted to 3.5 by addition of 1 M solution of HCl, the solution extracted with ethyl acetate (2×1 mL) and the combined organic phases washed with water (2×1 mL) and a conc. solution of sodium chloride (1 mL). The organic phase was dried over MgSO4, concentrated by evaporation under reduced pressure and the crude reaction product purified with column chromatography on silica eluting with ethyl acetate/acetone/acetic acid/water (6:2:1:1) providing 21.0 mg (96%) of the title compound. MS (ISP): 410.3 [M+H]+.
Reaction SMILES: CCO.[CH3:4][O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:12](=[O:30])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=3[O:28][CH3:29])[CH:14]=[CH:15][C:16]=2[C:17]=1[OH:18])=[O:7]>[Pd].CCOC(C)=O.C1COCC1>[CH3:4][O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:12](=[O:30])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=3[O:28][CH3:29])[CH2:14][CH2:15][C:16]=2[C:17]=1[OH:18])=[O:7]
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccc(OC)cc3OC)ccc2c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1ncc2c(c1O)CCN(Cc1ccc(OC)cc1OC)C2=O
Reaction time: 16 h
Yield: 74.6 %

Procedure:
A round bottom flask was charged with 10% palladium on carbon (50 mg) and EtOH (5 mL). 7-(2,4-Dimethoxy-benzyl)-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (20 mg, 0.054 mmol) dissolved in EtOAc/THF (10 mL, 1:1) was added, and the mixture was stirred under H2 atmosphere (1 atm) for 16 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (5-80% EtOAc/hexanes+2% AcOH) to give 15 mg of the title compound. MS: (+) m/z 373.33 (M+H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:27])=[N:14][C:15]2[N:16]([N:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=2)[C:17]=1I)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:28][CH:29]([CH3:36])[CH2:30]/[CH:31]=[CH:32]/B(O)O.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:27])=[N:14][C:15]2[N:16]([N:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=2)[C:17]=1/[CH:32]=[CH:31]/[CH2:30][CH:29]([CH3:36])[CH3:28])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(I)n2n1
Reactant: CC(C)C/C=C/B(O)O
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: CN(C)C=O
Product: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(/C=C/CC(C)C)n2n1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
A mixture of (S)-ethyl 6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (300 mg, 0.613 mmol), (E)-(4-methylpent-1-en-1-yl)boronic acid (94 mg, 0.736 mmol) and 2N Na2CO3 (0.613 mL, 1.226 mmol) in DMF (6 mL) was degassed for 15 min. Tetrakis(triphenylphosphine)palladium(0) (49.6 mg, 0.043 mmol) was then added and the degassing was continued for another 5 min. The mixture was then heated at 100° C. for 2 h. At this point LCMS indicated completion of reaction and presence of desired product. After cooling to room temperature, water was added (10 mL) and the mixture was extracted with ether (2×50 mL), washed with brine (25 mL), dried (Na2SO4), filtered and concentrated. the crude was then purified by biotage (5-30% EtOAc/hexane) to afford (S,E)-ethyl 6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-5-methyl-7-(4-methylpent-1-en-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (200 mg, 0.449 mmol, 73.2% yield) as off-white solid. 1H NMR (500 MHz, CDCl3) δ 7.09 (s, 1H), 7.07 (s, 0.6H), 7.04 (s, 1H), 5.57 (s, 1H), 4.49 (q, J=7.1 Hz, 2H), 4.33-4.20 (m, 2H), 2.70 (s, 3H), 2.40 (td, J=7.0, 1.3 Hz, 2H), 1.90 (dt, J=13.4, 6.7 Hz, 1H), 1.46 (t, J=7.1 Hz, 3H), 1.29 (t, J=7.1 Hz, 3H), 1.17 (s, 9H), 1.06 (dd, J=6.6, 2.7 Hz, 6H). LCMS (M+H)=446.4.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([O:16]CC)=O)[N:2]=1.[H-].[Na+].[F:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[CH2:24]Br.[NH2:31][OH:32]>CN(C=O)C.CO.O>[F:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[CH2:24][N:12]1[C:13]2[CH:1]=[N:2][C:3]([C:14]([NH:31][OH:32])=[O:16])=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Reactant: NO
Reactant: Fc1ccc(CBr)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NO)c1cc2c3ccccc3n(Cc3ccc(F)cc3F)c2cn1
Reaction time: 48 h
Yield: 36.8 %

Procedure:
To a stirred solution of ethyl 9H-β-carboline-3-carboxylate (370 mg, 1.54 mmol) in DMF (5 mL) under a nitrogen atmosphere was added NaH (61.6 mg, 60% in mineral oil, 1.54 mmol) portionwise, followed by 2,4-difluorobenzyl bromide (198 μL, 1.54 mmol). Stirring was continued for 48 hours at ambient temperature, water (100 mL) was then added to the mixture. The precipitate was filtered, washed with water and dried to give a solid that was dissolved in methanol (35 mL). To the resulting solution, H2NOH (30 mL, 50 wt. % solution in H2O, 0.45 mol) was added. The suspension was stirred for 4 days at ambient temperature. The mixture was then filtered, and the solid was recrystallized from methanol to give the title product (0.20 g, 37%). 1H NMR (400 MHz, DMSO-d6): δ 11.46 (1H, s), 9.15–9.22 (2H, m), 9.02 (1H, s), 8.64 (1H, d, J=8 Hz), 7.15–7.96 (6H, m), 6.06 (2H, s). HRMS (M+H)+ found: 354.1062. Calcd for C19H14F2N3O2FCl: 354.1054.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:35][O:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]12)=[O:6].[NH2:43][C:44]([NH2:46])=[S:45].C([O-])(=O)C.[Na+]>O1CCCC1.O>[NH2:46][C:44]1[S:45][CH:2]=[C:3]([C:4](=[N:35][O:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:5]([NH:7][CH:8]2[C:33](=[O:34])[N:10]3[C:11]([C:17]([O:19][CH:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]23)=[O:6])[N:43]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC)C(=O)CCl)[C@H]2SC1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC)c3csc(N)n3)[C@H]2SC1
Temperature: 40 °C
Reaction time: 4 h
Yield: 96.6 %

Procedure:
To a solution of benzhydryl 7-(4-chloro-2-methoxycarbonylmethoxyimino-3-oxobutyramido)-3-vinyl-3-cephem-4-carboxylate (syn isomer) (2.0 g) in a mixture of tetrahydrofuran (10 ml) and water (10 ml) were added thiourea (0.5 g) and sodium acetate (1.34 g). The mixture was stirred at 40° C. for 4 hours. The resultant solution was extracted with ethyl acetate (100 ml), and the extract was washed with a saturated aqueous sodium chloride twice. After the resultant solution was dried over magnesium sulfate, the solvent was removed by distillation under reduced pressure to give benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-methoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (2.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[N:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][C:42]=2[S:44](Cl)(=[O:46])=[O:45])[CH:37]=[CH:36][CH:35]=1.O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:44]([C:42]4[CH:41]=[CH:40][CH:39]=[C:38]5[C:43]=4[N:34]=[CH:35][CH:36]=[CH:37]5)(=[O:45])=[O:46])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(S(=O)(=O)c3cccc4cccnc34)c3cnc4ccc(Br)cc4c32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (24.4 mg, 0.36 mmol) in dichloromethane (6 ml) was added quinoline-8-sulfonyl chloride (40.98 mg, 0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 32 mg (36.26%); 1H NMR (DMSO-d6, 300 MHz): δ 9.60 (s, 1H), 8.70-8.836 (dd, 1H, J=7.5, 1.2 Hz), 8.561-8.757 (m, 1H), 8.54 (s, 1H), 8.46-8.492 (dd, 1H, J=8.4, 1.2 Hz), 8.0.25-8.058 (d, 1H, J=9.3 Hz), 7.869-7.921 (t, 1H, J=7.8 Hz), 7.74-7.79 (m, 3H), 7.581-7.623 (m, 1H), 7.534-7.563 (d, 2H, J=8.7 Hz), 6.752-6.758 (d, 1H, J=1.8 Hz), 1.21 (s, 6H); MS: m/z 598 (M+).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[O:19])[CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([O:22][CH3:23])=[C:7]([O:20][CH3:21])[CH:8]=2)[N:3]=1.[CH3:24][NH2:25]>CO>[CH3:21][O:20][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:22][CH3:23])[N:3]=[C:2]([NH:25][CH3:24])[N:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[O:19])[CH:13]=1
Reactant: COc1cc2nc(Cl)nc(-c3cccc(C=O)c3)c2cc1OC
Reactant: CN
Solvent: CO
Product: CNc1nc(-c2cccc(C=O)c2)c2cc(OC)c(OC)cc2n1

Procedure:
Starting from 1.50 g of 2-chloro-6,7-dimethoxy-4-(3-formylphenyl)quinazoline and 15 ml of 40% methylamine in methanol, 1.00 g of the title compound was obtained as yellow crystals in the same manner as in Production Example 8.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39](=[O:41])[CH3:40])=[CH:35][CH:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:39]([C:36]1[CH:37]=[CH:38][C:33]([NH:32][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10]2)=[O:29])=[CH:34][CH:35]=1)(=[O:41])[CH3:40]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(=O)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1ccc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)cc1
Yield: 27.4 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.35 g, 0.75 mmol) was reacted with 1-(4-amino-phenyl)-ethanone (Aldrich) (0.12 g, 0.9 mmol), HATU (0.5 g, 1.3 mmol) and iPr2NEt (0.33 mL, 2.6 mmol) in CH2Cl2 at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-acetyl-phenyl)-amide as a white solid (0.12 g, 27%).
Reaction SMILES: C([O:9][C:10]1[C:19](=[O:20])[C:18]2[C:13](=[C:14]([F:21])[CH:15]=[CH:16][CH:17]=2)[N:12]([CH3:22])[CH:11]=1)(=O)C1C=CC=CC=1.N1CCCCC1>ClCCl>[F:21][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[N:12]([CH3:22])[CH:11]=[C:10]([OH:9])[C:19]2=[O:20]
Reactant: Cn1cc(OC(=O)c2ccccc2)c(=O)c2cccc(F)c21
Solvent: ClCCl
Solvent: C1CCNCC1
Product: Cn1cc(O)c(=O)c2cccc(F)c21
Reaction time: 24 h

Procedure:
A mixture of 8-fluoro-1-methyl-4-oxo-1 ,4-dihydro-quinol-3-yl benzoate (10 g), piperidine (3.18 g) and dichloromethane (200 ml) was stirred for 24 hours, a further portion of piperidine (1.7 ml) was added and the stirring continued for a further 24 hours. The solvent was removed by distillation and the residue was triturated with diethyl ether (300 ml). The resultant solid was extracted with aqueous sodium hydroxide (0.1 M, 100 ml) and the extract was neutralised with hydrochloric acid (5M, 2 ml). The resultant precipitate was collected by filtration to give the novel compound 8-fluoro-3-hydroxy-1 -methyl-4-quinolone, m.p. 248°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9]2)=[N:6][CH:7]=1.Cl.[F:19][C@@H:20]1[CH2:24][CH2:23][NH:22][CH2:21]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]([N:22]3[CH2:23][CH2:24][C@@H:20]([F:19])[CH2:21]3)[CH2:9]2)=[N:6][CH:7]=1
Reactant: CS(=O)(=O)O[C@H]1CCN(c2ccc(Br)cn2)C1
Reactant: F[C@@H]1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: F[C@@H]1CCN([C@@H]2CCN(c3ccc(Br)cn3)C2)C1
Temperature: 70 °C
Yield: 38.8 %

Procedure:
Dissolve methanesulfonic acid (S)-1-(5-bromo-pyridin-2-yl)-pyrrolidin-3-yl ester (3 g, 9.34 mmol) and (R)-3-fluoro-pyrrolidine hydrochloride (1.00 g, 11.21 mmol) in DMF (50 mL) and add Cs2CO3 (9.13 g, 28.02 mmol). Warm to 70° C. overnight. Dilute with dichloromethane (3×40 mL), wash with H2O (50 mL) and brine. Dry with Na2SO4, filter, and concentrate the organic solution. Purify the crude material by chromatography, eluting with 0-50% EtOAc/hexane, to give 1.14 g (39%) of (3R,3′R)-1′-(5-Bromo-pyridin-2-yl)-3-fluoro-[1,3′]bipyrrolidinyl.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.O[CH:24]1[CH2:28][CH2:27][O:26][CH2:25]1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH:24]3[CH2:28][CH2:27][O:26][CH2:25]3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Reactant: OC1CCOC1
Product: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2C1CCOC1
Yield: 34.8 %

Procedure:
Compound 97 was synthesised from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine (50 mg, 0.16 mmol) following a similar procedure outlined in Example 86, using 3-hydroxytetrahydrofuran (28 mg, 0.32 mmol) instead of oxetan-3-ol. Compound 97 was purified using preparative HPLC followed by chromatography (silica gel, gradient CH2Cl2), yielding Compound 97 as an off-white solid (21 mg).
Reaction SMILES: [C:1]1([NH:7][NH:8][C:9]([NH2:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][C:13]([Cl:18])=[CH:14][C:15](Cl)=[O:16]>C(#N)C>[Cl:12][C:13]([Cl:18])=[CH:14][C:15]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[NH:8][C:9]([NH2:11])=[O:10])=[O:16]
Reactant: NC(=O)NNc1ccccc1
Reactant: O=C(Cl)C=C(Cl)Cl
Solvent: CC#N
Product: NC(=O)NN(C(=O)C=C(Cl)Cl)c1ccccc1
Yield: 63 %

Procedure:
To a suspension of 7 g of 1-phenylsemicarbazide in 100 ml of acetonitrile, cooled down to 0°-5° C., were added 7.4 g of β,β-dichloroacryloyl chloride, under stirring. The addition having been completed, the reaction mixture was stirred at 5° C. for 30 minutes and then at room temperature for 1 (one) hour. The solid that separated was collected by decanting and by filtration, then was washed with diethylether, thus obtaining 8 g of 1-(β,β-dichloroacryloyl)-1-phenyl-semicarbazide, in accordance with the elemental analysis and the I.R. and N.M.R. spectra.