Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[C:22]([Br:24])[CH:21]=[C:20](Br)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[OH:26][C:27]([C:30]1[CH:35]=[CH:34][C:33]([Sn](CCCC)(CCCC)CCCC)=[CH:32][N:31]=1)([CH3:29])[CH3:28]>CN(C)C=O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[C:22]([Br:24])[CH:21]=[C:20]([C:33]4[CH:32]=[N:31][C:30]([C:27]([OH:26])([CH3:29])[CH3:28])=[CH:35][CH:34]=4)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(C)(C)O)nc1
Reactant: O=C(NC1CC1)c1cn(-c2cc(Br)cc(Br)c2)c2ncccc2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(O)c1ccc(-c2cc(Br)cc(-n3cc(C(=O)NC4CC4)c(=O)c4cccnc43)c2)cn1
Temperature: 85 °C
Reaction time: 5 h

Procedure:
A mixture of N-cyclopropyl-1-(3,5-dibromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Step 2, 2-(1-hydroxy-1-methylethyl)-5-tributylstannylpyridine from Step 3 (1.4 eq), 1,1′-bis (diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 eq), and cuprous iodide (0.05 eq) in N,N-dimethylformamide (15 ml/mmol) was stirred at 85° C. for 5 hours. After cooling the resulting mixture was partitioned between ethyl acetate and water. The crude product from the organic phase was chromatographed on silica gel eluting with a 1:6:3 mixture of ethanol, ethyl acetate and methylene chloride to afford the N-Cyclopropyl-1-{5-bromo-3-[6-(1-hydroxy-1-methylethyl)pyridin-3-yl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide compound as a solid.
Reaction SMILES: [CH:1]1([C:7]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:8]=2[CH:9]=[C:10]2[C:16]4[CH:17]=[C:18]([C:21]([O:23]C)=[O:22])[CH:19]=[CH:20][C:15]=4[N:14]4[CH2:25][C:26]([CH3:28])=[N:27][C:13]4=[CH:12][N:11]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([C:7]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:8]=2[CH:9]=[C:10]2[C:16]4[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[CH:19]=[CH:20][C:15]=4[N:14]4[CH2:25][C:26]([CH3:28])=[N:27][C:13]4=[CH:12][N:11]23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(c1)-c1cc3c(C4CCCCC4)cccc3n1C=C1N=C(C)CN12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1=NC2=Cn3c(cc4c(C5CCCCC5)cccc43)-c3cc(C(=O)O)ccc3N2C1
Temperature: 70 °C
Yield: 88.2 %

Procedure:
To a solution of methyl 10-cyclohexyl-2-methyl-4H-imidazo[1,2-a]indolo[1,2-d][1,4]benzodiazepine-7-carboxylate (74 mg, 0.17 mmol) in THF (3 mL) and MeOH (1.5 mL) was added aq NaOH (1.0N, 0.8 mL, 0.8 mmol). The reaction mixture was heated at 70° C. for 2 h, cooled to rt, neutralized with aq. HCl (1.0N, 0.8 mL, 0.8 mmol) and concentrated to dryness. The solid residue was dissolved into MeOH/DCM, insoluble material was removed by filtration and the filtrate was concentrated and dried under N2 to yield crude 10-cyclohexyl-2-methyl-4H-imidazo[1,2-a]indolo[1,2-d][1,4]benzodiazepine-7-carboxylic acid (60 mg, 0.15 mmol, 86%) as an off-white solid which was used without further purification. 1H NMR (300 MHz, CD3OD) δ 1.16-1.56 (m, 4H), 1.72-2.22 (m, 6H), 2.31 (s, 3H), 2.80-3.01 (m, 1H), 5.12 (d, J=16.1 Hz, 1H), 5.91 (d, J=16.1 Hz, 1H), 7.62 (s, 1H), 7.72-7.86 (m, 5H), 7.97 (d, J=8.8 Hz, 1H), 8.39 (s, 1H). LCMS: m/e 412 (M+H)+, ret time 1.65 min.
Reaction SMILES: [CH2:1](OC1C=CC=CC=1)[C:2]1C=CC=[CH:4][CH:3]=1.[CH2:15]([N:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:29]1([N:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:15][C:16]2[C:17]3[C:18](=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:19]=[CH:20][CH:21]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: c1ccc(COc2ccccc2)cc1
Reactant: c1ccc(CN(c2ccccc2)c2ccccc2)cc1
Product: c1ccc(N(Cc2cccc3ccccc23)c2ccccc2)cc1
Yield: 74 %

Procedure:
N-phenylnaphthaldimine (2.20 g, 0.010 mol) and benzylphenyl ether (1.84 g, 0.010 mol) were reacted as above for the preparation of benzyldiphenylamine. Aqueous work-up afforded a precipitate which was isolated by filtration and recrystallized from 95% ethanol to yield 2.3 g (74%) of needles, mp 170°-172° C. Anal. calcd. for C23H19N: C 89.28, H 6.19, N 4.53%; found C 89.11, H 6.26, N 4.44%. 1H NMR (200 MHz, CDCl3)δ (assignment): 5.52 (s, 2H, CH2), 7.00-8.10 (m, 17H, aromatic). MS [m/e (70 ev, % of base peak)] (C10H7)CH2N(C6H5)2 309 (M+., 4.8), 308 (M+-H., 29.0), 168 (M+-((C10H7)CH2)., 18.0), 141 (((C10H7)CH2)+., 100). FTIR (CDCl3): 3063, 3040, 1606, 1602, 1594, 1584, 1574, 1559, 1512, 1501, 1497, 1488, 1485, 1474, 1465, 1460, 1451 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:15]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[N:16][S@@:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.[CH2:30]([Mg]Cl)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@@:15]([NH:16][S@@:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:11])[F:12])[CH:7]=1
Reactant: CC(C)(C)[S@@](=O)N=C(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Reactant: Cl[Mg]Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)N[C@@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
(R)—N-((3-Fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)(4-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (150 mg, 0.34 mmol) was stirred in anhydrous CH2Cl2 (7 mL) at −78° C. for 5 min under Argon. BF3Et2O (0.10 mL, 2.0 eq) was added dropwise. The mixture was stirred at −78° C. for 10 min. Benzylmagnesium chloride (1.0 M in Et20, 1.4 mL, 3.0 eq) was added slowly at −78° C., and the resulting mixture was stirred at −78° C. for 1.5 h. The reaction mixture was quenched with sat. NH4Cl and then extracted with Et2O (2×). The combined organic portion was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, EtOAc/hexanes=0-30%) to give the fast eluting fraction corresponding to (R)—N—((S)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide (29 mg): 1H NMR (400 MHz, CDCl3) δ ppm 1.23 (s, 9H) 3.63 (d, J=12.4 Hz, 1H), 3.94 (d, J=12.4 Hz, 1H), 4.21 (s, 1H), 6.90 (m, 1H), 5.90 (m, 1H), 6.94-7.09 (m, 4H), 7.16-7.20 (m, 4H), 7.31-7.39 (m, 2H); LC-MS (ESI) 530.36 (M+H), retention time=4.11 min (10-90% MeOH in H2O with 0.1% TFA in a 4-min run); and the slow eluting fraction corresponding to (R)—N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide (146 mg, total yield: 96.4%): 1H NMR (400 MHz, CDCl3) δ ppm 7.35-7.43 (m, 2H), 7.13-7.20 (m, 3H), 7.07 (t, J=8.72 Hz, 2H), 6.93 (dd, J=7.58, 1.77 Hz, 2H), 6.84 (d, J=8.59 Hz, 1H), 6.70 (m, 2H), 5.85 (tt, J=52, 4 Hz, 1H), 4.25 (s, 1H), 4.02 (d, J=12.63 Hz, 1H), 3.58 (d, J=12.63 Hz, 1H), 1.20 (s, 9H); 13C NMR (CDCl3) δ ppm 23.02, 46.99, 56.53, 65.70, 104.55, 104.96, 105.37, 107.06, 107.47, 107.92, 108.17, 109.56, 109.97, 112.32, 112.55, 115.37, 115.58, 116.13, 116.41, 116.69, 119.12, 127.21, 128.14, 130.91, 130.99, 132.07, 134.34, 137.48, 137.51, 149.09, 149.21, 150.52, 150.45, 161.20, 163.67; LC-MS (ESI) 530.36 (M+H), retention time=4.11 min (10-90% MeOH in H2O with 0.1% TFA in a 4-min run).
Reaction SMILES: [CH:1]1([CH:4]([O:6][C:7](=[O:39])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]([CH:35]4[CH2:38][CH2:37][CH2:36]4)[C:17]4[C:22]([C:23]=3[C:24]#[N:25])=[CH:21][CH:20]=[C:19](B3OC(C)(C)C(C)(C)O3)[CH:18]=4)=[CH:11][CH:10]=2)[CH3:5])[CH2:3][CH2:2]1.Cl[C:41]1[N:46]=[CH:45][CH:44]=[CH:43][N:42]=1.[F-].[Cs+]>COCCOC.CCOC(C)=O.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>[CH:1]1([CH:4]([O:6][C:7](=[O:39])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]([CH:35]4[CH2:38][CH2:37][CH2:36]4)[C:17]4[C:22]([C:23]=3[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([C:41]3[N:46]=[CH:45][CH:44]=[CH:43][N:42]=3)[CH:18]=4)=[CH:11][CH:10]=2)[CH3:5])[CH2:2][CH2:3]1
Reactant: Clc1ncccn1
Reactant: CC(OC(=O)Nc1ccc(-c2c(C#N)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3n2C2CCC2)cc1)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(OC(=O)Nc1ccc(-c2c(C#N)c3ccc(-c4ncccn4)cc3n2C2CCC2)cc1)C1CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 92.2 %

Procedure:
A mixture of {4-[3-cyano-1-cyclobutyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropyl-ethyl ester (0.2 g, 0.38 mmol), 2-chloropyrimidine (39 mg, 0.34 mg), Pd(PPh3)4 (22 mg, 0.095 mmol) and cesium fluoride (0.116 g, 0.76 mmol) in DME (2.0 mL) was stirred at 100° C. for 16 h. The mixture was then diluted with EtOAc (20 mL), washed with water and brine, dried over Na2SO4, concentrated and purified on silica gel (CH2Cl2/EtOAc) to provide [4-(3-cyano-1-cyclobutyl-6-pyrimidin-2-yl-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester as a solid (0.15 g, 82%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([C:19]([NH:21][NH2:22])=O)[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]=1>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([C:19]3[N:32]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][C:25]4=[N:22][N:21]=3)[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)C1(C2CCN(Cc3ccccc3)CC2)CCCC1
Reactant: COC1=NCCCCCC1
Solvent: Cc1ccccc1
Product: c1ccc(CN2CCC(C3(c4nnc5n4CCCCCC5)CCCC3)CC2)cc1
Yield: 50.6 %

Procedure:
1-(1-Benzylpiperidin-4-yl)cyclopentane-1-carbohydrazide (1.04 g) and 8-methoxy-2,3,4,5,6,7-hexahydroazocine (1.46 g) were reacted in toluene (10 ml) under heating to obtain 3-[1-(1-benzyl-4-piperidinyl)cyclopentyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (0.686 g). The resulting compound was reacted in ethanol under a hydrogen atmosphere using 10% palladium-active carbon (0.14 g) as a catalyst and, after filtration through celite, the resulting solution was concentrated to obtain 3-(1-piperidin-4-ylcyclopentyl)-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (0.610 g).
Reaction SMILES: [O:1]([CH2:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]2[CH:27]=[CH:26][C:17]([O:18][C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]([N:31]=[C:32]=[O:33])([CH3:30])[CH3:29].O.C(OCC)(=O)C>CN(C)C=O>[CH:28]([NH:31][C:32]([NH:23][C:22]1[CH:21]=[CH:20][C:19]([O:18][C:17]2[CH:26]=[CH:27][C:14]([C:12]3[N:13]=[C:9]([CH2:8][O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[NH:10][CH:11]=3)=[CH:15][CH:16]=2)=[CH:25][CH:24]=1)=[O:33])([CH3:30])[CH3:29]
Reactant: CC(C)N=C=O
Reactant: Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)NC(=O)Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
A mixture containing 4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}aniline (0.2 g, 0.56 mmol) and isopropylisocyanate (0.155 g, 1.8 mmol) in 3 ml of dimethylformamide is heated at 100° C. for two hours then stirred at ambient temperature for two hours. 20 ml of water and 30 ml of ethyl acetate are added, followed by extraction, then the organic phase is washed with a saturated sodium chloride solution. The organic phase is dried over sodium sulfate. After evaporation to dryness, the oil obtained is triturated in isopentane. After filtration then drying, the solid obtained is purified on a silica column (eluent dichloromethane-ethanol-ammonia 96/2/2) and a pink-cream coloured powder is obtained with a yield of 20%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.C([Li])CCC.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][CH:17]=1.O>O1CCCC1.CCCCCC.ClCCl>[F:8][C:5]1[CH:6]=[CH:7][C:2]([CH:22]([C:19]2[CH:18]=[CH:17][C:16]([C:15]([F:14])([F:24])[F:25])=[CH:21][CH:20]=2)[OH:23])=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: ClCCl
Solvent: O
Product: OC(c1ccc(F)cc1)c1ccc(C(F)(F)F)cc1
Reaction time: 0.25 h

Procedure:
1.00 g (5.71 mmol) of 4-bromofluorobenzene were dissolved in 10 ml of tetrahydrofuran at −78° C. Addition of 2.2 ml (6.86 mmol) of a 1.6N solution of n-butyllithium in hexane was followed by stirring for 15 min, and then 1.26 g (6.86 mmol) of trifluoro-p-tolualdehyde dissolved in 10 ml of tetrahydrofuran were added dropwise. The mixture was stirred at −78° C. for 1 h and then at RT for 1 h. The reaction solution was mixed with water and dichloromethane, and the phases were separated. The aqueous phase was extracted with dichloromethane, and the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered, and the solvents were removed in vacuo. The crude product was purified by preparative HPLC (mobile phase: acetonitrile-water gradient). 1.02 g (66% of theory) of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:44]/[O:45]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:8]([NH:10][C@@H:11]2[C:42](=[O:43])[N:13]3[C:14]([C:26]([O:28]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:27])=[C:15]([S:18][CH2:19][C:20]4[CH:25]=[CH:24][N:23]=[CH:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.Cl.C(OCC)(=O)C.CC(C)=O>C(O)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:44]/[OH:45])/[C:8]([NH:10][C@@H:11]2[C:42](=[O:43])[N:13]3[C:14]([C:26]([OH:28])=[O:27])=[C:15]([S:18][CH2:19][C:20]4[CH:25]=[CH:24][N:23]=[CH:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SCc4ccncn4)CS[C@H]23)cs1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=CO
Solvent: CC(C)=O
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(SCc4ccncn4)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.9 %

Procedure:
To a solution of diphenylmethyl 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(trityloxyimino)acetamido]-3-[(pyrimidin-4-yl)methylthio]-3-cephem-4-carboxylate (1.57 g, 1.74 m mol) in formic acid (6.28 ml) was added conc. HCl (0.435 ml, 5.22 m mol) at 5° C. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a mixture of ethyl acetate (43 ml) and acetone (22 ml). The precipitates were collected by filtration, and dried in vacuo. The crude product was desalted with HP-20. The eluent was concentrated to give precipitates. The precipitates were collected by filtration and dried in vacuo to give 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(hydroxyimino)acetamido]-3-[(pyrimidin-4-yl)methylthio]-3-cephem-4-carboxylic acid (128 mg, 0.259 m mol).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([Cl:7])[C:4]([Cl:8])=[C:3]([C:9]2[N:14]=[N:13][C:12]([NH2:15])=[N:11][C:10]=2[NH2:16])[CH:2]=1.[C:17]([OH:26])(=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23]>CO>[CH:1]1[CH:6]=[C:5]([Cl:7])[C:4]([Cl:8])=[C:3]([C:9]2[N:14]=[N:13][C:12]([NH2:15])=[N:11][C:10]=2[NH2:16])[CH:2]=1.[C:17]([O-:26])(=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O-:24])=[O:23]
Reactant: O=C(O)CCCCC(=O)O
Agent: Nc1nnc(-c2cccc(Cl)c2Cl)c(N)n1
Solvent: CO
Product: O=C([O-])CCCCC(=O)[O-]

Procedure:
16 mg of lamotrigine was dissolved in 2 ml of methanol, 11 mg of adipic acid was added to the solution to form a single solution. The solution was then allowed to stand for several hours to effect the slow evaporation of solvent. The solids gathered were stored in screw cap vials for subsequent analysis.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20]C3CCCCO3)[C@@H:13]3[C@H:18]([OH:19])[CH2:17][CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([OH:20])[C@@H:13]3[C@H:18]([OH:19])[CH2:17][CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(C2=NN3CC[C@@H](O)[C@H]3[C@@H]2OC2CCCCO2)ccc(C#N)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: Cc1c(C2=NN3CC[C@@H](O)[C@H]3[C@@H]2O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-chloro-4-((3S,3aS,4R)-4-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile (30 mg, 0.088 mmol) in methanol (1 mL) was added p-toluenesulfonic acid (20 mg, 0.1058 mmol) and the reaction mixture was stirred at room temperature for overnight. Methanol was evaporated from reaction mixture and extracted with EtOAc. Organic layer was washed with water, brine, dried over Na2SO4 and concentrated. Purification by column chromatography over silica gel using 3% MeOH in DCM provided the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:22])=[C:10]([C:14]3[N:15]=[C:16]([CH2:19]NC)[S:17][CH:18]=3)[C:11]=2[F:13])[C:6](=[O:23])[C:5]([C:24]([OH:26])=[O:25])=[CH:4]1)[CH3:2].[CH2:27]([NH:29]CC1SC=C(C2C(F)=C3C(C(=O)C(C(O)=O)=CN3CC)=CC=2F)N=1)C.NCC1SC=C(C2C(F)=C3C(C(=O)C(C(O)=O)=CN3CCF)=CC=2F)N=1.FC1C=C2C(=C(F)C=1C1N=C(CNC)SC=1)N(CCF)C=C(C(O)=O)C2=O.C(NCC1SC=C(C2C(F)=C3C(C(=O)C(C(O)=O)=CN3CCF)=CC=2F)N=1)C.NCC1SC=C(C2C(F)=CC3C(=O)C(C(O)=O)=CN4C(C)COC=2C=34)N=1>>[NH2:29][CH2:27][CH2:19][C:16]1[S:17][CH:18]=[C:14]([C:10]2[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:23])[C:5]([C:24]([OH:26])=[O:25])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=2[F:22])[N:15]=1
Reactant: CCNCc1nc(-c2c(F)cc3c(=O)c(C(=O)O)cn(CC)c3c2F)cs1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(-c3csc(CNC)n3)c(F)c21
Agent: CC1COc2c(-c3csc(CN)n3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Agent: CCNCc1nc(-c2c(F)cc3c(=O)c(C(=O)O)cn(CCF)c3c2F)cs1
Agent: CNCc1nc(-c2c(F)cc3c(=O)c(C(=O)O)cn(CCF)c3c2F)cs1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(-c3csc(CCN)n3)c(F)c21

Procedure:
In similar fashion the following compounds were prepared: 1-Ethyl-6,8-difluoro-1,4-dihydro-7-[2-[(methylamino) methyl]-4-thiazolyl]-4-oxo-3-quinolinecarboxylic acid, mp 172°-174° C. (35a); 7-[2-[(ethylamino)methyl]-4-thiazolyl]-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 155°-157° C. (35b); 7-[2-(aminomethyl)-4-thiazolyl]-6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 216°-218° C. (35c); 6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-7-[2[(methylamino)methyl]-4-thiazolyl]-4-oxo-3quinolinecarboxylic acid, mp 214°-215° C. (35d); 7-[2-[(ethylamino)methyl]-4-thiazolyl]-6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 197°-201° C. (35e), and 10-[2-(aminomethyl)-4-thiazolyl]-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid, mp 229°-231° C. (35f).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.Cl.Cl.[CH3:18][C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][CH:28]([CH2:31][N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[CH2:27][CH2:26]2)[CH:22]=[CH:21][N:20]=1.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:35]2[CH2:34][CH2:33][N:32]([CH2:31][CH:28]3[CH2:29][CH2:30][N:25]([C:23]4[CH:22]=[CH:21][N:20]=[C:19]([CH3:18])[N:24]=4)[CH2:26][CH2:27]3)[CH2:37][CH2:36]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Cc1nccc(N2CCC(CN3CCNCC3)CC2)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nccc(N2CCC(CN3CCN(S(=O)(=O)c4ccc(C(F)(F)F)cc4)CC3)CC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
A solution of 4-trifluoromethylphenylsulphonylchloride (367 mg) in methylene chloride (5 ml) was added dropwise over 5 minutes to a mixture of 4-[1-(2-methylpyrimidin-4-yl)-4-piperidylmethyl]piperazine trihydrochloride (625 mg) and triethylamine (1.04 ml) in dichloromethane (20 ml) at 0° C. The solution was stirred at ambient temperature for 18 hours. The solution was diluted with dichloromethane and washed with water, dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 1-2% methanol in dichloromethane. Filtration from ether gave 1-(4-trifluoromethylphenylsulphonyl)-4-[1-(2-methylpyrimidin-4-yl)-4-piperidyimethyl]piperazine (358 mg), as a solid, mp 135-136° C.
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=[O:8])=CC=1.[Br:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[C:24]3[S:25][CH:26]=[CH:27][N:28]=3)[CH:21]=2)[N+:16]([O-])=[CH:15][CH:14]=1>ClCCl.C([O-])([O-])=O.[Na+].[Na+].O>[Br:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[C:24]3[S:25][CH:26]=[CH:27][N:28]=3)[CH:21]=2)[NH:16][C:15](=[O:8])[CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: [O-][n+]1ccc(Br)c2cc(C(c3ccc(Cl)cc3)c3nccs3)ccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=c1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3nccs3)ccc2[nH]1
Reaction time: 1 h

Procedure:
p-Toluenesulfonyl chloride (628 mg, 3.293 mmol, 1.5 equip) was added to a biphasic mixture of 4-bromo-6-((4-chlorophenyl)(thiazol-2-yl)methyl)quinoline 1-oxide in dichloromethane (6 mL) and 10% Na2CO3 (42 mL) and the resulting mixture stirred for 1 h. The reaction mixture was diluted with dichloromethane and water, the layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by MPLC to yield 4-bromo-6-((4-chlorophenyl)(thiazol-2-yl)methyl)quinolin-2(1H)-one as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[N:3]=1.COC1C=C(C=CC=1OC)C=O.FC(F)(F)C(O)=O.C(C1C=CC(N[CH:43]([C:59]2[CH:64]=[C:63]([O:65][CH3:66])[C:62]([O:67][CH3:68])=[CH:61][C:60]=2F)[C:44]2NC(=O)N(C3C=CC=CC=3C(O)=O)[N:45]=2)=CC=1)(=N)N.C[Si](C#N)(C)C.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3]>ClCCl.C(OCC)(=O)C>[CH3:66][O:65][C:63]1[CH:64]=[C:59]([CH:43]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([C:4]3[N:3]=[C:2]([CH3:1])[O:6][N:5]=3)=[CH:8][CH:9]=2)[C:44]#[N:45])[CH:60]=[CH:61][C:62]=1[O:67][CH3:68]
Reactant: COc1cc(F)c(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)cc1OC
Reactant: Cc1nc(-c2ccc(N)cc2)no1
Agent: COc1ccc(C=O)cc1OC
Agent: C[Si](C)(C)C#N
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C(C#N)Nc2ccc(-c3noc(C)n3)cc2)cc1OC
Temperature: 25 °C
Reaction time: 22 h

Procedure:
After adding 0.887 g of 4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamine, 0.831 g of 3,4-dimethoxybenzaldehyde, 1g of MS3A and 1 ml of trimethylsilyl cyanide to a solution of 0.31 g of Yb(OTf)3 in 20 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred at room temperature for 22 hours. After then adding 200 ml of ethyl acetate to the reaction mixture, it was filtered through celite and the celite was washed with 200 ml of ethyl acetate. The organic layers were combined and washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (1.75 g) as a light yellow solid.