Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[CH:6][C:7]2[N:8]([CH2:17][C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[Cl:25])[C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[N-:26]=[N+:27]=[N-:28].[Na+]>C(O)C.C(Cl)Cl>[N:26]([CH2:3][C:4]1[N:5]=[CH:6][C:7]2[N:8]([CH2:17][C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[Cl:25])[C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:27]=[N-:28]
Reactant: ClCc1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: [N-]=[N+]=NCc1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
A suspension of 3-chloromethyl-9-(2,5-dichlorobenzyl)-9H-β-carboline hydrochloride (5.64 g, 15 mmol) and sodium azide (2.0 9, 30 mmol) in anhydrous ethanol (60 mL) was refluxed under nitrogen for 15 hours. The resulting suspension was cooled to room temperature, diluted with an equal volume of CH2Cl2, and washed with water (2×50 mL) and brine (2.5 mL), respectively. The organic extract was dried over anhydrous Na2SO4 and concentrated to give 5.70 grams (100%) of 3-azidomethyl-9-(2,5-dichlorobenzyl)-9H-β-carboline as a pale yellow solid. 1H NMR (CDCl3) δ8.75 (s, 1H), 8.20 (d, J=7.4 Hz, 1H), 8.04 (s, 1H), 7.58 (t,J=7.5 Hz, 1H), 7.32-7.40 (m, 3H), 7.20 (dd, J=9.6, 2.5 Hz, 1H), 6.53 (d, J=2.3 Hz,1H), 5.52 (s, 2H), 4.20 (s, 2H); MS monoisotopic mass (calculated) 381.1, MH+ (observed) 382.0, (MH+−N2) 354.2.
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:23][CH:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:24])[C:14](=[O:25])[CH:13]1[CH:9]([CH2:10][CH:11]([O:26][C:27]3[C:36]4[C:31](=[CH:32][C:33]([O:37][CH3:38])=[CH:34][CH:35]=4)[N:30]=[C:29]([C:39]4[N:40]=[C:41]([NH:44][CH:45]([CH3:47])[CH3:46])[S:42][CH:43]=4)[CH:28]=3)[CH2:12]1)[C:8](=[O:48])[NH:7]2)=[O:5])C.[Li+].[OH-].C(O)(=O)C.C1(C)C=CC=CC=1>C1COCC1.CO.O.C(Cl)(Cl)Cl>[CH:45]([NH:44][C:41]1[S:42][CH:43]=[C:39]([C:29]2[CH:28]=[C:27]([O:26][CH:11]3[CH2:10][CH:9]4[CH:13]([C:14](=[O:25])[N:15]([CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][CH:22]5[C:6]([C:4]([OH:5])=[O:3])([NH:7][C:8]4=[O:48])[CH2:23]5)[CH2:12]3)[C:36]3[C:31](=[CH:32][C:33]([O:37][CH3:38])=[CH:34][CH:35]=3)[N:30]=2)[N:40]=1)([CH3:47])[CH3:46]
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(-c4csc(NC(C)C)n4)nc4cc(OC)ccc34)CC1C(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3csc(NC(C)C)n3)nc2c1
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 99.6 %

Procedure:
To the solution of the ester 109 (21 mg, 0.031 mmol) in a mixture of THF (0.2 ml) and methanol (0.3 ml) was added solution of LiOH (4 mg, 0.17 mmol) in 0.15 ml water. The resulting mixture was stirred at 60° C. for 3.5 h. After cooling to room temperature, acetic acid was added (30 eq). The mixture was co-evaporated with toluene. The residue was distributed between chloroform and water, the water phase was extracted with chloroform 3 times, the organic phases were combined, dried over sodium sulphate and evaporated which gave 20 mg of pure product (yield 99%).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[I:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12].C1C=CC=CC=1>O1CCCC1>[CH:1]1([NH:7][C:11](=[O:12])[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[I:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccccc1I
Reactant: NC1CCCCC1
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)c1ccccc1I

Procedure:
In accordance with the procedure of Example 3, 12.1 g of cyclohexylamine was reacted with 8.0 g of o-iodobenzoyl chloride in 20 ml of tetrahydrofuran. There was obtained by recrystallization from benzene 5.7 g of fine white crystals of N-cyclohexyl-o-iodobenzamide, m.p. 148°-149°, Rf 0.74.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]([O:10][C@@H:11]1[C@@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:27]([O:33][C:34](=[O:36])[CH3:35])[CH2:26][S:25][CH:12]1[O:13][C:14]1[C:15]2[N:16]([CH:20]=[C:21]([CH2:23]Cl)[N:22]=2)[CH:17]=[CH:18][CH:19]=1)(=[O:9])[CH3:8].CO[CH2:39][CH2:40]OC>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:7]([O:10][C@@H:11]1[C@@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:27]([O:33][C:34](=[O:36])[CH3:35])[CH2:26][S:25][C@H:12]1[O:13][C:14]1[C:15]2[N:16]([CH:20]=[C:21]([CH2:23][C:40]3[CH:39]=[CH:27][CH:28]=[CH:11][CH:12]=3)[N:22]=2)[CH:17]=[CH:18][CH:19]=1)(=[O:9])[CH3:8]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)CSC(Oc2cccn3cc(CCl)nc23)[C@@H]1OC(C)=O
Reactant: COCCOC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccn2cc(Cc3ccccc3)nc12
Temperature: 120 °C
Yield: 42 %

Procedure:
A solution of 0.108 g (1.02 mM) of sodium carbonate in 2 ml of water, 0.055 g (0.0678 mM) of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) dichloromethane and 0.277 g (1.35 mM) of 4,4,5,5-tetramethyl-2-phenyl-1,2,3-dioxaborolane are added to a solution of 0.31 g (0.678 mM) of 2-chloromethylimidazo[1,2-α]pyridin-8-yl 2,3,4-tri-O-acetyl-5-thio-D-xylopyranoside obtained according to example 31, in 4 ml of DME. The reaction mixture is microwave-heated at 120° C. for 30 minutes. After cooling, water is added and the resulting mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and is concentrated under reduced pressure. The evaporation residue is purified by silica gel chromatography, elution being carried out with a dichloromethane/methanol mixture (97/3; v/v), and then crystallized from ether. The expected product is obtained in the form of a white solid with a yield of 42%.
Reaction SMILES: [BH4-].[Na+].CCO.[CH3:6][N:7]1[N:11]=[N:10][C:9]([N:12]=[CH:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=2)=[N:8]1.[NH4+].[Cl-]>O>[F:23][C:20]([F:21])([F:22])[C:18]1[CH:19]=[C:14]([CH:15]=[C:16]([C:24]([F:26])([F:27])[F:25])[CH:17]=1)[CH2:13][NH:12][C:9]1[N:10]=[N:11][N:7]([CH3:6])[N:8]=1
Reactant: Cn1nnc(N=Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cn1nnc(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaBH4 (1.2 g, 64 mmol) is added portionwise slowly to an EtOH (100 mL) solution of crude 2-methyl-N-[3,5-bis(trifluoromethyl)phenylmethylene]-2H-tetrazole-5-amine at 0° C., and the mixture is stirred at room temperature for 1 hour. After addition of sat. NH4Cl aq. and water at 0° C., the mixture is extracted with EtOAc. The combined organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated The residue is purified by silica gel column chromatography chromatography to give N-[3,5-bis(trifluoromethyl)benzyl]-N-(2-methyl-2H-tetrazol-5-yl)amine as a white crystalline solid.
Reaction SMILES: [O:1]=[O+][O-].[C:4]1([CH:10]([O:17][C:18](=[O:50])[CH:19]([N:23]2[CH:26]([S:27][S:28][C:29]3[S:30][C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)[CH:25]([NH:38][C:39](=[O:48])[CH2:40][O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:24]2=[O:49])[C:20](=C)[CH3:21])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(OCC)(=O)C>[C:11]1([CH:10]([O:17][C:18](=[O:50])/[C:19](/[N:23]2[CH:26]([S:27][S:28][C:29]3[S:30][C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)[CH:25]([NH:38][C:39](=[O:48])[CH2:40][O:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:24]2=[O:49])=[C:20](\[OH:1])/[CH3:21])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C=C(C)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2ccccc2s1
Reactant: O=[O+][O-]
Solvent: CCOC(C)=O
Product: C/C(O)=C(/C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1 equivalent of ozone (diluted with oxygen) is passed into a solution, cooled to -70° C., of 681 mg (1.0 mM) of 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyric acid diphenylmethyl ester in 30 ml of ethyl acetate. The reaction solution is allowed to warm up, concentrated to 10 ml in vacuo, mixed with 1.0 ml of dimethyl sulphide and stirred for 15 hours at room temperature. Solvent and excess reagent are removed in vacuo and the residue is chromatographed on 30 g of acid-washed silica gel, using toluene/ethyl acetate, 4:1 (15 ml fractions). 2-[4-(Benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin- 1-yl]-3-hydroxy-crotonic acid diphenylmethyl ester is obtained as a solid amorphous substance. [α]D = 130° ± 1° (CHCl3 ; c= 0.8) IR spectrum (CH2Cl2): 2.95, 5.60, 5.92, 6.04 and 8.10 μ.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:16]3[CH:15]=[CH:14][NH:13][C:12](=[O:17])[C:11]=3[C:10]([C:18]3[CH:19]=[C:20]([C:23]([O:25]C)=[O:24])[S:21][CH:22]=3)=[N:9]2)=[CH:5][CH:4]=1.CO.C1COCC1.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16]3[CH:15]=[CH:14][NH:13][C:12](=[O:17])[C:11]=3[C:10]([C:18]3[CH:19]=[C:20]([C:23]([OH:25])=[O:24])[S:21][CH:22]=3)=[N:9]2)=[CH:27][CH:28]=1
Reactant: COC(=O)c1cc(-c2nn(Cc3ccc(OC)cc3)c3cc[nH]c(=O)c23)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Cn2nc(-c3csc(C(=O)O)c3)c3c(=O)[nH]ccc32)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
A mixture of methyl 4-(1-(4-methoxybenzyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylate (46.5 mg) obtained in Example 113 in a mixed solvent of methanol (2 mL)/THF (2 mL)/water (2 mL) was added 8 M aqueous sodium hydroxide solution (0.037 mL) at 0° C. The reaction mixture was stirred at 90° C. for 2 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.1 N hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (40.8 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([CH2:10]Br)[C:6]=2[CH:12]=1.CN(C)C([N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1)=O.N>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([CH2:10][N:19]3[C:20]([CH3:22])=[CH:21][N:17]=[CH:18]3)[C:6]=2[CH:12]=1
Reactant: Cc1cn(C(=O)N(C)C)cn1
Reactant: Clc1ccc2onc(CBr)c2c1
Agent: N
Solvent: CC#N
Product: Cc1cncn1Cc1noc2ccc(Cl)cc12
Reaction time: 1 h

Procedure:
A solution containing 5-chloro-3-bromomethyl-1,2-benzisoxazole (2.5 g, 0.010 mole) and 1-dimethylcarbamoyl-4-methyl-imidazole (1.84 g, 0.012 mole) in anhydrous acetonitrile (25 mL) is stirred at reflux for 72 hours. The solution is cooled to 5° C. (ice-bath) and ammonia gas is bubbled through the solution for 5 minutes after which the solution is allowed to stand at ambient temperature for 1 hour. The solvent is evaporated and the residue is taken up in methylene chloride (25 mL). This solution is washed with water (2×20 mL), dried over anhydrous sodium sulphate, filtered and evaporated to give 5-chloro-3-[(5-methyl-1H-imidazol-1-yl)-methyl]-1,2-benzisoxazole as an oil. A solution of this product in acetone is treated with a slight excess of ethereal hydrogen chloride to afford the hydrochloride salt, m.p. 245-247° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[O:12]1[C:16]2([CH2:21][CH2:20][C:19](B(O)O)=[CH:18][CH2:17]2)[O:15][CH2:14][CH2:13]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCOCC1>[O:12]1[C:16]2([CH2:21][CH2:20][C:19]([C:2]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=3)=[CH:18][CH2:17]2)[O:15][CH2:14][CH2:13]1
Reactant: COC(=O)c1ccc(Br)nc1
Reactant: OB(O)C1=CCC2(CC1)OCCO2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(C2=CCC3(CC2)OCCO3)nc1
Temperature: 80 °C

Procedure:
Methyl 6-bromonicotinate (2.11 g, 9.78 mmol), 1,4-dioxaspiro[4,5]dec-7-en-8-ylboronic acid (2 g, 10.86 mmol), palladium(II) acetate (109 mg, 0.48 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.40 g, 0.97 mmol) and potassium phosphate (6.2 g, 29.1 mmol) were placed in a Schlenk tube and the tube was placed under vacuum and filled with argon. Dioxane (30 mL) and water (4 mL) were added and the tube was heated (80° C.) overnight. The mixture was partitioned with ether and water and the organic phase was washed with brine, dried (magnesium sulfate), filtered and evaporated. The residue was purified by silica gel chromatography using 30% ethyl acetate in hexanes to provide the title compound as a slightly yellow oil, which solidified upon standing.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19]CC)=[O:18])=[CH:12][CH:11]=1)=[O:5])C.[OH-].[K+]>>[C:4]([C:6]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:7]=1[CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:14][CH:15]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)Cc1ccc(OCc2ccc(F)cc2C(=O)OCC)cc1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)Cc1ccc(OCc2ccc(F)cc2C(=O)O)cc1

Procedure:
Reaction of ethyl 4-(2-ethoxycarbonyl-4-fluorobenzyloxy)phenylacetate with potassium hydroxide as described in Example 1c provides colorless crystals, m.p. 195°-197° C. of 4-(2-carboxy-4-fluorobenzyloxy)phenylacetic acid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13]O.S(Cl)([Cl:17])=O>C(Cl)Cl>[Cl:17][CH2:13][C:3]1[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[N:5][O:6][C:2]=1[CH3:1]
Reactant: O=S(Cl)Cl
Reactant: Cc1onc(-c2ccccn2)c1CO
Solvent: ClCCl
Product: Cc1onc(-c2ccccn2)c1CCl
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To a solution of (5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-methanol (3.0 g, 16 mmol) in DCM (30 mL) at 0° C. was added thionyl chloride (3.75 g, 32 mmol) and the resulting mixture stirred for 1 h and then evaporated. After 1 h the reaction mixture was quenched with a solution of sodium hydrogen carbonate (1N, 15 mL) and extracted with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate, filtered and concentrated to give the title compound (3.2 g, 96%) as a light brown solid. MS: m/e=209.1 [M+H]+.
Reaction SMILES: [C:1]1(S([O-])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Na+].Br[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.[O-2].[Ca+2]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN1CCCC1=O>[C:1]1([C:24]2[C:25]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:21]=[CH:22][CH:23]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=S([O-])c1cccc2ccccc12
Reactant: Brc1cccc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Ca+2]
Solvent: CN1CCCC1=O
Product: c1ccc2c(-c3cccc4ccccc34)cccc2c1
Yield: 64 %

Procedure:
4.28 g (20 mmol) of sodium 1-naphthalenesulfinate, 4.14 g (20 mmol) of 1-bromonaphthalene, 0.0225 g (0.1 mmol) of palladium acetate, 0.0478 g (0.12 mmol) of 1,2-bis(diphenylphosphino)ethane, 6.73 g (120 mmol) of calcium oxide and 60 ml of N-methyl-2-pyrrolidone were placed in a 100 ml round bottom flask and reacted at 150° C. in a nitrogen gas stream for 8 hours. After the completion of the reaction, the reaction mixture was analyzed by means of high performance liquid chromatography. The analysis showed that 12.8 mmol (yield 64%) of 1,1'-binaphthyl was formed in the reaction mixture solution.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1(N[S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])C=CC=CC=1.[CH3:24][O:25][C:26](=[O:41])[C:27]([NH:30][C:31]([C:33]1[C:38]([OH:39])=[CH:37][C:36]([OH:40])=[CH:35][N:34]=1)=[O:32])([CH3:29])[CH3:28]>CO>[CH3:24][O:25][C:26](=[O:41])[C:27]([NH:30][C:31]([C:33]1[C:38]([OH:39])=[CH:37][C:36]([O:40][S:17]([C:20]([F:21])([F:22])[F:23])(=[O:18])=[O:19])=[CH:35][N:34]=1)=[O:32])([CH3:29])[CH3:28]
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Reactant: COC(=O)C(C)(C)NC(=O)c1ncc(O)cc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)C(C)(C)NC(=O)c1ncc(OS(=O)(=O)C(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 40 h
Yield: 36 %

Procedure:
To a solution in 2-[(3,5-dihydroxy-pyridine-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester, 18, (0.312 g, 1.23 mmol) in MeOH (10 mL) containing diisopropylethylamine (0.214 mL, 1.23 mmol) at 0° C. under N2 is added N-phenyltrifluoromethanesulfonamide (0.439 g, 1.23 mmol). The reaction is warmed slowly to room temperature and stirred for 40 hours. The solvent is removed under reduced pressure and the crude oil which remains is purified over silica (EtOAc:heptane 1:9) to afford 0.170 g (36% yield) of the desired compound as a yellow oil.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:18]([O-])=O)[C:10]([F:17])=[C:11]([F:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1>C(O)C.CN(C=O)C.[H][H].[C].[Pd]>[NH2:18][C:9]1[C:10]([F:17])=[C:11]([F:16])[C:12]([O:14][CH3:15])=[C:13]2[C:8]=1[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5][N:4]2[CH:1]1[CH2:2][CH2:3]1
Reactant: COc1c(F)c(F)c([N+](=O)[O-])c2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 62.3 %

Procedure:
To a solution of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-5-nitro-4-oxo-3-quinolinecarboxylic acid (322 mg) in ethanol-DMF (4:1) was added 10% palladium-carbon (25 mg) and the mixture was stirred in hydrogen gas atomosphere for 6 hours at room temperature. The catalyst was filtered off and washed with a solution of chloroform-methanol-concentrated aqueous ammonia (10:10:3) The filtrate and washings were combined and concentrated. The residue was recrystallized from a solution of chloroform-methanol-concentrated aqueous ammonia (20:6:1) to give the title compound (183 mg) as yellow prisms, mp 291°-291.5° C. (decompd.).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[O:26][C:27]([C:30]([OH:32])=[O:31])([CH3:29])[CH3:28])/[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH2:18][NH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[C:33]([C:35]1[C:36]([O:44]C(C2C=CC=CC=2)C2C=CC=CC=2)=[N:37][S:38][C:39]=1S(OC)=O)#[N:34].C(N(CC)CC)C.CC(O)=O>CN(C=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[O:26][C:27]([C:30]([OH:32])=[O:31])([CH3:29])[CH3:28])/[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH2:18][NH:19][C:39]4[S:38][N:37]=[C:36]([OH:44])[C:35]=4[C:33]#[N:34])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(O/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CN)CS[C@H]12)c1csc(N)n1)C(=O)O
Reactant: COS(=O)c1snc(OC(c2ccccc2)c2ccccc2)c1C#N
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(O/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CNc3snc(O)c3C#N)CS[C@H]12)c1csc(N)n1)C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 61.9 %

Procedure:
A mixture of 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-aminomethylceph-3-em-4-carboxylic acid (900 mg) and methyl 4-cyano-3-diphenylmethoxyisothiazol-5-sulphinate (800 mg) in solution in DMF (15 ml) containing 1 ml triethylamine was stirred at ambient temperature for five hours. The mixture was neutralised with HOAc and evaporated. The residue was purified by HPLC eluting with a 70/30 v/v mixture of methanol and water, and then with methanol to yield 700 mg of the desired product, nmr in solvent A 1.5 (s, 6 H); 3.8-4.1 (m, 2 H); 4.1-4.3 (m, 2 H); 5.15 (d, 1 H); 5.85 (d, 1 H); 7.0 (s, 1 H); 7.2-7.6 (m, 10 H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.Cl[CH2:45][C:46]1[N:51]=[CH:50][CH:49]=[CH:48][N:47]=1.BrCC1OC(C(F)(F)F)=CC=1>>[N:47]1[CH:48]=[CH:49][CH:50]=[N:51][C:46]=1[CH2:45][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: ClCc1ncccn1
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2ncccn2)c2ccccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 2-(chloromethyl)pyrimidine to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, (pyrimidin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (84%) as a colorless solid: mp 203-205° C.; 1H NMR (300 MHz, CDCl3) δ8.68 (d, J=4.9 Hz, 2H), 7.24-7.15 (m, 3H), 7.03 (dd, J=7.5, 7.5 Hz, 1H), 6.75 (s, 1H), 6.73 (d, J=7.7 Hz, 1H), 6.42 (s, 1H), 5.22 (ABq, 2H), 4.89 (ABq, 2H), 4.53 (t, J=8.6 Hz, 2H), 3.07-2.93 (m, 2H) 13C NMR (75 MHz, CDCl3) δ178.0, 164.6, 161.6, 161.1, 157.4, 142.2, 132.9, 128.4, 123.7, 123.2, 120.5, 119.7, 119.7, 119.4, 108.7, 93.0, 80.5, 72.2, 57.7, 45.7, 29.0; MS (ES+) m/z 372.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[NH2:33][C:34]1([C:40]([OH:42])=[O:41])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[NH2:33][C:34]1([C:40]([OH:42])=[O:41])[CH2:39][CH2:38][N:37]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][C:4]=3[C:29]([F:32])([F:31])[F:30])[N:8]=[CH:9]4)[C:18](=[O:26])[N:19]=2)[CH2:36][CH2:35]1
Reactant: NC1(C(=O)O)CCNCC1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: NC1(C(=O)O)CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
4-Amino-1-{5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}piperidine-4-carboxylic acid was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and 4-amino-piperidine-4-carboxylic acid following General Procedure B.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10](=[O:12])[N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C1CNCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To 1.00 g (4.33 mmol) of (S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanoic acid was added 750 mg (8.66 mmol) of piperazine, 20 mL of DCM, 1.34 g (6.5 mmol) of DCC and 17.9 mL (12.99 mmol) of TEA. This was allowed to stir overnight at room temperature. The next morning, it was diluted with more DCM, and filtered. The filtrate was concentrated and purified in the ISCO using a 40 gram column and eluting with 0-10% MeOH/DCM to obtain the desired product in 79% yield.