Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](=[CH2:11])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:14])=O>>[C:1]1([C:7](=[CH2:11])[C:8]([Cl:14])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(C(=O)O)c1ccccc1
Reactant: O=S(Cl)Cl
Product: C=C(C(=O)Cl)c1ccccc1

Procedure:
is prepared by treating 2-phenyl-acrylic acid with thionyl chloride to afford 2-phenyl-acryloyl chloride. The latter is subsequently treated with N-methylalanine in dichloromethane according to the following literature: H. P. Ward, E. F. Jenkins J. Org. Chem. 1945, 10, 371-373.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[C:2]1[C:14]([O:16][CH3:17])=[O:15].C([O-])([O-])=O.[Cs+].[Cs+].[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1>CN(C=O)C>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[C:2]2[C:14]([O:16][CH3:17])=[O:15])=[CH:27][CH:26]=1
Reactant: COC(=O)c1[nH]c2ccccc2c1C(=O)OC
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C(=O)OC)n(Cc2ccc(F)cc2)c2ccccc12
Temperature: 90 °C
Reaction time: 2 h
Yield: 34.5 %

Procedure:
A 300 mL RBF was charged with N,N-Dimethylacetamide (DMA) (144 ml) and Acetic Acid (48.1 ml) was degassed with O2 for 5 min. To this was added aniline (2.94 ml, 32.2 mmol), dimethyl but-2-ynedioate (3.96 ml, 32.2 mmol), and Pd(OAc)2 (0.723 g, 3.22 mmol) and the reaction was heated to 115° C. under an atmosphere of O2. After 18 h, the reaction was cooled to ambient temperature, filtered through a pad of celite, diluted with EtOAc and washed with H2O. The organic was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by ISCO (0-50% EtOAc-hexanes: 120 g SiO2) to afford dimethyl 1H-indole-2,3-dicarboxylate (3 g, 12.86 mmol, 39.9% yield) as a yellow solid. The indole was dissolved in DMF (50 mL), treated with Cs2CO3 (6.30 g, 19.33 mmol), 4-Fluorobenzyl chloride (1.929 ml, 16.11 mmol) and KI (5.35 g, 32.2 mmol) and heated to 90° C. After 2 h, the reaction mixture was cooled to ambient temperature and partitioned between EtOAc and sat. aq. NH4Cl. The organic layer was washed with water (5×), brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified on ISCO (0-100% EtOAc-hexanes) to afford dimethyl 1-(4-fluorobenzyl)-1H-indole-2,3-dicarboxylate (3.79 g, 11.10 mmol, 34.5% yield) as a yellow solid. LCMS (m/z) ES+=342 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:17][CH:16]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCN4CCNCC4)cc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCN4CCNCC4)cc3)cc12
Temperature: 70 °C
Reaction time: 24 h
Yield: 11.4 %

Procedure:
To a solution of compound methyl 6-chloro-5-{4-[2-(piperazin-1-yl)ethoxy]phenyl}-1H-indole-3-carboxylate (80 mg, 0.22 mmol) in methanol (8 mL) was added aq. NaOH (2 mL, 1.0 N). The mixture was stirred at 70° C. for 24 hours. The mixture was adjusted to pH 7 and purified by reverse phase HPLC to give the title compound (10 mg, 11% yield) as a white solid. MS (ES+) 400.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 12.00 (s, 1H), 8.35 (s, 1H), 8.05 (s, 1H), 7.95 (s, 1H), 7.60 (s, 1H), 7.35 (d, 2H), 7.00 (m, 2H), 4.10 (m, 2H), 2.90 (m, 4H), 2.70 (m, 2H), 2.60 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1C(=O)C)[CH3:2].ClC1C=CC=C(C(OO)=[O:22])C=1>ClCCl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[OH:22])[CH3:2]
Reactant: CCOc1ccc(C)cc1C(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOc1ccc(C)cc1O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The solution of 14.5 g of 1-(2-ethoxy-5-methylphenyl)ethanone in 800 ml of dichloromethane is admixed with 36.8 g of 3-chloroperbenzoic acid and stirred at room temperature over 72 hours. The reaction mixture is concentrated by evaporation, and the residue is admixed with 400 ml of saturated aqueous sodium thiosulphate solution and extracted with tert-butyl methyl ether (2×800 ml). The organic phases are washed successively with saturated aqueous sodium carbonate solution (1×500 ml) and brine (500 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The residue is taken up in 75 ml of methanol, admixed with 25 ml of ammonia solution (25%) and stirred over 30 minutes. The reaction mixture is concentrated by evaporation, admixed with 0.5 M HCl (200 ml) and extracted with tert-butyl methyl ether (600 ml). The organic phase is washed with brine (500 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a brown solid from the residue by means of flash chromatography (SiO2 60F). Rt=3.89.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])=[N:6][CH:7]=1.Cl.Cl[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][CH2:18][CH:19]3[CH2:20][CH2:21][N:22]([C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)[CH2:23][CH2:24]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])=[N:6][CH:7]=1
Reactant: Clc1ccncc1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ncccc1NCC1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)cn1)c1ncccc1NCC1CCN(c2ccncc2)CC1
Reaction time: 16 h
Yield: 16.3 %

Procedure:
A pressure tube (Aldrich) was charged with N-(5-chloropyridin-2-yl)-3-[(piperidin-4-ylmethyl)amino]pyridine-2-carboxamide (500 mg, 1.45 mmol), 4-chloropyridine hydrochloride (435 mg, 2.90 mmol), triethylamine (293 mg, 2.90 mmol) and EtOH (5 mL), sealed, and placed in a 110° C. bath. After 16 h, the mixture was cooled, concentrated, and the residue purified by column chromatography (SiO2: 5 to 7.5% methanol:methylene chloride) yielding 100 mg (16%) of the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([CH:15]=[CH2:16])[CH:5]=1)C.C(N(CC)CC)C.[C:24]([C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl>[C:24]([C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:36])[NH:1][CH2:2][C:4]2[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:12])=[O:13])=[C:6]([CH:15]=[CH2:16])[CH:5]=2)=[CH:30][CH:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: C=Cc1cc(C(C)N)ccc1NS(C)(=O)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=Cc1cc(CNC(=O)Nc2ccc(C(C)(C)C)cc2)ccc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 39.3 %

Procedure:
N-[4-(1-Amino-ethyl)-2-vinyl-phenyl]-methanesulfonamide (236.7 mg, 0.985 mmol) and triethylamine (274.6 μl, 1.970 mmol, 2 eq) were added in methylene chloride. The reaction mixture was cooled down to 0° C. 4-tert-Butylphenyl isocyanate (192.5 μl, 1.083 mmol, 1.3 eq.) was added into the mixture. The reaction mixture was stirred for 40 min. A reaction solvent was removed in vacuo. The residue was purified with column chromatography (n-Hx:EA=2:1) to yield title compound (155.4 mg, 47%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][CH:29]=[CH:28]3)=[C:5]([C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[N:7][CH:8]=1)#[N:2].F[P-](F)(F)(F)(F)F.[N:41]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:45]2C=CC=CC=2N=N1.CN.CO>CN(C=O)C.CS(C)=O>[C:1]([C:3]1[C:4]([NH:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][CH:29]=[CH:28]3)=[C:5]([C:9]2[CH:10]=[C:11]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([NH:41][CH3:45])=[O:23])=[CH:19][CH:20]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[N:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cncc(-c2cccc(-c3ccc(C(=O)O)cc3)c2)c1Nc1ccc2[nH]ccc2c1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: CNC(=O)c1ccc(-c2cccc(-c3cncc(C#N)c3Nc3ccc4[nH]ccc4c3)c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40.1 %

Procedure:
To a solution of 3′-[5-cyano-4-(1H-indol-5-ylamino)pyridin-3-yl]biphenyl-4-carboxylic acid 134 (40 mg, 0.09 mmol) and BOP (41 mg, 0.09 mmol) in DMF (1 mL) was added methylamine solution in MeOH (2M, 47 uL, 0.09 mmol) followed by TEA (19 uL, 0.14 mmol). The reaction mixture was stirred for 12 h at r.t. The crude reaction mixture was then dissolved in dimethylsulfoxide (DMSO, 1 mL) and purified by reversed phase HPLC to give 16 mg 3′-[5-cyano-4-(1H-indol-5-ylamino)pyridin-3-yl]-N-methyl biphenyl-4-carboxamide 196 (39%). MS: 44.2 (M+H); HPLC retention time: 2.10 min.(a).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C1(N)CCCCC1>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1
Solvent: NC1CCCCC1
Solvent: CC(C)O
Product: O=C(O)CCCc1ccc(-c2ccc(Cl)c(Cl)c2)cc1
Yield: 62 %

Procedure:
Prepared analogous to Example 1 from 4-(3',4'-dichloro-4-biphenylyl)-4-oxo-butyric acid. Yield: 62% of theory. Melting point of the cyclohexylamine salt: 167°-168° C. (from isopropanol).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:24][C:25]2[N:35]=[C:34]3[C:28]([N:29]([CH3:42])[C:30](=[O:41])[CH2:31][CH2:32][N:33]3[CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:27][N:26]=2)=[CH:4][C:5]([F:23])=[C:6]([CH:22]=1)[C:7]([NH:9][C@@H:10]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]1)=[O:8].Cl.C(O)(C(F)(F)F)=O>O1CCOCC1>[Cl:1][C:2]1[C:3]([NH:24][C:25]2[N:35]=[C:34]3[C:28]([N:29]([CH3:42])[C:30](=[O:41])[CH2:31][CH2:32][N:33]3[CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:27][N:26]=2)=[CH:4][C:5]([F:23])=[C:6]([CH:22]=1)[C:7]([NH:9][C@@H:10]1[CH2:14][CH2:13][NH:12][CH2:11]1)=[O:8]
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)N[C@@H]4CCN(C(=O)OC(C)(C)C)C4)cc3Cl)ncc21
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)CCN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)N[C@@H]4CCNC4)cc3Cl)ncc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
tert-butyl (3R)-3-[[5-chloro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-2-fluoro-benzoyl]amino]pyrrolidine-1-carboxylate (Example 324; 175 mg, 0.29 mmol) was dissolved in 1,4-dioxane (5 mL) and 4M HCl(aq) in 1,4-dioxane (10 mL) added. The mixture was stirred at room temperature for 2 hours. TFA (2 mL) was added an the reaction stirred for a further 1 hour. The reaction was concentrated, dissolved in DCM (10 mL) and TFA (3 mL) added. The reaction was stirred at room temperature for 1 hour, concentrated and the residue dissolved in methanol, absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were combined and evaporated and the residue purified by column chromatography (7.5% ammonia in methanol/DCM) to yield the title compound as a white foam (112 mg, 77%).
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][O:23][CH3:24].[CH3:25][O:26][CH2:27][O:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH:31]=[O:32]>CCCCCC.O1CCCC1>[Cl:14][C:15]1[C:16]([O:21][CH2:22][O:23][CH3:24])=[C:17]([CH:31]([C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[O:28][CH2:27][O:26][CH3:25])[OH:32])[CH:18]=[CH:19][CH:20]=1
Reactant: COCOc1ccccc1Cl
Reactant: COCOc1ccccc1C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOc1ccccc1C(O)c1cccc(Cl)c1OCOC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 1.6M solution of n-butyl lithium in hexane (140 ml) was placed in a 1 1 flask and cooled in an ice bath. To this was added with stirring 34 ml of tetramethylethylenediamine and, after a 10 min reaction period, 34.5 g of 1-chloro-2-methoxymethoxybenzene (dropwise over a 30 min period). A pale orange suspension formed and this was stirred for 4 hours continuing the ice bath cooling. A solution of 34.5 g of 2-methoxymethoxybenzaldehyde in 30 ml of tetrahydrofuran was added with stirring and cooling. The reaction was exothermic. When the addition was complete, the mixture was allowed to warm to room temperature and was then quenched carefully with water. The resulting mixture was poured into a mixture of 1 l of ethyl acetate and 500 ml of aqueous ammonium chloride. The phases were separated and the organic phase was extracted twice with water and once with brine, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain a viscous, pale orange oil. This was purified by filtration chromatography, eluting with mixtures of hexane and dichloromethane starting with pure hexane and ending with pure dichloromethane, to obtain 52.2 g (77 percent of theory) of the title compound as a pale yellow oil. The proton and carbon NMR and infrared spectra were consistent with the assigned structure.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH3:21][S:22]SC.O>CCCCCC.O1CCCC1.C(OCC)(=O)C>[C:1]1([N:7]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[N:9]=[C:8]2[S:22][CH3:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-n2cnc3c2CCCC3)cc1
Reactant: CSSC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CSc1nc2c(n1-c1ccccc1)CCCC2
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 74 %

Procedure:
2.36 g (12 mmol) of 1-phenyl-4,5,6,7-tetrahydro-1H-benzimidazole are placed in a 100-ml three-necked flask under nitrogen, 20 ml of tetrahydrofuran are added and then the mixture is cooled to −78° C. 9 ml (14.3 mmol) of a 1.6 N butyllithium solution in hexane are then slowly added. The mixture is stirred at −80° C. for 5 minutes and then the temperature is allowed to rise to −20° C. and the mixture is stirred for a further 45 minutes at this temperature. The reaction medium is then cooled to −80° C. and a solution of 2.24 g (24 mmol) of dimethyl disulphide diluted in 10 ml of tetrahydrofuran is introduced into it dropwise. When the addition is complete, the medium is allowed to return to room temperature. It is then cooled to 0° C. before gently introducing 15 ml of water and then 15 ml of ethyl acetate. The phases are separated and then the aqueous phase is extracted twice with 10 ml of ethyl acetate. The combined organic phases are washed twice with 10 ml of water, once with 5 ml of brine and then dried over MgSO4 and concentrated under vacuum. The crude reaction product is purified on a silica gel using, as eluting solution, a methanol gradient from 1 to 2% in dichloromethane. 2.17 g of 1-phenyl-2-methylthio-4,5,6,7-tetrahydrobenzimidazole are obtained. Yield=74% (m.p.=112° C.).
Reaction SMILES: [CH:1]([CH:3]1[CH:8]([CH3:9])[CH:7]2[CH2:10][CH:4]1[CH:5]=[CH:6]2)=O.[C:11]([CH2:13]C(O)=O)#[N:12].[OH-].[NH4+].CN(C)C=O>C1C=CC=CC=1>[C:11]([CH2:13][CH:1]=[C:3]1[CH:8]([CH3:9])[CH:7]2[CH2:10][CH:4]1[CH:5]=[CH:6]2)#[N:12]
Reactant: N#CCC(=O)O
Reactant: CC1C2C=CC(C2)C1C=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC1C(=CCC#N)C2C=CC1C2
Yield: 75.4 %

Procedure:
A stirred solution of 136 g (1.0 mole) of 2-formyl-3-methylbicyclo[2.2.1]hept-5ene, 91 g (1.05 mol) of cyanoacetic acid, 3 g (0.05 mol) of ammonium hydroxide (58%), 132 ml of dimethylformamide, and 170 ml of benzene was heated to reflux and the water removed with a Dean-Stark trap. The reaction was allowed to continue until the carbon dioxide evolution ceased (approx. 31 hrs). Upon completion, the reaction was cooled and the solvent removed under reduced pressure. The residual oil was distilled under vacuum to give 120 g (75.5% yield) of 2(2-cyanoethylidene)-3-methylbicyclo[2.2.1]hept-5-ene: b.p. 70-80° C/1 mm; nD20 1.5080; ir 3060, 2250, 1460, 1380, 760, 740, 726, 700; nmr 1.15 (3H, d, J=7 Hz, methyl), 4.9-5.5 (1H, m, vinyl H), 5.7-6.1 (2H; m, vinyl H); ms 159.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][NH2:11]>C(#N)C>[CH3:10][NH:11][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccccc1F
Reactant: CN
Solvent: CC#N
Product: CNc1ccccc1C#N
Temperature: 60 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
2-Fluorobenzonitrile (10.0 g, 82.8 mmol) was dissolved in acetonitrile (100 ml), and 40% aqueous methylamine solution (200 ml) was added thereto, followed by stirring at 60° C. overnight. 40% aqueous methylamine solution (100 ml) was further added thereto, followed by stirring at 60° C. for 9 hours. The reaction mixture was concentrated under reduced pressure, then water was added to the resulting residue, the mixture was extracted with chloroform. After the organic layer was dried (over anhydrous magnesium sulfate), the drying agent was filtered off, and the organic layer was concentrated under reduced pressure. The resulting oily substances were purified by silica gel column chromatography (the substances were eluted with an increasing concentration of chloroform from chloroform/hexane=1/2 to chloroform/hexane=1/1) to give the title compound (5.38 g, 49%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](C(O)=O)[CH:6]=[C:5]2[C:15]([OH:17])=[O:16]>[N+](C1C=CC=CC=1)([O-])=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[C:15]([OH:17])=[O:16]
Reactant: O=C(O)c1cc(C(=O)O)c2cc(F)ccc2n1
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)c1ccnc2ccc(F)cc12
Temperature: 25 °C

Procedure:
6-Fluoroquinoline-2,4-dicarboxylic acid (14.2 g) in nitrobenzene (50 ml) was boiled for 30 min in a reaction vessel equipped with a Dean-Stark apparatus. The mixture was cooled to room temperature and the precipitated material triturated with 60-80 petroleum ether (500 ml). The solid precipitated title compound (10.50 g) was collected by filtration and dried in vacuao.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:18][C@H:17]2[C@H:13]([N:14]=[C:15]([N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[S:16]2)[C@@H:12]([F:28])[C@@H:11]1[OH:29])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(Cl)Cl.CCOCC>[Si:1]([O:8][CH2:9][C@H:10]1[O:18][C@H:17]2[C@H:13]([N:14]=[C:15]([N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[S:16]2)[C@@H:12]([F:28])[C:11]1=[O:29])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](F)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Solvent: CCOCC
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)C1=N[C@H]2[C@H](O[C@H](CO[Si](C)(C)C(C)(C)C)C(=O)[C@@H]2F)S1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of tert-butyl ((3aR,5R,6R,7R,7aR)-5-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-6-hydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (9.28 g, 20.6 mmol) in DCM (150 mL) was added DMP (13.1 g, 30.9 mmol). After stirring at room temperature for 1 h the reaction was diluted with Et2O (400 mL). The resulting suspension was filtered through Celite cake, and the filtrate was concentrated to dryness at room temperature. The residue was loaded onto a layered NaHCO3/silica gel plug, and the product was eluted with (EtOAc/hexanes, 1:4), affording tert-butyl ((3aR,5R,7R,7aR)-5-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-6-oxo-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a white crystalline solid (8.96 g, 97%). 1H NMR (400 MHz, CDCl3) δ 6.29 (d, J=7.0 Hz, 1H), 5.09 (dd, J=4.7, 48.4 Hz, 1H), 4.75-4.69 (m, 1H), 4.12-4.05 (m, 2H), 3.96-3.93 (m, 1H), 3.28 (s, 3H), 1.54 (s, 9H), 0.86 (s, 9H), 0.056 (s, 3H), 0.050 (s, 3H).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:28]([OH:30])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:32]=[C:33]([NH2:36])[CH2:34][CH3:35]>>[CH2:34]([C:33]1[N:36]=[C:28]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:8][CH2:7]3)=[O:10])[CH2:12]2)[O:30][N:32]=1)[CH3:35]
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1
Reactant: CCC(N)=NO
Product: CCc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCC(C#N)CC3)C2)n1

Procedure:
100 mg (about 0.153 mmol) of the compound from Example 108A and 27 mg (0.306 mmol) of N′-hydroxypropanimidamide were reacted according to the General Method 2. Yield: 7 mg (10% of theory)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[C@@H:16]([OH:17])[C:15](=[O:18])[N:14]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:13]3[CH:24]=[CH:25][CH:26]=[CH:27][C:12]=3[S:11]2)=[CH:6][CH:5]=1)[CH3:2].C(N(CC)CC)C.[Cl:35][C:36]1[CH:44]=[C:43]([N+:45]([O-:47])=[O:46])[CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39]>C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C@H:10]2[C@@H:16]([O:17][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][C:43]([N+:45]([O-:47])=[O:46])=[CH:44][C:36]=3[Cl:35])[C:15](=[O:18])[N:14]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:13]3[CH:24]=[CH:25][CH:26]=[CH:27][C:12]=3[S:11]2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OC(=O)c2ccc([N+](=O)[O-])cc2Cl)cc1
Yield: 61.3 %

Procedure:
1.04 g of (+)-cis-2-(4-ethoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are dissolved in 20 ml of anhydrous benzene, and 1 ml of triethylamine is added thereto. A solution of 0.62 g of 2-chloro-4-nitrobenzoyl chloride in 2 ml of anhydrous benzene is added to the mixture under stirring, and said mixture is stirred at room temperature for 0.5 hour. After the reaction, the mixture is washed with water, dried and condensed to dryness. The residue is recrystallized from ethanol, whereby 0.94 g of (+)-cis-2-(4-ethoxyphenyl)-3-(2-chloro-4-nitrobenzoyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is obtained as pale yellow needles. Yield: 61%.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[NH:4][C:5]1[CH2:6][S:7][CH2:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11].C12CC(CC1)=CC=2.C12CC(CC1)C=C2>[Pd].C1CCCCC=1>[NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[NH:4][C:5]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][S:7][CH:6]=1
Reactant: COC(=O)C1=C(Nc2ccccc2N)CSC1
Agent: [Pd]
Agent: C1=C2CCC(=C1)C2
Agent: C1=CC2CCC1C2
Solvent: C1=CCCCC1
Product: COC(=O)c1cscc1Nc1ccccc1N
Reaction time: 4 h

Procedure:
Methyl 3-(2-aminoanilino)-2,5-dihydrothiophene-4-carboxylate (2.5 g, 0.001 mol) was added to a flask containing palladium on charcoal catalyst (5%, 200 mg) in cyclohexene (or norbornadiene or norbornylene) (50 ml) and the reaction was heated at reflux with stirring for 4 hours, the reaction being followed by t.l.c.