Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].C(N(CC)CC)C.[Cl:13][C:14]1[N:15]=[C:16]([C:20](Cl)(Cl)Cl)[NH:17][C:18]=1[Cl:19]>C(O)C>[Cl:13][C:14]1[N:15]=[C:16]([C:20]2[S:4][C:3]([NH2:5])=[N:2][N:1]=2)[NH:17][C:18]=1[Cl:19]
Reactant: NNC(N)=S
Reactant: Clc1nc(C(Cl)(Cl)Cl)[nH]c1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1nnc(-c2nc(Cl)c(Cl)[nH]2)s1
Temperature: 50 °C
Yield: 76.2 %

Procedure:
9.1 g (0.1 mol) of thiosemicarbazide and 40.4 g (0.4 mol) of triethylamine were stirred in 200 ml of ethanol until a clear solution had formed. 25.4 g (0.1 mol) of 4,5-dichloro-2-trichloromethyl-imidazole were added to this solution incrementally at 0°-5° C., while stirring. The mixture was stirred for a further 1 hour with cooling, for 1 hour at room temperature and for 1 hour at 50° C. After cooling, the amine-hydrochloride was filtered off and the filtrate was evaporated in vacuo. The residue was treated with water, the mixture was acidified with hydrochloric acid and the product was filtered off, washed with water and dried. 18 g (76.5% of theory) of 2-(4,5-dichloro-imidazol-2-yl)-5-amino-1,3,4-thiadiazole were obtained. Melting point: 147° C. (with decomposition) (from ethyl acetate/ligroin).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:9]=2[CH3:18])[C:5]2[CH:19]=[C:20]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:21]=[C:22]([C:23](OC)=[O:24])[C:4]=2[N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:15])[F:17])[C:9]=2[CH3:18])[C:5]2[CH:19]=[C:20]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[CH:21]=[C:22]([CH2:23][OH:24])[C:4]=2[N:3]=1
Reactant: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C)n2Cc1cccc(C(F)(F)F)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Cn2c(C)nc3c(CO)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A solution of methyl 2-methyl-1-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-1H-benzimidazole-4-carboxylate, prepared as described in Example 30 (0.37 g, 0.827 mmol) in Tetrahydrofuran (THF) (10 mL) was cooled to 0° C. LiAlH4 (0.038 g, 1 mmol) in THF (3 mL) was added in and the reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was quenched with water (0.04 mL), NaOH (15%, 0.04 mL) then water (0.12 mL). Anhydrous MgSO4 was added and the reaction mixture was filtered through celite and washed with EtOAc. Evaporation of the solvent gave the crude product. The crude product was purified on a silica column (1˜4% MeOH/DCM) to give the solid (0.32 g, 88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.35 (s, 3H), 2.56 (s, 3H), 2.99-3.07 (m, 4H), 3.67-3.76 (m, 4H), 4.87 (d, J=5.81 Hz, 2H), 5.11 (t, J=5.68 Hz, 1H), 5.51 (s, 2H), 6.30 (d, J=7.83 Hz, 1H), 6.81 (d, J=2.27 Hz, 1H), 6.97 (d, J=2.02 Hz, 1H), 7.24 (t, J=7.83 Hz, 1H), 7.60 (d, 1H). MS(ES+) m/z 420.1 [M+H]+.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1.Cl>O.CN(C)C=O>[SH:7][C:4]1[S:3][C:2]([S:1][CH2:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[N:6][N:5]=1
Reactant: Sc1nnc(S)s1
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc(CSc2nnc(S)s2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.2 %

Procedure:
To a mixture of 1.5 g of 2,5-dimercapto-1,3,4-thiadiazole, 2.76 g of anhydrous potassium carbonate and 10 ml of N,N-dimethylformamide was added 1 g of p-(bromomethyl)benzoic acid followed by stirring at room temperature for 3 hours. The reaction mixture was diluted with 30 ml of water, made acidic with diluted hydrochloric acid and, extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was applied to silica gel column chromatography. Elution with a mixture of toluene-ethyl acetate (1:1) gave 400 mg of p-[(5-mercapto-1,3,4-thiadiazol-2-yl)thiomethyl]benzoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[H-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C.O>[CH2:12]([N:1]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(N)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(Cc2ccccc2)Cc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.6 %

Procedure:
To a solution of 5-amino-pyridine-2-carbonitrile (37) (800 mg, 6.72 mmol) in DMF (8 mL) was added NaH (60%) (806 mg, 20.2 mmol) portion wise at 0° C. Benzyl bromide (2.3 mL, 20.2 mmol) was subsequently added and the mixture allowed to stir at rt for 3 h. The reaction mixture was diluted with water (20 mL), extracted with EtOAc (2×50 mL), the combined organic layers were washed with brine (20 mL), dried (Na2SO4) and evaporated. The crude compound was purified by silica gel column chromatography (100-200 mesh, eluted with 30% EtOAc/pet-ether) to obtain compound 38 (1.3 g, 65%) as a pale yellow solid. Rf: 0.7 (10% MeOH/CHCl3); (m/z): 300 [MH]+; 1H NMR (400 MHz, DMSO-d6): δ 8.14 (1H, d, J=2.8 Hz), 7.65 (1H, d, J=9.2 Hz), 7.37-7.25 (10H, m), 7.08 (1H, dd, J=3.6, 9.6 Hz), δ 4.88 (4H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][N:18]=[CH:17]2>O>[NH:19]1[C:20]2[C:16](=[CH:15][C:14]([N:13]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]3=[O:11])=[CH:22][CH:21]=2)[CH:17]=[N:18]1
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: Nc1ccc2[nH]ncc2c1
Solvent: O
Product: O=C1Nc2ccc(F)cc2C1=Nc1ccc2[nH]ncc2c1
Yield: 44.2 %

Procedure:
The title compound (62 mg, 43%) was synthesized as a brick red solid (instead of stirring at it, 1 mL of H2O was added to crash out the product) according to the method described for Example A74 using 5-fluoroisatin (82.5 mg, 0.5 mmol), 5-aminoindazole (66.5 mg, 0.5 mmol). 1H NMR indicated a 3:1 mixture of E/Z isomers. 1H NMR (400 MHz, DMSO-d6) δ 13.22 (s, 1H), 11.00 (s, 1H), 8.10 (s, 1H), 6.67 (d, J=8.8 Hz, 1H), 7.39 (s, 1H), 7.22 (dt, J=9.2 Hz, 2.4 Hz, 1H), 7.10 (dd, J=8.8 Hz, 1.6 Hz, 1H), 6.90 (dd, J=8.8 Hz, 4.4 Hz, 1H), 6.14 (dd, J=8.8 Hz, 2.8 Hz, 1H); MS ESI 281.0 [M+H]+, calcd for [C15H9FN4O+H]+ 281.1.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[N:2]1.S(Cl)([Cl:13])(=O)=O>ClC1C=CC=CC=1>[Cl:13][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][N:2]=1
Reactant: c1ccc2sncc2c1
Reactant: O=S(=O)(Cl)Cl
Solvent: Clc1ccccc1
Product: Clc1nsc2ccccc12
Yield: 95.8 %

Procedure:
In a 300 ml four-necked flask equipped with a stirrer, a thermometer, and a condenser, 100 g of monochlorobenzene was placed in advance, to which 27.0 g (0.2 mol) of 1,2-benzisothiazole was added under nitrogen atmosphere. 32.4 g (0.22 mol) Of sulfuryl chloride was added dropwise thereto while stirring at a temperature of from 70° to 80° C. and allowed to react for 1 hour at the same temperature. After the termination of the reaction, the reaction mixture was subjected to distilling off of the solvent and then to distillation under reduced pressure to give 32.5 g of 3-chloro-1,2-benzisothiazole (boiling point: 116° to 118° C./5 mm Hg, melting point: 38° to 40° C.). The yield was 96% to the 1,2-benzisothiazole.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[O:10][C:9](=[O:19])[C:8]=2[CH:20]=1)(=[O:3])[CH3:2].[CH2:21](O)[CH2:22][OH:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:18][O:17][C:13]1[CH:12]=[C:11]2[C:16]([C:7]3[CH:6]=[CH:5][C:4]([C:1]4([CH3:2])[O:23][CH2:22][CH2:21][O:3]4)=[CH:20][C:8]=3[C:9](=[O:19])[O:10]2)=[CH:15][CH:14]=1
Reactant: OCCO
Reactant: COc1ccc2c(c1)oc(=O)c1cc(C(C)=O)ccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COc1ccc2c(c1)oc(=O)c1cc(C3(C)OCCO3)ccc12
Yield: 60.7 %

Procedure:
The compound from Step E (5.2 g, 19 mmol), ethylene glycol (4.4 g, 71 mmol) and a catalytic amount of p-toluenesulfonic acid (0.2 g) were dissolved in benzene (300 mL) and refluxed for 28 h. The solvent was removed and the crude product chromatographed on silica gel with hexane/ethyl acetate (2:1) to yield 3.6 g (60%) of the title compound. 1H-NMR (400 MHz, CDCl3) δH 1.75 (3H, s, CH3), 3.82 (2H, t, OCH2), 3.91 (3H, s, OCH3), 4.10 (2H, t, OCH2), 6.93 (1H, s, ArH), 6.98 (1H, d, ArH), 7.47 (3H, m, ArH), 8.04 (1H, s, ArH).
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[CH:16]=O.C([O-])(=O)C.[Na+].Cl.[NH2:24][OH:25]>O>[CH3:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[CH:16]=[N:24][OH:25]
Reactant: COc1ccc2ccccc2c1C=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc2ccccc2c1C=NO
Yield: 97.7 %

Procedure:
To 400 ml of ethanol and 180 ml of water were added 80 g (0.43 mole) of 2-methoxy-1-naphthaldehyde, 66 g (0.81 mole) of sodium acetate and 35.5 g (0.51 mole) of hydroxylamine hydrochloride, and the mixture was refluxed by heating for 2 hours. After the reaction, the reaction mixture was added to 1 liter of water. The precipitated crystals were collected by filtration to obtain 85 g (0.42 mole) of 2-methoxy-1-naphthaldoxime.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1>O.C(O)C.[Fe]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[CH2:5][S:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1
Reactant: Cc1cc(C)cc(CSc2ccc([N+](=O)[O-])cc2)c1
Agent: [Fe]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)cc(CSc2ccc(N)cc2)c1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
A mixture of 4-(3,5-dimethyl-benzylsulfanyl)-nitrobenzene (0.35 g, 1.28 mmol) calcium chloride (0.071 g, 0.64 mmol) and iron powder (−325 mesh) (0.573 g, 10.3 mmol) in 4 ml water and 17 ml ethanol was heated at reflux under nitrogen for 4.5 h. The reaction mixture was then cooled to room temperature, filtered through Celite and the filtrate was concentrated under reduced pressure. The residual oil was purified by column chromatography, eluting with 9:1 hexane/ethyl acetate to yield the title compound as a yellowish oil (0.29 g, 91% yield). MS: 244.3 (M+1)
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:5][O:6][CH3:7])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:16][Si:17](Cl)([CH3:19])[CH3:18]>ClCCl>[CH3:1][C:2]([CH3:8])([CH2:3][O:4][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH2:5][O:6][CH3:7]
Reactant: COCC(C)(C)CO
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(C)(C)CO[Si](C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1 g of 2,2-dimethyl-3-methoxy-1-propanol was dissolved in 20 ml of dichloromethane. The resultant solution was cooled in ice-water bath to below 5° C., and 1.65 ml of triethyl amine was added thereto. After stirring the mixture 5 minutes, 1.29 ml of trimethylsilyl chloride was added drop-wise to the reaction mixture, and the mixture was stirred in ice-water bath for further 2 hours, and at room temperature for further 1 hour. The reaction mixture was washed with water, and the organic layer separated was dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to give 1.33 g of concentrate. The crude product was purified by column chromatography using petroleum ether as eluent, to give colorless pure compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[C:31](=[O:40])[C:32]([CH3:39])=[CH:33][NH:34]2>>[CH3:39][C:32]1[C:31](=[O:40])[C:30]2[C:35](=[CH:36][CH:37]=[CH:38][C:29]=2[NH:28][C:2]2[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:26][CH:27]=3)[N:3]=2)[NH:34][CH:33]=1
Reactant: Cc1c[nH]c2cccc(N)c2c1=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4[nH]cc(C)c(=O)c34)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate and 5-amino-3-methylquinolin-4(1H)-one (Compound 203A). 1H NMR (DMSO-d6, 400 MHz): δ=1.18 (t, J=7.07 Hz, 6 H), 2.00 (s, 3 H), 3.15-3.25 (m, 2 H), 3.96 (qd, J=7.37, 7.20 Hz, 4 H), 7.16 (d, J=7.83 Hz, 1 H), 7.24 (dd, J=8.59, 2.27 Hz, 2 H), 7.51 (t, J=7.96 Hz, 1 H), 7.61 (d, J=6.82 Hz, 2 H), 7.97 (d, J=5.81 Hz, 1 H), 8.45 (s, 1 H), 8.71 (br. s., 1 H), 9.84 (s, 1 H), 12.01 (d, J=6.06 Hz, 1 H), 14.42 (br. s., 1 H). MS (ES+): m/z 562.13 [MH+] (TOF, polar).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:8][O:9][C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5].[CH3:21][Mg]Br>C1COCC1>[CH:11]1([C:10]2[O:9][N:8]=[C:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[C:4](=[O:5])[CH3:21])[CH2:12][CH2:13]1
Reactant: CON(C)C(=O)c1c(-c2ccccc2)noc1C1CC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1c(-c2ccccc2)noc1C1CC1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
To a solution of 5-cyclopropyl-3-phenyl-isoxazole-4-carboxylic acid methoxy-methyl-amide (4.00 g, 14.7 mmol) in THF (42 mL) cooled to −78° C. was added a solution of methylmagnesium bromide (3 M in diethylether, 9.80 mL, 29.4 mmol) dropwise within 5 min at −78° C. The cooling bath was removed and the reaction mixture was allowed to warm up to room temperature over 2.5 h. The reaction mixture was then re-cooled to −78° C., diluted with a saturated ammonium chloride solution (50 mL), allowed to warm up to room temperature and then diluted with water and extracted with ethyl acetate. The combined organic layers were then washed with brine and then dried over sodium sulphate and evaporated to afford the title compound (3.2 g, 94%) which was obtained as a light yellow solid. MS: m/e=228.3 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N+:12]([O-:14])=[O:13])=[C:8]([CH:11]=1)[CH:9]=O.[C:16](Br)(Br)([Br:18])[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:17][C:16]([Br:18])=[CH:9][C:8]1[CH:11]=[C:4]([O:3][CH:2]([F:15])[F:1])[CH:5]=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1cc(OC(F)F)ccc1[N+](=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(OC(F)F)cc1C=C(Br)Br
Temperature: 25 °C
Reaction time: 6 h
Yield: 131.1 %

Procedure:
To a solution of 5-difluoromethoxy-2-nitrobenzaldehyde (238 mg) and carbon tetrabromide (545 mg) in dichloromethane (5.4 mL) was added dropwise a solution of triphenylphosphine (863 mg) in dichloromethane (3.6 mL) under cooling with ice. The mixture was gradually warmed to room temperature and stirred for 6 hours. The reaction mixture was concentrated under reduced pressure. The residue was suspended in diethyl ether and this resulting mixture was stirred at room temperature for 16 hours. The precipitate was removed by filtration through celite (registered trademark) and washed with diethyl ether. The filtrate was concentrated under reduced pressure to obtain the title compound (536 mg).
Reaction SMILES: [Cl:1][C:2]1[C:23]2[O:22][C:9]3[C:10](=[O:21])[N:11]([C@@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14](O)=[O:15])[CH2:12][C:8]=3[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[N:29][CH:28]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[CH3:24][O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:14](=[O:15])[C@@H:13]([N:11]2[CH2:12][C:8]3[CH2:7][C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:23]=4[O:22][C:9]=3[C:10]2=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])=[N:29][CH:28]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC2=C(Oc3c(Cl)cccc3C2)C1=O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)[C@H](CC(C)C)N2CC3=C(Oc4c(Cl)cccc4C3)C2=O)nc1
Yield: 33.1 %

Procedure:
A solution of (S)-2-(5-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid (100 mg, 0.27 mmol), commercially available 6-aminonicotinic acid methylester (109 mg, 0.71 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (125 mg, 0.66 mmol), and N-hydroxybenzotriazole (HOBt) (88 mg, 0.66 mmol) in methylene chloride (5 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradient elution, afforded 6-[(S)-2-(5-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoyl-amino]-nicotinic acid methyl ester (42 mg, 15%), as a white solid. 1H NMR (DMSO-d6) δ: 11.35 (s, 1H), 8.88 (s, 1H), 8.29 (d, J=8.8 Hz, 1H), 8.15 (d, J=8.8 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.23 (d, J=7.3 Hz, 1H), 7.08-7.16 (m, 1H), 5.10 (d, J=7.3 Hz, 1H), 4.42 (d, J=19.1 Hz, 1H), 4.07 (d, J=18.6 Hz, 1H), 3.86 (s, 3H), 3.83 (br. s., 2H), 1.76-2.02 (m, 1H), 1.69 (t, J=9.3 Hz, 1H), 1.48 (br. s., 1H), 0.87-0.99 (m, 6H).
Reaction SMILES: C([NH:3][CH:4]1[C:12]2[CH:11]=[CH:10][S:9][C:8]=2[C:7](=[O:13])[CH2:6][CH2:5]1)=O.[ClH:14].C(O)C>>[ClH:14].[O:13]=[C:7]1[C:8]2[S:9][CH:10]=[CH:11][C:12]=2[CH:4]([NH2:3])[CH2:5][CH2:6]1
Reactant: O=CNC1CCC(=O)c2sccc21
Agent: Cl
Solvent: CCO
Product: NC1CCC(=O)c2sccc21

Procedure:
In the manner described in Example 36, N-formyl-4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine is hydrolyzed with 2N hydrochloric acid/ethanol to afford 4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine hydrochloride, melting point 230° C. to 232° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C@H:8]2[CH2:10][C@H:9]2[C:11](O)=[O:12])=O)=[CH:4][CH:3]=1.O.[NH2:17][NH2:18]>C(O)C>[NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]2[CH:8]3[CH:9]([C:11](=[O:12])[NH:17][N:18]=2)[CH2:10]3)=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)[C@H]2C[C@H]2C(=O)O)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc(C2=NNC(=O)C3CC23)cc1
Yield: 94.8 %

Procedure:
20 g (97.5 millimoles) of cis-2-(p-aminobenzoyl)-cyclopropanecarboxylic acid, 5.9 g (118 millimoles) of hydrazine hydrate and 100 ml of ethanol are refluxed for 5 hours. After filtering off the product at 10° C. and drying it under reduced pressure at 50° C., 18.6 g (95% of theory) of 2-(p-aminophenyl)-3,4-diaza-bicyclo[4.1.0]-hept-2-en-5-one are obtained as pale yellow crystals, which are identical with the compound from Example 8a.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[Cl:9][C:10]1[N:15]=[C:14]([CH2:16][OH:17])[CH:13]=[CH:12][CH:11]=1.[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[Cl:9][C:10]1[N:15]=[C:14]([CH2:16][O:17][C:2]2[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CSc1nsc(Cl)n1
Reactant: OCc1cccc(Cl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nsc(OCc2cccc(Cl)n2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.3 %

Procedure:
Into 3 g of N,N-dimethylformamide were dissolved 251 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole and 188 mg of 6-chloro-2-pyridylmethyl alcohol, 72 mg of sodium hydride (60% in oil) was added thereto at room temperature, and the reaction mixture was stirred for 30 minutes. The reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 44 mg of 5-(6-chloro-2-pyridylmethyloxy)-3-methylthio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (35)).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][NH:21][C:22](=[O:26])[CH2:23][CH2:24][SH:25])[CH:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:27](Cl)[CH2:28][OH:29]>CN(C)C=O>[N:3]1([CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][NH:21][C:22](=[O:26])[CH2:23][CH2:24][S:25][CH2:27][CH2:28][OH:29])[CH:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: OCCCl
Reactant: O=C(CCS)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CCSCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
105 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) were added, whilst ice-cooling and in an atmosphere of nitrogen, to a solution of 0.76 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-3-mercaptopropionamide (prepared as described in Preparation 3) in 24 ml of dimethylformamide, and the resulting mixture was stirred at room temperature for 30 minutes. At the end of this time, 0.16 ml of ethylene chlorohydrin were added to the reaction mixture, whilst ice-cooling. The reaction mixture was stirred at room temperature for 15 minutes, after which it was poured into ice-water and extracted with ethyl acetate. The extract was concentrated by evaporation under reduced pressure, and the residue thus obtained was purified by column chromatography through silica gel, using a 1:9 by volume mixture of methanol and methylene chloride as the eluent, to give 0.56 g of the title compound as an oil in a 65% yield.
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][C:12]([C:16](Cl)=[O:17])=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH:19]([N:22]([CH:25]([CH3:27])C)CC)([CH3:21])C.N1CCCC1>C(#N)C>[N:22]1([C:16]([C:12]2[CH:13]=[CH:14][C:15]3[C:2](=[O:1])[C:3]4[C:8]([O:9][C:10]=3[CH:11]=2)=[CH:7][CH:6]=[CH:5][CH:4]=4)=[O:17])[CH2:19][CH2:21][CH2:27][CH2:25]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)c1ccc2c(=O)c3ccccc3oc2c1
Solvent: C1CCNC1
Solvent: CC#N
Product: O=C(c1ccc2c(=O)c3ccccc3oc2c1)N1CCCC1
Reaction time: 2 h

Procedure:
9-oxo-9H-xanthene-3-carboxylic acid (9 g, 37.4 mmol) was added to thionyl chloride (28 mL, 334 mmol). The mixture was refluxed for 5 h. At that time, the thionyl chloride was removed under vacuum and the remaining residue was diluted with toluene and concentrated to dryness to give 9-oxo-9H-xanthene-3-carbonyl chloride. A portion of 9-oxo-9H-xanthene-3-carbonyl chloride (0.25 g, 0.96 mmol) was dissolved in acetonitrile (7 mL). Diisopropylethylamine (335 μL, 1.9 mmol) was then added to the mixture with the subsequent addition of pyrrolidine (113 μL, 1.3 mmol). After stirring 2 h, the solvent was concentrated and the residue was purified by reverse phase preparative HPLC, using a gradient of acetonitrile (10%- 90%) in water with trifluoroacetic acid (0.1%) to afford the 3-(pyrrolidine-1-carbonyl)-xanthen-9-one. MS m/z (MH+) 294.1.
Reaction SMILES: [Br:1]C1C=C(C2C(C(Cl)=O)=CC=CC=2)[ClH]C=1.[NH2:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[C:19](Cl)[N:18]=1.[Cl:27][C:28]1[CH:33]=[C:32](Cl)[CH:31]=[CH:30][C:29]=1[C:35]1[C:40]([C:41]2[NH:42][CH:43]=[C:44]([CH3:46])[N:45]=2)=[CH:39][N:38]=[C:37]([NH:47][CH2:48][CH2:49][NH:50]C2N=CC(C#N)=CC=2)[N:36]=1>>[NH2:16][C:17]1[N:18]=[C:19]([NH:50][CH2:49][CH2:48][NH:47][C:37]2[N:36]=[C:35]([C:29]3[CH:30]=[CH:31][C:32]([Br:1])=[CH:33][C:28]=3[Cl:27])[C:40]([C:41]3[NH:42][CH:43]=[C:44]([CH3:46])[N:45]=3)=[CH:39][N:38]=2)[CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24]
Reactant: Cc1c[nH]c(-c2cnc(NCCNc3ccc(C#N)cn3)nc2-c2ccc(Cl)cc2Cl)n1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Product: Cc1c[nH]c(-c2cnc(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc2-c2ccc(Br)cc2Cl)n1

Procedure:
{2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[4-(4-bromo-2-chlorophenyl)-5-(4-methylimidazol-2-yl)pyrimidin-2-yl]amine was prepared from 4-bromo-2-chlorolbenzoyl chloride and 2-amino-6-chloro-3-nitropyridine using the general method for 6-[(2-{[4-(2,4-dichlorophenyl)-5-(4-methylimidazol-2-yl)pyrimidin-2-yl]amino}ethyl)amino]pyridine-3-carbonitrile.