Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][N:3]=1.[Cl:11]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[OH:8][N:7]=[C:6]([Cl:11])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[N:3][CH:4]=1
Reactant: Cc1ccc(C=NO)cn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(Cl)=NO)cn1

Procedure:
To a stirring mixture of 6-methylnicotinaldehyde oxime (500 mg, 3.67 mmol) in 4 mL DMF at room temperature, was added N-chlorosuccinimide (490 mg, 3.67 mmol) in roughly one tenth portions over 5 min. Additional N-chlorosuccinimide (175 mg, 1.31 mmol) was added after about 4 h. After a total of 6 h, the reaction mixture was diluted with EtOAc, washed with water, saturated aqueous NaCl, dried (Na2SO4) and filtered. The filtrate was passed through a short silica gel column eluted with EtOAc. The eluant was concentrated under vacuum to provide the title compound as a light brown solid. All of this was used in the next step without further purification. HPLC: retention time=0.44 min.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([CH3:12])[C:9]([CH3:11])=[CH:10][C:4]=2[N:3]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCOCC>[CH3:11][C:9]1[C:8]([CH3:12])=[CH:7][C:5]2[NH:6][C:2](/[CH:1]=[CH:13]/[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:3][C:4]=2[CH:10]=1
Reactant: Cc1nc2cc(C)c(C)cc2[nH]1
Reactant: O=Cc1ccccc1
Solvent: CCOCC
Product: Cc1cc2nc(/C=C/c3ccccc3)[nH]c2cc1C
Temperature: 200 °C
Yield: 12.9 %

Procedure:
A mixture of 2,5,6-trimethyl-1H-benzimidazole (1.5 g, 9.4 mmol) and benzaldehyde (5.0 g, 47 mmol) was heated to 200° C. for 3 h in a sealed tube. The reaction mixture was cooled to room temperature and then ether (50 ml) was added. The precipitated solids were collected by filtration to afford 300 mg (13%) of (E)-5,6-dimethyl-2-styryl-1H-benzimidazole as light yellow solids. 1H-NMR (CDCl3) δ: 8.39-8.33 (1H, m), 7.58-7.47 (2H, m), 7.24-7.16 (5H, m), 6.82 (1H, d, J=16.5 Hz), 5.20 (1H, br.s), 2.13 (6H, s).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C:21]1[C:22]([CH2:34][CH:35]=[C:36]([CH3:39])[CH2:37]O)=[C:23]([O:32][CH3:33])[C:24]([CH3:31])=[C:25]2[C:29]=1[C:28](=[O:30])[O:27][CH2:26]2.C(Br)(Br)(Br)[Br:41]>ClCCl>[Br:41][CH2:37][C:36]([CH3:39])=[CH:35][CH2:34][C:22]1[C:21]([OH:20])=[C:29]2[C:25]([CH2:26][O:27][C:28]2=[O:30])=[C:24]([CH3:31])[C:23]=1[O:32][CH3:33]
Reactant: COc1c(C)c2c(c(O)c1CC=C(C)CO)C(=O)OC2
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1c(C)c2c(c(O)c1CC=C(C)CBr)C(=O)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.3 %

Procedure:
Polymer-supported triphenylphosphine (3 mmol/g, 0.5 g) was soaked in dichloromethane (10 mL) for 1 hour 7-Hydroxy-6-(4-hydroxy-3-methyl-but-2-enyl)-5-methoxy-4-methyl-3H-isobenzofuran-1-one 1A (100 mg, 0.36 mmol) and carbon tetrabromide (143 mg, 0.43 mmol) were sequentially added and the mixture was shaken for 1 hour at room temperature. More carbon tetrabromide (143 mg, 0.43 mmol) was added and the mixture was shaken further for 1 hour. The mixture was filtered and the filtrate was concentrated. The residue was chromatographed on silica gel (0% to 60% ethyl acetate/hexanes) to afford 6-(4-bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one 3B as an oil (52 mg, 42%); 1H NMR (300 MHz, CDCl3) δ 1.95 (s, 3H), 2.16 (s, 3H), 3.44 (d, J=7.2 Hz, 2H), 3.78 (s, 3H), 3.98 (s, 2H), 5.21 (s, 2H), 5.68 (t, J=7.2 Hz, 1H), 7.71 (brs, 1H) ppm.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:18][CH3:19])=[C:6]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:26].[Na+]>CO.C(#N)C>[NH2:26][CH:1]([C:4]1[C:5]([O:18][CH3:19])=[C:6]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)[CH3:2]
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1N1CCCC1=O
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: COc1c(C(C)N)cc(Cl)c(C)c1N1CCCC1=O
Temperature: 65 °C

Procedure:
A mixture of 1-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)pyrrolidin-2-one (20 mg, 0.07 mmol), ammonium acetate (55 mg, 0.71 mmol) and sodium cyanoborohydride (9.0 mg, 0.14 mmol) in methanol (0.2 mL) and acetonitrile (0.2 mL) was heated at 65° C. overnight in a sealed tube. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step (11 mg, 50%). LCMS calculated for C14H20ClN2O2 (M+H)+: m/z=283.1. found: 283.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][NH:13][CH2:14][CH2:15][NH:16][CH3:17].C(=O)([O-])[O-].[Na+].[Na+].O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:13]([CH3:12])[CH2:14][CH2:15][NH:16][CH3:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CNCCNC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CNCCN(C)S(=O)(=O)c1ccc(F)cc1

Procedure:
A solution of 4-fluorobenzenesulphonyl chloride (6.0 g) in chloroform (30 ml) was added dropwise to a well-stirred solution of N,N'-dimethyl-ethylenediamine (25 g) in chloroform (300 ml) at room temperature. After 2 hours the chloroform solution was vigorously shaken with aqueous sodium carbonate solution, separated, dried (MgSO4) and evaporated under reduced pressure to give an oil. The oil was treated with chloroform (60 ml) and water (100 ml). The two solvents were mixed thoroughly and were then separated. The chloroform layer was dried (MgSO4) and evaporated under reduced pressure to give an oil. Final traces of N,N'-dimethyl-ethylenediamine were removed by heating the oil under low vacuum to give 4-fluoro-N-methyl-N-[2-(methylamino)ethyl]benzenesulphonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH:17]=[O:18])=[N:9]2)=[CH:4][CH:3]=1.[CH2:22](O)[CH2:23][OH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:17]4[O:24][CH2:23][CH2:22][O:18]4)[CH:19]=[CH:20][CH:21]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Clc1ccc2ccc(C=Cc3cccc(C4OCCO4)c3)nc2c1

Procedure:
A mixture of 3-(2-(7-chloroquinolin-2-yl)ethenyl)benzaldehyde (step 1) (938 mg, 3.19 mmoles), ethylene glycol (200 μL, 1.15 equiv.), p-toluenesulfonic acid (296 mg, 0.5 equiv.) and toluene (1.5 mL) was heated at reflux overnight. 25% aqueous NH4OAc was then added and the mixture extracted with EtOAc. Flash chromatography of the residue on silica with EtOAc:hexane 20:80 afforded the title compound.
Reaction SMILES: [CH3:1][C:2]([S:19]([CH3:22])(=[O:21])=[O:20])([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)=[CH:10][CH:9]=1)[C:3]([OH:5])=O.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[O:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH:42]1[O:47][NH2:48]>C(Cl)Cl.O>[CH3:1][C:2]([S:19]([CH3:22])(=[O:21])=[O:20])([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)=[CH:10][CH:9]=1)[C:3]([NH:48][O:47][CH:42]1[CH2:43][CH2:44][CH2:45][CH2:46][O:41]1)=[O:5]
Reactant: CC(CCc1ccc(-n2cccn2)cc1)(C(=O)O)S(C)(=O)=O
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(CCc1ccc(-n2cccn2)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-Methyl-2-(methylsulfonyl)-4-[4-(1H-pyrazol-1-yl)phenyl]butanoic acid (286 mg, 0.887 mmol) in methylene chloride (8.87 mL) at ambient temperature was added 1,(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (240 mg, 1.2 mmol), 1-hydroxy benzotriazole monohydrate (240 mg, 1.6 mmol), triethyl amine (220 uL, 1.6 mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (150 mg, 1.3 mmol). The resulting mixture was stirred at ambient temperature overnight. The mixture was diluted with methylene chloride and water. The phases were separated and the aqueous layer was extracted with methylene chloride two times. The organic extracts were combined and dried over magnesium sulfate, filtered and concentrated in vacuo to a crude residue. The crude residue was purified via silica gel chromatography eluting with methylene chloride and methanol. The fractions containing desired product were combined and concentrated in vacuo to afford 2-methyl-2-(methylsulfonyl)-4-[4-(1H-pyrazol-1-yl)phenyl]-N-(tetrahydro-2H-pyran-2-yloxy)butanamide as a solid. 302.9 mg. LCMS: (M−1) 420.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:5]=1Br.C(N(CC)CC)C.[CH:21]#[C:22][CH2:23][CH2:24][CH3:25]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:5]=1[C:21]#[C:22][CH2:23][CH2:24][CH3:25]
Reactant: C#CCCC
Reactant: COC(=O)c1ccc(C=O)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC#Cc1cc(C=O)ccc1C(=O)OC
Temperature: 80 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a room temperature solution of 2-Bromo-4-formyl-benzoic acid methyl ester (500 mg, 2.05 mmol) in degassed DMF (5 mL) are added triethylamine (2.0 mL, 14.35 mmol), dichlorobis(triphenylphosphine)palladium (II) (144 mg, 0.205 mmol, 10 mol %), copper (I) iodide (20 mg, 0.103 mmol, 5 mol %), and 1-Pentyne (406 μL, 4.10 mmol). The reaction mixture is heated to 80° C. in a sealed tube. After 2 h, the reaction is concentrated and the residue is chromatographed (0% to 10% EtOAc/Hex) to yield the title compound (279 mg, 59%). 1H NMR (400 MHz, CDCl3) δ 10.03 (s, 1H), 8.02-7.98 (m, 2H), 7.80 (dd, 1H, J=7.9, 1.8 Hz), 3.95 (s, 3H), 2.48 (t, 2H, J=7.0 Hz), 1.73-1.63 (m, 2H), 1.09 (t, 3H, J=7.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([CH2:18][CH3:19])([OH:17])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15]Br)=[CH:8][CH:7]=1.[CH2:23]([NH:26][CH2:27][CH2:28]C)[CH2:24]C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([CH2:18][CH3:19])([OH:17])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][N:26]([CH2:27][CH3:28])[CH2:23][CH3:24])=[CH:8][CH:7]=1
Reactant: CCCNCCC
Reactant: CCC(O)(c1ccc(OCCCBr)cc1)c1cccc(Cl)c1
Product: CCN(CC)CCCOc1ccc(C(O)(CC)c2cccc(Cl)c2)cc1

Procedure:
19.2 g. of 3-chloro-4'-(3-bromopropoxy)-α-ethyl-benzhydrol and 51 ml. of dipropyl amine are refluxed for 8 hours, and the reaction mixture is then evaporated in vacuo. To the residue water is added and it is extracted with benzene. The benzene phase is washed with water, dried over anhydrous magnesium sulfate, and the solution is evaporated under reduced pressure. Distillation of the residue in vacuo yields 11.5 g. of the title compound, boiling at 203° to 206° C./13.3 Pa.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[C:13]([C:17]4[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=4)=[N:14][NH:15][CH:16]=3)=[CH:11][C:6]=2[N:5]([CH2:24][CH3:25])[C:4]1=[O:26])[CH3:2].[H-].[Na+].Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C(=O)(O)[O-].[Na+]>O1CCOCC1>[C:34]([O:33][C:31](=[O:32])[CH2:30][N:15]1[CH:16]=[C:12]([C:10]2[CH:9]=[CH:8][C:7]3[N:3]([CH2:1][CH3:2])[C:4](=[O:26])[N:5]([CH2:24][CH3:25])[C:6]=3[CH:11]=2)[C:13]([C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[N:14]1)([CH3:37])([CH3:36])[CH3:35].[C:34]([O:33][C:31](=[O:32])[CH2:30][N:14]1[C:13]([C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[C:12]([C:10]2[CH:9]=[CH:8][C:7]3[N:3]([CH2:1][CH3:2])[C:4](=[O:26])[N:5]([CH2:24][CH3:25])[C:6]=3[CH:11]=2)[CH:16]=[N:15]1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCn1c(=O)n(CC)c2cc(-c3c[nH]nc3-c3cccc(C)c3)ccc21
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCn1c(=O)n(CC)c2cc(-c3cn(CC(=O)OC(C)(C)C)nc3-c3cccc(C)c3)ccc21
Product: CCn1c(=O)n(CC)c2cc(-c3cnn(CC(=O)OC(C)(C)C)c3-c3cccc(C)c3)ccc21
Reaction time: 1 h

Procedure:
1,3-Diethyl-5-(3-m-tolyl-1H-pyrazol-4-yl)-1,3-dihydro-benzoimidazol-2-one (310 mg, 0.896 mmol) was diluted with dioxane (4 mL) and treated with sodium hydride (61.4 mg, 60% oil dispersion). After stirring at 23° C. for 0.5 hour t-butyl bromoacetate (0.25 mL) was added and the mixture was allowed to stir for 1 hour then was poured onto saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried with sodium sulfate and concentrated. Silica gel chromatography gave [4-(1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-3-m-tolyl-pyrazol-1-yl]-acetic acid tert-butyl ester (0.122 g) and [4-(1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-5-m-tolyl-pyrazol-1-yl]-acetic acid tert-butyl ester (0.135 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N-:11]Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.O.O.[Na+].[CH3:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>C(#N)C.C(OCC)(=O)C>[CH3:17][S:18]([C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1)=[N:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CSc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(S(=O)(=O)[N-]Cl)cc1
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)N=S(C)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 22 %

Procedure:
10.0 g (35.3 mmol) of chloramine-T trihydrate (Aldrich) are added to 5.0 g (29.6 mmol) of 1-methylsulphanyl-4-nitrobenzene in 120 ml of acetonitrile at room temperature. The mixture is stirred at room temperature for 4 hours and then diluted with ethyl acetate. The mixture is filtered with suction and the filter cake is washed with ethyl acetate. The combined organic phases are dried (Na2SO4), filtered and concentrated. The resulting residue is recrystallized from methanol. 2.2 g (6.5 mmol; yield: 22%) of the product are obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[C:12]([CH2:15][O:16][SiH:17]([CH3:19])[CH3:18])[CH:11]=[CH:10]2)([CH3:4])([CH3:3])[CH3:2].[Br:20]Br.C(OC(=O)C)C>ClCCl>[Br:20][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12]([CH2:15][O:16][SiH:17]([CH3:19])[CH3:18])=[N:13]2
Reactant: BrBr
Reactant: C[SiH](C)OCc1ccc2cccc(C(C)(C)C)c2n1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[SiH](C)OCc1ccc2c(Br)ccc(C(C)(C)C)c2n1
Yield: 64.2 %

Procedure:
To a 500 mL flask was added 400 mL dichloromethane and 31.5 g 8-(t-butyl)dimethylsiloxyquinaldine. The mixture was vigorously stirred while 33.14 g bromine (Aldrich) dissolved in 20 mL dichloromethane was added dropwise. The reaction progress was monitored by TLC (5:95 ethylacetate:hexanes). The starting material was found to be completely consumed. Excess bromine was removed by addition of 200 mL of saturated sodium thiosulfate (Aldrich). The organic layer was separated, washed with 150 ml water, 150 ml brine and then dried over MgSO4. After filtering off the salts, the filtrate was concentrated to an oil which was purified by column chromatography, eluting with 20% dichloromethane/hexanes to give 26.04 g of 5-bromo-8-(t-butyl)dimethylsiloxyquinaldine (compound 2ii) as a yellow oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][NH:11][C:12]1[CH:16]=[CH:15][NH:14][C:13]=1[C:17]([O:19]CC)=O.C(Cl)Cl.C([N:33]=[C:34]=[S:35])(=O)C1C=CC=CC=1>CO>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[CH2:10][N:11]1[C:12]2[CH:16]=[CH:15][NH:14][C:13]=2[C:17](=[O:19])[NH:33][C:34]1=[S:35]
Reactant: CCOC(=O)c1[nH]ccc1NCc1nc2ccccc2[nH]1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CO
Solvent: ClCCl
Product: O=c1[nH]c(=S)n(Cc2nc3ccccc3[nH]2)c2cc[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 168.2 %

Procedure:
Ethyl 3-[(1H-benzimidazol-2-ylmethyl)amino]-1H-pyrrole-2-carboxylate (0.33 g, 1.16 mmol) was added to CH2Cl2 (3 mL) and methanol was added until clear solution was obtained. The solution was stirred at r.t. for 1 h. Benzoyl isothiocyanate (0.73 mL, 0.46 mmol) was added and after stirring at r.t. for 30 minutes the mixture was concentrated. The residue was dissolved in ammonia (7N in methanol, 7 mL) and the mixture was heated at 80° C. in a sealed steel container for 2 h. After cooling to r.t. the precipitated product was filtrated and washed through with methanol, diethyl ether and ethyl acetate, obtaining 0.23 g (66%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(Cl)Cl>[C:19]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C(=O)O)ccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 60 h
Yield: 55.6 %

Procedure:
To a suspension of 4-amino-3-methylbenzoic acid (60 g, 0.40 mol) in methylene chloride (800 mL) was added triethylamine (121 g, 1.19 mol). The solution became clear. Then, acetic anhydride (81 g, 0.79 mol) was added and the reaction mixture was stirred for 60 h at room temperature. The solvent was evaporated. The residue was diluted with water (400 mL) and extracted with ethyl acetate (3×600 mL). The combined organic extracts were dried over magnesium sulfate, filtered and evaporated to give the title compound as a tan solid (43 g, 56% yield). 1H-NMR (d6-DMSO, 300 MHz) δ 9.36 (s, 1H), 7.77 (s, 1H), 7.10 (s, 2H), 2.27 (s, 3H), 2.10 (s, 3H). LC/MS: tR=1.22 min, 194 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[NH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: NCC1CCOCC1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Product: O=[N+]([O-])c1cc(Br)ccc1NCC1CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Step A of Example 5 from 4-bromo-1-flouro-2-nitrobenzene (Wako Pure Chemical Industries, Ltd.) and 4-aminomethyltetrahydropyran (Apollo Scientific Ltd.).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[N:9]=[CH:8][C:7]([C:10](=[O:13])[CH2:11][CH3:12])=[CH:6][CH:5]=1.Br>C(O)(=O)C>[Br:1][CH:11]([CH3:12])[C:10]([C:7]1[CH:8]=[N:9][C:4]([Cl:3])=[CH:5][CH:6]=1)=[O:13]
Reactant: CCC(=O)c1ccc(Cl)nc1
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Product: CC(Br)C(=O)c1ccc(Cl)nc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Bromine (45.4 g) is slowly added to the mixture of 1-(6-chloro-pyridin-3-yl)-propan-1-one (48.2 g), 0.4 ml of hydrobromic acid (33% solution in acetic acid) and 250 ml of acetic acid at room temperature under a nitrogen atmosphere. Subsequently, the mixture is slowly heated to 80° C. The reaction mixture is stirred at 80° C. for 30 min, during which a yellow suspension is formed, then cooled down to 10° C. and filtered. The solid remainder is washed with tert-butyl methyl ether to deliver 2-bromo-1-(6-chloro-pyridin-3-yl)-propan-1-one hydrobromide as a yellowish solid. To a suspension of this intermediate in 800 ml of tert-butyl methyl ether is added 400 ml of a saturated aqueous sodium bicarbonate solution and the reaction mixture is stirred for 15 min. The phases are separated, the organic layer is washed with brine, dried over sodium sulfate and concentrated under reduced pressure to obtain 2-bromo-1-(6-chloro-pyridin-3-yl)-propan-1-one as an oil.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]([O-:7])=O.[Cl:8][C:9]1[C:15]([O:16][CH2:17][C:18]#[CH:19])=[CH:14][C:12]([NH2:13])=[C:11]([F:20])[CH:10]=1.P(Cl)(Cl)Cl.O.C(=O)(O)[O-].[Na+]>C1(C)C(C)=CC=CC=1>[Cl:8][C:9]1[C:15]([O:16][CH2:17][C:18]#[CH:19])=[CH:14][C:12]([NH:13][C:5](=[O:7])[CH:4]=[N:3][O:2][CH3:1])=[C:11]([F:20])[CH:10]=1
Reactant: CON=CC(=O)[O-]
Reactant: C#CCOc1cc(N)c(F)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClP(Cl)Cl
Solvent: Cc1ccccc1C
Product: C#CCOc1cc(NC(=O)C=NOC)c(F)cc1Cl
Yield: 49.1 %

Procedure:
0.58 g of the obtained 2-(methoxyimino)acetate was dissolved in 30 ml of xylene and 1.00 g of 4-chloro-2-fluoro-5-propargyloxyaniline was added thereto. 0.17 ml of phosphorus trichloride was then added to the resulting solution and the entire mixture was heated to reflux for 1 hour. After cooling the resulting reaction solution, sodium bicarbonate water was added thereto and the resultant solution was then extracted with ethyl acetate. After washing with saturated saline, the organic layer was dried with anhydrous magnesium sulfate and filtered. The concentrate obtained by evaporating solvents from the filtrate under reduced pressure was washed with a mixed solvent of ether-normal hexane to obtain 0.70 g of N-(4-chloro-2-fluoro-5-propargyloxyphenyl)-2-(methoxyimino)acetamide (yield 49%).
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]=1.Cl.Cl.[NH2:15][CH:16]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C:17]([NH:19][C:20]1([C:29]#[N:30])[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:21]1)=[O:18]>>[C:29]([C:20]1([NH:19][C:17](=[O:18])[CH:16]([NH:15][C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:4](=[O:12])(=[O:11])[N:3]=2)[CH2:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH3:28])[CH2:24][CH2:25]1)#[N:30]
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Reactant: CCCN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Agent: Cl
Product: CCCN1CCC(C#N)(NC(=O)C(CC2CCCCC2)NC2=NS(=O)(=O)c3ccccc32)CC1

Procedure:
The title compound was prepared starting from 3-chloro-benzo[d]isothiazole 1,1-dioxide and 2-amino-N-(-4-cyano-1-propyl-piperidin-4-yl)-3-cyclohexylpropionamide bis hydrochloride salt according to the procedure from Example 81, except that the compound was further purified by HPLC using a 20×250 mm C18 reverse phase column with the method being 20% acetonitrile in water to acetonitrile. MS, m/z 486=M+1.
Reaction SMILES: CO[C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[N:12][CH:11]=2)[C:7]([C:16]([F:19])([F:18])[F:17])=[CH:6][C:5]=1[NH2:20].ClC([O:25][C:26]1C=CC(Cl)=CC=1)=O.[CH3:33][S:34]([NH:37][NH2:38])(=[O:36])=[O:35].CCN(C(C)C)C(C)C>O1CCOCC1>[O:25]=[C:26]1[N:38]([NH:37][S:34]([CH3:33])(=[O:36])=[O:35])[C:3](=[O:21])[C:4]2[C:5](=[CH:6][C:7]([C:16]([F:19])([F:18])[F:17])=[C:8]([C:10]3[CH:15]=[CH:14][N:13]=[N:12][CH:11]=3)[CH:9]=2)[NH:20]1
Reactant: COC(=O)c1cc(-c2ccnnc2)c(C(F)(F)F)cc1N
Reactant: CS(=O)(=O)NN
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(-c3ccnnc3)cc2c1=O
Temperature: 80 °C
Yield: 39 %

Procedure:
A solution containing 2-amino-5-pyridazin-4-yl-4-trifluoromethyl-benzoic acid methyl ester (65.5 mg, 0.22 mmol) and 4-chlorophenyl chloroformate (34 μL, 0.24 mmol) in dioxane (3 mL) was heated at 80° C. for 1.5 h. After allowing the reaction mixture to cool down to r.t., CH3SO2NHNH2 (48.5 mg, 0.44 mmol) and i-Pr2NEt (38.5 μL, 0.22 mmol) were added. The mixture was heated to 80° C. for 1 h and, after cooling to r.t., the solvent was removed in vacuo. The residue was dissolved in DCM and the product was precipitated by addition of Et2O. Filtration and drying provided the title product (34.4 mg, 39%) as a white solid. API-ES: m/z 402 [M+H]+, rt 2.02 min.
Reaction SMILES: Cl.[C:2]1([CH2:7][NH2:8])[S:6][CH:5]=[CH:4][CH:3]=1.[S-:9][C:10]#[N:11].[NH4+]>BrC1C=CC=CC=1>[C:2]1([CH2:7][NH:8][C:10]([NH2:11])=[S:9])[S:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1cccs1
Reactant: N#C[S-]
Agent: Cl
Agent: [NH4+]
Solvent: Brc1ccccc1
Product: NC(=S)NCc1cccs1
Yield: 32.6 %

Procedure:
2-thenylamine hydrochloride (13.35 grams, 0.089 moles) and ammonium thiocyanate (7.4 grams, 0.089 moles) in 20 ml bromobenzene were heated to reflux temperature for 90 minutes. The reaction mixture was cooled and the filtered solids washed three times with water. Recrystallization from chloroform and drying over phosphorous pentoxide yielded 5.0 grams (33%) of N-thenylthiourea, m.p. 99°-101° C.