Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:15][C:16]1[N:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:15][C:16]1[N:21]=[C:20]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH:19]=[CH:18][N:17]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(Cl)n2)CC1
Temperature: 80 °C
Yield: 80.7 %

Procedure:
To tert-butyl 4-hydroxypiperidine-1-carboxylate (389 mg, 1.933 mmol) and 2,4-dichloropyrimidine (240 mg, 1.611 mmol) in DMF (6.4 mL) was added cesium carbonate (1050 mg, 3.22 mmol) and the mixture was heated at 80° C. for 1 h and then to 70° C. overnight. TLC indicated no remaining 2,4-dichloropyrimidine. The reaction was cooled to ambient temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with water (3×) and brine. The combined organic layer was dried (MgSO4), filtered and solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel to give tert-butyl 4-[(2-chloropyrimidin-4-yl)oxy]piperidine-1-carboxylate (410 mg, 1.3 mmol, 81%) as white solid. MS ESI: [M+H]+ m/z 314.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([C:13]([C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([OH:30])[CH:23]=1)=[O:20])([CH3:15])[CH3:14])#[N:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[C:11]([C:13]([C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH:23]=1)=[O:20])([CH3:15])[CH3:14])#[N:12]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc([N+](=O)[O-])cn1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 2-chloro-5-nitropyridine (547 mg, 3.45 mmol) and 3-(1-cyano-1-methylethyl)-N-(3-hydroxy-4-methoxyphenyl)benzamide (1.03 g, 3.33 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (1.92 g, 13.9 mmol), and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was cooled to room temperature, and diluted with ethyl acetate (75 mL)/hexane (75 mL). The obtained suspension was washed with water (50 mL×3), and the combined aqueous layer was extracted with ethyl acetate (75 mL)/hexane (75 mL). The organic layer were combined, washed with saturated aqueous ammonium chloride solution (100 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give 3-(1-cyano-1-methylethyl)-N-{4-methoxy-3-[(5-nitropyridin-2-yl)oxy]phenyl}benzamide as a brown oil. This was used for the next reaction without further purification.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][OH:12].[OH-].[K+]>C(O)C>[OH:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCCNCC1
Reactant: OCCCCl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: OCCCN1CCCCCC1
Yield: 88 %

Procedure:
A solution of 1 mole of azepane and 0.5 mole of 3-chloro-1-propanol in 500 ml of ethanol was refluxed for 18 hours. The reaction mixture was treated with 0.55 mole of KOH and refluxed for 0.75 hour. Cooling, filtration and distillation yielded 88% of N-(3-hydroxypropyl)azepane (b.p.=136° C. at 21 mm; analysis for C9H19NO, calculated: %N=8.91; found: %N=8.30).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@@H:28]([C:34]#[C:35][CH3:36])[CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[OH-].[Li+]>C1COCC1.CCO>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@@H:28]([C:34]#[C:35][CH3:36])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CC#C[C@@H](CC(=O)OC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC#C[C@@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Reaction time: 16 h
Yield: 89.3 %

Procedure:
To a stirred solution of 4.2 (0.052 g, 0.11 mmol) in THF (2.00 mL) and EtOH (2.00 mL) at 23° C. was added 1N lithium hydroxide (2.00 mL, 2.00 mmol). Stirring continued for 16 hours. The reaction mixture was concentrated in vacuo, 1N HCl was added to reach pH 1, and the resulting mixture was extracted with EtOAc (3×10 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (SiO2 gel 60, eluted with 0%-20% EtOAc in hexanes) to give compound 4 as a clear oil (0.0466 g, 92% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.58 (1H, d, J=8.2 Hz), 7.41 (1H, dd, J=8.2, 2.0 Hz), 7.30 (2H, d, J=8.6 Hz), 7.08 (1H, d, J=2.0 Hz), 7.00 (1H, t, J=8.8 Hz), 6.93 (2H, d, J=8.6 Hz), 6.86 (1H, m), 6.80 (1H, dd, J=5.9, 3.3 Hz), 5.00 (2H, s), 4.06 (1H, m), 3.80 (3H, s), 2.81 (1H, dd, J=15.6, 8.4 Hz), 2.72 (1H, dd, J=15.6, 6.6 Hz), 1.84 (3H, d, J=2.3 Hz), 1.24 (9H, s). MS ESI (neg.) m/e: 947.3 (2M−H)+, 473.2 (M−H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[NH:25]1[CH:29]=[N:28][CH:27]=[N:26]1>>[N:25]1([CH2:2][C:3]2[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[CH:11]=3)=[O:8])=[CH:5][CH:4]=2)[CH:29]=[N:28][CH:27]=[N:26]1
Reactant: c1nc[nH]n1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CBr)cc1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(Cn2cncn2)cc1

Procedure:
88 mg of 4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was coupled to 45 mg of 1H-1,2,4-triazole via Procedure P. The reaction was evaporated to dryness and purified by reverse phase HPLC to yield 4-((1H-1,2,4-triazol-1-yl)methyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 390 (M)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[OH:12].[Cl:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:15]=1[C:16](Cl)=[O:17].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>CC(N(C)C)=O.O>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[O:12][C:16](=[O:17])[C:15]1[C:14]([Cl:13])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:23]
Reactant: Nc1cccc2c(O)ccnc12
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: Nc1cccc2c(OC(=O)c3c(Cl)cccc3Cl)ccnc12
Reaction time: 1 h
Yield: 38.5 %

Procedure:
A mixture of 8-amino-4-hydroxyquinoline (300 mg), 2,6-dichlorobenzoyl chloride (432 mg), triethylamine (569 mg) and catalytic amount of dimethylaminopyridine in dimethylacetamide (3 ml) was stirred for 1 hour under ice-cooling. To the mixture was added water (3 ml) and the resulting precipitate was collected by filtration. The residue was suspended in hot ethanol (10 ml) with stirring. The resulting precipitate was collected by filtration, and the residue was purified by flash chromatography (ethyl acetate-dichloromethane) to give 8-amino-4-(2,6-dichlorobenzoyloxy)quinoline (240 mg).
Reaction SMILES: [Cl:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[F:22])[S:7]1(=[O:24])=[O:23].[CH3:25][NH:26][CH3:27]>>[ClH:1].[F:22][C:16]1[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=1[N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:6]([CH2:5]/[CH:4]=[CH:3]\[CH2:2][N:26]([CH3:27])[CH3:25])[S:7]1(=[O:24])=[O:23]
Reactant: Cc1ccc(N2c3ccccc3N(C/C=C\CCl)S2(=O)=O)c(F)c1
Reactant: CNC
Product: Cc1ccc(N2c3ccccc3N(C/C=C\CN(C)C)S2(=O)=O)c(F)c1
Product: Cl

Procedure:
In an analogous manner to general procedure V, 1-[(2Z)-4-chlorobut-2-en-1-yl]-3-(2-fluoro-4-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide was reacted with dimethylamine to provide (2Z)-4-[3-(2-fluoro-4-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylbut-2-en-1-amine hydrochloride:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[F:9][C:10]([F:25])([F:24])[C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[C:14](Cl)=[O:15].Cl.[OH-].[Na+]>ClCCl.N1C=CC=CC=1>[F:9][C:10]([F:24])([F:25])[C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:19]=1)[C:14]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])=[O:15]
Reactant: Nc1ccccc1O
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
2-Aminophenol (120 mg, 1.1 mmol) was dissolved in dichloromethane (5 mL). A solution of 3,5-bis(trifluoromethyl)benzoyl chloride (300 mg, 1.1 mmol) in dichloromethane (3 mL) and pyridine (0.5 mL) was added dropwise under ice cooling and argon atmosphere, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 2 N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine one after another, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethanol (5 mL), added dropwise 2 N sodium hydroxide (0.1 mL, 0.2 mmol), and stirred at room temperature for 30 minutes. The reaction mixture was poured into 2 N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine one after another, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give the title compound (288 mg, 73.6%) as a light pink crystal.
Reaction SMILES: [C:1]([N:4]1[CH:10]([CH3:11])[CH2:9][C:8]2[CH:12]=[C:13]([Cl:17])[C:14]([Cl:16])=[CH:15][C:7]=2[C:6]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[C:20]([Cl:27])[CH:19]=2)=[N:5]1)(=[O:3])[CH3:2].O.NN>CO.ClCCl.[Ni]>[C:1]([N:4]1[CH:10]([CH3:11])[CH2:9][C:8]2[CH:12]=[C:13]([Cl:17])[C:14]([Cl:16])=[CH:15][C:7]=2[C:6]([C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([Cl:27])[CH:19]=2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1N=C(c2ccc([N+](=O)[O-])c(Cl)c2)c2cc(Cl)c(Cl)cc2CC1C
Agent: [Ni]
Agent: NN
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC(=O)N1N=C(c2ccc(N)c(Cl)c2)c2cc(Cl)c(Cl)cc2CC1C
Reaction time: 0.75 h
Yield: 70.6 %

Procedure:
4.26 g (10 mmoles) of (±)-3-acetyl-4,5-dihydro-7,8-dichloro-1-(3-chloro-4-nitrophenyl)-4-methyl-3H-2,3-benzodiazepine are dissolved in a mixture of 40 cm3 of methanol and 40 cm3 of dichloromethane, then 3.0 g of wet Raney nickel catalyst and, under vigorous stirring, 1.7 cm3 (35 mmoles) of 98% hydrazine hydrate are added. The reaction mixture is stirred for further 45 minutes, the catalyst is filtered, washed with dichloromethane, the filtrate is evaporated, and the residue is rubbed with 50 cm3 of water to obtain solid matter. The crude product is recrystallized from acetonitrile. Thus, 2.80 g (71%) of the title compound are obtained in the form of butter coloured solids melting at 127–129° C.
Reaction SMILES: O[CH:2]1[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>C1C=CC=CC=1>[CH3:13][C:9]1([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=3)[CH:5]=[CH:4][C:3]=2[CH:2]=[CH:11][CH2:10]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3O)cc1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3)cc1
Temperature: 50 °C

Procedure:
To a solution of 0.13 g (0.38 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 9) in 15 ml of dry benzene was added 0.67 g (2.90 mmol) of (methoxycarbonylsulfamoyl) triethylammonium hydroxide (Burgess Reagent). The resulting mixture was heated at 50° C. for 30 minutes, cooled to room temperature, partitioned between water (10 ml) and EtOAc (20 ml) and the layers separated. The organic layer was dried over Na2 SO4, concentrated in vacuo and purified by flash chromatography (silica, 10% EtOAc-hexane) to yield the title compound as a clear oil.
Reaction SMILES: NC1C=CC=CC=1.[CH3:8][N:9]([CH3:24])[S:10]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11].C(N(CC)CC)C.[CH3:32][C:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>O1CCCC1>[CH3:8][N:9]([CH3:24])[S:10]([C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:36]([C:33]2([CH3:32])[CH2:35][CH2:34]2)=[O:37])=[CH:15][C:14]=1[C:20]([F:21])([F:23])[F:22])(=[O:11])=[O:12]
Reactant: CC1(C(=O)Cl)CC1
Reactant: CN(C)S(=O)(=O)c1ccc(N)cc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: Nc1ccccc1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1ccc(NC(=O)C2(C)CC2)cc1C(F)(F)F
Temperature: 0 °C
Yield: 86 %

Procedure:
To a solution of 6.7 g (0.025 mole) of the aniline prepared as in (c) above and 2.5 g of triethylamine in 50 ml of tetrahydrofuran was added dropwise 3.0 g (0.025 mole) of 1-methylcyclopropanecarboxylic chloride. The mixture was refluxed for one hour, poured into ice water, filtered and recrystallized from methanol to give 7.5 g (86%) of product as a white crystalline solid; m.p. 153°-156° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:7]=23)[CH:3]=[N:2]1.[CH2:23]([O:25][C:26](=[O:31])[CH:27]=[C:28]([CH3:30])[CH3:29])[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:29][C:28]([N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:7]=23)[CH:3]=[N:2]1)([CH3:30])[CH2:27][C:26]([O:25][CH2:23][CH3:24])=[O:31]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ccnc21
Reactant: CCOC(=O)C=C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC(C)(C)n1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.8 %

Procedure:
4-(1H-Pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (220 mg, 0.0006996 mol) and 3-methyl-2-butenoic acid ethyl ester (292 μL, 0.00210 mol) were dissolved in DMF (10 mL). Cesium carbonate (912 mg, 0.00280 mol) was added and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water, and the product was extracted with MTBE several times. The combined extracts were dried over sodium sulfate and concentrated. The crude residue was purified by flash column chromatography (0-60% EtOAc/Hexanes) to afford ethyl 3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butanoate (244 mg, 79%). 1H NMR (300 MHz, CDCl3): 8.37 (d, 1H), 8.11 (s, 1H), 8.09 (s, 1H), 7.45 (d, 1H), 7.24 (d, 1H), 6.79 (d, 1H), 5.77 (s, 2H), 4.10 (q, 2H), 3.62 (dd, 2H), 3.04 (s, 2H), 1.88 (s, 6H), 1.20 (t, 3H), 0.98 (dd, 2H), 0.00 (s, 9H); MS (ES): 443 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9][OH:10])=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.O.[C:18]1(C)C=[CH:22][C:21](S(O)(=O)=O)=[CH:20][CH:19]=1.C(OCC)(=[O:31])C>C1COCC1.C(=O)([O-])[O-].[Na+].[Na+]>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9][O:10][CH:22]2[CH2:21][CH2:20][CH2:19][CH2:18][O:31]2)=[C:4]([C:13]([F:14])([F:15])[F:16])[CH:3]=1
Reactant: CCOC(C)=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCCCOc1ccc(Br)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)c1cc(Br)ccc1OCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(4-bromo-2-(trifluoromethyl)-phenoxy)propan-1-ol (12 g), 3,4-dihydro-2H-puran (6.75 g) and p-toluenesulfonic acid hydrate (0.76 g) in THF (100 ml) was stirred at room temperature for 1 hour then diluted with 10% sodium carbonate (50 ml) and extrated with ethyl acetate (2×150 ml). Organic layer was then dried over sodium sulphate, solvent removed under reduced pressure to give expected product (15 g).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].C([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])C.[C:21]1([CH3:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH:6][C:19](=[N:16][C:17]1[C:18]([CH:9]([CH3:10])[CH3:8])=[CH:23][CH:24]=[CH:25][C:26]=1[CH:21]([CH3:22])[CH3:27])[C:20]1[CH:7]=[CH:5][CH:4]=[CH:1][CH:2]=1)([CH3:13])[CH3:12]
Reactant: Cc1ccccc1
Reactant: CCN(CC)CC
Reactant: CC(C)c1cccc(C(C)C)c1N
Product: CC(C)c1cccc(C(C)C)c1N=C(Nc1c(C(C)C)cccc1C(C)C)c1ccccc1
Yield: 85 %

Procedure:
Alternatively, the compound was prepared from the corresponding imidoyl chloride and 2,6-diisopropyl aniline. A solution of 2,6-diisopropylaniline (0.885 g, 5 mmol), triethylamine (2.5 mL), and N-2,6-diisopropylbenzimidoyl chloride (1.50 g, 5 mmol) in 10 mL of toluene was refluxed for 24 h. The mixture was washed with water, dried (over Na2SO4), and concentrated. After a single crystallization from ethanol/water, 1.88 g (85%) of the benzamidine was obtained; it was identical to the compound described above as seen by MP and NMR spectroscopy.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[CH2:8][S:9][CH2:10][CH2:11][NH2:12].COC1C(OC)=NS(=O)(=O)N=1.OCC1NC=NC=1CSC[CH2:34][NH:35][C:36]1[C:40](OC)=[N:39][S:38](=[O:44])(=[O:43])[N:37]=1.CN>>[OH:1][CH2:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[CH2:8][S:9][CH2:10][CH2:11][NH:12][C:40]1[C:36]([NH:35][CH3:34])=[N:37][S:38](=[O:44])(=[O:43])[N:39]=1
Reactant: COC1=NS(=O)(=O)N=C1NCCSCc1nc[nH]c1CO
Reactant: NCCSCc1nc[nH]c1CO
Agent: CN
Agent: COC1=NS(=O)(=O)N=C1OC
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1nc[nH]c1CO

Procedure:
2-[(5-Hydroxymethyl-1H-imidazol-4-yl)methylthio]ethylamine [prepared according to the procedure described in Belgian Pat. No. 843,840] is reacted with 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide and the resultant 3-{2-[(5-hydroxymethyl-1H-imidazol-4-yl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1,1-dioxide is treated with excess methylamine according to the general procedure described in Example 2, and the title compound is thereby produced.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:15][OH:16])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]1.Cl[C:18]1[NH:22][C:21]2[C:23]([N+:31]([O-:33])=[O:32])=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[CH:26][C:20]=2[N:19]=1>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:15][OH:16])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:18]2[NH:22][C:21]3[C:23]([N+:31]([O-:33])=[O:32])=[CH:24][C:25]([C:27]([F:29])([F:28])[F:30])=[CH:26][C:20]=3[N:19]=2)[C@H:10]([CH3:14])[CH2:9]1
Reactant: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc2nc(Cl)[nH]c12
Solvent: CCO
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc([N+](=O)[O-])c2[nH]1

Procedure:
A mixture of {5-chloro-6-[(3R)-3-methyl-piperazin-1-yl]-pyridin-3-yl}-methanol (1.21 g, 5.0 mmol, Example 150a) and 2-chloro-7-nitro-5-trifluoromethyl-1H-benzoimidazole (1.33 g, 5.0 mmol, Example 57c) in EtOH (4 mL) reacted under the conditions of Example 3c to give the title compound as a yellow solid. MS (ESI, pos. ion) m/e: 471 (M+1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:13]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)(=[O:15])[CH3:14].N1CCCCC1>CO>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1/[CH:11]=[CH:14]/[C:13]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[O:15])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CC(=O)c1ccncc1
Reactant: Cc1[nH]c2ccccc2c1C=O
Solvent: C1CCNCC1
Solvent: CO
Product: Cc1[nH]c2ccccc2c1/C=C/C(=O)c1ccncc1
Yield: 69.6 %

Procedure:
To a dried 500 mL round bottom flask under argon, 2-methylindole-3-carboxaldehyde (400 mg, 2.51 mmol) was dissolved in anhydrous MeOH (10 mL). 4-Acetyl-pyridine (305 μL, 2.76 mmol, 1.1 equiv.) and piperidine (82 μL, 0.83 mmol) were added and the reaction was stirred under reflux. A red-orange precipitate gradually formed, and after twelve hours this solid was isolated by filtration, rinsed with chilled methanol and dried under vacuum, producing 458 mg (69%) of yellow solid. NMR: 1H NMR (600 MHz, d6-DMSO): δ 12.017 (s, 1H, N—H), 8.816-8.806 (dd, J1=4.5, J2=2.1, 2H, pyr-2,6H), 8.121-8.095 (d, J=15.6, 1H, C═CH), 8.077-8.063 (m, 1H, indole-4H), 7.975-7.965 (dd, J1=4.5, J2=1.5, 2H, pyr-3,5H), 7.489-7.464 (d, J=15.6, 1H, C═CH), 7.415-7.400 (m, 1H, indole-7H), 7.220-7.200 (m, 2H, indole-5,6H), 2.596 (s, 3H, methyl). 13C NMR (150 MHz, d6-DMSO): δ 188.0, 150.7, 145.6, 144.9, 139.5, 136.3, 125.8, 122.4, 121.50, 121.46, 120.4, 113.1, 111.7, 109.4, 11.9. Melting Point: 268-272° C. TLC: (ethyl acetate:hexanes 4:1) Rf=0.18. Elemental analysis calculated for C17H14N2O: C, 77.84; H, 5.38; N, 10.68. found: C, 77.96; H, 5.28; N, 10.59.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH2:19][OH:20])[CH:18]=1)[CH2:6][CH2:5]2.[H-].[Na+].[H][H].[CH3:25]I>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH2:19][O:20][CH3:25])[CH:18]=1)[CH2:6][CH2:5]2
Reactant: CI
Reactant: [H][H]
Reactant: O=C1c2ccc(Cl)cc2CCN1c1cncc(CO)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.9 %

Procedure:
To a solution of 6-chloro-2-(5-hydroxymethyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one (example 3) (28.8 mg, 0.1 mmol) in THF (5 mL) was added NaH (8 mg, 0.2 mmol, 60% dispersion in mineral oil) at room temperature. After hydrogen evolution ceased, a solution of methyliodide (0.2 mmol) in THF (5 mL) was added dropwise, and the resulting mixture was stirred at room temperature for 1 hour. The mixture was then treated with satd. aqueous NH4Cl solution and extracted three times with EtOAc. The combined organic layer was washed with water and brine, dried over anhy. Na2SO4 and concentrated in vacuo. The crude product was purified by prep-HPLC to give the title compound (4.5 mg, 14.8%) as a white solid. MS: (M+H)+ 303.1
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[CH:8]=[C:9]([SH:13])[CH:10]=[CH:11][CH:12]=1>CCOCC>[Cl:6][C:7]1[CH:8]=[C:9]([S:13][CH2:3][CH2:2][C:1]([OH:5])=[O:4])[CH:10]=[CH:11][CH:12]=1
Reactant: Sc1cccc(Cl)c1
Reactant: C=CC(=O)O
Solvent: CCOCC
Product: O=C(O)CCSc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 88 h
Yield: 29.9 %

Procedure:
Acrylic acid (2.66 g, 37 mmol) and 3-chlorothiophenol (4.85 g, 34 mmol) were dissolved in ether (15 mL) and stirred at room temperature for 88.0 hours. The reaction mixture solidified, was dissolved in ether and extracted with 5% NaOH. The aqueous layer was acidified with concentrated hydrochloric acid, extracted with ether, washed with brine, dried over MgSO4, and concentrated in vacuo to give the 3-(3-chlorophenylthio)propanoic acid (2.20 g, 34%): 1H NMR (acetone-d6) 300 MHz 7.33-7.40 (m, 3H) 7.24 (m, 1H) 3.25 (t, J=7.1 Hz, 2H) 2.67 (t, J=7.1 Hz, 2H). Mass spectrum: M+H=217.