Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C@@H:12]1([OH:19])[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]1[OH:18].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([O:18][C@@H:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C@@H:12]2[OH:19])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: O[C@@H]1CCCC[C@@H]1O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1O[C@@H]1CCCC[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2,4-Difluoronitrobenzene (0.549 ml) and cis-1,2-cyclohexanediol (0.581 g) in THF (10.0 ml), cooled with an ice-bath, was added lithium bis(trimethylsilyl)amide (1 mol/1 solution in THF; 5.00 ml). The mixture was stirred overnight at rt, and then evaporated to dryness. The residue was taken up in ethyl acetate, extracted once with hydrochloric acid (1 mol/l) and twice with NaOH solution (1 mol/l), dried with magnesium sulphate, filtered and evaporated to dryness. The residue was purified by column chromatography (silica; methylene chloride/methanol 100:0=>97:3) to yield a yellowish oil.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:12][CH:11]=2)=[N:8][CH:9]=1.[H-].[Na+].Br[CH2:27][CH2:28][CH3:29]>O1CCCC1>[OH:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:27][CH2:28][CH3:29])=[CH:12][CH:11]=2)=[N:8][CH:9]=1
Reactant: C[Si](C)(C)Oc1ccc(-c2ccc(CCCCCO)cc2)nc1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCOCCCCCc1ccc(-c2ccc(O)cn2)cc1
Yield: 77.7 %

Procedure:
5.1 g of 5-trimethylsilyloxy-2-(4-[5-hydroxy-1-pentyl]phenyl)pyridine, 0.7 g of sodium hydride (60-65 wt. %), 2.5 g of 1-bromopropane and 100 ml of tetrahydrofuran were reacted analogously to Example 1(f) to give 3.6 g of 5-hydroxy-2-(4-[5-(propyloxy)-1-pentyl]phenyl)pyridine.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[N:7]=1)=[O:4].[C:21](=O)([O:24]C)[O:22][CH3:23]>O1CCCC1.CCCCCC>[CH3:15][C:14]([CH3:17])([CH3:16])[C:13]([NH:12][C:8]1[N:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:20])([CH3:19])[CH3:1])[CH:11]=[CH:10][C:9]=1[C:21]([O:22][CH3:23])=[O:24])=[O:18]
Reactant: COC(=O)OC
Reactant: CC(C)(C)C(=O)Nc1cccc(NC(=O)C(C)(C)C)n1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1ccc(NC(=O)C(C)(C)C)nc1NC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 12 h
Yield: 15565.2 %

Procedure:
In a 5 L, 4-necked round bottom flask, immersed in ice-cold ethanol-isopropanol (isopropanol 13%, −15° C.) bath, to a solution of 2,6-bis[(2,2-dimethylpropanoyl)amino]pyridine (J. Am. Chem. Soc. 1986, 108, 3310–3318, 126 g, 454 mmol) in anhydrous tetrahydrofuran (1.5 L) was added 2.66 M solution of n-buthyllithium in hexane (598 mL) dropwise from a dropping funnel (1 L) during the period of 6 h under nitrogen atmosphere (internal temperature was maintained at −15° C.˜−5° C.). The resulting solution was stirred at 0° C. (internal temperature) for 12 h under nitrogen atmosphere. The formation of yellowish precipitate was noticed. Then the suspension was cooled to −15° C., dimethyl carbonate (194 mL, 2.3 mmol) was added in one portion. The reaction solution was stirred at 0° C. for 1 h, quenched with 1.5 L of 1 N aqueous hydrochloric acid, pH value was controlled to ˜4.5 by adding 1 N aqueous hydrochloric acid, then 600 mL of ethyl acetate was added. After the layers were separated, the organic layer was washed with 1 L of 0.2 N aqueous NaOH (1 L) and brine (500 mL). Each aqueous layer was extracted with ethyl acetate (300 mL) twice. Combined organic layer was dried over sodium sulfate (˜300 g) and concentrated. The residue was diluted with diisopropylether (300 mL) and the solution was evaoprated to remove the residual ethyl acetate azeotropically. The residue was dissolved with diisopropylether (360 mL) at 60° C. with gentle stirring, and then the small portion of the crystalline of the desired product (˜5 mg) was added as seed. The formation of a pale yellow precipitate was noticed. The resulting suspension was cooled to room temperature (during the period of 2 h), and stirred at room temperature for 2 h. The suspension was filtered through paper filter, then the cake was washed with diisopropylether (80 mL). The solid was dried under reduced pressure at room temperature for 1 day to give the title compound (120 g, 358 mmol, 79%) as a pale yellow solid.
Reaction SMILES: [Na].Br[C:3]1[C:8]([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=2)=[C:7]([C:17](=[O:19])[CH3:18])[CH:6]=[C:5]([Cl:20])[C:4]=1[CH3:21].[CH2:22]([O:24][CH:25]([N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1)[CH3:26])[CH3:23]>O.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:20][C:5]1[C:4]([CH3:21])=[C:3]([C:30]2[CH:29]=[N:28][N:27]([CH:25]([O:24][CH2:22][CH3:23])[CH3:26])[CH:31]=2)[C:8]([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=2)=[C:7]([C:17](=[O:19])[CH3:18])[CH:6]=1
Reactant: CCOC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(=O)c1cc(Cl)c(C)c(Br)c1-c1cc(F)cc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(C)n1cc(-c2c(C)c(Cl)cc(C(C)=O)c2-c2cc(F)cc(F)c2)cn1
Temperature: 90 °C
Yield: 40.1 %

Procedure:
To a solution of sodium hydrogenecarbonate (0.093 g, 1.1 mmol) in water (2 mL) was added a solution of 1-(6-bromo-4-chloro-3′,5′-difluoro-5-methylbiphenyl-2-yl)ethanone (0.20 g, 0.56 mmol) in toluene (2 mL) followed by 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.18 g, 0.67 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.064 g, 0.056 mmol). The mixture was bubbled with N2 for 5 min and then heated at 90° C. overnight. The organic layer was concentrated and flashed on silica gel (eluting with 0-20% of ethyl acetate in hexanes) to afford the desired product (94 mg, 40%). LCMS calculated for C22H22ClF2N2O2 (M+H)+: m/z=419.1. found: 419.1.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.[NH2:8][C:9]1[N:10]=[C:11](Cl)[C:12]([C:15]#[N:16])=[N:13][CH:14]=1.Cl>O1CCOCC1>[NH2:8][C:9]1[N:10]=[C:11]([O:7][CH2:6][CH:3]2[CH2:5][CH2:4]2)[C:12]([C:15]#[N:16])=[N:13][CH:14]=1
Reactant: OCC1CC1
Reactant: N#Cc1ncc(N)nc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1ncc(N)nc1OCC1CC1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
To a solution of sodium hydride (93 mg, 3.882 mmol) in dioxane (4 mL) was added cyclopropylmethanol (280 mg, 3.882 mmol) dropwise. The solution was stirred for 30 minutes and then 5-amino-3-chloropyrazine-2-carbonitrile (300 mg, 1.941 mmol) was added and the reaction mixture heated at 90° C. for 14 hours. The reaction mixture was poured into aqueous HCl (1 M) and extracted with ethyl acetate. The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to dryness to give the title compound (305 mg, 1.605 mmol, 83%) which was used in subsequent steps without further purification. LC-MS (3) Rt=1.49 min; m/z (ESI+) 191 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([C:23]([OH:26])([CH3:25])[CH3:24])[CH2:18]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][NH2:28]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([C:23]([OH:26])([CH3:25])[CH3:24])[C:20]([NH:28][CH3:27])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1C[C@@H](C(C)(C)O)C(=O)O1
Reactant: CN
Solvent: CO
Product: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(C)(C)O
Reaction time: 8 h
Yield: 95 %

Procedure:
A solution of 1.93 g (5.22 mmoles) of (3S, 5S)-5-[(1S)-1-(N-t-butoxycarbonylamino)-2-cyclohexylethyl]-3-(1-hydroxy-1-methylethyl)dihydrofuran-2(3H)-one (prepared as described in Preparation 6) in 50 ml of methanol was saturated with gaseous methylamine by passing the gas through the solution whilst ice-cooling, and then the flask containing the reaction mixture was stoppered tightly and allowed to stand at room temperature overnight. The reaction mixture was then concentrated by evaporation under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (using a 20:1 by volume mixture of methylene chloride and methanol as eluent), followed by recrystallization from hexane, to give 1.98 g (yield 95%) of the title compound as white crystals, melting at 174°-175° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][CH2:11][CH2:12]Cl.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[F:10][CH2:11][CH2:12][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: FCCCl
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCF)cc1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
4-Hydroxybenzaldehyde (26.0 g), 20.7 g of 1-fluoro-2-chloroethane and 42.4 g of anhydrous potassium carbonate were added to 100 ml of dimethylformamide, and reacted at 130° C. for 5 hours. After the reaction, the reaction mixture was cooled to room temperature, poured into water, and then extracted with toluene. The toluene layer was washed with water, and dried over anhydrous sodium sulfate. Toluene was evaporated under reduced pressure to give 35.6 g of crude 4-(2-fluoroethoxy)benzaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[N+:19]([O-])=O)=[CH:7][CH:6]=1)=[O:4].C(OCC)(=O)C>C(O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[NH2:19])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(-c2ccc(OC)cc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1ccc(-c2ccc(OC)cc2N)cc1
Reaction time: 18 h
Yield: 98.3 %

Procedure:
To 4′-Methoxy-2′-nitro-biphenyl-4-carboxylic acid methyl ester (4.00 g) suspended in ethanol (150 mL) and ethyl acetate (150 mL) is added 5% palladium on carbon (0.300 g). The reaction mixture is placed under an atmosphere of hydrogen (50 psi) and is shaken on a Parr apparatus. After 18 h, the reaction mixture is degassed with nitrogen and is filtered through a plug of silica gel, eluting with 700 mL ethyl acetate and 600 mL methylene chloride. The filtrate is evaporated to afford the title compound (3.52 g, >99%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][O:4][N:3]=1.[Br:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([S:25](Cl)(=[O:27])=[O:26])=[CH:22][CH:23]=3)[C:18]([CH3:29])=[CH:17][C:16]2=[O:30])=[C:10]([O:31][CH3:32])[CH:9]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O1CCOCC1>C1COCC1>[Br:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([S:25]([NH:1][C:2]4[CH:6]=[CH:5][O:4][N:3]=4)(=[O:26])=[O:27])=[CH:22][CH:23]=3)[C:18]([CH3:29])=[CH:17][C:16]2=[O:30])=[C:10]([O:31][CH3:32])[CH:9]=1
Reactant: COc1cc(Br)c(Cl)cc1-n1c(=O)cc(C)c2cc(S(=O)(=O)Cl)ccc21
Reactant: Nc1ccon1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COc1cc(Br)c(Cl)cc1-n1c(=O)cc(C)c2cc(S(=O)(=O)Nc3ccon3)ccc21
Yield: 24.9 %

Procedure:
A solution of 3-aminoisoxazole (0.867 ml, 11.74 mmol) and 1-(4-bromo-5-chloro-2-methoxyphenyl)-4-methyl-2-oxo-1,2-dihydroquinoline-6-sulfonyl chloride (1.120 g, 2.347 mmol) in 10 mL THF, was cooled to 0° C. LHMDS 1N in THF (11.74 ml, 11.74 mmol) was added, and the cooling bath was removed. After stirring for an additional hour, the reaction mixture was treated with hcl 4N in dioxane (5.87 ml, 23.47 mmol) and was concentrated. Purification of the crude residue by reverse phase column chromatography [Redisep Gold C18, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazol-3-yl)-4-methyl-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.307 g, 0.585 mmol, 24.92% yield). In/z (ESI) 525.9 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(C)=O)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f36) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[S:4][CH:5]=[C:6]([C:8](=[O:11])[CH2:9]Br)[N:7]=1.CS(C)=[O:16]>>[F:1][C:2]([F:13])([F:12])[C:3]1[S:4][CH:5]=[C:6]([C:8](=[O:11])[CH:9]=[O:16])[N:7]=1
Reactant: CS(C)=O
Reactant: O=C(CBr)c1csc(C(F)(F)F)n1
Product: O=CC(=O)c1csc(C(F)(F)F)n1
Temperature: 25 °C

Procedure:
3 g (0.011 mol) of 2-Trifluoromethyl-4-bromoacetyl-thiazole are dissolved in 30 ml of dimethyl sulphoxide and the solution is maintained at room temperature for 70 hours. It is then poured onto 100 g of ice, and the mixture is extracted several times with ether, the organic phase is dried over sodium sulphate and concentrated, and the residue is purified on a silica gel column using toluene/ethyl acetate =7/3 as eluant.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]([C:27](=O)[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23]C(=O)C)=[CH:19][CH:18]=3)=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:39]>C(O)(=O)C>[CH2:28]([C:27]1[N:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][C:5]3[CH:33]=[CH:34][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:8][CH:9]=2)[CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:39]=1)[CH2:29][CH2:30][CH3:31]
Reactant: [NH4+]
Reactant: CCCCC(=O)N(CC(=O)c1ccc(OC(C)=O)cc1)c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCCCc1nc(-c2ccc(O)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 105 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
A mixture of acetic acid 4-(2-{[4-(4-chloro-phenoxy)-phenyl]-pentanoyl-amino}-acetyl)-phenyl ester (from above, based on 200 mmol) with ammonium acetate (308 g, 4000 mmol, 20.0 eq) in acetic acid (300 mL) was stirred at 100-110° C. overnight. After completion of the reaction (indicated by HPLC), the mixture was cooled below 60° C. and poured over ice. After stirring, the solid was filtered, washed with diethyl ether (twice), ethyl acetate (twice), ether (once) and air dried, yielding ˜55.0 g (65.6%) of 4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenol as a finely divided off-white solid.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20]OS(C)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:28][O:29][CH2:30][CH2:31][NH:32][CH3:33]>>[CH3:28][O:29][CH2:30][CH2:31][N:32]([CH3:33])[CH2:20][C:19]#[C:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:27])[F:26])=[CH:4][CH:5]=3)=[N:10][S:11][C:12]=2[CH:17]=1
Reactant: CNCCOC
Reactant: CS(=O)(=O)OCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Product: COCCN(C)CC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 17.1, Methanesulfonic acid 3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl ester and 2-Methoxyethylmethylamine were converted to yield (2-Methoxy-ethyl)-methyl-{3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-amine as light brown oil, MS: 405 (MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.Cl[C:10]1[C:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:14]([CH3:23])[N:13]=[N:12][C:11]=1[CH3:24].C(OCC)(=O)C>CN(C=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]2[C:10]([N:6]3[CH:5]=[C:4]([CH3:3])[CH:8]=[N:7]3)=[C:11]([CH3:24])[N:12]=[N:13][C:14]=2[CH3:23])=[CH:21][CH:20]=1
Reactant: Cc1cn[nH]c1
Reactant: Cc1nnc(C)c(-c2ccc(Cl)cc2)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cnn(-c2c(C)nnc(C)c2-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
87 mg of sodium hydride (55% oil dispersion) was added to 3 ml of DMF, and to this was added a solution of 0.16 g of 4-methylpyrazole in 3 ml of DMF, and the mixture was stirred for 0.5 hours at room temperature. To the resultant mixture was added 0.25 g of 4-chloro-5-(4-chlorophenyl)-3,6-dimethylpyridazine, and the mixture was stirred for 3 hours on an oil bath of 80° C. To the reaction mixture was added ethyl acetate, and washed with brine four times. The organic layer was dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.40 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.21 g of 5-(4-chlorophenyl)-3,6-dimethyl-4-(4-methyl-1-pyrazolyl)pyridazine (hereinafter, described as compound (5) of the present invention.).
Reaction SMILES: S([N:11]1[C:23]2[C:22]([C:29]([F:32])([F:31])[F:30])([O:24][Si](C)(C)C)[CH2:21][CH2:20][CH2:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[C:15]([C:33]#[N:34])[CH:16]=2)(C1C=CC(C)=CC=1)(=O)=O.[OH-].[K+]>C1COCC1.O>[OH:24][C:22]1([C:29]([F:32])([F:30])[F:31])[C:23]2[NH:11][C:12]3[C:17](=[CH:16][C:15]([C:33]#[N:34])=[CH:14][CH:13]=3)[C:18]=2[CH2:19][CH2:20][CH2:21]1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4cc(C#N)ccc42)CCCC3(O[Si](C)(C)C)C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc2[nH]c3c(c2c1)CCCC3(O)C(F)(F)F
Temperature: 55 °C
Yield: 89.2 %

Procedure:
9-Tosyl-1-(trifluoromethyl)-1-(trimethylsilyloxy)-2,3,4,9-tetrahydro-1H-carbazole-6-carbonitrile (0.03 g, 0.06 mmol) was dissolved in THF (2 mL) and KOH (11 mg, 0.2 mmol), in H2O (2 mL) was added. The reaction mixture was heated to 55° C. for 24 h, then cooled to room temperature, diluted with water (5 mL) and extracted with EtOAc (3×5 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give the crude compound which was purified by column chromatography [EtOAc-hexane (1:9) as eluant] to afford the title compound as a white solid (15 mg, 79%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.4 (bs, 1H), 7.9 (s, 1H), 7.49 (d, J=9.0 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 2.89-2.85 (m, 1H), 2.76-2.74 (m, 1H), 2.45 (s, 1H), 2.32-2.28 (m, 1H), 2.14-2.12 (m, 2H), 2.05-2.03 (m, 1H).
Reaction SMILES: [CH3:1][CH:2]([SH:6])[CH:3]([SH:5])[CH3:4].Cl[CH2:8][C:9](=O)[CH2:10][CH3:11]>>[CH2:10]([C:9]1[S:5][CH:3]([CH3:4])[CH:2]([CH3:1])[S:6][CH:8]=1)[CH3:11]
Reactant: CC(S)C(C)S
Reactant: CCC(=O)CCl
Product: CCC1=CSC(C)C(C)S1
Yield: 53 %

Procedure:
The procedure of Example 1 (a) is followed using 2,3-butanedithiol and 1-chloro-2-butanone to give 2-ethyl-5,6-dihydro-5,6-dimethyl-1,4-dithiin as a colorless oil, b.p. 55°-58°10.03- 0.05 mm, yield 53%. NMR 1.08 (3t), 1.36 (6d), 2.18 (2q), 2.7-3.1 (2m), 5.78 (1s, broadened) (CDCl 3). IR 3000 (shoulder), 2955, 1570, 1440, 1365, 1110, 825, 705.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]([CH3:28])([CH3:27])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[N:11]1[CH2:16][CH2:15][C:14]2[NH:17][CH:18]=[CH:19][C:13]=2[CH2:12]1)C.C(O)C.[OH-].[Na+]>O>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:10]([N:11]1[CH2:16][CH2:15][C:14]2[NH:17][CH:18]=[CH:19][C:13]=2[CH2:12]1)[CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:28])([CH3:27])[C:4]([OH:29])=[O:3]
Reactant: CCOC(=O)C(C)(C)CCCCC(c1ccccc1Cl)N1CCc2[nH]ccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(CCCCC(c1ccccc1Cl)N1CCc2[nH]ccc2C1)C(=O)O
Temperature: 96.5 °C
Reaction time: 26 h
Yield: 55.5 %

Procedure:
7-(2-Chlorophenyl)-2,2 dimethyl-7-(1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-yl)-heptanoic acid ethyl ester (0.21 g, 0.51 mmol) was added to a mixture of ethanol (10 mL), water (2.70 mL), and sodium hydroxide (0.14 g, 3.54 mmol). The mixture was heated to reflux (95-98° C. oil bath) for 16 hours. After 26 hours, the flask was cooled to room temperature and the solvent was evaporated under reduced pressure. Water (15 mL) was added to the residue and the product was extracted with diethyl ether (15 mL). The extract was discarded and the aqueous portion was adjusted pH=6 with 10 N hydrochloric acid. The product was extracted with dichloromethane (3×15 mL) and the combined dichloromethane layers were washed with water (20 mL) and brine (20 mL). The dichloromethane solution was dried over sodium sulfate, filtered, and concentrated in under reduced pressure. The crude product was purified by column chromatography (silica gel, MeOH/CH2Cl2=1/9) to afford 7-(2-chlorophenyl)-2,2 dimethyl-7-(1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-yl)-heptanoic acid (Compound Ik, 0.11 g, 57.9% yield) as a yellow oil. 1H NMR (Field: 300 MHz, Solvent: DMSO/TMS) δ (ppm): 12.10 (br, 1H), 10.30 (br, 1H), 7.53 (m, 1H), 7.43 (d, 1H, J=7.2 Hz), 7.36-7.25 (m, 2H), 6.50 (s, 1H), 5.71 (s, 1H), 4.10 (m, 1H), 3.39 (m, 5H), 2.75 (m, 1H), 1.14 (m, 2H), 1.34 (m, 2H), 1.23-1.07 (m, 4H), 1.03 (s, 6H). 13C NMR (Field: 75 MHz, Solvent: DMSO/TMS) 6 (ppm) 178.45, 178.97, 133.83, 129.07, 128.23, 126.93, 123.97, 115.83, 113.99, 104.19, 63.11, 48.27, 47.60, 41.19, 40.06, 31.59, 25.84, 25.03, 24.96, 24.55, 23.34.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1([Cl:14])[CH:13]=[CH:12][CH:11]=[N:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:16](Br)[CH:17]=[CH2:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:15])[N:7]([CH2:18][CH:17]=[CH2:16])[C:8]1([Cl:14])[CH:13]=[CH:12][CH:11]=[N:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)NC1(Cl)C=CC=NC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCN(C(=O)OC(C)(C)C)C1(Cl)C=CC=NC1
Reaction time: 1 h
Yield: 84.3 %

Procedure:
A mixture of (3-chloro-pyridin-3-yl)-carbamic acid tert-butyl ester (8.4 g, 36.8 mmol), allyl bromide (7.46 g, 39.1 mmol) and cesium carbonate (24.9 g, 76.4 mmol) in DMF (100 mL) is heated at 600 C. for 1 h. The reaction is quenched with water, extracted with EtOAc. The organic layer is dried (Na2SO4), filtered, and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0-40% EtOAc in heptane to afford allyl-(3-chloro-pyridin-3-yl)-carbamic acid tert-butyl ester (8.4 g, 85%). MS: 269 (M+H); 1H NMR (300 MHz, CDCl3): δ=8.66 (s, 1H), 8.49 (d, 1H), 7.18 (d, 1H), 5.80-5.96 (m, 1H) 5.15 (s, 1H), 5.10(d, 1H), 4.2 (broad s, 1H), 1.43 (s, 9H).