Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH2:13])[S:11][CH:12]=2)=[CH:4][CH:3]=1.Br[C:15]1[S:16][C:17]([C:20](O)=O)=[CH:18][N:19]=1>>[CH2:8]([NH:9][C:15]1[S:16][C:17]([CH2:20][NH:13][C:10]2[S:11][CH:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=2)=[CH:18][N:19]=1)[C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: Nc1nc(-c2ccc(Cl)cc2)cs1
Reactant: O=C(O)c1cnc(Br)s1
Product: Clc1ccc(-c2csc(NCc3cnc(NCc4ccccc4)s3)n2)cc1
Reaction time: 2 h

Procedure:
Compound 2ak was prepared as described for 2 h starting from 4-(4-chlorophenyl)thiazol-2-amine and 2-bromothiazole-5-carboxylic acid (31 mg, 49%). Mp. 105-106° C.
Reaction SMILES: [CH2:1]([N:5]([CH2:26][CH2:27][CH2:28][CH3:29])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[C:21]([CH3:22])=[CH:20][C:17]([CH:18]=O)=[C:16]([CH3:23])[CH:15]=2)=[C:8]([O:24][CH3:25])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:30]([C:32]1[C:33](=[C:40]([C:43]#[N:44])[C:41]#[N:42])[O:34][C:35]([CH3:39])([CH3:38])[C:36]=1[CH3:37])#[N:31].C([O-])(=O)C.[NH4+]>C(O)C.O1CCCC1>[CH2:26]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[C:21]([CH3:22])=[CH:20][C:17]([CH:18]=[CH:37][C:36]3[C:35]([CH3:38])([CH3:39])[O:34][C:33](=[C:40]([C:41]#[N:42])[C:43]#[N:44])[C:32]=3[C:30]#[N:31])=[C:16]([CH3:23])[CH:15]=2)=[C:8]([O:24][CH3:25])[CH:7]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Reactant: CCCCN(CCCC)c1ccc(C=Cc2cc(C)c(C=O)cc2C)c(OC)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=Cc2cc(C)c(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C)cc2C)c(OC)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 55.7 %

Procedure:
In 6 ml of ethanol and 2 ml of tetrahydrofuran were dissolved 250 mg (0.64 mmol) of 4-[2-(4-dibutylamino-2-methoxyphenyl) vinyl]-2,5-dimethylbenzaldehyde and 140 mg (0.70 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene) propanedinitrile. To this mixture was added 49 mg of ammonium acetate, and the mixture was stirred at 70° C. for 4 hours. The solvent was evaporated off, and the residue was purified by silica gel column chromatography and washed with ethanol to give 205 mg of a black powder (yield: 56.2%; mp: 242-244° C.)
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=1>C(Cl)(Cl)(Cl)Cl>[Br:2][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=1
Reactant: COC(=O)Cc1ccc(CCO)cc1
Reactant: BrP(Br)Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)Cc1ccc(CCBr)cc1
Temperature: 25 °C

Procedure:
Phosphorus tribromide (1.42 g) was added, dropwise, to a solution of methyl 4-(2-hydroxyethyl)phenylacetate (2.7 g-see Preparation 21) in carbon tetrachloride (20 ml) at 0°. When the addition was complete, the mixture was allowed to warm to room temperature and then heated under reflux for 2 hours. Ice (100 g) was added and the mixture was partitioned between dichloromethane (50 ml) and saturated aqueous sodium bicarbonate (50 ml). The layers were separated and the aqueous layer extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing hexane (40%) then with dichloromethane. The product-containing fractions were combined and concentrated in vacuo to give the title compound as an oil, yield 1.02 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH2:8]Br.[C:27]([NH2:30])(=[S:29])[CH3:28]>>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:16])([F:18])[F:17])[O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][NH:30][C:27](=[S:29])[CH3:28]
Reactant: CC(N)=S
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(CBr)c(Br)c2)=NO1
Product: CC(=S)NCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Temperature: 80 °C
Reaction time: 1 h
Yield: 32.1 %

Procedure:
3-[3-bromo-4-(bromomethyl)phenyl]-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (0.3 g) was mixed with thioacetamide (0.04 g), and the mixture was then stirred for one hour at 80° C. The residue was purified by silica gel chromatography to yield N-{2-bromo-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}ethanethioamide (0.09 g).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:11][C:10]=2[F:24])=[O:5])C.[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1.C(O)(=O)C.Cl>C1(C)C=CC=CC=1>[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2[OH:16])=[CH:13][C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[CH:11][C:10]=3[F:24])=[O:5])=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cnc2c(F)cc(-c3ccccc3C)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1ccccc1-c1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 190 °C

Procedure:
6-Iodo-8-fluoro-4-hydroxy-3-quinolinecarboxylic acid ethyl ester (903 mg) from Example No. 5 and o-tolueneboronic acid (374 mg) are dissolved in DMF (50 mL) and at 50° C. a solution of barium hydroxide octahydrate (1.18 g) in water (5 mL) is added followed by palladium tetrakistriphenylphosphine (58 mg). The mixture is heated at 80° C. for 20 h, allowed to cool to rt, poured into water (200 mL), and extracted with ethyl acetate (3×100 mL). The organic layer is washed with brine (25 mL), dried (MgSO4), and concentrated. The solid is then triturated with MTBE, and filtered to afford 382 mg of 6-(2-methylphenyl)-8-fluoro-4-hydroxy-3-quinoline-carboxylic acid ethyl ester. The crude ester is mixed with 4-chlorobenzylamine (380 mg) and is heated to 190° C. for 1 h. The mixture is diluted with toluene (4 mL), allowed to cool to rt, poured into a mixture of 50% acetic acid (10 mL) and 1 N hydrochloric acid (25 mL), and is extracted with ethyl acetate (3×25 mL). The organic layer is dried (MgSO4) and allowed to crystallize. Recrystallization from acetic acid/water affords 166 mg of the title compound.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Br:5][C:6]1[CH:29]=[CH:28][C:9]([CH2:10][N:11]([CH2:22][CH:23](OC)OC)S(C2C=CC(C)=CC=2)(=O)=O)=[CH:8][CH:7]=1>ClCCl>[Br:5][C:6]1[CH:29]=[C:28]2[C:9](=[CH:8][CH:7]=1)[CH:10]=[N:11][CH:22]=[CH:23]2
Reactant: COC(CN(Cc1ccc(Br)cc1)S(=O)(=O)c1ccc(C)cc1)OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Brc1ccc2cnccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.2 %

Procedure:
To a mechanically stirred suspension of 95.2 g (699.5 mmol) AlCl3 in 400 ml dichloromethane a solution of 59.9 g (139.8 mmol) N-(4-Bromo-benzyl)-N-(2,2-dimethoxy-ethyl)-4-methyl-benzenesulfonamide (2) in 400 ml dichloromethane was added and the reaction was stirred at room temperature for 4 h. After standing overnight, the reaction mixture was poured on ice, the organic layer was separated and the aqueous layer was extracted twice with dichloromethane. The combined dichloromethane solutions were washed with 1 N NaOH (2×) and saturated NaHCO3-solution (2×). After drying with MgSO4 and evaporation of the solvent, the crude product was purified by silicagel chromatography (heptane/ethyl acetate 1:1) to yield 17.5 g of the title compound. Rt=0.68 min (Method C). Detected mass: 208.1/210.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[F:8].CCN(CC)CC.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:18][S:19]([O:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[CH:3]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(F)c(Br)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(F)c(Br)c1
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To a solution of (3-bromo-4-fluorophenyl)methanol (53 g, 0.258 mol) in DCM (500 mL) at 0° C. was added Et3N (108 mL, 775 mmol, 3 eq) and methanesulfonyl chloride (24 mL, 310 mmol, 1.2 eq) successively. After stirring 30 min, the reaction mixture was partitioned in DCM and water. The organic layer was dried over MgSO4 and evaporated in vacuo to give 3-bromo-4-fluorobenzyl methanesulfonate (60 g), which used to the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.65-7.62 (m, 1H), 7.37-7.33 (m, 1H), 7.16 (t, J=4.4 Hz, 1H), 5.17 (s, 2H), 2.99 (s, 3H).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[CH3:27][N:28]([CH3:40])[C@H:29]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:30](O)=O>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:30]([C@H:29]([N:28]([CH3:40])[CH3:27])[CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: CN(C)[C@H](Cc1ccccc1)C(=O)O
Product: CON=C1C[C@@H](c2noc([C@@H](Cc3ccccc3)N(C)C)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and (2R)-2-(dimethylamino)-3-phenylpropanoic acid, the title compound was obtained in 54% purity by HPLC. MS(ESI+): m/z=510.6.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH2:14][CH2:15][N:16]([S:22](Cl)(=[O:24])=[O:23])[CH2:17]2.[N:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[N:28][CH:27]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH2:14][CH2:15][N:16]([S:22]([NH:32][C:29]1[CH:30]=[CH:31][N:26]=[CH:27][N:28]=1)(=[O:24])=[O:23])[CH2:17]2
Reactant: Nc1ccncn1
Reactant: O=S(=O)(Cl)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2Br)C1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccncn1)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2Br)C1
Temperature: 25 °C
Yield: 65.9 %

Procedure:
A 15-mL round-bottom flask was charged with 5-(2-bromo-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate D, 287.2 mg, 0.731 mmol) and triethylamine (224 μl, 1.609 mmol) in DCM (3.8 mL) to give a brown solution. The flask was cooled in an ice-bath for 10 min, then sulfuryl chloride (125 μl, 1.536 mmol) was added dropwise. Stirring was continued for 2 hours at which time the mixture was quenched with water, then extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on a 40 g silica gel column with 0 to 40% EtOAc/Heptane to give 5-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonyl chloride (253.01 mg, 0.556 mmol) as a clear, very viscous oil that was immediately used in the next step. A vial was charged with 5-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonyl chloride (40.045 mg, 0.088 mmol), pyrimidin-4-amine (41.9 mg, 0.440 mmol), chloroform (587 μl), and pyridine (71.2 μl, 0.881 mmol) and was placed into a 50° C. bath. The mixture was heated overnight before being allowed to cool to rt. The mixture was concentrated under a vacuum, and the residue was chromatographed on a 12 g silica gel column with 0 to 6% MeOH/DCM to give 5-(2-bromo-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (29.77 mg, 0.058 mmol) as a yellow solid. [M+H]+=513.0. 1H NMR (400 MHz, DMSO-d6) δ ppm=9.55 (br. s., 1H), 9.07 (br. s., 1H), 8.57 (br. s., 1H), 8.13 (d, J=1.3 Hz, 1H), 7.99 (br. s., 1H), 7.83 (dd, J=1.1, 8.0 Hz, 1H), 7.55-7.44 (m, 1H), 7.35-7.21 (m, 2H), 7.02 (dd, J=2.0, 6.8 Hz, 1H), 4.71 (d, J=6.4 Hz, 1H), 4.32-4.17 (m, 2H), 3.24-3.07 (m, 2H), 2.45 (br. s., 2H).
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>C(O)C>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([N:18]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])=[CH:16][CH:15]=1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: Nc1ccc(Cl)cc1
Solvent: CCO
Product: O=C(O)C1CCN(c2ccc(Cl)cc2)C1=O
Yield: 67.3 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g; 1.45 mmol) and 4-chloroaniline (0.568 g; 4.36 mmol) in ethanol (3 mL). 1-(4-chlorophenyl)-2-oxopyrrolidine-3-carboxylic acid 0.234 g (67%) was obtained as a white solid.
Reaction SMILES: CC(C)([O-])C.[K+].Br.[Cl:8][C:9]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:10]=1[NH2:11].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21](S(C)(=O)=O)[N:20]=1>CN(C)C=O>[Cl:8][C:9]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:21]2[N:22]=[C:23]([O:25][CH3:26])[CH:24]=[C:19]([O:18][CH3:17])[N:20]=2)[C:10]=1[NH2:11]
Reactant: Nc1c(O)cccc1Cl
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Oc2cccc(Cl)c2N)n1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 3 %

Procedure:
Potassium t-butoxide (22.4 g) was added portionwise to stirred, cooled 2-chloro-6-hydroxyaniline hydrobromide (22.5 g) in dimethylformamide (100 ml) under nitrogen. After 10 minutes, 4,6-dimethoxy-2-methylsulphonyl pyrimidine (21.8 g) was added, and the mixture was heated at 80° C. with stirring for 22 hours. After addition to ice/water, the precipitated solid was separated by filtration, washed thoroughly with water, dried and recrystallised from isopropanol yielding 17.5 g of the desired product, mp 84°-86° C. Reduction in volume of the mother liquors gave a further 0.85 g of product, mp 86°-87° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:4](=[O:21])[CH:5]2[CH2:20][C:8]3([CH2:19][C:18]4[C:14]5[N:15]=[N:16][NH:17][C:13]=5[CH:12]=[CH:11][C:10]=4[C:9]=13)[CH2:7][CH2:6]2>C(O)C.CO>[F:22][C:2]([F:1])([F:23])[C:3]1[C:4](=[O:21])[C@H:5]2[CH2:20][C@:8]3([CH2:19][C:18]4[C:14]5[N:15]=[N:16][NH:17][C:13]=5[CH:12]=[CH:11][C:10]=4[C:9]=13)[CH2:7][CH2:6]2
Reactant: O=C1C(C(F)(F)F)=C2c3ccc4[nH]nnc4c3CC23CCC1C3
Solvent: CCO
Solvent: CO
Product: O=C1C(C(F)(F)F)=C2c3ccc4[nH]nnc4c3C[C@@]23CC[C@@H]1C3

Procedure:
6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta-[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one [1.8 g, (8R,10aS):(8S,10aR) enantiomeric ratio ˜2:1] was dissolved in 1/1 ethanol/methanol (130 mL) and resolved by chiral HPLC on a 2.0×25 cm Daicel Chiralcel OJ column (4 mL injections, elution with 35% EtOH:Heptane at 7.5 L/min, fractions monitored at 310 nm). The pure fractions containing the first enantiomer to elute (enantiomer A) were combined and concentrated to give (8R,10aS)-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one as a white solid which had a negative rotation. The fractions containing the second enantiomer to elute (enantiomer B) were combined and concentrated to give (8S,10aR)-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5d][1,2,3]triazol-7(8H)-one as a solid which had a positive rotation.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:23]1[CH:24]=[CH:25][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:21][CH:22]=1)[CH:9]=2)=[O:4]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Product: COC(=O)c1c(O)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2sc1=O

Procedure:
4-Hydroxy-2-oxo-7-(4-trifluoromethyl-phenyl)-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5 e) and 4-trifluoromethylphenylboronic acid under conditions analogous to Example 7(a). MS ESI(−) m/e: 379.05 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[CH3:12].Br[C:14]1[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)=[CH:5][C:4]=1[CH3:12]
Reactant: COc1ccc(B(O)O)cc1C
Reactant: Cn1cc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2cnn(C)c2)cc1C
Yield: 65.9 %

Procedure:
Under nitrogen atmosphere, a mixture of 4-methoxy-3-methyl-phenylboronic acid 1.62 g, 4-bromo-1-methyl-1H-pyrazole 1.57 g, 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex 0.79 g, sodium carbonate 3.51 g, dioxane 100 ml and water 30 ml was stirred with heating under reflux for four hours. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, and was dried over anhydrous magnesium sulfate and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 4-(4-methoxy-3-methyl-phenyl)-1-methyl-1H-pyrazole 1.3 g.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=2[O:2]1.S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][CH2:19][CH3:20])=[O:12])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc2c(c1)OCO2

Procedure:
To a solution of 3,4-methylenedioxyphenylacetic acid (10 g) in ethanol (100 ml) was added conc. sulfuric acid (3 ml). After being refluxed for 90 minutes, the mixture was concentrated in vacuo. The residue was dissolved in diethyl ether (150 ml). The solution was washed with 1M aqueous sodium bicarbonate solution and brine successively and dried over magnesium sulfate, and concentrated in vacuo to give ethyl 3,4-methylenedioxyphenylacetate (11.0 g) as an oil.
Reaction SMILES: C[O-].[Na+].[C:4]([C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[N:11][CH:12]=1)(=[NH:6])[NH2:5].C[C:21](C)([C:25]([O-])=[O:26])[C:22]([O-])=[O:23].Cl>CO.O>[OH:26][C:25]1[N:6]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:18])[CH3:17])=[N:11][CH:12]=2)[NH:5][C:22](=[O:23])[CH:21]=1
Reactant: CC(C)(C(=O)[O-])C(=O)[O-]
Reactant: CC(C)(C)C(=O)Nc1ccc(C(=N)N)cn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)C(=O)Nc1ccc(-c2nc(O)cc(=O)[nH]2)cn1
Temperature: 82 °C

Procedure:
A suspension of sodium methoxide (432 mg, 8.0 mmol), N-(5-carbamimidoylpyridin-2-yl)pivalamide (880 mg, 4.0 mmol) and dimethylmalonate (457 μL, 4.0 mmol) in 15 mL methanol is refluxed at 82° C. for 14 hours. The resulting suspension is dissolved in 15 mL water and acidified using 6M HCl. The precipitate is filtered, rinsed with water, air/vacuum dried and used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:13][CH3:14].[CH3:15][O:16][CH2:17]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:14][O:13][C:3]1[C:4]([N+:10]([O-:12])=[O:11])=[C:5]([CH:8]=[CH:9][C:2]=1[O:1][CH2:15][O:16][CH3:17])[C:6]#[N:7]
Reactant: COc1c(O)ccc(C#N)c1[N+](=O)[O-]
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(C#N)c([N+](=O)[O-])c1OC
Temperature: 50 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A mixture of 4-hydroxy-3-methoxy-2-nitrobenzonitrile 1.00 g, chloromethyl methyl ether 0.47 mL (6.18 mmol) and potassium carbonate 3.56 g (25.8 mmol) in N,N-dimethylformamide 10 mL was stirred at 50° C. for 2 hours. The reaction mixture was poured into water and extracted into diethyl ether. The organic layer was washed with brine, dried over MgSO4, filtrated and the solvent was evaporated. Silica gel chromatography (n-hexane/AcOEt=4/1) afforded the title compound 1.03 g as colorless solid. Yield 83.5%.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[Cl:8].Cl[CH2:11][C:12]([CH3:14])=[CH2:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:3](=[O:9])[N:4]([CH2:13][C:12]([CH3:14])=[CH2:11])[N:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=c1[nH]ncc(Cl)c1Cl
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)Cn1ncc(Cl)c(Cl)c1=O
Temperature: 40 °C
Reaction time: 5 h
Yield: 36.9 %

Procedure:
To 50 ml of N,N-dimethylformamide were suspended 10 g of 4,5-dichloro-3(2H)-pyridazinone, 27 g of 3-chloro-2-methylpropene and 8.4 g of potassium carbonate. The mixtured solution was stirred for 5 hours at 40° C. Then, the procedures in Preparation Example 2 were repeated to give 4.9 g of the intended compound.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:34]=[CH:33][CH:32]=[CH:31][C:12]=3[C:13]=2[C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:18][CH:17]=2)=[O:15])=[CH:5][CH:4]=1>CO>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:34]=[CH:33][CH:32]=[CH:31][C:12]=3[C:13]=2[CH:14]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][N:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)=[CH:20][CH:21]=2)[OH:15])=[CH:5][CH:4]=1
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)oc2ccccc12
Agent: Cl
Solvent: CO
Product: Oc1ccc(-c2oc3ccccc3c2C(O)c2ccc(OCCN3CCCCC3)cc2)cc1
Yield: 84.7 %

Procedure:
2.0 g (4.23 mmol) of [2-(4-hydroxyphenyl)-benzofuran-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone hydrochloride was reduced to the carbinol using the method described in Example 1. This yielded 1.59 g of the title compound as an amorphous powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[N:5]=[C:4]2[CH2:12][CH2:13][CH2:14][C:3]=12.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1>>[CH:9]([O:8][C:6]1[N:5]=[C:4]2[CH2:12][CH2:13][CH2:14][C:3]2=[C:2]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=2)[CH:7]=1)([CH3:11])[CH3:10]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CC(C)Oc1cc(Cl)c2c(n1)CCC2
Product: CCOC(=O)Cc1ccc(Nc2cc(OC(C)C)nc3c2CCC3)cc1
Yield: 85.3 %

Procedure:
Following general procedure B1, 4-chloro-2-isopropoxy-6,7-dihydro-5H-cyclopenta[b]pyridine (0.090 g, 0.43 mmol) was reacted with ethyl 2-(4-aminophenyl)acetate (0.114 g, 0.64 mmol) to afford the title compound (0.130 g, 86%) as a yellow gel. MW=354.44. APCI MS m/z 355 [M+H]+.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[NH:2][NH2:3].C(O)C.[CH3:11][C:12]1[NH:13][CH:14]=[C:15]([CH:17]=O)[N:16]=1>C(O)C.C(O)(=O)C>[CH2:6]([O:5][C:1](=[O:4])[NH:2][N:3]=[CH:17][C:15]1[N:16]=[C:12]([CH3:11])[NH:13][CH:14]=1)[CH3:7]
Reactant: CCOC(=O)NN
Reactant: Cc1nc(C=O)c[nH]1
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)NN=Cc1c[nH]c(C)n1

Procedure:
A solution of 16.68 gm. of ethyl carbazate in 50 ml. of hot ethanol is added to a solution of 16.50 gm. of 2-methyl-4-imidazolecarboxaldehyde in 100 ml. of hot ethanol containing 2 drops of acetic acid. The reaction is carried out as described in Example 32 giving the desired product, m.p. 210.5°-211.5° C.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br>C(O)(=O)C>[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(S(=O)(=O)c2ccccc2)cc1
Agent: Br
Solvent: CC(=O)O
Product: O=S(=O)(c1ccccc1)c1ccc(O)cc1
Temperature: 0 °C
Yield: 98.2 %

Procedure:
To a solution of 24.8 g (100 mmole) of the compound obtained in step 1 dissolved in 50 ml of acetic acid was added 40% HBr, which was heated to reflux for 8 hours. The reaction solution was poured into ice-water. The resultant solution was extracted with ethyl acetate (100 ml×3), dried over Na2SO4 and concentrated to obtain residue, which was purified by silica gel column chromatography using a mixture of hexane and ethyl acetate (1:1) to obtain 23.0 g (yield 100%) of the title compound containing a portion of orthoisomer (approximately one-eighth).