Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=1)(=O)=O.[CH:22]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)([CH3:24])[CH3:23].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCCC1>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>[CH:22]([C:25]1[CH:30]=[C:29]([C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=2)[CH:28]=[CH:27][CH:26]=1)([CH3:24])[CH3:23]
Reactant: CC(C)c1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)c1cccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1

Procedure:
A mixture of tert-butyl 4-[(trifluoromethyl)sulfonyl]oxy-3,6-dihydropyridine-1(2H)-carboxylate (11.0 g, 0.0332 mol), (3-isopropylphenyl)boronic acid (5.44 g, 0.0332 mol) and potassium phosphate (21.1 g, 0.0996 mol) in tetrahydrofuran (150.0 mL, 1.849 mol) was degassed for 15 min, then tetrakis(triphenylphosphine)palladium(0) (2 g, 0.002 mol) was added and the resulting mixture was refluxed overnight. After evaporation of most of THF, the residue was diluted with water, extracted with EtOAc. The combined organic layers were washed with brine, dried and evaporated to dry. The residue was applied on silica gel column, eluting with 0 to 20% EtOAc in hexane (9.1 g, 91%). MS (ESI): (M-Bu) 246.1.
Reaction SMILES: [C:1]([CH:3]1[CH2:9][CH:8]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:5]([CH2:6][CH2:7]2)[CH2:4]1)#N.[H-].C([Al+]CC(C)C)C(C)C.[O:28]1CCCC1>>[CH:1]([CH:3]1[CH2:9][CH:8]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:5]([CH2:6][CH2:7]2)[CH2:4]1)=[O:28]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(C#N)C2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CC(C)(C)OC(=O)N1C2CCC1CC(C=O)C2

Procedure:
tert-Butyl 3-cyano-8-azabicyclo[3.2.1]octane-8-carboxylate was reacted in the presence of diisobutyl aluminum hydride in tetrahydrofuran to produce tert-butyl 3-formyl-8-azabicyclo[3.2.1]octane-8-carboxylate.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(C)=O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:8]([O:7][CH2:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:8]=2)=[C:9]([CH:13]=1)[C:10]([O:12][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:11]
Reactant: COc1ccc(O)c(C(=O)O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
Potassium carbonate (690 mg, 5.00 mmol) was added to a stirred solution of 2-hydroxy-5-(methyloxy)benzoic acid (336 mg, 2.00 mmol) in acetone (20 ml) followed by the addition of ((bromomethyl)benzene (854 mg, 5.00 mmol). The mixture was refluxed for 12 h and then cooled to room temperature. The mixture was filtered and the filtrate was concentrated to a yellow solid. Flash chromatography over silica gel eluting with 1:10 ethyl acetate:petroleum ether yielded the title compound as a pure, white powder. 500 mg.
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][C:12]([C:15]2[CH2:22][S:21][CH:20]3[N:17]([C:18](=[O:31])[CH:19]3[NH:23]C(OC(C)(C)C)=O)[C:16]=2[C:32]([O:34][CH:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])=[CH:13][N:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O)(=O)=O>C(#N)C>[NH2:23][CH:19]1[C:18](=[O:31])[N:17]2[CH:20]1[S:21][CH2:22][C:15]([C:12]1[S:11][C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:14][CH:13]=1)=[C:16]2[C:32]([O:34][CH:35]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(NC(=O)c4ccccc4)s3)CSC12
Agent: CS(=O)(=O)O
Solvent: CC#N
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(NC(=O)c4ccccc4)s3)CSC12
Yield: 81.1 %

Procedure:
A solution of 3-(2-benzamido-thiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (2.9 g) in acetonitrile (29 cc) is treated with methanesulphonic acid (2.9 cc) using the working method of Example 15. Crude 7-amino-3-(2-benzamido-thiazol-5-yl)-2-benzhydryloxycarbonyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (2 g) is obtained in the form of a yellow froth.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([C:13]2[C:22]3[C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[S:25][C:21]=3[C:20]([Br:30])=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[CH:18]3)[CH:10]=[C:9]([Br:31])[C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].[Na]>>[Br:1][C:2]1[CH:12]=[C:11]([C:13]2[C:22]3[C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[S:25][C:21]=3[C:20]([Br:30])=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[CH:18]3)[CH:10]=[C:9]([Br:31])[C:3]=1[O:4][CH2:5][C:6]([O:8][C:11]([CH3:13])([CH3:12])[CH3:10])=[O:7]
Reactant: O=C(O)COc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Agent: [Na]
Product: CC(C)(C)OC(=O)COc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br

Procedure:
[2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenoxy]-acetic acid, sodium salt;
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH3:12])[CH:6]=1)=O.[CH:13]([NH2:15])=[O:14]>>[O:14]1[CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH3:12])[CH:6]=2)[N:15]=[CH:13]1
Reactant: Cc1cc(C(=O)CBr)ccc1O
Reactant: NC=O
Product: Cc1cc(-c2cocn2)ccc1O
Yield: 33 %

Procedure:
A solution of 2-bromo-1-(4-hydroxy-3-methylphenyl)ethanone (200 mg, 0.87 mmol) in formamide (10 mL) was heated to 110° C. for 24 h. The excess formamide was removed by distillation under reduced pressure. The resulting residue was partitioned between a pH 7.0 buffer solution (10 mL) and EtOAc (50 mL). The organic layer was washed with water (10 mL) and brine (10 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Hexane:EtOAc, 1:1) to yield the title compound (51 mg, 33% yield).
Reaction SMILES: [NH2:1][CH:2]([CH2:8][C:9]([CH3:11])=[CH2:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.CCN(CC)CC.Cl>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][CH:2]([CH2:8][C:9]([CH3:11])=[CH2:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: C=C(C)CC(N)C(=O)OCC
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)CC(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)OCC
Reaction time: 4 h
Yield: 50.6 %

Procedure:
A solution of ethyl 2-amino-4-methyl-4-pentenoate (2.84 g, 18.1 mmol, prepared as in Reaction Scheme 19 from (benzhydrylideneamino)acetic acid ethyl ester and 1-bromo-2-methyl-2-propene) in CH2Cl2 (250 mL) was reacted with 4-chlorobenzenesulfonyl chloride (4.20 g, 19.9 mmol) and Et3N (3.78 mL, 27.2 mmol). After 4 h, the resulting mixture was poured into 1 N aqueous HCl (500 mL) and extracted with EtOAc (3×150 mL). The organic layer was washed with brine (50 mL), dried (MgSO4), filtered, and concentrated in vacuo. The crude concentrate was purified using silica gel column chromatography (10:1 to 5:1 gradient, hexanes/EtOAc) to afford 3.04 g (25% yield over 3 steps) of ethyl 2-(4-chlorobenzenesulfonylamino)-4-methyl-4-pentenoate: LCMS (M+Na)+ 354.2; 1H NMR (400 MHz, CDCl3) 7.77 (d, 2H, J=9.1), 7.46 (d, 2H, J=8.8), 5.07 (d, 1H, J=9.0), 4.84 (s, 1H), 4.73 (s, 1H), 4.05 (m, 1H), 3.95 (q, 2H, J=7.1), 2.40 (m, 2H), 1.66 (s, 3H), 1.13 (t, 3H, J=7.1).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]1[C:22]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=3)[N:27]=[CH:26][N:25]=2)=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:37])[NH:18]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:57][CH2:58][CH2:59][CH2:60]O>C(Cl)Cl>[Br:57][CH2:58][CH2:59][CH2:60][O:36][C:30]1[CH:29]=[C:28]2[C:33]([C:24]([O:23][C:22]3[C:14]([F:13])=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:37])=[CH:16]4)=[N:25][CH:26]=[N:27]2)=[CH:32][C:31]=1[O:34][CH3:35]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1O
Reactant: OCCCBr
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
Diethyl azodicarboxylate (557 μl, 3.53 mmol) was added to a solution of 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (1 g, 2.95 mmol), triphenylphosphine (1.15 g, 4.42 mmol) and 3-bromo-1-propanol (293 ul, 3.24 mmol) in methylene chloride (25 ml). The mixture was stirred at ambient temperature for 1 hour and the residue was purified by column chromatography eluting with increasingly polar mixtures of methylene chloride and methanol. The fractions containing the expected product were combined and evaporated. The residue was triturated under diethyl ether and the solid was filtered, washed with diethyl ether and evaporated to give 7-(3-bromopropoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline (1.35 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[NH:5][CH:6]=[C:7]([C:13]([O:15]CC)=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:21](OC(=O)C)(=[O:23])[CH3:22].C(O)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:18]([C:13]([OH:15])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[N:5]2)=[CH:19][CH:20]=1)(=[O:23])[CH3:22]
Reactant: CCOC(=O)C(=CNc1cccc(N)c1)C(=O)OCC
Reactant: CC(=O)OC(C)=O
Solvent: CCO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2cc(NC(C)=O)ccc2c1O
Temperature: 250 °C

Procedure:
10.5 Grams of diethyl 3-aminoanilino-methylenemalonate are dissolved in 80 ml of diphenyl oxide, 8 ml of acetic anhydride are added and the mixture is gradually heated to 250° C. and maintained under reflux for 10 minutes. The mixture is allowed to cool, 20 ml of ethanol are added and the solid is filtered off and washed with ethanol. The product is recrystallized in dimethylformamide and 4.6 grams of a solid are obtained, of melting point 295° to 300° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[NH2:9].[BrH:16].BrBr>O>[NH2:9][C:8]1[C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][C:5]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][C:7]=1[Br:16]
Reactant: Nc1ccc(S(N)(=O)=O)cc1C(F)(F)F
Reactant: Br
Agent: BrBr
Solvent: O
Product: Nc1c(Br)cc(S(N)(=O)=O)cc1C(F)(F)F

Procedure:
A suspension of 0.69 g. (0.029 moles) of 3-trifluoromethyl-4-aminobenzenesulfonamide in 7 ml. of water and 7 ml. of 48% hydrobromic acid is treated dropwise with 0.16 ml. of liquid bromine and stirred for 3 hours at room temperature. The reaction mixture is filtered, the solid material washed with 10% aqueous sodium bicarbonate, water and dried. The dried solid is recrystallized from toluene affording 0.76 g. of 4-amino-3-bromo-5-trifluoromethylbenzenesulfonamide m.p. 248°-252° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3[NH:18][C:19]([CH:21]=O)=[CH:20][C:12]2=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1[CH2:33][C:34](=[O:40])[NH:35]2>N1CCCCC1.C(O)C>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1/[C:33](=[CH:21]/[C:19]1[NH:18][C:13]3[CH2:14][CH2:15][CH2:16][CH2:17][N:11]([C:9](=[O:10])[CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[C:12]=3[CH:20]=1)/[C:34](=[O:40])[NH:35]2
Reactant: O=Cc1cc2c([nH]1)CCCCN2C(=O)CCN1CCCCC1
Reactant: O=C1Cc2c(cccc2-c2c(F)cccc2F)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2cccc(-c3c(F)cccc3F)c2/C1=C/c1cc2c([nH]1)CCCCN2C(=O)CCN1CCCCC1
Yield: 60.3 %

Procedure:
4-(3-Piperidin-1-yl-propionyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine-2-carbaldehyde (80 mg, 0.26 mmol) was condensed with 4-(2,6-difluoro-phenyl)-1,3-dihydro-indol-2-one (61 mg, 0.25 mmol) and piperidine (1 drop) in ethanol (3 mL) at rt for over the weekend. The precipitate was filtered, washed with ethanol and dried to give 80 mg of the titled compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6]2/[C:7](=[O:11])[O:8][CH2:9][CH2:10]/2)[C@H:3]1[C:12]([OH:14])=[O:13].[CH:16](NC(=NC(C)C)OC)(C)C>C(O)C>[CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6]2/[C:7](=[O:11])[O:8][CH2:9][CH2:10]/2)[C@H:3]1[C:12]([O:14][CH3:16])=[O:13]
Reactant: COC(=NC(C)C)NC(C)C
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C1\CCOC1=O
Solvent: CCO
Product: COC(=O)[C@@H]1[C@H](/C=C2\CCOC2=O)C1(C)C
Yield: 28.8 %

Procedure:
Using the procedure of Example 17, 3.9 g of (1R,cis) 2,2-dimethyl-3-[(E) (dihydro-2-oxo-3-(2H)-furanylidene)-methyl]-cyclopropane-1-carboxylic acid and 3.5 g of methyl N,N'-diisopropylcarbamimidate were reacted to obtain 1.2 g of methyl (1R,cis) 2,2-dimethyl-3-[(E) (dihydro-2-oxo-3-(2H)-furanylidene)-methyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+43°±2.5° (c=0.5% in ethanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[H-].[Na+].Cl[C:14]1[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]3)=[C:24]([O:34][CH3:35])[CH:23]=2)[N:15]=1.[OH-].[Na+]>CN1CCCC1=O>[CH3:35][O:34][C:24]1[CH:23]=[C:22]([NH:21][C:16]2[N:17]=[C:18]([CH3:20])[CH:19]=[C:14]([O:10][C:4]3[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=3)[N:15]=2)[CH:27]=[CH:26][C:25]=1[N:28]1[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]1
Reactant: Oc1cc(F)c(F)c(F)c1
Reactant: COc1cc(Nc2nc(C)cc(Cl)n2)ccc1-n1cnc(C)c1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: COc1cc(Nc2nc(C)cc(Oc3cc(F)c(F)c(F)c3)n2)ccc1-n1cnc(C)c1
Temperature: 200 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
To a solution of 3,4,5-trifluorophenol (33 mg, 0.22 mmol) in 1-methyl-2-pyrrolidone (2 mL) was added at 20° C. under an atmosphere of nitrogen a 55% dispersion of sodium hydride in oil (10 mg, 0.22 mmol). The reaction was stirred for 30 min and then, (4-chloro-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (66 mg, 0.2 mmol) was added. The mixture was heated in a microwave oven to 200° C. for 30 min and then poured onto 1 N aqueous sodium hydroxide solution. The mixture was stirred for 15 min, and the precipitate formed was filtered off, washed with water and dried to yield the title compound (72 mg, 8%) as a pale-brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([N:19]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:20][CH:21]([OH:24])[CH2:22][CH3:23])=[O:18])[CH:8]=2)[N:3]=1.C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([N:19]([CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)[CH2:20][CH:21]([O:24][C:38](=[O:40])[CH3:39])[CH2:22][CH3:23])=[O:18])[CH:8]=2)[N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCC(O)CN(C(=O)NCCCOc1ccc2nc(Cl)ccc2c1)C1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CN(C(=O)NCCCOc1ccc2nc(Cl)ccc2c1)C1CCCCC1)OC(C)=O
Yield: 97 %

Procedure:
To a solution of 2-chloro-6-{3-[3-cyclohexyl-3-(2-hydroxybutyl)ureido]-propoxy}quinoline (6.3 g), 4-dimethylaminopyridine (0.1 g) and triethylamine (2.3 g) in methylene chloride (80 ml) is added dropwise with stirring acetic anhydride (1.8 g) at room temperature. The methylene chloride layer is washed successively with diluted hydrochloric acid, water and a saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous magnesium sulfate. The resultant is concentrated under reduced pressure to remove the solvent to give 2-chloro-6-[3-[3-cyclohexyl-3-(2-acetyloxybutyl)ureido]-propoxy]quinoline (6.7 g) as a colorless oil.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=O)[C:11](=[CH:17][C:18]([O:20][CH3:21])=[O:19])[CH2:10][CH2:9]2>C(OCC)C>[CH3:1][C:12]1[C:13]2[C:8](=[CH:7][C:6]([O:5][CH3:4])=[CH:15][CH:14]=2)[CH:9]=[CH:10][C:11]=1[CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)C=C1CCc2cc(OC)ccc2C1=O
Reactant: C[Mg]Br
Solvent: CCOCC
Product: COC(=O)Cc1ccc2cc(OC)ccc2c1C
Temperature: 180 °C
Reaction time: 1 h

Procedure:
To a mixture of 12 g. of methyl magnesium bromide and 200 ml. of diethyl ether, 25 g. of 6-methoxy-2-(methoxycarbonylmethylene)-1-tetralone are added. The alkylating mixture is refluxed for one hour after it has been allowed to stand for one hour; the mixture is made acidic to litmus by the addition of 1N methanolic HC1, filtered, and evaporated. The residue, containing methyl 1-methyl-6-methoxy-3,4-dihydro-2-naphthylacetate, is added to 1 g. of 10% palladium-on-charcoal and the resulting mixture is heated to 180°C for six hours. The mixture is cooled, diluted with 200 ml. of chloroform, filtered, and evaporated to yield methyl 1-methyl-6-methoxy-2-naphthylacetate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[CH:10](O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([N:17](CC)CC)C.CS(Cl)(=O)=O.O>ClCCl>[CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@H:10]([C:15]#[N:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: CC1CN(Cc2ccccc2)CC1O
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccccc2)C[C@H]1C#N
Reaction time: 1 h

Procedure:
c is-1-Benzyl-3-hydroxy-4-methylpyrrolidine (6.81 g) was dissolved in dichloromethane (70 mL). While this solution was cooled on a dry ice/acetone bath, triethylamine (5.21 mL) was added. Methanesulfonyl chloride (2.89 mL) was then added dropwise and the mixture was further stirred for 1 hour. Following addition of water (50 mL), the temperature of the mixture was allowed to rise to room temperature and the dichloromethane layer was separated. The aqueous layer was extracted with dichloromethane (50 mL) and the extract was combined with the dichloromethane layer. The combined dichloromethane layer was then washed with water, followed by drying over anhydrous sodium sulfate and concentration under reduced pressure. The resulting residue was dissolved in acetonitrile (180 mL). To this solution, tetrabutylammonium cyanide (23.9 g) was added and the mixture was refluxed for 7 hours while heated. Subsequently, the reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in ethyl acetate (300 mL). The solution was washed with water, was dried over anhydrous sodium sulfate, and was concentrated under reduced pressure. The resulting residue was purified on a silica gel column (hexane:ethyl acetate=1:1) to give 4.61 g of cis-1-benzyl-4-methyl-3-pyrrolidinecarbonitrile as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([N:12]([CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:13][CH3:14])[CH3:11])=[CH:5][CH:4]=1.[CH3:22][N:23]=[C:24]=[O:25]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH:10]([N:12]([CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:24]([NH:23][CH3:22])=[O:25])[CH2:18][CH2:17]2)[CH2:13][CH3:14])[CH3:11])=[CH:7][CH:8]=1
Reactant: CN=C=O
Reactant: CCN(CC1CCNCC1)C(C)Cc1ccc(OC)cc1
Solvent: CCOCC
Product: CCN(CC1CCN(C(=O)NC)CC1)C(C)Cc1ccc(OC)cc1
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a solution of N-[2-(4-methoxyphenyl)-1-methylethyl]-N-ethyl-(piperidin-4-ylmethyl)amine (0.23 grams, 0.79 mmole) in ethyl ether (10 ml) was added methyl isocyanate (0.2 ml, 3.4 mmole). After 1.0 hour at 22° C., the solution was concentrated under reduced pressure and the residue was recrystallized from ethyl ether/hexane to give N-[2-(4-methoxyphenyl)-1-methylethyl]-N-ethyl-[1-(methylaminocarbonyl)piperidin-4-ylmethyl]amine (0.249 grams, 91%) m.p. 97-98° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:31])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH:6]=[CH:5]2.[H][H]>CO.[Pd]>[OH:1][C:2]1[C:3]([CH3:31])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][CH2:5]2
Reactant: [H][H]
Reactant: Cc1c(C)c2c(c(C)c1O)C=CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Agent: [Pd]
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2

Procedure:
Following the procedure described in Preparation 58, 120 mg of 5-[4-(6-hydroxy-2,5,7,8-tetramethyl-2H-chromen-2-ylmethoxy)benzyl]thiazolidine -2,4-dione (prepared as described in Example 32) were dissolved in 4 ml of methanol and, in the presence of 40 mg of 10% w/w palladium-on-carbon, it was reduced under 3-5 atmospheres (about 3-5 bars) pressure of hydrogen, to give the title compound. The melting point and nuclear magnetic resonance spectrum of this compound accorded with those of the compound obtained in Example 27(b).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.C1COCC1.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([S:21]([N:1]2[C:9]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[CH:3]=[CH:2]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1cc2[nH]ccc2cn1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2cnccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.5 %

Procedure:
A 100 mL round-bottomed flask was charged with a solution of 1H-pyrrolo[3,2-c]pyridine (1.0 g, 8.4 mmol) in anhydrous THF (50 mL) NaH (60% in mineral oil, 0.41 g, 10.2 mmol) was added and the reaction mixture was stirred for 5 min at room temperature. To this solution was added dropwise, at 0° C., benzenesulfonyl chloride (1.35 mL, 10.2 mmol) and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (3×100 mL) The organic layers were combined, dried (Na2SO4) and concentrated in vacuo to give the title compound as a white solid (1.29 g, 55%). 1H NMR (DMSO, 300 MHz): δ 8.95 (s, 1 H); 8.49 (d, J=5.8 Hz, 1 H); 8.13-8.05 (m, 2 H); 8.02-7.94 (m, 2 H); 7.79-7.71 (m, 1 H); 7.69-7.59 (m, 2 H); 7.01 (dd, J=3.7, 0.9 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:13]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:13][C:9]1[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Clc1cccnc1-n1cccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cccnc1-n1cccc1Br
Temperature: 25 °C
Reaction time: 6 h
Yield: 25.4 %

Procedure:
To a solution of 3.0 g of 3-chloro-2-(1H-pyrrol-1-yl)pyridine in 30 ml of N,N-dimethylformamide was added 3.1 g of N-bromosuccinimide. The resulting mixture was stirred at room temperature for 6 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.1 g of 2-(2-bromo-1H-pyrrol-1-yl)-3-chloropyridine of the formula: