Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-].[C:8](Cl)(=[O:10])[CH3:9].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]3[CH2:26][CH2:27][S:28][C:29]4[S:33][CH:32]=[CH:31][C:30]=4[C:21]3=[N:20]2)=[CH:15][CH:14]=1>O>[C:8]([C:32]1[S:33][C:29]2[S:28][CH2:27][CH2:26][C:22]3[C:21](=[N:20][N:19]([C:16]4[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=4)[C:24](=[O:25])[CH:23]=3)[C:30]=2[CH:31]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: O=c1cc2c(nn1-c1ccc(Cl)cc1)-c1ccsc1SCC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1cc2c(s1)SCCc1cc(=O)n(-c3ccc(Cl)cc3)nc1-2

Procedure:
To a mixture of 50 ml of methylene chloride and 1.9 g of aluminum chloride is added 1.0 ml of acetyl chloride with stirring under ice-cooling and then the mixture is stirred at room temperature for 10 minutes. To the mixture is further added 2.0 g of 2-(4-chlorophenyl)-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one under ice-cooling and the mixture is stirred for 3 hours at room temperature. To the mixture is added water and the solution is extracted with chloroform. The extract is washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The resulting crystals are recrystallized from a mixed solvent of chloroform and ethanol to give 2.0 g of 9-acetyl-2-(4-chlorophenyl)-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one, as white crystals, melting at 248°-250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[C:9]([CH3:22])=[C:10]([CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pt]=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:9]([CH3:22])=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:23][CH:24]=1
Reactant: [H][H]
Reactant: Cc1c(C=CCCCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Agent: O=[Pt]
Solvent: CCO
Product: Cc1c(CCCCCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Yield: 79.5 %

Procedure:
5.425 g of 6-[3'-(4-chlorobenzoyl)-2'-methyl-phenyl]-hex-5-enoic acid dissolved in 100 ml of ethanol in the presence of 110 mg of platinum oxide had hydrogen pased therethrough and then the catalyst was filtered off. The filtrate was evaporated to dryness and the residue was taken up in ether. The solution was treated with activated carbon, filtered and evaporated to dryness. The residue was crystallized from a 1:1 isopropyl ether-petroleum ether mixture to obtain 4.34 g of 6-[3'-(4-chlorobenzoyl)-2'-methyl-phenyl]-hexanoic acid melting at 82° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[CH:32]=[CH:31][N:30]=[C:29]([O:33][CH3:34])[CH:28]=2)=[CH:21][N:20]=1)([O-])=O>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([O:33][CH3:34])[CH:28]=3)=[CH:21][N:20]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: COc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)ccn1
Solvent: CCO
Product: COc1cc(Cc2cnc(NCCSCc3ccc(CN(C)C)o3)[nH]c2=O)ccn1

Procedure:
A mixture of 2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamine (2.50 g), 2-nitroamino-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone (2.77 g) and ethanol (15 ml) was boiled under reflux for 19 hours and evaporated. The residue was triturated with hot water to leave 2-[2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamino]-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone. A mixture of this pyrimidone (3.04 g), 2N hydrogen chloride in ethanol (20 ml) and ethanol (80 ml) was boiled under reflux for 48 hours and evaporated to dryness. The residue was recrystallised from methanol/ethanol to give 2-[2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamino]-5-(2-hydroxy-4-pyridylmethyl)-4-pyrimidone trihydrochloride m.p. 181°-185°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=1.[CH3:15][N:16]1[CH:20]=[C:19]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[N:17]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:21]([C:19]2[CH:18]=[N:17][N:16]([CH3:15])[CH:20]=2)(=[O:23])=[O:22])[CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=1
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Reactant: O=Cc1c[nH]c(-c2ccccc2F)c1
Product: Cn1cc(S(=O)(=O)n2cc(C=O)cc2-c2ccccc2F)cn1

Procedure:
By a similar operation as in Reference Example 65 and using 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (189 mg) and 1-methyl-1H-pyrazole-4-sulfonyl chloride (217 mg), the title compound was obtained as yellow crystals (yield 217 mg, 65%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12].[S:17](N)(N)(=[O:19])=[O:18]>COCCOCCOC>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:5]1[C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]=2[CH2:2][NH:1][S:17]1(=[O:19])=[O:18]
Reactant: NS(N)(=O)=O
Reactant: NCc1ccccc1Nc1ccccc1F
Solvent: COCCOCCOC
Product: O=S1(=O)NCc2ccccc2N1c1ccccc1F
Temperature: 25 °C
Yield: 69.6 %

Procedure:
A solution of 2-(aminomethyl)-N-(2-fluorophenyl)aniline (2.07 g, 9.6 mmol) and sulfamide (1.1 g, 11.5 mmol) in digylyme (10 mL) was added to a flask containing refluxing diglyme (15 mL) over 10 min. The reaction mixture was stirred at reflux for 1 h, then cooled to room temperature and was evaporated to a brown oil. The crude reaction product was purified by flash chromatography (SiO2, 3-50% ethyl acetate/heptane) to afford 1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (1.86 g, 70%) as a white solid:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][C:5]2[O:9][CH2:8][CH:7](O)[C:6]=2[CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:11]=1
Reactant: OC1COc2cc(N3CCCCC3)c(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Clc1cc2ccoc2cc1N1CCCCC1

Procedure:
A solution of 2.40 g (9.4 mmole) of 5-chloro-3-hydroxy-6-(piperidin-1-yl)-2,3-dihydrobenzofuran in 25 g of polyphosphoric acid is maintained at 60° for 20 minutes, then ice and water are added and the whole is adjusted to pH 7 with solid sodium carbonate. The reaction mixture is extracted twice with methylene chloride. The organic phases are washed with water, combined, dried over magnesium sulphate and concentrated in a vacuum rotary evaporator. The residue is chromatographed over silica gel using methylene chloride as eluant (Rf =0.63). In that manner, 5-chloro-6-(piperidin-1-yl)-benzofuran is obtained in the form of an oil which distills at 96°-97°/1.5 torr.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].Cl[C:15]1[CH:31]=[C:19]2[N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:22][CH2:23][N:18]2[C:17](=[O:32])[N:16]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[CH2:9][CH2:10][O:11][C:15]1[CH:31]=[C:19]2[N:20]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:21][CH2:22][CH2:23][N:18]2[C:17](=[O:32])[N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCCn2c1cc(Cl)nc2=O
Reactant: OCCc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCn2c1cc(OCCc1ccc(F)c(F)c1)nc2=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(3,4-difluorophenyl)ethanol (221 mg, 1.400 mmol) in THF (5 mL) was added NaH (112 mg, 2.80 mmol) at 0° C. The reaction mixture was stirred for 10 min at 0° C., and then tert-butyl 8-chloro-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido[1,6-a]pyrimidine-1-carboxylate (400 mg, 1.400 mmol) was added and stirred for another 0.5 hr at 0° C. The mixture was poured into ice water and extracted with DCM (10 mL×3). The combined extracts were washed with water (10 mL) then brine (10 mL) and then dried over Na2SO4. The mixture was concentrated to give tert-butyl 8-(3,4-difluorophenethoxy)-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido[1,6-a]pyrimidine-1-carboxylate. A solution of the crude compound in 1,4-dioxane (10 mL) was added 4N HCl, stirred for 3 h at rt, and then concentrated. The residue was purified by MDAP to afford the HCl salt of the title product as a white solid (46 mg, 10.8% yield).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7]1([CH2:16][CH2:15][CH:14]([CH:17]([F:19])[F:18])[CH2:13][CH2:12]1)[C:6]2=[N:20]S(C(C)(C)C)=O>O1CCOCC1>[Br:2][C:3]1[CH:4]=[C:5]2[C:9]([CH2:8][C:7]3([CH2:16][CH2:15][CH:14]([CH:17]([F:18])[F:19])[CH2:13][CH2:12]3)[C:6]2=[NH:20])=[CH:10][CH:11]=1
Reactant: CC(C)(C)S(=O)N=C1c2cc(Br)ccc2CC12CCC(C(F)F)CC2
Agent: Cl
Solvent: C1COCCO1
Product: N=C1c2cc(Br)ccc2CC12CCC(C(F)F)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HCl (4 M in 1,4-dioxane) (3.26 mL, 13.0 mmol) was added to a suspension of N-(5′-bromo-4-(difluoromethyl)spiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide (Example 128 Step 1, 0.564 g, 1.30 mmol) in 1,4-dioxane (5 mL) and the resulting mixture was stirred under a nitrogen atmosphere at r.t. overnight. The formed precipitate was filtered off and washed with Et2O. The solid was then dissolved in DCM and sat. aq. NaHCO3. The mixture was poured into a phase separator, the organic layer was collected and concentrated to yield the title compound that was used as such in the next step: MS (CI) m/z 328 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.Br[CH2:14][C:15]1[CH:36]=[CH:35][C:18]2/[C:19](=[C:29](/[CH:32]3[CH2:34][CH2:33]3)\[C:30]#[N:31])/[C:20]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=3[O:22][CH2:23][C:17]=2[CH:16]=1>>[CH:32]1(/[C:29](=[C:19]2\[C:20]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=3[O:22][CH2:23][C:17]3[CH:16]=[C:15]([CH2:14][N:8]4[C:7]5[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=5[N:5]=[C:4]4[CH:1]4[CH2:3][CH2:2]4)[CH:36]=[CH:35][C:18]\2=3)/[C:30]#[N:31])[CH2:34][CH2:33]1
Reactant: c1ccc2[nH]c(C3CC3)nc2c1
Reactant: N#C/C(=C1\c2ccc(CBr)cc2COc2cc(F)ccc21)C1CC1
Product: N#C/C(=C1\c2ccc(Cn3c(C4CC4)nc4ccccc43)cc2COc2cc(F)ccc21)C1CC1
Yield: 93 %

Procedure:
Using 2-cyclopropyl-1H-benzo[d]imidazole (European Journal of Organic Chemistry, 2000, p 1229, 58 mg, 0.33 mmol) and (E)-2-(8-bromomethyl-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)-2-cyclopropylacetonitrile (120 mg, 0.31 mmol) obtained in Reference Example 6, and in the same manner as in Reference Example 1A, the title compound (133 mg, 93%) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:11][CH2:10]2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCC1CCN(c2ccc(Br)cn2)CC1
Temperature: 130 °C

Procedure:
10.37 g (43.80 mmol) of 2,5-dibromopyridine, 10.00 g (43.80 mmol) of tert-butyl 2-piperidin-4-ylethylcarbamate and 6.05 g (43.80 mmol) of potassium carbonate are placed in an autoclave. The mixture is then heated at 130° C. for 12 hours. The reaction mixture is allowed to cool to room temperature and then taken up in chloroform and saturated aqueous sodium hydrogen carbonate solution. The aqueous phase is separated out and extracted twice with chloroform, and the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate is concentrated under reduced pressure.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][CH2:5][C:6]1[CH:38]=[CH:37][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[C:17]([CH2:19][O:20][C:21]4[CH:34]=[CH:33][C:24]([CH2:25][CH:26]5[S:30][C:29](=[O:31])[NH:28][C:27]5=[O:32])=[CH:23][CH:22]=4)[N:16]([CH3:35])[C:15]=3[CH:36]=2)=[CH:8][CH:7]=1.[C:39]12([N:49]=[C:50]=[O:51])[CH2:48][CH:43]3[CH2:44][CH:45]([CH2:47][CH:41]([CH2:42]3)[CH2:40]1)[CH2:46]2.C(N(CC)CC)C.Cl>O1CCCC1.O1CCOCC1.CN(C)C=O>[ClH:1].[ClH:1].[C:39]12([NH:49][C:50]([NH:3][CH2:4][CH2:5][C:6]3[CH:7]=[CH:8][C:9]([O:10][C:11]4[CH:12]=[CH:13][C:14]5[N:18]=[C:17]([CH2:19][O:20][C:21]6[CH:34]=[CH:33][C:24]([CH2:25][CH:26]7[S:30][C:29](=[O:31])[NH:28][C:27]7=[O:32])=[CH:23][CH:22]=6)[N:16]([CH3:35])[C:15]=5[CH:36]=4)=[CH:37][CH:38]=3)=[O:51])[CH2:48][CH:43]3[CH2:44][CH:45]([CH2:47][CH:41]([CH2:42]3)[CH2:40]1)[CH2:46]2
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(CCN)cc3)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(CCNC(=O)NC45CC6CC(CC(C6)C4)C5)cc3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 152.9 %

Procedure:
1-(Adamant-1-yl)-3-[2-(4-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)ethyl]urea was obtained by a similar procedure to that described in Example 31 using 5-[4-[6-[4-(2-aminoethyl)phenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (0.3 g), 1-adamantyl isocyanate (94 mg), triethylamine (65 mg) and anhydrous N,N-dimethylformamide (15 ml). To a solution of the product in tetrahydrofuran (10 ml) was added 4N hydrogen chloride in dioxane (10 ml) and the mixture was stirred at room temperature for 3 hours. The precipitate was isolated by filtration and washed with tetrahydrofuran and n-hexane to afford the title compound (0.3 g, mp 174-176° C.).
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]>C(Cl)(Cl)Cl>[Br:1][C:11]1[C:12]([CH3:14])=[CH:13][C:4]([OH:3])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(C)cc1O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Br)c(C)cc1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Bromine (0.47 ml, 9.03 mmol) was added dropwise to a solution of methyl 2-hydroxy-4-methylbenzoate (may be prepared as described in Description 1; 1.5 g, 9.03 mmol) in chloroform (20 ml) at 0° C. The solution was stirred for 1 hour at 0° C. The reaction was quenched with saturated sodium sulphite (10 ml), then extracted with dichloromethane (2×10 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4) and the solvent removed in vacuo to yield the title compound as a white solid. 2.24 g.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]([C:26]([OH:28])=[O:27])=[N:14][CH:15]=[C:16]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:17]=2)=[CH:7][CH:6]=1)=[O:4].CO.[CH3:32][Si](C=[N+]=[N-])(C)C.CO.ClCCl>C(#N)C>[CH3:29][N:2]([CH3:1])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]([C:26]([O:28][CH3:32])=[O:27])=[N:14][CH:15]=[C:16]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:17]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1ccc(Nc2cc(Cc3ccc(F)cc3)cnc2C(=O)O)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CC#N
Solvent: CO
Product: COC(=O)c1ncc(Cc2ccc(F)cc2)cc1Nc1ccc(C(=O)N(C)C)cc1
Yield: 49.5 %

Procedure:
3-({4-[(dimethylamino)carbonyl]phenyl} amino)-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylic acid (79 mg, 0.201 mmol) was dissolved in a 9:1 acetonitrile:methanol solution (5 mL) and trimethylsilyldiazomethane (0.3 mL, 0.603 mmol) was added and the reaction was stirred at ambient temperature until complete by TLC (10% methanol/dichloromethane). The mixture was concentrated under reduced pressure, aqueous sodium bicarbonate was added, and the aqueous layer was extracted with chloroform. The combined organics were washed with brine and dried over sodium sulfate to yield methyl 3-({4-[(dimethylamino)carbonyl]phenyl}amino)-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate (40.5 mg, 49% yield). 1H NMR (CDCl3) δ 9.49 (s, 1 H), 8.00 (s, 1 H), 7.34-7.36 (m, 3 H), 7.12-7.05 (m, 4 H), 6.97-6.94 (m, 2 H), 3.97 (s, 3 H), 3.87 (s, 2 H), 3.07 (br s, 3 H), 3.02 (br s, 3 H); MS m/z 408 (M+1).
Reaction SMILES: [C:1](O)(=O)[CH3:2].[NH2:5]/[C:6](=[N:20]\[OH:21])/[C@@H:7]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:8][CH:9]1[CH2:11][CH2:10]1>CN(C=O)C>[CH:9]1([CH2:8][C@H:7]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])[C:6]2[N:5]=[C:1]([CH3:2])[O:21][N:20]=2)[CH2:10][CH2:11]1
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CC1)/C(N)=N/O
Solvent: CN(C)C=O
Product: Cc1nc([C@H](CC2CC2)NC(=O)OC(C)(C)C)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
To a solution of acetic acid (0.224 g, 4 mmol) in DMF (5 mL) was added N,N′-carbonyldiimidazole (0.6 g, 4 mmol) and the mixture was stirred for 0.5 h at room temperature. (S,Z)-tert-butyl 1-amino-3-cyclopropyl-1-(hydroxyimino)propan-2-ylcarbamate (0.84 g, 3 mmol) was added and the mixture was heated to 120° C. and stirred for 4 h. After evaporation of solvents, the residue was purified by column chromatography (silica gel, 20 g, eluting with 10% ethyl acetate in petroleum ether) to give the title compound (0.5 g; 54%) as yellow solid; MS (EI): m/e 290.1 [M+Na]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[CH:32]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C1COCC1>[CH:32]1([NH:38][C:16]2[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]3[CH:12]=[CH:11][C:10](=[O:31])[N:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[C:14]=3[N:15]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: NC1CCCCC1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(NC2CCCCC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 18 h

Procedure:
The product of Example 48 (200 mg, 0.45 mmol) and cyclohexyl amine (100 mg, 1 mmol) were combined in THF (10 mL) and stirred under Ar at 23° for 18 h. The solvents were removed in vacuo, and the residue was flash chromatographed with 50-100% CH2Cl2/hexane. Recrystallization from CH2Cl2/hexane gave the title compound as a white-crystalline solid. mp 218-219° C., LC MS m/z=465 (MH+) Retention time=2.8 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][C:13]=2[F:20])=[CH:9][C:8](Cl)=[N:7][CH:6]=1)[CH3:2].S([O:28][CH3:29])(OC)(=O)=O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][C:13]=2[F:20])=[CH:9][C:29](=[O:28])[N:7]([CH3:8])[CH:6]=1)=[O:22])[CH3:2]
Reactant: CCOC(=O)c1cnc(Cl)cc1Nc1ccc(CC)cc1F
Reactant: COS(=O)(=O)OC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(C)c(=O)cc1Nc1ccc(CC)cc1F
Temperature: 25 °C
Yield: 44.9 %

Procedure:
6-Chloro-4-(4-ethyl-2-fluoro-phenylamino)-nicotinic acid ethyl ester (23.0 g, 72.0 mmol) was dissolved in CHCl3 (200 mL) and the solution cooled (ice/water). Dimethyl sulfate (42.0 mL, 432.0 mmol) was added, the solution allowed to warm to room temperature then heated at reflux for 20 hours as in Example 1, alternate Step B to give 4-(4-Ethyl-2-fluoro-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester as a white solid (10.30 g, 45%). 1H NMR [(CDCl3, 400 MHz] δ 9.17 (s, 1H), 8.19 (s, 1H), 7.23 (dd, J=10.1, 1.9 Hz, 1H), 6.99 (dd, J=8.3, 1.0 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 5.76 (s, 1H), 4.33 (q, J=7.1 Hz, 2H), 3.52 (s, 3H), 2.64 (q, J=7.2 Hz, 2H), 1.39 (t, J=6.9 Hz, 3H), 1.23 (t, J=7.1 Hz, 3H). (APCI+) calcd for C17H19FN2O3 318.34 (M+1), found 319.1.
Reaction SMILES: [CH2:1]([NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:24]([O:30]CC)(=O)[CH2:25][C:26]([CH3:28])=O>>[CH2:1]([N:19]1[CH2:20][CH2:21][CH2:22][N:23]=[C:26]([CH3:28])[CH2:25][C:24]1=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCCCCCCCC=CCCCCCCCCNCCCN
Product: CCCCCCCCC=CCCCCCCCCN1CCCN=C(C)CC1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 324.1 g (1 mole) of N-(9-octadecenyl)-1,3-propylenediamine and 130.1 g (1 mole) of ethyl acetoacetate. At 110° to 120° C. and under a reduced pressure of 50 mmHg, 18 g of water and 46 g of ethanol had been distilled off to obtain 1-(9-octadecenyl)-4-methyl-3,6,7,8-tetrahydro-1,5-diazocin-2-one.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:11]([CH:13]2[C:22]3[C:17](=[C:18]([OH:23])[CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1.Br[CH2:35][CH2:36][OH:37]>>[CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:26][CH:25]=2)[C:11]([CH:13]2[C:22]3[C:17](=[C:18]([O:23][CH2:35][CH2:36][OH:37])[CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1
Reactant: OCCBr
Reactant: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3c(O)cccc32)cc1
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3c(OCCO)cccc32)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 106 using N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.66 g) and 2-bromoethanol (0.32 mL) as starting materials, N-[(4-dimethylaminophenyl)methyl]-5-(2-hydroxyethoxy)-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.49 g) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([C:21](=[O:23])[NH2:22])=[CH:19][C:18]([N+:24]([O-])=O)=[CH:17][C:16]=2[Cl:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Sn]>C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[C:20]([C:21](=[O:23])[NH2:22])=[CH:19][C:18]([NH2:24])=[CH:17][C:16]=2[Cl:27])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(Cl)cc([N+](=O)[O-])cc2C(N)=O)CC1
Agent: [Sn]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(Cl)cc(N)cc2C(N)=O)CC1
Temperature: 25 °C
Reaction time: 11 h
Yield: 83.5 %

Procedure:
To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-5-carbamoyl-3-chloronitrobenzene (2.2 g) in acetic acid (100 ml) was added tin powder (9.9 g) and the mixture was stirred at room temperature for 11 hours. The reaction mixture was filtered through Celite (trade mark) and the filtrate was concentrated in vacuo. The residual pale yellow solid was dissolved in aqueous potassium carbonate and extracted with ethyl acetate. The extract was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo to give the desired compound (1.7 g, yield 83%) as a yellow amorphous solid.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[C:10]1([C:5]2([CH2:3][OH:2])[CH2:9][CH2:8][CH2:7][CH2:6]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)C1(c2ccccc2)CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCC1(c2ccccc2)CCCC1
Yield: 79.8 %

Procedure:
A solution of the product of Step A (3.00 g, 14.71 mmol) in 10 mL THF was added dropwise to a suspension of LiAlH4 (1.25 g, 33.09 mmol) in 25 mL dry THF. The reaction mixture was stirred at reflux for three hours. The excess LiAlH4 was destroyed following the method described in Reagents for Organic Synthesis, Vol 1 [1967] p. 584 (J. Wiley & Son), by quenching the cooled reaction mixture with the addition of 1.25 mL water, followed by the addition of 1.25 mL 154 sodium hydroxide (w/v), followed by the addition of 3.75 mL water. The resulting aluminum salts were separated by filtration and washed with water (5×1 mL). The product was extracted with ether (3×25 mL) and dried (Na2SO4). Evaporation of the solvent gave 2.07 g (88%) of 1-phenylcyclopentanemethanol as a white solid, mp 41°-44° C.(the literature value of mp, J. Org. Chem. 27:3434 (1962), is 43°-44° C.).