Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][S:9][C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:6]2=[C:5]([C:15]([O:17][CH3:18])=[O:16])[CH:4]=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)Cl>[O:1]=[C:2]1[N:7]2[CH2:8][S:9](=[O:33])[C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:6]2=[C:5]([C:15]([O:17][CH3:18])=[O:16])[CH:4]=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1SC2
Solvent: ClCCl
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1S(=O)C2

Procedure:
4 g of methyl 7-oxo-8-phenyl-pyrido[1,2-c]thieno[2,3-e][1,3]thiazine-10-carboxylate were dissolved in 100 ml of methylene chloride, whereupon the solution was cooled to 0° and a solution of 2.43 g of m-chloroperbenzoic acid in 40 ml of methylene chloride was added dropwise. After the reaction was completed, the precipitated m-chlorobenzoic acid was removed by filtration and the filtrate was washed with saturated sodium hydrogen carbonate solution and water, dried over sodium sulfate, filtered and evaporated. After chromatography on silica gel, the product was recrystallized from acetonitrile. There was obtained methyl 7-oxo-8-phenyl-pyrido[1,2-c]thieno[2,3-e]-[1,3]thiazine-10-carboxylate 4-oxide as yellow crystals of m.p. 183°-186°.
Reaction SMILES: [Si](O[C:9]1[C:10](=[O:28])[N:11]([CH2:21][CH:22]([O:24][CH2:25][O:26][CH3:27])[CH3:23])[C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([O:19][CH3:20])[CH:13]=2)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:47]1CCCC1>ClCCl>[OH:47][CH2:23][CH:22]([O:24][CH2:25][O:26][CH3:27])[CH2:21][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[C:14]([O:19][CH3:20])[CH:13]=2)[N:18]=[CH:9][C:10]1=[O:28]
Reactant: C1CCOC1
Reactant: COCOC(C)Cn1c(=O)c(O[Si](C)(C)C(C)(C)C)nc2ccc(OC)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: COCOC(CO)Cn1c(=O)cnc2ccc(OC)cc21
Reaction time: 3 h
Yield: 80 %

Procedure:
1-[3-{[Tert-butyl(dimethyl)silyl]oxy}-2-(methoxymethoxy)propyl-7-methoxyquinoxalin-2(1H)-one (863 mg, 2.11 mmol) was dissolved in tetrahydrofuran (10 ml). Tetrabutyl ammonium fluoride (1M tetrahydrofuran solution; 2.74 ml, 2.74 mmol) was added to this solution under cooling on ice, and the mixture was stirred for 3 hours. The reaction solution was diluted with dichloromethane and washed with saturated sodium bicarbonate water. After drying with anhydrous sodium sulfate, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol) to yield 495 mg (80%) of the title compound in the form of a yellowish solid.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.[F-].[K+]>C1COCC1>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH3:10])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cc1ccccc1B(O)O
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccc(C=O)cc1
Yield: 94.4 %

Procedure:
4-Chlorobenzaldehyde (144 mg, 1.02 mmol) reacted with 2-methylphenylboronic acid (204 mg, 1.50 mmol) using 1/2 mol % of Pd(OAc)2/Ph5FcP(t-Bu)2 and KF (180 mg, 3.10 mmol) in THF at 50° C. to give the title compound (189 mg, 96%) as a white solid: 1H-NMR (400 MHz, CDCl3): δ 9.98 (s, 1H), 7.85 (d, 2H, J=8.2 Hz), 7.41 (d, 2H, J=8.1 Hz), 7.22-7.13 (m, 4H), 2.19 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 191.98, 148.36, 140.51, 135.06, 134.87, 130.54, 129.88, 129.55, 129.42, 128.03, 125.94, 20.34. GC/MS(EI): m/z 196 (M+), 165, 167, 152. Anal. Calcd for C14H12O: C, 85.68; H, 6.16. Found: C, 85.64; H, 6.39.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][CH:5]([Br:9])[C:6]([CH3:8])=[O:7].COC(=O)CCC(CBr)=O.COC(=O)CC(Br)C(CBr)=O.COC(=O)CCC(C)=O>CO.[H][H]>[BrH:9].[CH3:1][O:2][C:3](=[O:10])[CH2:4][CH2:5][C:6]([CH3:8])=[O:7]
Reactant: COC(=O)CC(Br)C(C)=O
Reactant: [H][H]
Agent: COC(=O)CC(Br)C(=O)CBr
Agent: COC(=O)CCC(=O)CBr
Agent: COC(=O)CCC(C)=O
Solvent: CO
Product: Br
Reaction time: 5 h

Procedure:
Distillation of the solvent from the combined mother liquors obtained from the low-temperature crystallisation of 5-bromolevulinic acid methyl ester according to Example 1 in vacuo afforded a mixture consisting of 3-bromolevulinic acid methyl ester (61%), 5-bromolevulinic acid methyl ester (23%), 3,5-dibromolevulinic acid methyl ester (8%) and levulinic acid methyl ester (8%). The mixture (5 g) was dissolved in bulk grade methanol (20 ml), a hydrogen catalyst (palladium on carbon) was then added and the mixture was hydrogenated for 5 h while passing in hydrogen at a pressure of 20 bar at 20–25° C. By monitoring the hydrogenation, it was found that the reaction was completed after 5 h (1H-NMR, 13C-NMR) and besides hydrogen bromide only levulinic acid methyl ester has been formed. Water was added (20 ml) and the resulting mixture was extracted with dichloro methane (3×20 ml). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate (3×10 ml) and saturated aqueous sodium chloride. Drying of the organic layer with Na2SO4, followed by distillation of the solvent in vacuo yielded 2.5 g (80%) levulinic acid methyl ester. The obtained product may be used for the preparation of 5-bromolevulinic acid methyl ester according to Example 2. The further purification of the obtained levulinic acid methyl ester by distillation is not necessary, so that the raw-product may be directly lead back to the bromination step after removing the hydrogen bromide for the most part.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:7])[CH2:4][CH2:5][Cl:6].[C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)#[N:9]>>[Cl:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]#[N:9])=[CH:11][CH:12]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: OC(CCl)CCCl
Product: N#Cc1ccc(OCC(O)CCCl)cc1
Yield: 13 %

Procedure:
Utilizing the procedure of Preparation 16, 1,4-dichloro-2-butanol was reacted with 4-cyanophenol to give white title compound, m.p. 78°-80° C. in 13% yield.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14](O)[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36]1(=[O:46])[NH:40][C:39](=[O:41])[C:38]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14]([N:40]1[C:36](=[O:46])[C:37]2[C:38](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:39]1=[O:41])[CH3:15]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1cccc2nc(C(C)O)c(Br)c(=O)n12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccc2nc(C(C)N3C(=O)c4ccccc4C3=O)c(Br)c(=O)n12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-bromo-2-(1-hydroxyethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.909 g, 3.21 mmol), triphenylphosphine (1.010 g, 3.85 mmol), phthalimide (0.567 g, 3.85 mmol), and THF (21.39 mL) was stirred at rt for 5 min to dissolve all reactants. The mixture was then cooled to 0° C. and to the cooled homogenous mixture was added dropwise over 3 min to diisopropyl azodicarboxylate (0.758 mL, 3.85 mmol) at 0° C. After stirring at 0° C. for 30 min, the cooling bath was removed and the mixture was stirred at rt. After 1.5 h, the mixture was partitioned between EtOAc (50 mL) and water (50 mL) and the organic layer was separated, dried over Na2SO4, filtered and concd under reduced pressure to give the crude material as a yellow solid. The yellow solid was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and 50% isocratic of EtOAc in hexane for 25 min to give the desired product 2-(1-(3-bromo-6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)ethypisoindoline-1,3-dione as a light yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.82-7.92 (4 H, m), 7.70 (1 H, dd, J=9.0, 7.0 Hz), 7.32 (1 H, dd, J=8.6, 0.8 Hz), 7.04 (1 H, ddd, J=6.8, 1.4, 1.2 Hz), 5.47-5.57 (1 H, m), 2.94 (3 H, s), 1.82 (3 H, d, J=7.0 Hz); Mass Spectrum (ESI) m/e=412.0 [M+1 (79Br)] and 414.0 [M+1 (81Br)].
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2Br)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25].ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:21]2[CH:22]=[CH:23][C:24]([F:25])=[C:19]([Cl:18])[CH:20]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: Brc1cccc2ccn(Cc3ccccc3)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: Fc1ccc(-c2cccc3ccn(Cc4ccccc4)c23)cc1Cl
Yield: 23.4 %

Procedure:
1-Benzyl-7-(3-chloro-4-fluorophenyl)-1H-indole was prepared by coupling 1-benzyl-7-bromo-1H-indole (0.691 g, 2.41 mmol), and 3-chloro-4-fluorophenylboronic acid (0.538 g, 3.09 mmol), using [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.0628 g, 0.0769 mmol), and potassium carbonate (0.502 g, 3.63 mmol) in dioxane (18 mL) and water (1.8 mL) following the procedure described in Step 1 of Example 11. Purification by HPLC using 1.5% ethyl acetate in hexane as the mobile phase furnished the title compound as a clear gum (0.189 g, 23%). 1HNMR (300 MHz, DMSO-d6): δ 7.65 (d, 1H, J=7.5 Hz), 7.5 (s, 1H), 7.3 (t, 1H, J=8.3 Hz), 7.05-7.2 (m, 6H), 6.85 (d, 1H, J=7.5 Hz), 6.65 (d, 1H, J=3.8 Hz), 6.3-6.4 (m, 2H), and 4.95-5.2 ppm (m, 2H).
Reaction SMILES: Cl.[C:2]([C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].[OH-].[Na+].Br.Br[CH2:20][CH2:21][CH2:22][NH2:23].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[NH2:23][CH2:22][CH2:21][CH2:20][N:7]1[CH2:6][CH2:5][C:4]([C:2]#[N:3])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][CH2:8]1
Reactant: NCCCBr
Reactant: N#CC1(c2ccccc2)CCNCC1
Agent: Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: N#CC1(c2ccccc2)CCN(CCCN)CC1
Yield: 59 %

Procedure:
4-Cyano-4-phenylpiperidine hydrochloride (5.01 g, 22.5 mmol, 1.00 equiv, Aldrich) was added to water (100 mL), and the solution was basified to pH 10-11 by addition of 6 N aqueous NaOH. The aqueous phase was extracted with CH2Cl2 (3×100 mL). The combined organic solutions were dried over MgSO4 and concentrated. To the residue were added 3-bromopropylamine hydrobromide (4.92 g, 22.5 mmol, 1.00 equiv, Aldrich), anhydrous K2CO3 (3.42 g, 24.8 mmol, 1.10 equiv), and 1,4-dioxane (100 mL). The mixture was stirred at reflux for 24 hours under a CaSO4 drying tube. The solvent was removed, and the product was purified by flash chromatography (SiO2, CHCl3-MeOH-methanolic ammonia (2 M) 100:8:4 to 100:20:8) to give 3.23 g (59%) of colorless oil, which was characterized spectroscopically.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:15]2[S:16][C:17]([CH2:20]Cl)=[CH:18][CH:19]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH2:22]([C:24]1[NH:25][C:26]2[C:27]([N:34]=1)=[N:28][C:29]([CH3:33])=[CH:30][C:31]=2[CH3:32])[CH3:23]>>[CH2:1]([O:3][C:4]([C:6]1([C:15]2[S:16][C:17]([CH2:20][N:34]3[C:27]4=[N:28][C:29]([CH3:33])=[CH:30][C:31]([CH3:32])=[C:26]4[N:25]=[C:24]3[CH2:22][CH3:23])=[CH:18][CH:19]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Reactant: CCOC(=O)C1(c2ccc(CCl)s2)Cc2ccccc2C1
Product: CCOC(=O)C1(c2ccc(Cn3c(CC)nc4c(C)cc(C)nc43)s2)Cc2ccccc2C1

Procedure:
The product of Step 4, above (26), was alkylated as described in Example 1, Step 5 using 2-ethyl-5,7-dimethylimidazo[4,5-b]pyridine (7) to yield the title compound (27).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[O:12]=[C:13]1[CH2:21][C@@H:20]2[C@@:15]3([C:22]4[N:23]([CH:26]=[CH:27][CH:28]=4)[CH2:24][CH2:25][N:14]13)[CH2:16][CH2:17][CH2:18][CH2:19]2.FC(F)(F)C(O)=O>ClCCl>[O:12]=[C:13]1[CH2:21][C@@H:20]2[C@@:15]3([C@H:22]4[CH:28]=[CH:27][C:26](=[O:9])[N:23]4[CH2:24][CH2:25][N:14]13)[CH2:16][CH2:17][CH2:18][CH2:19]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1C[C@H]2CCCC[C@]23c2cccn2CCN13
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1C=C[C@H]2N1CCN1C(=O)C[C@H]3CCCC[C@@]321
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4.05 g (20 mmol) of m-chloroperbenzoic acid are added in portions at room temperature, with stirring, to a solution of 2.3 g (10 mmol) of (9bR*,13aR*)-2-oxo-1,4,5,10,11,12,13,13a-octahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indole in 50 ml of dichloromethane (the exothermic reaction is maintained at room temperature using an ice-bath). 2.28 g (20 mmol) of trifluoroacetic acid are then added dropwise to the reaction mixture which is then stirred for 16 hours at room temperature. The reaction mixture is diluted with 100 ml of dichloromethane and then washed in succession with sodium hydrogen sulfite solution (5%) and sodium hydrogen carbonate solution (5%). The organic phase is separated off, dried over sodium sulfate and concentrated by evaporation in vacuo. The crude product obtainable in that manner is chromatographed on 210 g of silica gel (0.040-0.063 mm) using trichloromethane as eluant. In this manner (9aR*,9bR*,13aR*)-2,7-dioxo-1,4,5,7,9a,10,11,12,13,13a-decahydro-2H-pyrrolo[2',1' :3,4]pyrazino[2,1-i]indole is obtained in the form of an oil, which is crystallised from dichloromethane/diethyl ether and melts at 159°-162°.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:10]1([NH:16][C:17]2([C:23](=[O:26])[CH2:24][CH3:25])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.CN(C)C(=O)C>O>[C:10]1([NH:16][C:17]2([C:23](=[O:26])[CH2:24][CH3:25])[CH2:22][CH2:21][N:20]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:19][CH2:18]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCCc1ccccc1
Reactant: CCC(=O)C1(Nc2ccccc2)CCNCC1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(=O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1

Procedure:
A solution of 2.7 parts of (2-bromoethyl)benzene), 3.1 parts of 1-[4-(phenylamino)-4-piperidinyl]-1-propanone and 2.6 parts of N,N-diethylethanamine in 18 parts of N,N-dimethylacetamide is stirred for 4h. 30 at 80° C. The reaction mixture is poured onto 100 parts of water and the product is extracted with benzene. The extract is washed with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is crystallized from 2,2'-oxybispropane, yielding 1-[4-(phenylamino)-1-(2-phenylethyl)-4-piperidinyl]-1-propanone; mp. 105.6° C.
Reaction SMILES: C12(COC3C(I)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.[CH:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH:25]1[CH:34]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:35]1[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][C:36]=1[Cl:44])[CH2:31]2.N1(S(N)(=O)=O)CCC1.[CH3:61][S:62]([NH2:65])(=[O:64])=[O:63]>>[CH:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH:25]1[CH:34]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:35]1[CH:43]=[CH:42][C:38]([C:39]([NH:65][S:62]([CH3:61])(=[O:64])=[O:63])=[O:40])=[CH:37][C:36]=1[Cl:44])[CH2:31]2
Reactant: O=C(O)c1ccc(C(OCc2ccccc2)C2C3CC4CC(C3)CC2C4)c(Cl)c1
Reactant: CS(N)(=O)=O
Agent: NS(=O)(=O)N1CCC1
Agent: O=C(O)c1cc(I)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Product: CS(=O)(=O)NC(=O)c1ccc(C(OCc2ccccc2)C2C3CC4CC(C3)CC2C4)c(Cl)c1

Procedure:
Following the procedure as described in Example 299 Step 2 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid with 4-(adamantan-2-yl(benzyloxy)methyl)-3-chlorobenzoic acid and to replace azetidine-1-sulfonamide with methanesulfonamide, the title compound was obtained as a colorless solid (0.312 g, 61%): 1H NMR (300 MHz, DMSO-d6) δ 12.24 (br s, 1H), 8.04 (d, J=1.7 Hz, 1H), 7.97 (d, J=7.9 Hz, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.37-7.22 (m, 5H), 5.08 (d, J=9.9 Hz, 1H), 4.27 (d, J=11.8 Hz, 1H), 4.16 (d, J=11.8 Hz, 1H), 3.37 (s, 3H), 2.38-2.31 (m, 1H), 2.09-1.34 (m, 13H), 1.08-1.02 (m, 1H); MS (ES−) m/z 486.2, 488.2 (M−1).
Reaction SMILES: [CH2:1]([S:5]([NH:8][C:9]1[C:10](=[O:20])[N:11]([CH2:16][C:17]([OH:19])=O)[C:12]([CH3:15])=[CH:13][CH:14]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].Br.Br.[S:23]1[C:27]2[CH2:28][CH:29]([NH2:32])[CH2:30][CH2:31][C:26]=2[N:25]=[C:24]1[NH2:33]>>[NH2:33][C:24]1[S:23][C:27]2[CH2:28][CH:29]([NH:32][C:17](=[O:19])[CH2:16][N:11]3[C:12]([CH3:15])=[CH:13][CH:14]=[C:9]([NH:8][S:5]([CH2:1][CH2:2][CH2:3][CH3:4])(=[O:6])=[O:7])[C:10]3=[O:20])[CH2:30][CH2:31][C:26]=2[N:25]=1
Reactant: Nc1nc2c(s1)CC(N)CC2
Reactant: CCCCS(=O)(=O)Nc1ccc(C)n(CC(=O)O)c1=O
Agent: Br
Product: CCCCS(=O)(=O)Nc1ccc(C)n(CC(=O)NC2CCc3nc(N)sc3C2)c1=O

Procedure:
The title compound was prepared from 2-[3-[(butylsulfonyl)amino]-6 -methyl-2-oxo-1(2H)-pyridinyl]acetic acid and 4,5,6,7-tetrahydro-1,3-benzothiazol-2,6-diamine dihydrobromide using the procedure of EXAMPLE 1 (STEP 6). The product was recrystallized from methanol to give a pale brown solid compound.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-])=O)=[CH:9][CH:10]=2)[NH:5][CH:4]=1)#[N:2].[CH:15]1(Br)[CH2:18][CH2:17][CH2:16]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[NH2:12][C:8]1[CH:7]=[C:6]2[C:11]([C:3]([C:1]#[N:2])=[CH:4][N:5]2[CH:15]2[CH2:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=1
Reactant: BrC1CCC1
Reactant: N#Cc1c[nH]c2cc([N+](=O)[O-])ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cn(C2CCC2)c2cc(N)ccc12
Temperature: 90 °C
Reaction time: 72 h
Yield: 74.1 %

Procedure:
A mixture of 3-cyano-6-nitroindole (3.74 g, 20.0 mmol), cyclobutylbromide (2.27 mL, 24.0 mmol), Cs2CO3 (13.04 g, 40.0 mmol) in DMF (20 mL) was stirred at 90° C. in a sealed tube for 3 days. After cooling, the mixture was poured into ice-water (200 mL) and the precipitate was filtered, washed with water and transferred to a Paar hydrogenator. The hydrogenation was carried out with 5% Pd/C (1.0 g), in MeOH (50 mL) and EtOAc (50 mL) at 60 psi of H2 for 24 h. The mixture was filtered through Celite, washed with MeOH and concentrated to dryness to provide 6-amino-1-cyclobutyl-3-cyanoindole (3.13 g, 74%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6]([CH3:9])([CH3:8])[N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:4]1[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.[CH3:24]C([Si](Cl)(C)C)(C)C.N1C=CN=C1>>[OH:1][CH2:2][C@H:3]1[O:7][C:6]([CH3:8])([CH3:9])[N:5]([C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[C@H:4]1[CH2:17][C:18]1[CH:19]=[CH:20][N:21]=[C:22]([CH3:24])[CH:23]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccncc2)[C@@H](CO)OC1(C)C
Agent: c1c[nH]cn1
Product: Cc1cc(C[C@H]2[C@@H](CO)OC(C)(C)N2C(=O)OC(C)(C)C)ccn1

Procedure:
The title compound was synthesized in manner analogous to that described in Example 472, using (4S,5S)-tert-butyl 5-(hydroxymethyl)-2,2-dimethyl-4-(pyridin-4-ylmethyl)oxazolidine-3-carboxylate in the presence of TBSCl and imidazole, and was used without further purification.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH3:34][O:35][CH2:36][C:37]([NH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)=[O:38]
Reactant: COCC(=O)Cl
Reactant: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c13)OCO2
Product: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)COC)CC4)c[nH]c13)OCO2

Procedure:
Starting from cis-4-[5-(2-methoxy-ethoxy)-benzo[1,3]dioxol-4-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A186) and methoxy-acetyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][O:29][C:30]1[N:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][C:31]=1[C:32]#[N:33]>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:6]2[CH:21]=[C:2]([C:35]3[CH:36]=[N:37][C:30]([O:29][CH3:28])=[C:31]([C:32]#[N:33])[CH:34]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[O:8])=[CH:11][CH:12]=1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1C#N
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: COc1ncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cnc2N2CC[C@@H](O)C2)cc1C#N

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 298 using (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 171.1) and 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afford an off-white powder. UPLC-MS (Condition 11), tR=1.13 min, m/z=516.2/518.2 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 1.67-1.78 (m, 1H) 1.79-1.93 (m, 1H) 2.90 (d, J=11.29 Hz, 1H) 3.19-3.29 (m, 2H) 3.35-3.43 (m, 1H) 4.06 (s, 3H) 4.21 (br. s, 1H) 4.90 (br. s, 1H) 7.33 (d, J=8.66 Hz, 2H) 7.85 (d, J=8.85 Hz, 2H) 8.02 (d, J=1.88 Hz, 1H) 8.35 (s, 1H) 8.50 (s, 1H) 8.77 (d, J=1.88 Hz, 1H) 10.18 (s, 1H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([CH2:6][CH2:7][CH2:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[C:10]1[CH2:22][CH2:23][CH3:24])[CH3:5].CON=CCCCN1C2C3C=CC=CC=3N=CC=2N=C1CCC>>[CH3:1][O:2][NH:3][CH:4]([CH3:5])[CH2:6][CH2:7][CH2:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[C:10]1[CH2:22][CH2:23][CH3:24]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(C)=NOC
Agent: CCCc1nc2cnc3ccccc3c2n1CCCC=NOC
Product: CCCc1nc2cnc3ccccc3c2n1CCCC(C)NOC
Yield: 60.7 %

Procedure:
A modification of the general procedure of Part E of Example 6 was followed to treat 5-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one O-methyloxime (4.6 g, 14.17 mmol) in lieu of 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyraldehyde O-methyloxime. Purification with flash column chromatography on silica gel (eluting with 5% methanol in dichloromethane) afforded 2.81 g of O-methyl-N-[1-methyl-4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]hydroxylamine.
Reaction SMILES: [N+](=C)=[N-].N(CN[C:8](N)=[O:9])=O.[OH-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=O)=[O:21])=[CH:16][CH:15]=1>CCOCC.O1CCOCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([C:22]2([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[CH2:8][O:9]2)=[O:21])=[CH:18][CH:19]=1
Reactant: O=C(C(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: NC(=O)NCN=O
Agent: C=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(c1ccc(Cl)cc1)C1(c2ccc(Cl)cc2)CO1
Reaction time: 16 h

Procedure:
With cooling and stirring, an ethereal diazomethane solution prepared by reaction of 5.34 g of N-nitrosomethylurea with aqueous sodium hydroxide solution in ether is added dropwise to a solution of 5 g of 4,4'-dichlorobenzil in 50 ml of dioxane. When the dropwise addition is complete, stirring is continued for 16 hours at room temperature, and the reaction solution is then concentrated by evaporation. The residual oil is crude 2-(4-chlorobenzoyl)-2-(4-chlorophenyl)oxirane which is purified by high vacuum distillation.