Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:3][CH3:4])=[O:2].[C]=O.[C:7]([CH2:10][CH:11](C)[C:12]([O:14][CH3:15])=[O:13])(=[O:9])[NH2:8]>CO>[CH3:7][CH:10]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:1]([O:3][CH3:4])=[O:2].[CH:7]([NH2:8])=[O:9]
Reactant: COC(=O)C(C)CC(N)=O
Reactant: COC=O
Agent: [C]=O
Solvent: CO
Product: COC(=O)CC(C)C(=O)OC
Product: NC=O

Procedure:
The procedure in Example 3 (3) was repeated to proceed with heating stirring reaction except that in place of 180 g of methyl formate and 96 g of methanol, 200 g of methanol was charged in the autoclave and carbon monoxide was pressurized into the autoclave so as to maintain the internal pressure at 40 kg/cm2G. After the temperature of the content in the autoclave reached 60° C., carbon monoxide was fed in the autoclave so as to maintain the internal pressure at 40 kg/cm2G to proceed with the reaction for 3 hours. Subsequently, the content therein was cooled, internal pressure was gradually lowered to atmospheric pressure, and the reaction product was taken out. As a result of analysis therefor, the conversion of methyl 3-carbamoylisobutyrate was 81.4% and there were obtained dimethyl methylsuccinate at a selectivity of 95.7% and formamide at a selectivity of 94.4%, each based on the reacted methyl 3-carbamoylisobutyrate.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[CH2:20]([O:27][C:28](=[O:60])[CH2:29][CH2:30][C:31]([O:33][C:34]1([CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:52][C@H:51]([CH2:53][NH:54][C:55](=[O:57])[CH3:56])[O:50][C:49]3=[O:58])=[CH:44][C:43]=2[F:59])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)=[O:32])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.C[Si](C)(C)Cl>CN1CCCC1=O>[CH2:20]([O:27][C:28](=[O:60])[CH2:29][CH2:30][C:31]([O:33][C:34]1([CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:52][C@H:51]([CH2:53][NH:54][C:55](=[O:57])[CH3:56])[O:50][C:49]3=[O:58])=[CH:44][C:43]=2[F:59])[CH2:39][CH2:38][N:37]([C:2]2[C:3]([F:19])=[CH:4][C:5]3[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]([CH:12]4[CH2:14][CH2:13]4)[C:10]=3[N:11]=2)[CH2:36][CH2:35]1)=[O:32])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OC(=O)CCC(=O)OCc4ccccc4)CCNCC3)c(F)c2)C(=O)O1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Agent: C[Si](C)(C)Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OC(=O)CCC(=O)OCc4ccccc4)CCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)c(F)c2)C(=O)O1

Procedure:
In analogy to example 72 step 7, with 113 mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-[1,8]naphthyridine-3-carboxylic acid (MW: 282.66, 0.4 mmol), 230 mg succinic acid 4-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenoxymethyl}-piperidin-4-yl ester benzyl ester (MW: 571.60, 0.4 mmol), 161 mg triethylamine (MW: 101.19, 1.6 mmol) and 87 mg trimethylchlorsilan (MW: 108.64, 0.8 mmol) in 2 ml N-methyl-pyrrolidin-2-one. Yield: 25 mg, 7.6%. MS: 819 (M+H)+, 817.8, Method ESI+, ESI−.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([N:11]=1)=[C:9]1[NH:12][C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:14]([C:15]([NH2:17])=[O:16])[C:8]1=[CH:7][CH:6]=2.[C:24](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([N:11]=1)=[C:9]1[N:12]([CH3:24])[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:14]([C:15]([NH2:17])=[O:16])[C:8]1=[CH:7][CH:6]=2
Reactant: NC(=O)c1c(-c2ccccc2)[nH]c2c1ccc1cnc(N)nc12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(-c2ccccc2)c(C(N)=O)c2ccc3cnc(N)nc3c21
Temperature: 70 °C
Yield: 78 %

Procedure:
To a solution of 8-amino-2-phenyl-1H-1,7,9-triaza-cyclopenta[a]naphthalene-3-carboxylic acid amide N9 (0.16 mmol) in dry DMF (5 mL), caesium carbonate (0.7 mmol) and methyl iodide (0.7 mmol) were added. The reaction mixture was heated at 70° C. in a sealed tube for 1 h then the solvent was evaporated. The solid residue was washed with water and dried, giving the title compound (78% yield). ESI (+) MS: m/z 391 (MH+). 1H NMR: 4.21 (s, 3H), 6.15 (bs, 1H), 6.76 (bs, 2H), 7.08 (bs, 1H), 7.42 (d, J=8.50, 1H), 7.52-7.65 (m, 5H), 7.83 (d, J=8.50, 1H), 9.03 (s, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][N:15]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][C:28]([F:31])([F:30])[F:29])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[C:9]2=[O:32])=[CH:4][CH:3]=1.O.C([O-])([O-])=O.[K+].[K+].B1(/[CH:49]=[CH:50]/[CH2:51][O:52][CH3:53])OC(C)(C)C(C)(C)O1>C(O)C.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.C1(C)C=CC=CC=1>[CH3:53][O:52][CH2:51]/[CH:50]=[CH:49]/[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:13][CH2:14][N:15]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][C:28]([F:30])([F:29])[F:31])(=[O:19])=[O:20])[CH2:16][CH2:17]3)[C:9]2=[O:32])=[CH:6][CH:7]=1
Reactant: O=C1N(c2ccc(I)cc2)CCC12CCN(S(=O)(=O)c1ccccc1OC(F)(F)F)CC2
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COC/C=C/c1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4OC(F)(F)F)CC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(4-Iodo-phenyl)-8-(2-trifluoromethoxy-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one (0.01 g), product of example 104), was taken up in a mixture of ethanol (1 ml), water (1 ml) and toluene (8 ml), treated with K2CO3 (0.071 g) and (E)-2-(3-methoxypropenyl)-4,4,5,5-tetramethyl-(1,3,2)-dioxaboroane and stirred 30 minutes at RT under an argon atmosphere. Then tetrakis(triphenylphosphine)palladium(0) (0.02 g) was added and the mixture was heated at 85° C. for 4 h. It was then cooled to RT, partitioned between AcOEt and water, the layers were separated, the organic layer was dried over sodium sulphate, the solvent was removed in vacuo and the residue chromatographed over silica gel (AcOEt/heptane, gradient from 0 to 50%) to give the desired 2-[4-((E)-3-methoxy-propenyl)-phenyl]-8-(2-trifluoromethoxy-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one (0.077 g) as an off white solid. MS (ESI): 525.16 (MH+).
Reaction SMILES: [CH2:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)[CH2:2][CH3:3].[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:17]=1)[CH:15]=O>>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH2:15][C:6]2[S:5][C:4]([CH2:1][CH2:2][CH3:3])=[CH:8][CH:7]=2)[CH:17]=1
Reactant: CCCc1cccs1
Reactant: COc1ccc(Br)cc1C=O
Product: CCCc1ccc(Cc2cc(Br)ccc2OC)s1

Procedure:
2-n-Propylthiophene and 5-bromo-2-methoxybenzaldehyde were used and treated in a manner similar to Reference Example 7 to give the target compound. APCI-Mass m/Z 325/327 (M+H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].C([O-])(O)=O.[Na+].Cl[CH2:16][C:17](Cl)=[O:18]>CC(C)CC(=O)C.O>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][CH2:16][C:17](=[O:18])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Br)ccc1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=C1COc2ccc(Br)cc2N1
Temperature: 80 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
To a solution of 2-amino-4-bromophenol (25 g, 133.0 mmol), NaHCO3 (22.4 g, 266.0 mmol) in 4-methylpentan-2-one (50 mL) and water (50 mL) at 0° C. was added 2-chloroacetyl chloride (10.0 mL, 200.0 mmol) dropwise. The reaction mixture was stirred at 80° C. for 24 h then cooled to ambient temperature and filtered. The filtrate was washed with water (3×10 mL) and dried over anhydrous Na2SO4. After filtration, the organic phase was evaporated to give 6-bromo-4H-benzo[1,4]oxazin-3-one as a white solid (27 g, 89%). 1H NMR (CDCl3, 400 MHz): δ 8.49 (brs, 1H), 7.08 (dd, J=8.4 Hz, J=2.0 Hz, 1H), 6.93 (d, J=2.0 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 4.61 (s, 2H).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]([CH2:28][CH2:29][C:30]([O:32]C)=[O:31])[C:20]3=[O:34])[CH:13]=[C:14]([Cl:17])[CH:15]=2)[CH:10]=[CH:9]1)=O)(C)(C)C.[OH-].[Li+].Cl>O1CCOCC1.O.C(OCC)(=O)C>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][NH:8]2)=[C:12]([CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:20]2=[O:34])[CH:13]=1
Reactant: COC(=O)CCn1c(=O)n(Cc2cc(Cl)cc3c2ccn3C(=O)OC(C)(C)C)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCn1c(=O)n(Cc2cc(Cl)cc3[nH]ccc23)c2ccccc21
Reaction time: 2 h
Yield: 75 %

Procedure:
6-Chloro-4-[3-(2-methoxycarbonyl-ethyl)-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl]-indole-1-carboxylic acid tert-butyl ester 270 mg (0.56 mmol) is taken up in dioxane 4 mL and then the lithium hydroxide 53 mg 2.23 mmol in water is added to the solution. The reaction is stirred for 2 hours and then made acidic by the addition of 1N HCl. The compound is then extracted into ethyl acetate and then the ethyl acetate is dried (MgSO4) filtered and evaporated in vacuo. The oil is taken up in dichloromethane and TFA is added. The reaction is stirred for 1 hour and then evaporated in vacuo to give a solid that is taken up in ethyl acetate and precipitated with hexanes. The solid is collected and washed with hexanes to give the title compound (156 mg, 0.42 mmol, 76%). LCMS (ESMS): m/z 370.8 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][N:15]1[C:27](=[O:28])[C:26]2[C:17](=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH:22]([CH3:29])[NH:21][CH2:20][CH2:19]3)[CH2:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][CH:25]=[C:26]5[C:27](=[O:28])[N:15]([CH3:14])[CH2:16][C:17]5=4)[CH:22]3[CH3:29])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2c1ccc1c2CN(C)C1=O
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2ccc3c(c2CCN1C(=O)c1cc2ncc(Br)cn2n1)CN(C)C3=O

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2,6-Dimethyl-1,2,6,7,8,9-hexahydro-pyrrolo[3,4-f]isoquinolin-3-one to provide the title compound in moderate yield.
Reaction SMILES: C(OC(=O)[N:10]([CH2:25][CH3:26])[C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([C:19]([O:21][CH3:22])=[O:20])=[CH:13][C:12]=1[O:23][CH3:24])C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:22][O:21][C:19](=[O:20])[C:14]1[CH:15]=[C:16]([O:17][CH3:18])[C:11]([NH:10][CH2:25][CH3:26])=[C:12]([O:23][CH3:24])[CH:13]=1
Reactant: CCN(C(=O)OCc1ccccc1)c1c(OC)cc(C(=O)OC)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCNc1c(OC)cc(C(=O)OC)cc1OC

Procedure:
A suspension of 77.5 g. of N-ethyl-2,6-dimethoxy-4-(methoxy-carbonyl)-carbanilic acid benzyl ester in 1 liter of methanol was hydrogenated in the presence of 2 g. of palladium on carbon (5%) until hydrogen uptake ceased. The suspension was heated to boiling and filtered. The filtrate was evaporated under vacuum. After recrystallization of the residue from cyclohexane, there was obtained 4-(ethylamino)-3,5-dimethoxy-benzoic acid methyl ester having a melting point of 50°-51° C.
Reaction SMILES: C1(CO[C:9](=[O:16])[NH:10][C@H:11]2[CH2:14][NH:13][C:12]2=[O:15])C=CC=CC=1.C(N(CC)CC)C.CN(C=O)C.[C:29]1([CH2:35]C(Cl)=O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>[Pd].C(O)C>[O:15]=[C:12]1[C@@H:11]([NH:10][C:9](=[O:16])[CH2:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:14][NH:13]1
Reactant: O=C(N[C@H]1CNC1=O)OCc1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(Cc1ccccc1)N[C@H]1CNC1=O
Reaction time: 2.5 h
Yield: 36.4 %

Procedure:
A mixture of 5.50 g (0.025 mol) of (S)-(2-oxo-3-azetidinyl) carbamic acid phenylmethyl ester, 250 mL of ethanol, and 2.0 g of 10% palladium on carbon catalyst was hydrogenated (2 hours) on a Parr apparatus at an initial gauge pressure of 50 psi. After filtration of the catalyst, the solution was concentrated to dryness under reduced pressure. A mixture of the residue with 4.2 mL (0.03 mol) of triethylamine and 30 mL of DMF was stirred and cooled in ice. A solution of 3.88 g (0.025 mol) of phenylacetyl chloride in 25 mL of ethanol-free chloroform was added over a period of 30 minutes. The mixture was stirred another 30 minutes with cooling, and then for 2.5 hours at room temperature. The chloroform was evaporated under reduced pressure, and 300 mL of ether was added to the residue. The mixture was cooled in ice for 20 minutes. The precipitate was filtered and washed successively with ether, aqueous NaHCO3 solution, water, and ether. After drying in the air, the solid (2.15 g) was recrystallized from 50 mL of ethanol to obtain 1.86 g of pure (S)-N-(2-oxo-3-azetidinyl)benzeneacetamide, m.p. 194°-195° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1Br.N12[CH2:16][CH2:15]N(CC1)CC2.[CH:17]12[PH:25][CH:21]([CH2:22][CH2:23][CH2:24]1)[CH2:20][CH2:19][CH2:18]2.Br.N12[CH2:34][CH2:33]N(CC1)CC2>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.C1(C)C(C)=CC=CC=1>[C:21]12([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:16]34[PH:25][CH:21]([CH2:33][CH2:34][CH2:15]3)[CH2:20][CH2:19][CH2:18]4)[PH:25][CH:17]([CH2:24][CH2:23][CH2:22]1)[CH2:18][CH2:19][CH2:20]2
Reactant: C1CC2CCCC(C1)P2
Reactant: C1CN2CCN1CC2
Reactant: Brc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Br
Solvent: Cc1ccccc1C
Product: c1ccc(C23CCCC(CCC2)P3)c(C23CCCC(CCC2)P3)c1
Temperature: 100 °C

Procedure:
A 300 ml Schlenk vessel under nitrogen atmosphere is charged with 9.44 g (40 mmol) of 1,2-dibromobenzene, 22.4 g (200 mmol) of 1,4-diazabicyclo[2,2,2]octane, 13 g (91 mmol) of 9-phosphabicyclo[3.3.1]nonane, 2.32 g (2 mmol) of tetrakis(triphenylphosphine)palladium(0) and 150 ml of xylene (solvent). The mixture is stirred overnight at 140° C., during which period a precipitate of 1,4-diazabicyclo[2,2,2]octane hydrogenbromide is formed. After cooling to 100° C. the mixture is filtered hot. Upon cooling of the xylene solution, crystals of 1,2-bis-([3.3.1]-9-phosphabicyclononane) benzene are formed. The liquid is decanted, and the product recrystallized from 100 ml of hot toluene. 1,2-bis(9-phosphabicyclo[3.3.1]nonyl) benzene is obtained in a yield of 7.1 g (20 mmol, 50%), pure according to 31p and 1H NMR, 31P NMR (CD2Cl2): −16.6 ppm 1H NMR (CD2Cl2): 7.15 ppm (m, 2H), 7.10 ppm (m, 2H), 2.63 ppm (s, 4H), 12-2.2 ppm (m, 24H)
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11](=[S:13])[NH2:12])=[CH:5][CH:4]=1.[Cl:16][CH2:17][C:18]([CH2:20]Cl)=[O:19]>CC(C)=O>[ClH:16].[Cl:16][CH2:17][C:18](=[O:19])[CH2:20][S:13][C:11](=[NH:12])[CH:10]=[CH:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=S)C=Cc1ccc(C(F)(F)F)cc1
Solvent: CC(C)=O
Product: Cl
Product: N=C(C=Cc1ccc(C(F)(F)F)cc1)SCC(=O)CCl
Yield: 70.1 %

Procedure:
2.30 g (9.95 mmol) 3-(4-Trifluoromethyl-phenyl)-acrylthioamide, 2.52 g (19.90 mmol) 1,3-dichloroacetone and 75 ml acetone were stirred at room temperature for 24 h. The precipitate was isolated and dried, yielding 2.50 g (70%) 3-(4-trifluoromethyl-phenyl)-thioacrylimidic acid 3-chloro-2-oxo-propyl ester hydrochloride.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:28])[CH2:7][N:8]2[CH2:12][CH2:11][C:10]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:9]2=[O:27])[CH2:2]1.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[C:38]([F:41])([F:40])[F:39])[CH:33]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C:10]2([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:11][CH2:12][N:8]([CH2:7][C:6]([NH:5][CH:3]3[CH2:4][N:1]([CH2:33][C:32]4[CH:35]=[CH:36][C:37]([C:38]([F:39])([F:40])[F:41])=[C:30]([F:29])[CH:31]=4)[CH2:2]3)=[O:28])[C:9]2=[O:27])=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(C(F)(F)F)c(F)c1
Reactant: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)NC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)NC1CN(Cc2ccc(C(F)(F)F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N-azetidin-3-yl-2-[3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl]acetamide (0.083 g, 0.215 mmol; Example 239A) in dichloromethane (5 mL) was added 3-fluoro-4-(trifluoromethyl)benzaldehyde (0.062 g, 0.323 mmol), sodium triacetoxyborohydride (0.088 g, 0.323 mmol) and a few drops of acetic acid. The reaction mixture was stirred at ambient temperature for 16 hours. The mixture was then diluted with dichloromethane and washed with saturated aqueous NaHCO3 solution. The separated organic layer was dried over MgSO4, concentrated, and purified by silica gel flash chromatography eluting with 5-10% methanol/dichloromethane. 1H NMR (300 MHz, CDCl3) δ ppm 7.54 (t, J=7.6 Hz, 1H), 7.28-7.33 (m, 4H), 7.12-7.16 (m, 2H), 6.98-7.05 (m, 4H), 6.30-6.37 (m, 1H), 4.40-4.59 (m, 1H), 3.99 (s, 2H), 3.54-3.66 (m, 4H), 3.50 (t, J=6.5 Hz, 2H), 2.77 (t, J=6.4 Hz, 4H); MS (ESI+) m/z 562 (M+H)+.
Reaction SMILES: [OH-].[K+].C[O:4][C:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]([CH2:37][CH3:38])([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH2:34][CH3:35])[CH:28]([OH:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:22]([CH3:36])[CH:21]=3)[CH2:18][CH3:19])[CH:13]=2)[CH:8]=1)=[O:6].C1COCC1.CO>O>[CH2:18]([C:17]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:5]([OH:6])=[O:4])[CH:16]=[CH:15]2)([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH2:34][CH3:35])[CH:28]([OH:33])[C:29]([CH3:32])([CH3:30])[CH3:31])=[C:22]([CH3:36])[CH:21]=1)[CH2:37][CH3:38])[CH3:19]
Reactant: CCC(Oc1ccc(C(CC)(CC)c2ccc3cc(C(=O)OC)ccc3c2)cc1C)C(O)C(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCC(Oc1ccc(C(CC)(CC)c2ccc3cc(C(=O)O)ccc3c2)cc1C)C(O)C(C)(C)C
Temperature: 60 °C
Reaction time: 14 h
Yield: 97.5 %

Procedure:
Add KOH (321 mg, 5.724 mmol) to a mixture of diastereomeric isomer pair 1 of 6-{1-ethyl-1-[4-(1-ethyl-2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]propyl}-naphthalene-2-carboxylic acid methyl ester (702 mg, 1.431 mmol), THF (9 ml), MeOH (3 ml), and H2O (1 ml). Heat the reaction mixture to 60° C. and stir it for 14 h. Cool and partition the reaction mixture between Et2O and 1N HCl. Dry the organic layer over MgSO4, filter, and concentrate the filter in vacuo to give the title compound as a glassy solid (665 mg, 97%). 1NMR (400 MHz, CDCl3) δ ppm: 0.64 (t, J=7.6 Hz, 6H), 0.93 (t, J=8.4 Hz, 3H), 0.93 (s, 9H), 1.72 (m, 1H), 1.82 (m, 1H), 2.12 (s, 3H), 2.19 (q, 4H), 3.28 (s, 1H), 4.28 (dd, J=6.0, 3.2 Hz, 1H), 6.65 (d, J=8.4 Hz, 1H), 6.90 (d, J=2.0 Hz, 1H), 6.94 (dd, J=6.0, 2.4 Hz, 1H), 7.21 (dd, J=7.2, 1.6 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.86 (s, 1H), 7.89 (d, J=8.8 Hz, 1H), 8.09 (dd, J=6.8, 1.6 Hz, 1H), 8.62 (s, 1H). High Res. ES-MS: 499.2832; calc. for C31H40O4+Na: 499.2825.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=3)[C:13]=1[O:14][CH3:15])[CH2:10][C:9]([CH3:26])=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[Li]CCCC.[Cl:39][Si:40](Cl)([CH3:42])[CH3:41]>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]2[C:11]([CH:10]=[C:9]([CH3:26])[CH:8]2[Si:40]([Cl:39])([CH3:42])[CH3:41])=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:13]=1[O:14][CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)(C)C)cc2c(c1-c1ccc(C(C)(C)C)cc1)CC(C)=C2
Reactant: C[Si](C)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1c(C(C)(C)C)cc2c(c1-c1ccc(C(C)(C)C)cc1)C=C(C)C2[Si](C)(C)Cl
Temperature: -20 °C
Reaction time: 10 h
Yield: 99.7 %

Procedure:
To a solution of 10.5 g (30.0 mmol) of 5-tert-butyl-7-(4-tert-butylphenyl)-6-methoxy-2-methyl-1H-indene in 200 ml of toluene 12.0 ml (30.0 mmol) of 2.5 M nBuLi in hexanes was added at room temperature. The resulting viscous solution was stirred for 10 h, and then 10 ml of THF was added. The formed mixture was stirred for 2 h at 60° C., then cooled to −20° C., and 19.4 g (150 mmol, 5 eq.) of dichlorodimethylsilane was added in one portion. The resulting solution was warmed to room temperature, refluxed for 1 h, and then filtered through glass frit (G3). The precipitate was additionally washed by 2×10 ml of toluene. The combined filtrate was evaporated to dryness to give 13.2 g (99%) of the title product as a yellowish oil which was further used without an additional purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][O:22][CH3:23].[NH:24]1[C:32]2[C:27](=[CH:28][C:29]([C:33](O)=[O:34])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][O:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:33]([C:29]3[CH:28]=[C:27]4[C:32](=[CH:31][CH:30]=3)[NH:24][CH:25]=[CH:26]4)=[O:34])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1ccc2[nH]ccc2c1

Procedure:
According to the general method of Example 50, 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine and indole-5-carboxylic acid were combined to provide N5-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-5-indolecarboxamide as an off white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.31 (s, 1H), 8.34 (t, J=5.5 Hz, 1H), 8.06 (m, 2H), 7.63-7.58 (m, 2H), 7.42-7.38 (m, 3H), 7.22 (t, J=7.1 Hz, 1H), 6.67 (broad s, 2H), 6.50 (s, 1H), 4.58 (m, 2H), 3.81 (t, J=6.6 Hz, 2H), 3.34 (m, 2H), 3.25 (s, 3H), 3.21 (t, J=6.6 Hz, 2H), 1.89 (m, 2H), 1.72 (m, 2H); MS (EI) m/e 456.2264 (456.2274 calcd for C26H28N6O2).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1.CI.[C:19]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][C:2]1([CH3:16])[C:7](=[O:8])[N:6]([CH3:19])[C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2NC1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)C(C)(C)Oc2ccc([N+](=O)[O-])cc21

Procedure:
2,2-Dimethyl-6-nitro-4H-benzo[1,4]oxazin-3-one (1.1 g) was mixed with MeI (850 mg, Aldrich), K2CO3 (1.38 g, Aldrich) and DMF (30 ml, Aldrich) at 40° C. for 48 h. The DMF was removed in vacuo and the residue was diluted with EtOAc (80 ml). The organic phase was washed with H2O (50 ml), aqueous Na2SO3 (50 ml) and brine (50 ml). The resulting solution was dried (MgSO4) and concentrated to provide the compound which was used as is.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:18])[CH2:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][C:28](=[O:31])[CH:29]=[CH2:30]>C(O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:18])[CH2:11][N:12]1[CH2:13][CH2:14][N:15]([CH2:30][CH2:29][C:28](=[O:31])[CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH3:19])[CH2:16][CH2:17]1
Reactant: C=CC(=O)Cc1ccccc1OC
Reactant: Cc1cccc(C)c1NC(=O)CN1CCNCC1
Solvent: CCO
Product: COc1ccccc1CC(=O)CCN1CCN(CC(=O)Nc2c(C)cccc2C)CC1

Procedure:
A mixture of N-(2,6-dimethylphenyl)-2-piperazinylacetamide (100 mg, 0.4 mmol) and 1-(2-methoxyphenyl)but-3-en-2-one (100 mg, 0.56 mmol), a compound of formula (12), in ethanol (2 mL) was heated at reflux for 16 hours. Ethanol was removed under reduced pressure and the residue was purified by preparative TLC, using 10% methanol in dichloromethane as mobile phase, to afford N-(2,6-dimethylphenyl)-2-{4-[4-(2-methoxyphenyl)-3-oxobutyl]piperazin-1-yl}acetamide, a compound of formula (13).