Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[C:4]=1[CH3:14])=O.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][C:16]1=[O:24].[OH-].[Na+]>O>[CH3:8][C:6]1[NH:7][C:3]([CH:1]=[C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:15][C:16]2=[O:24])=[C:4]([CH3:14])[C:5]=1[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: O=C1Cc2ccccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1[nH]c(C=C2C(=O)Nc3ccccc32)c(C)c1CCC(=O)O
Temperature: 50 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
Alternatively, a mixture of 3-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid (10 g, 51 mmol), 2-oxindole (6.5 g, 49 mmol) and sodium hydroxide (40 g, 58 mmol) dissolved in 50 ml of water was stirred at 50° C. for 4 hours. The reaction mixture was cooled to room temperature, filtered and the filtrate acidified with to pH 3 with 12 N hydrochloric acid. The solid which precipitated was collected by vacuum filtration, washed with 10 ml of water and dried under vacuum overnight. The crude solid slurry washed with hot ethanol twice. The solid was then collected by vacuum filtration, washed with 10 ml of ethanol and dried under vacuum to give 13.8 g (91%) of 3-[2,4-dimethyl-5-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrol-3-yl]-propionic acid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([C:16]([C:18]2[N:19](C(OCC)=O)[C:20]3[C:25]([C:26]=2[NH:27][C:28](=[O:31])[CH2:29][CH3:30])=[CH:24][CH:23]=[C:22]([Cl:32])[CH:21]=3)=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C(O)C.C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[C:11]([C:16]([C:18]2[NH:19][C:20]3[C:25]([C:26]=2[NH:27][C:28](=[O:31])[CH2:29][CH3:30])=[CH:24][CH:23]=[C:22]([Cl:32])[CH:21]=3)=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCOC(=O)n1c(C(=O)c2ncccc2CO[Si](C)(C)C(C)(C)C)c(NC(=O)CC)c2ccc(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCC(=O)Nc1c(C(=O)c2ncccc2CO[Si](C)(C)C(C)(C)C)[nH]c2cc(Cl)ccc12
Reaction time: 1.5 h
Yield: 85.6 %

Procedure:
To a solution of 2-[3-(tert-butyldimethylsilyloxymethyl)pyridine-2-carbonyl]-6-chloro-1-ethoxycarbonyl-3-(propionylamino)indole (step 4, 890 mg, 1.64 mmol) in ethanol-THF (2:1, 30 ml) was added 2N aqueous NaOH (5 ml) at 0° C. After stirring for 1.5 h, the mixture was neutralized with 2N aqueous HCl (5 ml). The mixture was concentrated and the residue was diluted with ethyl acetate (200 ml). The organic solution was washed with water (50 ml×2), dried (MgSO4), and concentrated. The residue was purified by flash column chromatography eluting with ethyl acetate/hexane (1:15) to afford 663 mg (82%) of the title compound.
Reaction SMILES: [OH-].[Na+].Cl.Cl.[NH:5]=[C:6]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)N1C=CC=N1.Cl.Cl.[NH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>O>[NH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([N:5]=[CH:6][NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:29][CH2:28]1
Reactant: NCC1CCNCC1
Reactant: N=C(NC(=O)OCc1ccccc1)n1cccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NCC1CCN(N=CNC(=O)OCc2ccccc2)CC1
Yield: 95 %

Procedure:
Sodium hydroxide (4.45 g, 111.25 mmole) was dissolved in 150 mL of deionized water. The mixture of [imino(1H-pyrazol-1-yl)methyl]carbamic acid, phenylmethyl ester, dihydrochloride salt and 4-aminomethyl piperidine, dihydrochloride salt (prepared above, 16.18 g, 44.54 mmole) was added (pH of the cloudy solution was 13) and the mixture was extracted with dichloromethane (1×200 mL and 2×100 mL). The organic layers were combined and washed with brine (1×200 mL), dried (MgSO4), filtered and concentrated in vacuo to provide the title compound as a white foam (12.29 g, 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([CH2:20][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].I[CH2:33][CH2:34][CH3:35]>C(C(C)=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([CH2:20][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:10]([O:12][CH2:33][CH2:34][CH3:35])=[O:11]
Reactant: COc1ccccc1C(Cc1ccccc1)(Cn1cncn1)C(=O)O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCOC(=O)C(Cc1ccccc1)(Cn1cncn1)c1ccccc1OC
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A mixture of 2-(2-methoxyphenyl)-3-phenyl-2-[(1,2,4-triazol-1-yl)methyl]propanoic acid (6.0 g, 0.0178 mole) and potassium carbonate (3.6 g, 0.0213 mole) in methyl ethyl ketone (50 mL) was stirred and heated to reflux for 1 hour. Iodopropane (3.6 g, 0.0213 mole) was added and the mixture continued heating at reflux for an additional 4 hours and then allowed to cool to room temperature. The solvent was removed by distillation and 100 mL of water and 100 mL of ethyl acetate added. The organic phase was then separated, dried and concentrated on a rotary evaporator to afford 5.5 g of solid product (melting point 129°-130° C.; yield 82% ), Example 100 of Table 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11](C=O)[CH2:10][CH2:9][C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][C:6]=2[CH:19]=1.C(=O)([O-])O.[Na+]>Cl.C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][C:6]=2[CH:19]=1
Reactant: CCOC(=O)C1=Cc2cc(Br)ccc2N(C=O)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=Cc2cc(Br)ccc2NCC1
Yield: 59 %

Procedure:
In 1N hydrochloric acid (25 ml) and ethanol (20 ml) was dissolved ethyl 7-bromo-1-formyl-2,3-dihydro-1-benzazepine-4-carboxylate (1165 mg), and the mixture was refluxed for 2 hours. The mixture was neutralized with saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate (300 ml). The organic layer was washed with water (100 ml) and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (15.0 g, hexane/ethyl acetate=9:1) to give ethyl 7-bromo-2,3-dihydro-1-benzazepine-4-carboxylate (628 mg, 59%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([C:7]1[N:11]2[CH2:12][CH2:13][CH2:14][CH:15]([C:16]([O:18][CH3:19])=[O:17])[C:10]2=[CH:9][CH:8]=1)=[O:6].BrC1C=CC([C:28](C2N3CCCC(C(OC)=O)C3=CC=2)=[O:29])=CC=1>>[CH3:28][O:29][C:22]1[CH:21]=[CH:20][C:4]([C:5]([C:7]2[N:11]3[CH2:12][CH2:13][CH2:14][CH:15]([C:16]([O:18][CH3:19])=[O:17])[C:10]3=[CH:9][CH:8]=2)=[O:6])=[CH:3][CH:2]=1
Reactant: COC(=O)C1CCCn2c(C(=O)c3cccc(Br)c3)ccc21
Reactant: COC(=O)C1CCCn2c(C(=O)c3ccc(Br)cc3)ccc21
Product: COC(=O)C1CCCn2c(C(=O)c3ccc(OC)cc3)ccc21

Procedure:
methyl 3-m-bromobenzoyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylate, and p0 methyl 3-p-bromobenzoyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylate; and
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[O:9]1[CH2:14][CH2:13][CH:12](O)[CH2:11][CH2:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:12]2[CH2:13][CH2:14][O:9][CH2:10][CH2:11]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: OC1CCOCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1ccc(OC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-bromophenol (15.0 g), tetrahydropyran-4-ol (9.Og) and triphenylphosphine (23.08 g) in THF (100 ml) was added dropwise at 0° C. diethyl azodicarboxylate (40% toluene solution) (38.3 g), and the mixture was stirred at room temperature for 3 days and concentrated under reduced pressure. To the residue was added diethylether, and precipitated crystals were removed by filtration. The filtrate was concentrated, and the residue was dissolved in ethyl acetate. The solution was washed with 1N sodium hydroxide solution (×3) and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane=1:4) to give colorless crystals of 4-(4-bromophenyloxy)tetrahydropyran (15.94 g).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15](OC)=[O:16])[CH:11]=2)=[CH:6][CH:5]=1.[NH2:21][NH2:22].O>CCO>[F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]([NH:21][NH2:22])=[O:16])[CH:11]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)on1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)on1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.8 %

Procedure:
To a solution of methyl 5-(4-(trifluoromethoxy)phenyl)isoxazole-3-carboxylate (6.50 g, 22.6 mmol) in EtOH (200 mL) was added NH2NH2.H2O (80%, 7 mL, 113 mmol) and the mixture was stirred at RT for 3 h. The mixture was then concentrated under reduced pressure and purified by silica gel chromatography (Petroleum ether:EtOAc=1:2) to give the ttitle compound as a white solid (4.4 g, 67.8%). MS (ES+) C11H8F3N3O3 requires: 287. found: 288 [M+H]+.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([Br:24])[N:9]([CH:21]([CH3:23])[CH3:22])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[CH3:20])O)=[O:5])C.[NH2:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][N:27]=1>>[Br:24][C:8]1[N:9]([CH:21]([CH3:22])[CH3:23])[C:10]2[CH:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[CH3:20])[N:25]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][N:27]=3)[C:4](=[O:5])[C:6]=2[N:7]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1C
Product: Cc1cc(Cl)ccc1C1c2c(nc(Br)n2C(C)C)C(=O)N1c1cc(Cl)ccn1

Procedure:
The title compound was prepared in analogy to the procedure described for step E2 using 2-bromo-5-[(4-chloro-2-methyl-phenyl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylic acid ethyl ester (intermediate C) and 2-amino-4-chloro-pyridine as starting materials. tR: 1.42 min (LC-MS 1); ESI-MS: 527.2 [M+H]+ (LC-MS 1).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21]O)[CH:16]=[CH:17][CH:18]=3)[CH:10]=[C:9]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:25][CH2:24]3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:39]([N:41](CC)[CH2:42]C)C.CS(Cl)(=O)=O>C(Cl)Cl>[CH3:39][N:41]([CH3:42])[CH2:21][CH2:20][CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:11]2[CH:10]=[C:9]([N:23]3[CH2:24][CH2:25][N:26]([C:29]4[C:34]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:27][CH2:28]3)[N:8]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:12]=2)[CH:14]=1
Reactant: OCCCc1cccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(N3CCOCC3)n2)c1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CN(C)CCCc1cccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(N3CCOCC3)n2)c1
Reaction time: 2 h

Procedure:
Dissolve 3-(3-{2-morpholin-4-yl-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidin-4-yl}-phenyl)-propan-1-ol (104 mg, 0.197 mmol) in methylene chloride and add triethylamine (55 μL, 0.394 mmol). Bring the solution to 0° C. with an ice bath and add methanesulfonyl chloride (23 μL, 0.394 mmol) dropwise. After 2 hours, dilute the reaction with additional methylene chloride and wash the mixture with brine (1×) in a separatory funnel. Dry the organic layer (Na2SO4) and concentrate under reduced pressure to give the title compound, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:24]=[CH:23][C:20](C=O)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7](/[CH:10]=[CH:11]/[C:20]2[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O=C(O)CS(=O)(=O)Cc1ccc(Cl)cc1
Product: O=S(=O)(/C=C/c1ccc(Cl)cc1)Cc1ccc(Cl)cc1
Yield: 80 %

Procedure:
A solution of 4-chlorobenzyl sulfonylacetic acid (0.01 mol) and 4-chlorobenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B. The title compound was obtained in 80% yield.
Reaction SMILES: [O:1]1[CH2:4][C:3](=O)[CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:20][C:21]1[N:25]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)[N:24]=[CH:23][C:22]=1[C:36]([NH:38][C:39]1[CH:40]=[N:41][C:42]([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[C:43]([CH3:45])[CH:44]=1)=[O:37].O>ClCCl>[CH3:20][C:21]1[N:25]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:28][N:27]=2)[N:24]=[CH:23][C:22]=1[C:36]([NH:38][C:39]1[CH:44]=[C:43]([CH3:45])[C:42]([CH:46]2[CH2:51][CH2:50][N:49]([CH:3]3[CH2:2][O:1][CH2:4]3)[CH2:48][CH2:47]2)=[N:41][CH:40]=1)=[O:37]
Reactant: O=C1COC1
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCN(C2COC2)CC1
Reaction time: 5 h
Yield: 35.5 %

Procedure:
3-Oxetanone (121 mg) and sodium triacetoxyborohydride (143 mg) were added at room temperature to a solution of 5-methyl-N-[5-methyl-6-(piperidin-4-yl)pyridin-3-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (250 mg) described in Reference Example 171 in dichloromethane (24 ml), and stirred at the same temperature for five hours. After completion of the reaction, water was added and extracted with ethyl acetate. The organic solution was dried over anhydrous sodium sulfate and concentrated. 1N Aqueous solution of sodium hydroxide (20 ml) was added to the resulting residue, solid was collected by filtration purified with silica gel column chromatography (chloroform/methanol) to give the titled compound (100 mg) as a white solid.
Reaction SMILES: C(S)C.[Li].[C:5]([C:7]1[CH:8]=[C:9]([C:18]2[S:19][C:20]3[C:26]([O:27]C)=[CH:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH:15]([CH3:17])[CH3:16])#[N:6].Cl>CN(C=O)C>[C:5]([C:7]1[CH:8]=[C:9]([C:18]2[S:19][C:20]3[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH:15]([CH3:17])[CH3:16])#[N:6]
Reactant: COc1cccc2nc(-c3ccc(OCC(C)C)c(C#N)c3)sc12
Agent: Cl
Agent: [Li]
Solvent: CN(C)C=O
Solvent: CCS
Product: CC(C)COc1ccc(-c2nc3cccc(O)c3s2)cc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.9 %

Procedure:
Ethane thiol (0.45 mL, 6.08 mmol) was added to lithium metal (14 mg, 2.02 mmol), and the mixture was stirred for one hour at room temperature. To tire mixture were then added dry DMF (5 mL) and 2-(3-cyano-4-isobutyloxyphenyl)-7-methoxy-1,3-benzothiazole (150 mg, 0.44 mmol). The resulting mixture was stirred at 80° C. for 8.5 hours, cooled to room temperature, and, after addition of icewater (10 mL), made to pH 7 by addition of aqueous 1M hydrochloric acid. The mixture was then extracted with ethyl acetate (20 mL). The ethyl acetate portion was washed successively with water (10 mL) and aqueous saturated brine (10 mL), dried over anhydrous sodium sulfate, and placed under reduced pressure to distill the solvent off. The residue was purified by silica, gel column chromatography (ethyl acetate/hexane=1/3), and suspended in hexane. The obtained crystalline product was collected by filtration, washed with hexane, and dried in air, to give 17 mg (yield 12%) of the desired compound in the form of a pale yellow crystalline product.
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:7]([CH2:22][OH:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>CN(C)C=O>[CH2:29]([O:23][CH2:22][C:7]1[C:8]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][C:6]=1[CH:24]([CH3:25])[CH3:26])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(COCc2ccccc2)c1-c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
4.5 g (12.5 mmol) of the compound from Example 4 in 50 ml of dimethylformamide are added dropwise under nitrogen to a suspension of 414 mg (13.8 mmol) of 80% strength sodium hydride in 20 ml of dimethylformamide at 0° C. and the mixture is stirred for 30 minutes at the same temperature. Subsequently, 1.65 ml (13.8 mmol) of benzyl bromide in 20 ml of dimethylformamide are added dropwise and the mixture is stirred for a further 3 h at room temperature. The mixture is poured into 300 ml of water at 0° C. and extracted three times using 150 ml of ether each time. The combined organic phases are washed once with saturated sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. The residue is chromatographed on a column (100 g of silica gel 70-230 mesh, φ3.5 cm, using ethyl acetate/petroleum ether 1:10).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]=[C:6]([C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15]([C:22]#[N:23])=[CH:16][NH:17]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].CCOC(C)=O>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH:6]([C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15]([C:22]#[N:23])=[CH:16][NH:17]2)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Reaction time: 19 h

Procedure:
To a solution of 3-(3-cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII (620 mg, 1.96 mmol) in EtOH (30 ml) and EtOAc (15 ml) was added Degoussa-type catalyst (10% Pd/C wet, 70 mg). The reaction mixture was hydrogenated in a Parr apparatus at 55 psi of H2 for 19 hours. The reaction mixture was filtered through celite with EtOH, MeOH and EtOAc. The filtrate was concentrated to afford 3-(3-cyano-1H-Indol-4-yl)-3-phenyl-propionic acid ethyl ester LIX as a white solid in quantitative yield (648 mg).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[CH3:24][N:25]=[C:26]=[O:27]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:25]([CH3:24])[C:26]2=[O:27])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: CN=C=O
Product: COc1cccc2c1ncc1c(=O)n(C)c(=O)n(C3CCCC3)c12
Yield: 55.3 %

Procedure:
1-Cyclopentyl-7-methoxy-3-methyl-1H-pyrimido[5,4-c]quinoline-2,4-dione (18 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and methyl isocyanate (0.5 mmol) following general procedure C. LCMS: m/z 326 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N+:5]([O-])=[CH:4][CH:3]=1.[CH3:17][S:18]([O:21]S(C)(=O)=O)(=[O:20])=[O:19].C(=O)([O-])[O-].[K+].[K+].O>ClCCl>[CH3:17][S:18]([O:21][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=2)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: [O-][n+]1ccc(O)c2ccc(C(F)(F)F)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)Oc1cnc2cc(C(F)(F)F)ccc2c1O
Reaction time: 2 h

Procedure:
A mixture of 4-hydroxy-7-trifluoromethyl-quinoline-1-oxide (2.0 g), methanesulphonic anhydride (1.7 g) and potassium carbonate (1.3 g) in dichloromethane (100 ml) was stirred at 0° for 2 hours. Further methanesulphonic anhydride (1.7 g) and potassium carbonate (1.3 g) were then added and the mixture was stirred at ambient temperature overnight. Water (50 ml) was added and the precipitated solid collected by filtration to give a first crop of the novel compound 4-hydroxy-7-trifluoromethylquinol-3-yl methanesulphonate, m.p. 220°. The dichloromethane layer of the filtrate was separated and the aqueous layer subsequently extracted with dichloromethane (2×25 ml). The combined dichloromethane layer and extracts were evaporated to dryness. The residue was purified by flash chromatography on a silica gel column eluted with dichloromethane:methanol (20:1) to give a second crop of 4-hydroxy-7-trifluoromethylquinol-3-yl methanesulphonate, m.p. 220°.
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH:4][C:5]1([CH2:11][CH2:12][N:13]2[C:17](=[O:18])[CH2:16][S:15][CH:14]2[CH2:19][CH2:20][CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(O)(=O)C>CCOCC>[OH:4][C:5]1([CH2:11][CH2:12][N:13]2[C:17](=[O:18])[CH2:16][S:15][CH:14]2[CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:3])=[O:27])=[CH:29][CH:30]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Reaction time: 6 h

Procedure:
A solution of diazomethane (approximately 2.5 g., 0.06 mole) in ether (100 ml.) is mixed with a solution of 4-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid (11.7 g., 0.03 mole) in ether (100 ml.). The resulting solution is allowed to stand at room temperature for 6 hours. Acetic acid is then added to destroy the excess diazomethane, and the solution is washed with dilute sodium bicarbonate solution and dried over sodium sulfate. Evaporation of volatile materials in vacuo yields the title compound as a nearly colorless, viscous oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[O:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27]O)=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:13][O:12][C:10](=[O:11])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:27][CH2:26][S:25][CH2:24][CH2:23][O:22][CH:21]([C:18]2[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=2)[C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: OCCSCCOC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COC(=O)CCc1ccc(OCCSCCOC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Reaction time: 18 h
Yield: 71.8 %

Procedure:
A solution of methyl 3-(4-hydroxyphenyl)propionate (1.40 g, 7.77 mmol), 2-[2-[bis(4-chlorophenyl)methoxy]ethylthio]ethanol (2.80 g, 7.80 mmol) and triphenylphosphine (2.0 g, 7.8 mmol) in dry benzene (30 ml) was treated at 22° C. with diethyl azodicarboxylate (1.34 g, 7.8) added dropwise over 5 min. After 18 h at 22° C., the reaction mixture was diluted with ethyl acetate (200 ml) washed with saturated sodium bicarbonate and dried over magnesium sulfate. Evaporation of the solvent gave an oil which was triturated in a mixture of hexane and toluene (6:4) to crystallize the triphenylphosphine oxide and the hydrazine side products. The filtrate was chromatographed on silica gel (elution ethyl acetate 0-5% in toluene) to give 2.90 g (71%) of the title material as an oil.