Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])#[CH:2].I[C:17]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][N:20]=[C:19]([S:27][CH3:28])[N:18]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:28][S:27][C:19]1[N:18]=[C:17]([C:2]#[C:1][C:3]2[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=2)[C:6]([O:8][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:7])[C:22]([C:23]([F:26])([F:24])[F:25])=[CH:21][N:20]=1
Reactant: C#Cc1cccc(C(=O)OC(C)(C)C)c1
Reactant: CSc1ncc(C(F)(F)F)c(I)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CSc1ncc(C(F)(F)F)c(C#Cc2cccc(C(=O)OC(C)(C)C)c2)n1
Temperature: 120 °C

Procedure:
t-Butyl 3-ethynylbenzoate (I17) (1.603 g, 7.93 mmol), 4-iodo-2-(methylthio)-5-(trifluoromethyl)pyrimidine (I14) (1.647 g, 5.15 mmol), PdCl2(PPh3)2 (0.316 g, 0.45 mmol), PPh3 (0.355 g, 1.35 mmol), Cu(I)I (0.232 g, 1.22 mmol) and trethylamine (4.00 mL, 28.7 mmol) were combined in DMF (20 mL) and the resulting mixture heated at 120° C. under microwave irradiation for 25 minutes. The mixture was then concentrated under reduced pressure and purified twice using silica gel column chromatography (10-20% EtOAc/petroleum benzine 40-60° C. then 50-100% DCM/petroleum benzine 40-60° C.) to give the title compound (I18) (0.624 g, 31%) as a yellow solid; 1H NMR (400 MHz, CDCl3) δ 8.73 (d, J=0.8 Hz, 1H), 8.25 (m, 1H), 8.08 (m, 1H), 7.78 (m, 1H), 7.48 (m, 1H), 2.63 (s, 3H), 1.61 (s, 9H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)O)C1C=CC=CC=1.Cl>CO.[OH-].[Pd+2].[OH-]>[F:24][C:23]([F:25])([F:26])[C:20]1[CH:21]=[CH:22][C:17]([CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[OH:8])=[CH:18][CH:19]=1
Reactant: OC(c1ccc(C(F)(F)F)cc1)c1ccccc1OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: Oc1ccccc1Cc1ccc(C(F)(F)F)cc1
Reaction time: 3.5 h
Yield: 86.2 %

Procedure:
To a solution of (2-benzyloxyphenyl)-(4-trifluoromethylphenyl)-methanol (2.46 g, 6.85 mmol) in methanol (68.5 mL), a 20% palladium hydroxide catalyst (246 mg) was added and furthermore 36% HCl (0.59 mL) was added thereto, and the mixture solution was stirred under a hydrogen atmosphere for 3.5 hours, and then the catalyst was filtered off. The solvent was distilled under reduced pressure and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:8)] to obtain the title compound (1.49 g, 86%).
Reaction SMILES: II.[Mg].Br[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:18]([O:20][C:21](=[O:22])[C:13]=12)=[O:19]>C1COCC1>[CH3:11][C:8]1[CH:9]=[CH:10][C:5]([C:18]([C:14]2[C:13]([C:21]([OH:20])=[O:22])=[N:12][CH:17]=[CH:16][CH:15]=2)=[O:19])=[CH:6][CH:7]=1
Reactant: O=C1OC(=O)c2ncccc21
Reactant: Cc1ccc(Br)cc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2cccnc2C(=O)O)cc1
Reaction time: 1 h

Procedure:
Iodine (catalytic amount) was added to a THF (30 ml) suspension of magnesium (2.4 g) in a nitrogen atmosphere at room temperature with stirring, and then a THF (20 ml) solution of 4-bromotoluene (17.1 g) was dropwise added thereto and stirred for 1 hour. The resulting mixture was added to a THF (50 ml) solution of 2,3-pyridinedicarboxylic acid anhydride (12.7 g) at 0°-5° C. with stirring, and this was stirred for additional 30 minutes as it was and then for 1 hour at room temperature. The solvent was removed from the reaction mixture by distillation, and water (30 ml) was added to the residue, which was then adjusted the pH to 1.0 with hydrochloric acid. The mixture was extracted with dichloromethane, washed with water and dried. Then, the solvent was removed by distillation. Dichloromethane (about 10 ml) was added to the residue, and then isopropyl ether (about 70 ml) was added thereto. This was stirred for 16 hours at room temperature, and 3-(4-methylbenzoyl)-2-pyridinecarboxylic acid was obtained as colorless crystals (5.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:16][CH2:15][CH2:14][C:13]3[C:8](=[N:9][N:10]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[C:11](=[O:17])[CH:12]=3)[C:6]=2[CH:7]=1.CC(C)=[O:27].O.O.O.Br[O-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:16](=[O:27])[CH2:15][CH2:14][C:13]3[C:8](=[N:9][N:10]([C:18]4[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=4)[C:11](=[O:17])[CH:12]=3)[C:6]=2[CH:7]=1
Reactant: CC(C)=O
Reactant: O=c1cc2c(nn1-c1ccc(Cl)cc1)-c1cc(Cl)ccc1SCC2
Agent: [Na+]
Agent: [O-]Br
Solvent: O
Product: O=c1cc2c(nn1-c1ccc(Cl)cc1)-c1cc(Cl)ccc1S(=O)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 2.4 g of 10-chloro-2-(4-chlorophenyl)-5,6-dihydro-[1]benzothiepino[5,4-c]pyridazin-3(2H)-one, prepared in Example 11 in 25 ml of water and 300 ml of acetone is added 2.8 g of sodium hypobromite trihydrate. The mixture is stirred for 18 hours at room temperature and concentrated under reduced pressure. To the residue is added water, the precipitated crystals are collected by filtration and recrystallized from dimethylformamide-water to give 1.0 g of 10-chloro-2-(4-chlorophenyl)-5,6-dihydro-[1]benzothiepino[5,4-c]-pyridazin-3(2H)-one 7-oxide, melting at 239°-241° C. with decomposition.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:18][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[Cl:14])[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: NCc1ccccc1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=c1[nH]nc(Cl)c2cc(NCc3ccccc3Cl)ccc12
Yield: 11.3 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.578 mmol), 2-chlorobenzylamine (0.078 mL, 0.644 mmol), Pd2(dba)3 (47 mg, 0.051 mmol), rac-BINAP (112 mg, 0.180 mmol) and NaOtBu (139 mg, 1.445 mmol) in DMA (6 mL) was heated at 80° C. for 2 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(2-chloro-benzylamino)-2H-phthalazin-1-one (21 mg) as a beige solid, 1H (400 MHz, CDCl3) δ: 4.45 (s, 2H), 6.82 (d, 1H), 6.95 (dd, 1H), 7.14 (m, 2H), 7.30 (m, 2H), 8.00 (d, 1H), 11.20 (s, 1H) ppm; m/z (M+1) 319.93.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.O=S(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-].[CH2:20]=[CH2:21]>ClC(Cl)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH2:8][C:9](=[O:11])[CH2:21][CH2:20]2
Reactant: C=C
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: O=C1CCc2cc(F)ccc2C1
Temperature: 0 °C

Procedure:
4-fluorophenylacetic acid (1 equivalent) was dissolved in dichloroethane (1.3 M) containing SOCl2 (3 equivalents), the mixture was refluxed for 90 minutes and the solvent was removed. Solution of this crude product in CH2Cl2 was added dropwise within 60 minutes to AlCl3 (2 eq) in CH2Cl2 (0.4 M) while stirring at 0° C. Thereafter, ethylene was introduced at 0° C. over 45 minutes, whereupon the mixture was stirred further at room temperature for 1 hour, and thereafter was treated at 0° C. with ice-water. The organic phase was washed with 1 N HCl (2×), NaHCO3 (sat. sol.), dried and evaporated. The residue was triturated with hexane, yielding the product as a bright yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([NH:14]C(=O)C(C)(C)C)=[N:11][C:12]=2[CH3:13])[CH2:3][CH2:2]1.[OH-].[Na+]>>[CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([NH2:14])=[N:11][C:12]=2[CH3:13])[CH2:3][CH2:2]1
Reactant: Cc1nc(NC(=O)C(C)(C)C)ccc1COCC1CC1
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(N)ccc1COCC1CC1

Procedure:
This material was prepared in analogy to example 86 step B] from N-(5-cyclopropylmethoxymethyl-6-methyl-pyridin-2-yl)-2,2-dimethyl-propionamide (0.357 g) and 3M aqueous NaOH (2.68 mL) as a dark red oil (0.163 g). MS (EI): 192.2 (M+).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:28])[NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:18]=[C:17]([CH2:19][OH:20])[CH:16]=[C:15]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][C@@H:22]4[CH3:27])[N:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[CH:1]1([NH:4][C:5](=[O:28])[NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][C@@H:22]4[CH3:27])[CH:16]=[C:17]([CH2:19][O:20][S:37]([CH3:36])(=[O:39])=[O:38])[N:18]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1COCCN1c1cc(CO)nc(-c2ccc(NC(=O)NC3CC3)cc2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1cc(COS(C)(=O)=O)nc(-c2ccc(NC(=O)NC3CC3)cc2)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
3-Cyclopropyl-1-[4-[4-(hydroxymethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea (1.83 g) was partially dissolved in DCM (50 mL) and triethylamine (1 mL) and the solution was cooled to 0° C. Methane sulfonyl chloride was added (0.56 mL) and the reaction was stirred for 45 mins at RT. The reaction was then washed with water (10 mL) and the organics dried over magnesium sulphate. The solution was vacuumed to dryness to give the desired material as a yellow solid.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])[CH:3]([CH3:5])[CH3:4].[N:30]1([NH-:36])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CO.[Pd]>[NH2:1][C@H:2]([C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])[CH:3]([CH3:5])[CH3:4].[N:30]1([NH-:36])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Pd]
Agent: [NH-]N1CCOCC1
Solvent: CO
Product: CC(C)[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
In a manner analogous to Example 1 e), 3.9 g of Z-(L)-Val-(L)-Phe-morpholin-4-ylamide in 150 ml of methanol are converted by hydrogenolysis over 0.5 g of 10% Pd/C into the crude title compound, which is purified by column chromatography (SiO2, methylene chloride→methylene chloride/methanol: 97.5 to 2.5 (v/v)). TLC Rf (D)=0.4.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH3:10])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:17]([O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[C:18]#[CH:19].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[Cl-].[Na+].O.CC#N.CC#N.Cl[Pd]Cl.C(#N)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:19]#[C:18][CH2:17][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[CH:3][C:4]=1[CH3:10]
Reactant: COc1ccc(Br)cc1C
Reactant: C#CCOC1CCCCO1
Agent: Cl[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COc1ccc(C#CCOC2CCCCO2)cc1C
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 4-bromo-2-methylanisole (3.02 g), cesium carbonate (12.7 g), 2-(2-propynyloxy)tetrahydropyran (3.16 ml), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (429 mg), bis(acetonitrile)palladium(II) dichloride (77.8 mg) and acetonitrile (100 ml) was stirred at 80° C. for 5 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-90:10) to give the object product (1.76 g) as a pale-brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][O:27][CH2:28][C:29]([O:31]C)=[O:30])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[OH-].[Li+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][CH2:19]1)[N:11]=2)[CH2:26][O:27][CH2:28][C:29]([OH:31])=[O:30]
Reactant: COC(=O)COCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reaction time: 0.17 h

Procedure:
To a solution of methyl 2-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)methoxy)acetate (0.040 g, 0.089 mmol) in THF (2.00 mL) was added a solution of lithium hydroxide (0.011 g, 0.45 mmol) in 1.0 mL of water. The reaction mixture was stirred for 10 min. The THF was removed, and the reaction mixture acidified to pH 1 with 5N HCl. The resulting solid was rinsed with water and diethyl ether, and the solid was dried in vacuo at 50° C. for 2 h to give 2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyloxy)acetic acid. MS (ESI) m/z: calculated: 434.1; Observed: 435.0 (M++1).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][C@:13]([CH3:49])([CH2:47]O)[C:14](=[O:46])[C@@H:15]([NH:23][C:24](=[O:45])[C@@H:25]([NH:29][C:30](=[O:44])[C@@H:31]([NH:35][C:36]([C:38]1[S:42][C:41]([CH3:43])=[N:40][CH:39]=1)=[O:37])[CH2:32][O:33][CH3:34])[CH2:26][O:27][CH3:28])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:9][CH2:49][C@:13]([OH:12])([CH3:47])[C:14](=[O:46])[C@@H:15]([NH:23][C:24](=[O:45])[C@@H:25]([NH:29][C:30](=[O:44])[C@@H:31]([NH:35][C:36]([C:38]2[S:42][C:41]([CH3:43])=[N:40][CH:39]=2)=[O:37])[CH2:32][O:33][CH3:34])[CH2:26][O:27][CH3:28])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:8])=[CH:3][CH:2]=1
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)COS(=O)c1ccc(C)cc1

Procedure:
Prepared according to procedures described above, by reacting p-toluenesulfonyl chloride with N—((S)-1-(((S)-1-(((2S,4R)-4,5-dihydroxy-4-methyl-3-oxo-1-phenylpentan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide. MS for C32H40N4O10S2 m/z: 705 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[N:11]([CH3:19])[C:10]=2[CH3:20])[CH:6]=[CH:7][CH:8]=1.[CH2:23]([O:25][C:26](=[O:31])[C:27](Br)([CH3:29])[CH3:28])[CH3:24]>>[CH2:23]([O:25][C:26](=[O:31])[C:27]([O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:19])[C:10]([CH3:20])=[C:9]2[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=1)([CH3:29])[CH3:28])[CH3:24]
Reactant: Cc1c(-c2cccc(C(F)(F)F)c2)c2cc(O)ccc2n1C
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1cccc(C(F)(F)F)c1)c(C)n2C

Procedure:
The above compound was prepared from 3-(3-trifluoromethyl-phenyl)-1,2-dimethyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH:15]3[O:19]CCO3)[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:20].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(OCC)(=O)C.O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[C:10]([CH:15]=[O:19])[C:9]=3[CH2:8][CH2:7][C:6]2=[O:20])=[CH:24][CH:23]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: O=C1CCc2c(C3OCCO3)cccc2N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: O=Cc1cccc2c1CCC(=O)N2CCCSc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
1-(3-Bromopropyl)-5-(1,3-dioxolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (797 mg, 2.34 mmol), 4-chlorothiophenol (407 mg, 2.81 mmol) and potassium carbonate (421 mg, 3.05 mmol) were added to acetonitrile (16 ml), followed by heating under reflux for 5 hours. After cooling to room temperature, water was added to the reaction mixture, and extraction with ethyl acetate was performed. The extract was dried over sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1→2:1). The purified product was concentrated under reduced pressure, and the residue was dissolved in acetone (16 ml). p-Toluenesulfonic acid monohydrate (53.5 mg) and water (3 ml) were added, followed by stirring at room temperature overnight. An aqueous solution of potassium carbonate was added to the reaction mixture, and extraction with dichloromethane was performed. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to thereby obtain 700 mg (yield: 83%) of 1-[3-(4-chlorophenylsulfanyl)propyl]-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[S:17][C:16]([NH:18][C:19](=[O:21])[CH3:20])=[N:15][C:14]=2[CH3:22])[CH:5]=[C:6]([Cl:12])[C:7]=1[S:8](=[O:11])(=[O:10])N.[CH3:23][NH:24][CH3:25]>>[Cl:12][C:6]1[CH:5]=[C:4]([C:13]2[S:17][C:16]([NH:18][C:19](=[O:21])[CH3:20])=[N:15][C:14]=2[CH3:22])[CH:3]=[C:2]([Cl:1])[C:7]=1[S:8](=[O:10])(=[O:11])[N:24]([CH3:25])[CH3:23]
Reactant: CNC
Reactant: CC(=O)Nc1nc(C)c(-c2cc(Cl)c(S(N)(=O)=O)c(Cl)c2)s1
Product: CC(=O)Nc1nc(C)c(-c2cc(Cl)c(S(=O)(=O)N(C)C)c(Cl)c2)s1

Procedure:
The title compound is prepared by an analagous procedure to N-[5-(3,5-dichloro-4-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 6) by replacing ammonia with dimethylamine.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:7][CH2:6][CH:5]([S:8][C:9]2[CH:15]([CH3:16])[CH:14]3[N:11]([C:12](=[O:20])[CH:13]3[CH:17]([OH:19])[CH3:18])[C:10]=2[C:21]([OH:23])=[O:22])[CH2:4]1>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].CN1CC(=O)OC1=O.O1CCOCC1>[OH:19][CH:17]([CH:13]1[C:12](=[O:20])[N:11]2[CH:14]1[CH:15]([CH3:16])[C:9]([S:8][CH:5]1[CH2:4][CH:3]([CH2:2][NH:1][C:21](=[O:22])[CH2:10][NH:11][CH3:12])[O:7][CH2:6]1)=[C:10]2[C:21]([OH:23])=[O:22])[CH3:18]
Reactant: CC(O)C1C(=O)N2C(C(=O)O)=C(SC3COC(CN)C3)C(C)C12
Agent: CN1CC(=O)OC1=O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CNCC(=O)NCC1CC(SC2=C(C(=O)O)N3C(=O)C(C(C)O)C3C2C)CO1
Yield: 87.7 %

Procedure:
The title compound is prepared by the procedure of Example 47 using 0.068 g of product from Example 46 in 2.0 ml of sodium phosphate buffer (pH 8.5) and 0.029 g of 3-methyl-2,5-oxazolidinedione, prepared by the procedure described in J. Org. Chem., 34, No. 1, 243(1969), in 1 ml of dioxane to give 0.036 g of the desired product.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](/[CH:12]=[CH:13]/[CH:14]([OH:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[N:7]=1.[OH-].[Na+]>CO>[OH:23][CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])/[CH:13]=[CH:12]/[C:8]1[N:7]=[C:6]([O:5][CH2:4][C:3]([OH:24])=[O:2])[CH:11]=[CH:10][CH:9]=1
Reactant: CCCCCCCCC(O)/C=C/c1cccc(OCC(=O)OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCC(O)/C=C/c1cccc(OCC(=O)O)n1
Yield: 83.5 %

Procedure:
Under the conditions of example 2, 25 mg of 2-{6-[(1E)-(3RS)-3-hydroxy-1-undecenyl]-2-pyridyloxy}-acetic acid methyl ester in 1.5 ml of methanol is saponified with 1.5 ml of 1 n sodium hydroxide solution and worked up. 20 mg of the title compound is obtained as bright yellow oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[N:13]=[C:12]([NH:14][C:15](=O)[CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[CH:21]=3)[NH:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCOCC1>[C:1]1([CH2:7][CH2:8][C:9]2[N:13]=[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[CH:21]=3)[NH:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CCCOc1cccc(CN2CCCCC2)c1)Nc1nc(CCc2ccccc2)n[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: c1ccc(CCc2n[nH]c(NCCCCOc3cccc(CN4CCCCC4)c3)n2)cc1
Yield: 59.4 %

Procedure:
A suspension of N-[3-(2-phenylethyl)-1H-1,2,4-triazol-5yl]-4-[3-(1-piperidinylmethyl)phenoxy]butanamide (0.4 g) and lithium aluminium hydride (0.33 g) in dioxan (50 ml) was heated under reflux in a nitrogen atmosphere during 12 h. The cool mixture was quenched with water (50 ml) and extracted with ethyl acetate. The combined organic extracts were evaporated and the residue was crystallized from ethyl acetate to give the title compound as a white solid (0.23 g) m.p. 146°-7° tlc System A, Rf 0.71.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:29][CH3:30])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.B1([C:38]2[CH:43]=[CH:42][CH:41]=[N:40][CH:39]=2)OCCCO1>O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:29][CH3:30])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: CCc1nc2c(N)nc3cc(Br)ccc3c2n1CC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O
Product: CCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 16 h
Yield: 59.2 %

Procedure:
tert-Butyl 4-[(4-amino-7-bromo-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate (9.24 g, 18.9 mmol) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (3.39 g, 20.8 mmol) were coupled according to the method described in Examples 118–121. Additional reagents were added after the reaction was heated for 16 hours, and the reaction was continued for 16 hours. Water (20 mL) was added, and the n-propanol was removed under reduced pressure. The remaining mixture was extracted with chloroform (2×200 mL), and the combined organic fractions were purified by column chromatography on silica gel (eluting with chloroform and chloroform:CMA). The resulting solid was recrystallized from acetonitrile to provide 5.44 g of tert-butyl 4-{[4-amino-2-ethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidine-1-carboxylate as a white, fluffy solid, mp 229–231° C.