Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:30][N:46]4[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)=[CH:28][N:29]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc(Cc2nnc(N3CCN(c4ccc(CN5CCOCC5)cn4)CC3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
To a solution of 6-[4-(4-benzyl-phthalazin-1-yl)-piperazin-1-yl]-pyridine-3-carbaldehyde (40 mg, 0.1 mmol) in 5 mL DCM is added a drop of acetic acid, NaBH(OAc)3 (41.4 mg, 0.2 mmol) and morpholine (7.5 mL, 0.12 mmol). The reaction mixture is stirred for 30 min at rt. Aqueous NaHCO3 solution is added and the reaction mixture is stirred for an additional 30 min. The layers are separated and the aqueous layer is extracted with DCM. The combined organic layers are washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography on silica gel (EtOAc/heptane 10%-70%) to yield the title compound (37.8 mg, 80%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10]C(=O)C[C:7]2=[O:13].C([O:18]O)(C)(C)C.C[O-].[Na+].O>CO.C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:7]([OH:13])=[O:18])[C:11]=1[NH2:10]
Reactant: O=C1CC(=O)c2cccc(F)c2N1
Reactant: CC(C)(C)OO
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(F)cccc1C(=O)O
Reaction time: 48 h
Yield: 376 %

Procedure:
A solution of 0.1 g (0.6 mmol) of 8-fluoroquinolin-2,4-dione, 0.1 g (7.8 mmol) of 70 percent t-butyl hydroperoxide, 0.2 g of 25 percent sodium methoxide in methanol and an additional 2 mL of methanol was heated at 75° C. with stirring for 48 hr. An additional 0.2 g of t-butyl hydroperoxide and 0.5 mL of 25 percent sodium methoxide in methanol were added and heating was continued for 24 more hr. The reaction mixture was cooled, poured into water, and neutralized with acetic acid. The mixture was extracted with methylene chloride and the organic phase was collected. Evaporation of the solvent gave 0.35 g (40 percent yield) of 3-fluoroanthranilic acid, mp 172° C.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]2[C@@H:4]([CH2:5][CH2:6][NH:7]2)[N:3]1[S:9]([OH:12])(=[O:11])=[O:10].CC#N.C([O-])(O)=O.[Na+].[NH2:21][CH2:22][CH2:23][NH:24][C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35](ON2C(=O)CCC2=O)=[O:36])=[CH:30][CH:29]=1)=[O:26]>O>[NH2:21][CH2:22][CH2:23][NH:24][C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([N:7]2[CH2:6][CH2:5][C@@H:4]3[C@H:8]2[C:2](=[O:1])[N:3]3[S:9]([OH:12])(=[O:11])=[O:10])=[O:36])=[CH:30][CH:29]=1)=[O:26]
Reactant: O=C1[C@H]2NCC[C@H]2N1S(=O)(=O)O
Reactant: NCCNC(=O)Nc1ccc(NC(=O)ON2C(=O)CCC2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NCCNC(=O)Nc1ccc(NC(=O)N2CC[C@@H]3[C@H]2C(=O)N3S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
(1S,5R)-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulfonic acid (Compound B of Reaction Scheme 2, 2.0 g, 10.41 mmol, 1.0 eq) is dissolved in H2O (12.5 mL). Then CH3CN (100 mL) is added at room temperature to the solution, followed by NaHCO3 (1.57 g, 18.73 mmol, 1.8 eq) and [(2-aminoethyl)amino]-N-{4-[(2,5-dioxoazolidinyloxy)carbonylamino]phenyl}carboxamide (Compound C-1) (6.89 g, 14.57 mmol, 1.4 eq). After stirring overnight at room temperature, the reaction mixture is filtered to afford 3.27 g of the expected (1S,5R)-2-[N-(4-{[(2-aminoethyl)amino]carbonylamino}phenyl)carbamoyl]-7-oxo-2,6-diazabicyclo[3.2.0] heptane-6-sulfonic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:13]1[O:15][C@H:14]1[CH2:16]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O.[OH-].[Na+]>CN(C)C=O.CCCCCC.CCOCC>[CH2:16]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]#[N:10])[C@@H:14]1[O:15][CH2:13]1
Reactant: N#Cc1c(O)cccc1Cl
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: N#Cc1c(Cl)cccc1OC[C@H]1CO1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
3-Chloro-2-cyanophenol (0.55 g, 3.58 mmol) was dissolved in 10 mL of dimethylformamide, and the solution cooled to 0° C. Sodium hydride (0.158 g, 3.94 mmol 60% in oil), washed with hexane and dimethylformamide, was added to cooled solution over a period of one minute. After stirring for 10 minutes at room temperature, (2R)-(−)-glycidyl 3-nitrobenzenesulfonate was added and stirred 16 hours. The reaction was poured into ether and dilute sodium hydroxide. The ether layer was separated and the aqueous layer extracted once more with ether. The combined ether extracts were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 0.7 g of (R)-3-chloro-2-cyanophenyl glycidyl ether.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:14]([O:16]C)=[O:15])=[O:10])=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:14]([OH:16])=[O:15])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C)c(C(=O)Nc2ccc(N)nc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)O)cc1C(=O)Nc1ccc(N)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To methyl 3-((6-aminopyridin-3-yl)carbamoyl)-4-methylbenzoate (0.11 g, 0.39 mmol) dissolved in tetrahydrofuran (1.5 mL) was added a solution of lithium hydroxide, monohydrate (24 mg, 0.58 mmol) in water (1.5 mL). The reaction mixture was stirred at RT for 4 h. THF was removed in vacuo and to the aqueous layer was added 2N HCl until pH 4-5. The precipitate formed was collected by filtration, washed with water, dried to give 3-((6-aminopyridin-3-yl)carbamoyl)-4-methylbenzoic acid as a tan solid. MS (ESI, pos. ion) m/z: 272.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4](Cl)[CH:3]=1.C[O:13][C:14]1[CH:15]=[C:16]([OH:22])[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].Cl>[Cu].[Cu]I.C(OCC)(=O)C.C1C=CC=CC=1.CN1CCCC1=O>[Br:1][C:2]1[CH:10]=[CH:9][C:21]2[O:20][C:18]3[CH:19]=[C:14]([OH:13])[CH:15]=[C:16]([OH:22])[C:17]=3[C:6](=[O:7])[CH2:5][C:4]=2[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: COc1cc(O)cc(OC)c1
Agent: [Cu]
Agent: [Cu]I
Agent: Cl
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=C1Cc2cc(Br)ccc2Oc2cc(O)cc(O)c21
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
To a mixture of 88.3 g (F.W. 235.46, 375 mmol) of 4-bromo-2-chlorobenzoic acid (3), 57.8 g (F.W. 154.165, 375 mmol) of 3,5-dimethoxyphenol (13), 93.2 g (F.W. 138.21, 670 mmol) of potassium carbonate and 400 mL of N-methyl-2-pyrrolidone was added benzene (200 mL), and the resulting solution was dried by a Dean-Stark water separator (140-170° C.) for three hours and then, 6.0 g (F.W. 63.55, 93.7 mmol) of copper (powder) and 17.8 g (F.W. 190.45, 93.7 mmol) of copper (I) iodide were added thereto and stirred at 120° C. for 30 minutes. This reaction mixture was cooled by standing and ice water and ethyl acetate were added thereto and then, the obtained solution was made pH 2 with concentrated hydrochloric acid and filtered. The organic layer was separated and then, thoroughly washed with water and subjected to salting out with a saturated sodium chloride aqueous solution. The resulting solution was dried with anhydrous magnesium sulfate and concentrated and the residue was purified by silica gel column chromatography (developing solvent; ethyl acetate:hexane=1:3) and recrystallized from ethyl acetate-hexane to obtain 75.4 g (57%) a desired compound (20). (TLC; ethyl acetate:hexane=1:2 or 1:1).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][S:17]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH2:23]3)(=[O:19])=[O:18])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH:30][C@@H:31]1[CH2:35][CH2:34][N:33]([C:36]([C:38]2[C:39]([CH3:46])=[C:40]([CH:44]=O)[NH:41][C:42]=2[CH3:43])=[O:37])[CH2:32]1>N1CCCCC1.C(O)C>[OH:30][C@@H:31]1[CH2:35][CH2:34][N:33]([C:36]([C:38]2[C:39]([CH3:46])=[C:40](/[CH:44]=[C:23]3\[C:24](=[O:29])[NH:25][C:26]4[C:22]\3=[CH:21][C:20]([S:17]([CH2:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)(=[O:19])=[O:18])=[CH:28][CH:27]=4)[NH:41][C:42]=2[CH3:43])=[O:37])[CH2:32]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CC[C@@H](O)C1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3OCCN3CCOCC3)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4OCCN4CCOCC4)cc32)c(C)c1C(=O)N1CC[C@@H](O)C1
Yield: 69.3 %

Procedure:
5-[2-(2-Morpholin-4-yl-ethoxy)-phenylmethanesulfonyl]-1,3-dihydro-indol-2-one (42 mg, 0.1 mmol) was condensed with 4-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (24 mg, 0.1 mmol) and piperidine (1 drop) in ethanol (1.5 mL) at rt for 48 hours. The solvent was removed and the residue was purified on a silica gel column to give 44 mg (69%) of the titled compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][OH:12].[CH3:13]N(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.O>C(Cl)Cl>[CH3:13][O:12][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][OH:1]
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: OCCCc1ccccc1CO
Solvent: O
Solvent: ClCCl
Product: COCCCc1ccccc1CO
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of the title A compound, 3-(2-hydroxymethyl-phenyl)-propan-1-ol (14.9 g, 90 mmol) and proton-sponge (25 g, 1.3 eq.) in methylene chloride (500 mL) is added at 0° C. under nitrogen trimethyloxonium-tetrafluoroborate (17.3 g, 117 mmol). The reaction mixture is further stirred for 5 h at room temperature before filtration. The filtrate is poured into water and the aqueous layer extracted twice with methylene chloride. The combined organic extracts are dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (hexane/EtOAc 7/3 to 1/1 and to AcOEt/MeOH 9/1) to afford the title compound: TLC, Rf (hexane/AcOEt 4/1)=0.57. MS 198.0 [M+18].
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:13]1[CH:18]=[C:17]([N:19]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:16]2[N:36]=[CH:37][CH:38]=[C:15]2[N:14]=1.[NH4+].[Cl-]>CN(C=O)C>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:13]2[CH:18]=[C:17]([N:19]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:16]3[N:36]=[CH:37][CH:38]=[C:15]3[N:14]=2)=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2ccnn12
Reactant: CSc1ccc(O)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CSc1ccc(Oc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 919.6 %

Procedure:
The 4-(methylthio)phenol (280 mg, 2.0 mmol) was dissolved in dry DMF (3 mL) and NaH (88 mg, 60% in oil, 2.2 mmol) was added and the mixture was stirred at room temperature for 5 min. Then, 5-chloro-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (430 mg, 0.1 mmol) was added and the resulting mixture was heated up to 130° C. with Microwave and stirred for 30 min. After cooling to room temperature, NH4Cl (aq) was added to quench the reaction and extracted with EtOAc (50 mL×3). The combined organics were washed with water and brine and dried over Na2SO4. After concentration, the residue was purified with column (silica gel, 20% EtOAc/Hexane) gave the product 5-(4-(methylthio)phenoxy)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (490 mg) HPLC-MS tR=2.98 min (UV254 nm); mass calculated for formula C25H40N4O3SSi2 532.2, observed LCMS m/z 533.2 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH:17]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:28]>CO>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:17]=[C:16]([CH2:15][N:14]3[C:10]4[C:9]5[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=5[N:3]=[C:2]([NH2:28])[C:11]=4[N:12]=[CH:13]3)[O:20][N:19]=2)=[CH:22][CH:23]=1
Reactant: N
Reactant: Fc1ccc(-c2cc(Cn3cnc4c(Cl)nc5ccccc5c43)on2)cc1
Solvent: CO
Product: Nc1nc2ccccc2c2c1ncn2Cc1cc(-c2ccc(F)cc2)no1
Temperature: 150 °C

Procedure:
A mixture of 4-chloro-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c]quinoline (0.2322 g, 0.6130 mmol) and 7 N ammonia in methanol (10 mL) was sealed in a pressure vessel and heated at 150° C. for 22 hours and allowed to cool to room temperature. The volatiles were removed under reduced pressure, and the resulting orange solid was triturated with diethyl ether. The solid was then purified by column chromatography on silica gel (7 g, eluting with 10% to 20% CMA in chloroform), triturated with diethyl ether, isolated by filtration, and dried. The solid was then boiled in methanol in the presence of a small amount of 0.5 N sodium hydroxide in methanol. The mixture was allowed to cool to room temperature, and the solid was isolated by filtration and dried to provide 0.0259 g of 1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c]quinolin-4-amine as a tan powder, mp 259.0-260.0° C.
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4](=[O:35])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12]/[CH:13]=[CH:14]/[C:15]2[C:16]([CH:32]([CH3:34])[CH3:33])=[N:17][C:18]3[C:23]([C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16]([CH:32]([CH3:33])[CH3:34])[C:15]=2/[CH:14]=[CH:13]/[CH2:12][O:11][C:8]2[CH:7]=[CH:6][C:5]([C:4](=[O:35])[C:3]([OH:36])=[O:2])=[CH:10][CH:9]=2)=[CH:26][CH:27]=1
Reactant: COC(=O)C(=O)c1ccc(OC/C=C/c2c(C(C)C)nc3ccccc3c2-c2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1nc2ccccc2c(-c2ccc(F)cc2)c1/C=C/COc1ccc(C(=O)C(=O)O)cc1
Yield: 100.5 %

Procedure:
As in Example 19, (E)-4-[3-[4-(4-fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]-2propenyloxy]-alpha-oxobenzeneacetic acid methyl ester (0.84 g) in a mixture of methanol (10 mL) and tetrahydrofuran (1.5 mL) was treated with 1N sodium hydroxide (1.9 mL). The usual work up furnished 0.82 g of a solid, which was crystallized from ethyl acetate to yield 0.63 g of (E)-4-[3-[4-(4-fluorophenyl)-2-(1-methylethyl)-3-quinolin]-2-propenyloxy]-alpha-oxobenzeneacetic acid, mp 232°-234° C.
Reaction SMILES: [CH:1]1([CH2:11][C:12]([O:14]CC)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([CH2:11][C:12]([OH:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC1CCCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl (1,2,3,4-tetrahydronaphthalen-1-yl)acetate (31.0 g) in ethanol (100 ml) was added sodium hydroxide (4N, 100 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated to a half volume under reduced pressure, and the residue was washed with ethyl acetate. The aqueous layer was acidified with dilute hydrochloric acid, and extracted with chloroform. The obtained organic layer was washed with water and saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure to give (1,2,3,4-tetrahydronaphthalen-1-yl)acetic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:35])[C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27]CN(CC4C=NC=CC=4)CC3)=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)[CH3:2].N1C2C(=CC=CC=2)C=[C:39](C(O)=O)[CH:38]=1>>[CH2:1]([O:3][C:4](=[O:36])[CH:5]=[CH:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][NH:14][C:15]([C:16]2[CH:27]=[N:22][C:19]3[C:20]([CH:21]=2)=[CH:39][CH:38]=[CH:17][CH:18]=3)=[O:35])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(CNC(=O)c2ccc(N3CCN(Cc4cccnc4)CC3)cc2)cc1
Reactant: O=C(O)c1cnc2ccccc2c1
Product: CCOC(=O)C=Cc1ccc(CNC(=O)c2cnc3ccccc3c2)cc1
Yield: 89 %

Procedure:
The titled compound was prepared as described in the process (1-2) by using 3-quinolinecarboxylic acid.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:16][C:17](=[O:29])[CH2:18][N:19]1[C:23](=[O:24])[C:22]([CH3:26])([CH3:25])[N:21]([CH3:27])[C:20]1=[O:28].O>CN(C)C=O>[CH2:1]([S:8][CH2:16][C:17](=[O:29])[CH2:18][N:19]1[C:23](=[O:24])[C:22]([CH3:25])([CH3:26])[N:21]([CH3:27])[C:20]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: CN1C(=O)N(CC(=O)CBr)C(=O)C1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)N(CC(=O)CSCc2ccccc2)C(=O)C1(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.1 %

Procedure:
Benzyl mercaptan (256 μl, 2.2 mmol) was stirred with cesium carbonate (712 mg, 2.2 mmol) in dimethyl formamide (5 ml) at room temperature for 1 hour. 3-(3-bromo-2-oxopropyl)-1,5,5-trimethylimidazolidine-2,4-dione (552 mg, 1.99 mmol) prepared as in WO99/06361 was added and the mixture stirred 18 hours at room temperature. The reaction mixture was treated with water, extracted into ethyl acetate (3×25 ml), the organic phases combined, brine washed and dried. The product was purified by silica chromatography, eluting with 50% ethyl acetate/iso-hexane to give 300 mg product.
Reaction SMILES: [OH:1]O.[OH-].[Na+].C[C:6]1[CH2:11][CH2:10][CH2:9][C:8]([CH3:13])([CH3:12])[C:7]=1[CH:14]=O.O>CO.S(=O)(=O)(O)O>[CH3:14][CH:7]1[CH2:6][CH2:11][CH2:10][C:9](=[O:1])[C:8]1([CH3:13])[CH3:12]
Reactant: CC1=C(C=O)C(C)(C)CCC1
Reactant: OO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1CCCC(=O)C1(C)C
Reaction time: 0.25 h

Procedure:
110 ml of a solution of 30 % H2O2 followed by 28 ml of a 6N aqueous solution of NaOH were added dropwise, while stirring and within 45 minutes and 15 minutes, respectively, to a cooled solution (0°-5°) of 40 g of β-cyclocitral (0.26 mole) in 300 ml of methanol which had been acidified beforehand with 40 drops of concentrated sulphuric acid. The reaction mixture was then kept at room temperature for 3 days, while stirring. After having added water thereto, the said mixture was extracted three times with ether and the combined organic extracts were subjected to the usual treatments of washing (water), drying (MgSO4) and concentration. There were obtained 21.5 g of trimethyl-cyclohexanone by fractional distillation; b.p. 66°-69°/12 Torr (66 %).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][S:17]([C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)(=[O:19])=[O:18])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:34]>CO.C(Cl)Cl.CCOCC>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][S:17]([C:20]2[CH:21]=[C:22]([C:30]([F:31])([F:32])[F:33])[CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=2)(=[O:18])=[O:19])=[O:15])[CH2:10][CH2:9]1.[ClH:34]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NS(=O)(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCNCC1

Procedure:
2 g of 4-(3,5-bis-trifluoromethyl-benzenesulfonylaminocarbonyl)-piperidine-1-carboxylic acid tert.-butyl ester are dissolved in a mixture of 1 ml MeOH and 9 ml of CH2Cl2. The resulting mixture is treated at RT with 20 ml of 3 N HCl in (C2H5)2O for ca. 16 hours. Solvent is evaporated and N-(piperidine-4-carbonyl)-3,5-bis-trifluoromethyl-benzenesulfonamide in the form of a hydrochloride is obtained. m.p. 285-291°.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=1.[N:29]1C=CC=[CH:31][CH:30]=1.Br.BrCCN.[OH-].[Na+]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[NH2:29][CH2:30][CH2:31][NH:1][C:2]1[CH:22]=[C:21]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=1
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2N)cc(OC)c1C
Reactant: c1ccncc1
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: NCCBr
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCCN)cc(OC)c1C
Temperature: 80 °C
Reaction time: 48 h
Yield: 49.4 %

Procedure:
To a solution of compound 1g (114 mg, 0.3 mmol) and pyridine (0.049 mL, 0.60 mmol) in DMF was added 2-bromoethylamine hydrobromide (92 mg, 0.45 mmol). The reaction mixture was heated at 80° C. for three days. After two days, additional 2-bromoethylamine hydrobromide (100 mg) and tetrabutylammonium iodide (5 mg) was added. The reaction was diluted with water and made basic by addition of 1 N NaOH. The solid was recovered by filtration and washed with water. The solid was purified by preparative thin layer chromatography (9:1 chloroform/methanol) to give compound 44a (63 mg, 49%). ESI-MS m/e 426.3 (M+1).
Reaction SMILES: [CH3:1][C:2]([N:11]1[CH:15]=[C:14]([N+:16]([O-])=O)[N:13]=[CH:12]1)([CH3:10])[CH2:3][NH:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7].[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28]([NH:30][C@@H:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:32](O)=[O:33])=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28]([NH:30][C@@H:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:32]([NH:16][C:14]2[N:13]=[CH:12][N:11]([C:2]([CH3:10])([CH3:1])[CH2:3][NH:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH:15]=2)=[O:33])=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: O=C(Cc1cc(F)cc(F)c1)N[C@H](C(=O)O)c1ccccc1
Reactant: CC(C)(C)CNCC(C)(C)n1cnc([N+](=O)[O-])c1
Product: CC(C)(C)CNCC(C)(C)n1cnc(NC(=O)[C@@H](NC(=O)Cc2cc(F)cc(F)c2)c2ccccc2)c1

Procedure:
2-methyl-N-neopentyl-2-(4-nitro-1H-imidazol-1-yl)propan-1-amine (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) was reduced and coupled with (S)-2-(2-(3,5-difluorophenyl)acetamido)-2-phenylacetic acid to afford the title compound: MS 512 m/z (M+1).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([OH:11])[CH2:6]2.C(=O)([O-])[O-].[Na+].[Na+].C.[PH2]([O-])=O.[Na+]>O.[Pd].O1CCCC1>[CH2:4]1[C:3]2[C:7](=[CH:8][CH:9]=[CH:10][CH:2]=2)[CH2:6][CH:5]1[OH:11]
Reactant: OC1Cc2cccc(Br)c2C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: O=[PH2][O-]
Solvent: O
Solvent: C1CCOC1
Product: OC1Cc2ccccc2C1
Reaction time: 2 h

Procedure:
3.0 g of 4-bromo-2-indanol (RS), 60 ml of tetrahydrofuran, 1.6 g of anhydrous sodium carbonate and 0.28 g of palladium at 10% on active charcoal are agitated for 5 minutes. A solution of 1.36 g of sodium hypophosphite in 8 ml of water is introduced over 10 minutes and the whole is taken to 50° C. for 2 hours. 1.60 g of sodium carbonate is added, then at 50° C. 1.36 g of sodium hypophosphite in 8 ml of water is added drop by drop. The mixture is heated for 3 hours, and after cooling it is filtered. The filtrate is rinsed with isopropyl ether, with methanol, and concentrated to dryness under reduced pressure. The residue is taken up in 150 ml of isopropyl ether and 150 ml of water. After decanting, extraction is carried out with isopropyl ether; the extracts are dried and brought to dryness under reduced pressure. The residue is chromatographed on silica in a hexane-ethyl acetate mixture (7-3) and 1.6 g is obtained, M.p.=69° C.