Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])C.[CH3:4][O:5][C:6]1[C:7]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)=[C:8]2[C:13](=[C:14]([N:16]3[C:20](=[O:21])[C:19]4=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]4[C:17]3=[O:26])[CH:15]=1)[N+:12]([O-])=[CH:11][CH:10]=[C:9]2[CH3:28].O=P(Cl)(Cl)[Cl:42].[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:42][C:11]1[CH:10]=[C:9]([CH3:28])[C:8]2[C:13](=[C:14]([N:16]3[C:17](=[O:26])[C:18]4=[CH:25][CH:24]=[CH:23][CH:22]=[C:19]4[C:20]3=[O:21])[CH:15]=[C:6]([O:5][CH3:4])[C:7]=2[O:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:38])([F:37])[F:39])[CH:31]=2)[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(N2C(=O)c3ccccc3C2=O)c2c(c(C)cc[n+]2[O-])c1Oc1cccc(C(F)(F)F)c1
Agent: CC[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: COc1cc(N2C(=O)c3ccccc3C2=O)c2nc(Cl)cc(C)c2c1Oc1cccc(C(F)(F)F)c1

Procedure:
From 6-methoxy-4-methyl-8-phthalimido-5-(3-trifluoromethylphenoxy)quinoline-1-oxide Ethanolate (III): A solution of 6-methoxy-4-methyl-8-phthalimido-5-(3-trifluoromethylphenoxy)quinoline-1-oxide ethanolate (32.7g, 60.5 mmol) in CHCl3 (500 mL) was treated with POCl3 (55 mL, 92 g, 602 mmol) over 15 min. The solution was refluxed 2 hours, cooled, poured onto ice (1500 mL) and the pH was adjusted to 12 with 20% NaOH (700 g). The separated aqueous layer was extracted with CHCl3 (2×200 mL). The extract was washed with H2O (2×200 mL), saturated NaHCO3 (20 mL), dried (MgSO4) and evaporated in vacuo to a white solid. Recrystallization from ethanol gave 23.2 g (75%) of 1st crop title compound, mp 227°-229° C. Further recrystallizations did not change the melting point.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6].[CH:10]1(CO)[CH2:12][CH2:11]1>>[C:1]([O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1)(=[O:7])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6]
Reactant: OCC1CC1
Reactant: CCC/C=C/C(=O)OC
Product: CCC/C=C/C(=O)OCC1CC1

Procedure:
Prepared from (E)-methyl hex-2-enoate and cyclopropanemethanol according to the ester preparation method B described above.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][S:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([O:40][CH3:41])=[O:39])=[CH:34][CH:33]=3)=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].ClC1C=CC=C(C(OO)=[O:50])C=1>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][S:31]([C:32]3[CH:33]=[CH:34][C:35]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:37]=3)=[O:50])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(SCc2ccc(Cn3c(C(=O)OC)c(-c4ccccc4)c4cc(Br)ccc4c3=O)cc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(S(=O)Cc2ccc(Cn3c(C(=O)OC)c(-c4ccccc4)c4cc(Br)ccc4c3=O)cc2)cc1
Yield: 49 %

Procedure:
To a solution of 6-bromo-2-[4-(4-methoxycarbonylphenylsulfanylmethyl)benzyl]-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (189 mg) in dichloromethane (20 ml) was added 3-chloroperbenzoic acid (74 mg) under ice-cooling and the mixture was stirred under ice-cooling for 1 hr. The mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=7/3→1/4) to give the title compound (95 mg, 49%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[C:18]3=[N:19][CH:20]=[CH:21][N:22]=[C:17]3[N:16]([CH:23]3[CH2:25][CH2:24]3)[C:15]2=[O:26])[CH2:10][CH2:9]1)(C)(C)C.Cl.O1CCOCC1>>[NH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[C:18]3=[N:19][CH:20]=[CH:21][N:22]=[C:17]3[N:16]([CH:23]3[CH2:25][CH2:24]3)[C:15]2=[O:26])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](n2c(=O)n(C3CC3)c3nccnc32)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CC[C@H](n2c(=O)n(C3CC3)c3nccnc32)CC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a round bottomed flask was added tert-butyl(trans-4-(3-cyclopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclohexyl)carbamate (0.7301 g, 1.955 mmol, Step 3) and hydrogen chloride, 4.0M solution in 1,4-dioxane (4.89 ml, 19.55 mmol, Sigma-Aldrich Chemical Company, Inc.) to stir at room temperature for 7 h. Precipitate was noted to form. The reaction mixture was filtered and the solid was washed with diethyl ether to give the title compound (209.9 mg, 0.678 mmol, 34.7% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95-1.10 (m, 4 H) 1.47-1.62 (m, 2 H) 1.85 (d, J=11.15 Hz, 2 H) 2.10 (d, J=11.35 Hz, 2 H) 2.26-2.41 (m, 2 H) 2.93-3.02 (m, 1 H) 3.11 (t, J=11.93 Hz, 1 H) 4.22 (ddd, J=12.23, 8.51, 3.72 Hz, 1 H) 7.91-7.95 (m, 1 H) 7.95-7.99 (m, 1 H) 8.12 (br. s., 2 H)
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[S:9](=O)(=[O:18])([O:11]C1C=CC=CC=1)[NH2:10].C1(C)C=CC=CC=1>N1C=CC=CC=1>[CH3:7][O:6][C:4]([CH:3]([CH3:8])[CH2:2][O:1][S:9](=[O:18])(=[O:11])[NH2:10])=[O:5]
Reactant: NS(=O)(=O)Oc1ccccc1
Reactant: COC(=O)[C@@H](C)CO
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)C(C)COS(N)(=O)=O
Yield: 39.6 %

Procedure:
A mixture of 5.9 g (0.05 mole) of (S)-(+)methyl 3-hydroxy-2-methylpropionate, 9.5 g (0.055 mole) of phenyl sulfamate, 25 ml of toluene and 0.5 g of pyridine was heated at reflux for 2 hr. The reaction solution was concentrated under vacuum, and the residue was chromatographed, using silica gel and eluting with 2% methanol in methylene chloride. The desired fractions were concentrated under vacuum to give 3.9 g (40%) of a pale yellow oil.
Reaction SMILES: [Cl:1]NC(=O)CCC(N)=O.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](=[O:20])[CH3:19])=[CH:13][CH:12]=1>C(Cl)(Cl)Cl>[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18](=[O:20])[CH3:19])=[CH:15][C:16]=1[Cl:1]
Reactant: CC(=O)Cc1ccc(N)cc1
Reactant: NC(=O)CCC(=O)NCl
Solvent: ClC(Cl)Cl
Product: CC(=O)Cc1ccc(N)c(Cl)c1
Reaction time: 1 h

Procedure:
N-Chlorosuccinamide (1.79 g, 13.4 mmol) is added to a stirred solution of 1-(4-amino-phenyl)-propan-2-one (2.0 g, 13.4 mmol) in chloroform at 0° C. After 1 hour the reaction is complete. The solvent is removed to give the title compound.
Reaction SMILES: [S:1]1[CH:6]=[CH:5][C:4](=[O:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.FC(F)(F)S(O[Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])(=O)=O>C(Cl)Cl>[O:7]([C:4]1[CH:3]=[CH:2][S:1][CH2:6][CH:5]=1)[Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: O=C1C=CSCC1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1=CCSC=C1
Reaction time: 0.17 h
Yield: 60.8 %

Procedure:
2,3-Dihydro-4H-thiopyran-4-one (1.50 g, 13.1 mmol, synthesized as described in Richards et al. J. Org. Chem. 46, 4836-4842 (1981)) was dissolved in CH2Cl2 (130 mL) and triethylamine (5.47 mL, 39.4 mmol) was added. tert-Butyldimethylsilyl trifluoromethanesulfonate (3.62 mL, 15.8 mmol) was then added. After 10 minutes, the volatiles were removed in vacuo at 25° C. The resulting yellow oil was passed through a short column of SiO2 eluting with 3% TEA in hexanes to yield 1.82 g (7.97 mmol, 61%) of compound 1A as an orange oil.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19]([CH2:34][CH3:35])[CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH:32]=O)=[CH:26]2)[CH3:18].N1CCCCC1>C(O)C>[CH2:34]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH:32]=[C:11]1[C:10]3[C:14](=[CH:15][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][CH:9]=3)[NH:13][C:12]1=[O:16])=[CH:26]2)[CH3:35]
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Reactant: CCN(CC)CCCc1ccc2[nH]c(C=O)cc2c1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCCc1ccc2[nH]c(C=C3C(=O)Nc4cc(-c5ccccc5)ccc43)cc2c1
Temperature: 95 °C
Yield: 57.4 %

Procedure:
A mixture of 6-phenyl-2-oxindole (41 mg, 0.19 mmol)-5-(3-diethylamino-propyl)-1H-indole-2-carbaldehyde (50 mg, 0.19 mmol) and piperidine(0.1 mL) in ethanol (1 mL) was heated in a sealed tube at 95° C. for 20 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 49 mg (56%) of the title compound as an orange crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1.[C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])#[CH:13].C(N(CC)CC)C.O>O1CCCC1.[Cu]I>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:13]#[C:12][Si:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1ccccc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
20.60 g (78.61 mmol) of 4-Iodobenzoic acid methyl ester and 9.26 g (94.33 mmol) of ethynyl trimethylsilane were dissolved in 200 ml of tetrahydrofuran, and thereto 23.86 g (235.83 mmol) of triethylamine, 1.65 g (2.36 mmol) of dichloro(bistriphenylphosphine)palladium(II) and 0.45 g (2.36 mmol) of copper(I) iodide were added. The mixture was stirred at room temperature for 8 hours. At the end of reaction, added water and extracted with ethylacetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and separated by column chromatography to obtain trimethylsilylethynylbenzoic acid methyl ester 18.30 g (Yield 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[Cl:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[Cl:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:21]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CC1

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 2-chloro-4-fluorobenzoyl chloride (32 μL, 0.229 mmol) and mixing for 24 h, 44.9 mg (>100%) of the title compound were recovered.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([Cl:13])[CH:7]=1)[CH3:2].[Br:15][C:16]1[CH:17]=[CH:18][C:19](F)=[C:20]([CH:23]=1)[CH:21]=[O:22]>>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:7]=[C:8]([Cl:13])[CH:9]=[C:10]([O:12][C:19]2[CH:18]=[CH:17][C:16]([Br:15])=[CH:23][C:20]=2[CH:21]=[O:22])[CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cc(O)cc(Cl)c1
Reactant: O=Cc1cc(Br)ccc1F
Product: CCOC(=O)Cc1cc(Cl)cc(Oc2ccc(Br)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 4, using the following starting materials: (3-chloro-5-hydroxy-phenyl)-acetic acid ethyl ester and 5-bromo-2-fluorobenzaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1Cl.CC(C)([O-])C.[K+].CN(C=O)C.[F:23][C:24]([F:31])([C:27]([F:30])([F:29])[F:28])[CH2:25][OH:26]>C(OCC)(=O)C.C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1[O:26][CH2:25][C:24]([F:31])([F:23])[C:27]([F:30])([F:29])[F:28]
Reactant: O=C(O)c1ccc(Br)c(Cl)n1
Reactant: OCC(F)(F)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Br)c(OCC(F)(F)C(F)(F)F)n1
Temperature: 140 °C
Yield: 19.8 %

Procedure:
5-Bromo-6-chloro-2-pyridinecarboxylic acid (CAN 959958-25-9; 0.6 g, 2.54 mmol) and potassium tert-butoxide (712 mg, 6.34 mmol) were combined with DMF (30 mL) and THF (10 mL) to give a yellow suspension. To this suspension was added 2,2,3,3,3-pentafluoro-1-propanol (CAN 422-05-9; 3.01 g, 2 ml, 20.1 mmol) and the mixture was heated to 140° C. for 20 hours. After cooling the mixture was poured was poured into ethyl acetate (75 mL) and the combined mixture was washed with cold 1 M HCl (1×10 mL). The aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were combined, dried with Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (silica gel, 20 g, 0% to 100% ethyl acetate in heptane) and further purified by preparative HPLC to give the title compound (0.176 g 20%) as off white solid; MS (EI) 350.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([C:20](OC)=[O:21])[O:17][N:16]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][OH:21])[O:17][N:16]=1
Reactant: COC(=O)c1cc(OCc2nc(-c3ccccc3)oc2C)no1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1cc(CO)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
To a solution of methyl 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolecarboxylate (7.86 g) in tetrahydrofuran (150 ml) was slowly added diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 60 ml) at 0° C. and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into dilute hydrochloric acid and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethanol (5.93 g, yield 86%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 99–100° C.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:19][C:20]1[C:24](B(O)O)=[C:23]([CH3:28])[O:22][N:21]=1>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>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]=2[C:24]2[C:20]([CH3:19])=[N:21][O:22][C:23]=2[CH3:28])=[CH:12][CH:13]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: COc1ccc(-c2c(Br)[nH]c3ccccc23)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(-c2c(-c3c(C)noc3C)[nH]c3ccccc23)cc1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
2-bromo-3-(4-methoxyphenyl)-1H-indole (93 mg, 0.31 mmol), 3 mol % tetrakis(triphenylphosphine)palladium and 3,5-dimethylisoxazol-4-ylboronic acid (3 eq) were mixed in 1.5 ml degassed DME under nitrogen. 1.24 ml sodium hydrogen carbonate (1 M) was added drop wise over 5 min. The resulting mixture was stirred at 90° C. for 45 min and then cooled to rt. The solvent was evaporated under nitrogen flow and the residue was taken up in DCM. Filtering through a short plug of silica gave a crude product which was purified again on silica (EtOAc/n-Heptane 1:9-3:7). 40.5 mg 4-(3-(4-methoxyphenyl)-1H-indol-2-yl)-3,5-dimethylisoxazole was obtained as a yellow solid.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:6][CH3:7])[CH2:3][CH2:4][OH:5].N1C=CC=NC=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>>[CH3:14][S:15]([O:5][CH2:4][CH2:3][C@@H:2]([CH3:1])[CH2:6][CH3:7])(=[O:17])=[O:16]
Reactant: CC[C@H](C)CCO
Reactant: CS(=O)(=O)Cl
Solvent: c1cncnc1
Product: CC[C@H](C)CCOS(C)(=O)=O
Yield: 43.3 %

Procedure:
In a flask were charged 15.89 g of (S)-3-methylpentanol and 65 ml of pyrimidine. After cooling to 0° to 50° C., 23.63 g of methanesulfonyl chloride was added thereto dropwise, and the mixture was allowed to react at the same temperature for 1 hour. The reaction mixture was extracted with diethyl ether, and the extract was washed with water and concentrated to obtain 12.14 g (46.42%) of the titled compound.
Reaction SMILES: [CH2:1]1[O:9][C@@H:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:10][C:11]1[CH:20]=[C:19]([SH:21])[CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]>>[Cl:10][C:11]1[CH:20]=[C:19]([S:21][CH2:1][C@H:2]([OH:9])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: c1ccc([C@@H]2CO2)cc1
Reactant: COC(=O)c1ccc(S)cc1Cl
Product: COC(=O)c1ccc(SC[C@H](O)c2ccccc2)cc1Cl

Procedure:
150 mg of (R)-styrene oxide was reacted with methyl 2-chloro-4-mercaptobenzoate via Procedure S to afford (R)-methyl 2-chloro-4-(2-hydroxy-2-phenylethylthio)benzoate. 190 mg of (R)-methyl-2-chloro-4-(2-hydroxy-2-phenylethylthio)benzoate was hydrolyzed via Procedure M to give (R)-2-chloro-4-(2-hydroxy-2-phenylethylthio)benzoic acid. 170 mg of (R)-2-chloro-4-(2-hydroxy-2-phenylethylthio)benzoic acid was reacted via Procedure R to give (R)-2-chloro-4-(2-hydroxy-2-phenylethylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (R)-2-chloro-4-(2-hydroxy-2-phenylethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (R)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxy-2-phenylethylsulfonyl)benzamide. MS (Q1) 527.2 (M)+.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[CH2:28]([NH:35][CH2:36][CH2:37][OH:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:35]([CH2:36][CH2:37][OH:38])[C:23]([C:22]1[CH:21]=[CH:20][C:19]([C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:12][CH2:13]2)=[O:18])=[CH:27][CH:26]=1)=[O:25])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: OCCNCc1ccccc1
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N(CCO)Cc3ccccc3)cc2)CC1
Yield: 81 %

Procedure:
By the same procedure as described in the example 1, synthesis was carried out starting with 4-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid and using 2-(benzylamino)ethanol. Then, the product was recrystallized using isopropanol and isopropyl ether, filtered and dried to give the desired compound.
Reaction SMILES: C([O:4][CH2:5][C:6]1([CH2:23][CH3:24])[CH:15]2[N:10]([CH2:11][CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][C:14]=32)[CH2:9][CH2:8][CH2:7]1)(=O)C.CO.[OH-].[Na+]>O>[OH:4][CH2:5][C:6]1([CH2:23][CH3:24])[CH:15]2[N:10]([CH2:11][CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][C:14]=32)[CH2:9][CH2:8][CH2:7]1
Reactant: CCC1(COC(C)=O)CCCN2CCc3c([nH]c4ccccc34)C21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC1(CO)CCCN2CCc3c([nH]c4ccccc34)C21

Procedure:
1.50 g. (4.6 mmoles) of 1-acetoxymethyl-1-ethyl-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizine are dissolved in 15 ml. of methanol, and a solution of 0.40 g. (10 mmoles) of sodium hydroxide in 4 ml. of distilled water is added. The mixture is refluxed for 45 minutes, then diluted with 30 ml. of distilled water. The separated crystals are filtered off and washed with distilled water. 1.05 g. of the title compound are obtained; m.o.: 230°-233° C.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH3:10][C:11]1([CH3:35])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21](O)=[O:22])[CH:19]=2)[NH:14][CH:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:25]=2)[CH2:12]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:10][C:11]1([CH3:35])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:22])[CH:19]=2)[NH:14][CH:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:25]=2)[CH2:12]1
Reactant: NS(=O)(=O)C1CC1
Reactant: CC1(C)CC(c2cccc(N3CCCC3)c2)Nc2ccc(C(=O)O)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(c2cccc(N3CCCC3)c2)Nc2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.2 %

Procedure:
To a suspension of 60% sodium hydride (800 mg, 20 mmol) in N,N-dimethylformamide (4 mL) was added cyclopropanesulfonic acid amide (2.4 g, 20 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A52. A solution of 4,4-dimethyl-2-(3-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (1 g, 2.86 mmol) and 1,1′-carbonyldiimidazole (930 mg, 5.71 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B52. Solution B52 was added to Solution A52 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [4,4-dimethyl-2-(3-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (107 mg, 8%) as a brown solid: MS (ESI) M+1=454.2.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]([C:22](=[O:31])[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[S:9][CH:10]=1)=[O:5])C.C(O)(=O)C.Cl>O1CCOCC1>[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[C:22]([N:11]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)[C:8]1[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=1)=[O:31]
Reactant: CCOC(=O)c1csc(N(C(=O)c2ccc(Cl)cc2Cl)c2ccc(OC)c(OC)c2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COc1ccc(N(C(=O)c2ccc(Cl)cc2Cl)c2nc(C(=O)O)cs2)cc1OC
Temperature: 60 °C

Procedure:
A mixture of 2.25 g (4.68 mmol) 2-[(2,4-Dichloro-benzoyl)-(3,4-dimethoxy-phenyl)-amino]-thiazole-4-carboxylic acid ethyl ester, 2.5 ml acetic acid and 7.5 ml HCl conc. in 10 ml dioxane was heated to 60° C. for 2 h. The precipitate was filtered off and washed with dioxane to yield after drying 0.566 g (22%) of the title compound. MS (m/e): 453.0 (MH+, 100%)
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.C(N(CC)C(C)C)(C)C.[C:37](O)(=[O:39])[CH3:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:37](=[O:39])[CH3:38])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (Intermediate A) (50 mg, 0.136 mmol) in DMF (1 ml) was added N,N-diisopropylethylamine (62 mg, 0.0831 ml, 0.476 mmol), acetic acid (9.8 mg, 9.33 μl, 0.163 mmol) and TBTU (52.4 mg, 0.163 mmol). The mixture was allowed to stir at room temperature for 4 h and poured into ice/water (0.5 ml). The crude reaction mixture was concentrated in vacuo. The reaction mixture was solved with sat NaHCO3 (1×10 mL). and extracted with dichloromethane (2×20 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 100 g, 0% to 20% MeOH in dichloromethane) to yield the title compound as an off-white solid (53 mg, 62%), MS (ISP) m/z=374.3 [(M+H)+].