Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1CCN(C(C2C=C3C(=CC=2)NC(C(O)=O)=C3)=O)CC1)(C)C.[CH:24]1([N:29]2[CH2:34][CH2:33][N:32]([C:35]([C:37]3[CH:38]=[C:39]4[C:43](=[CH:44][CH:45]=3)[NH:42][C:41]([C:46]([N:48]3[CH2:53]CS(=O)(=O)CC3)=[O:47])=[CH:40]4)=[O:36])[CH2:31][CH2:30]2)[CH2:28]CC[CH2:25]1.[F:56][C:57]1(NC)[CH2:60][O:59][CH2:58]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:56][C:57]1([CH2:53][NH:48][C:46]([C:41]2[NH:42][C:43]3[C:39]([CH:40]=2)=[CH:38][C:37]([C:35]([N:32]2[CH2:33][CH2:34][N:29]([CH:24]([CH3:25])[CH3:28])[CH2:30][CH2:31]2)=[O:36])=[CH:45][CH:44]=3)=[O:47])[CH2:60][O:59][CH2:58]1
Reactant: CNC1(F)COC1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)NCC4(F)COC4)cc3c2)CC1
Yield: 42 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride (example 1, intermediate b), (3-fluoro-oxetan-3-yl)-methylamine (commercially available), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a colorless solid (42%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:3]=1[CH3:25].[CH3:26][C:27]1([CH3:42])[C:31]2=[N:32][CH:33]=[C:34]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH:35]=[C:30]2[NH:29][CH2:28]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1>[CH3:26][C:27]1([CH3:42])[C:31]2=[N:32][CH:33]=[C:34]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH:35]=[C:30]2[N:29]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:3]=2[CH3:25])[CH2:28]1
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Reactant: Cc1c(Cc2cccc(C(F)(F)F)c2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(Cc2cccc(C(F)(F)F)c2)nc2cc(F)cc(F)c2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y by stirring 4-chloro-5,7-difluoro-3-methyl-2-(3-(trifluoromethyl)benzyl)quinoline (50 mg, 0.135 mmol), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine (31.4 mg, 0.135 mmol), Pd2dba3 (12 mg, 0.013 mmol), XPhos (13 mg, 0.027 mmol), sodium tert-butoxide (39 mg, 0.404 mmol), and toluene (1.3 mL) at 100° C. for 30 min. Purification by reverse-phase HPLC (0-90% acetonitrile in water) gave 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5,7-difluoro-3-methyl-2-(3-(trifluoromethyl)benzyl)quinoline. 1H NMR (400 MHz, chloroform-d) δ ppm 7.60-7.66 (1H, m), 7.40-7.55 (5H, m), 6.94-7.01 (1H, m), 5.53-5.56 (1H, m), 4.47 (2H, s), 3.78-3.85 (1H, m), 3.67-3.78 (4H, m), 3.57 (1H, d, J=8.8 Hz), 2.86-2.97 (4H, m), 2.22 (3H, s), 1.48-1.58 (3H, m), 1.46 (3H, s). Mass Spectrum (ESI) m/e=569.0 (M+1).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=1.C(=O)(O)[O-].[Na+]>CCO>[Cl:13][C:14]1[N:19]=[C:18]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:17]=[CH:16][N:15]=1
Reactant: c1ccc(C2CCCCN2)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Clc1nccc(N2CCCCC2c2ccccc2)n1
Yield: 66 %

Procedure:
2-Phenylpiperidine, Intermediate 15, (0.5 g, 2.52 mmol), 2,4-dichloropyrimidine (0.41 g, 2.77 mmol) and sodium bicarbonate (0.59 g, 5.55 mmol) in dry EtOH (10 mL) were refluxed for 2 hours, under an atmosphere of nitrogen. The mixture was filtered and the filtrate evaporated in vacuo to give a yellow oil. The oil was purified by flash chromatography (EtOAc and isohexane (1:3)/silica) to give the title compound as a colourless oil (46 g, 66%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[N:14]=[N:15]NN=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](Cl)(=[O:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.O.[OH-].[Na+]>N1C=CC=CC=1>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[O:28][C:18]([C:19]4[CH:27]=[CH:26][C:22]([C:23]5[O:24][C:13]([C:9]6[N:8]=[C:7]([C:1]7[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=7)[CH:12]=[CH:11][CH:10]=6)=[N:14][N:15]=5)=[CH:21][CH:20]=4)=[N:15][N:14]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: c1ccc(-c2cccc(-c3nn[nH]n3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: c1ccc(-c2cccc(-c3nnc(-c4ccc(-c5nnc(-c6cccc(-c7ccccc7)n6)o5)cc4)o3)n2)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 58 %

Procedure:
5.0 g of 2-phenyl-6-(2H-tetrazol-5-yl)pyridine was dissolved in 125 ml of dehydrated pyridine. Temperature was elevated to 120° C., and 75 ml was dehydrated by azeotropy. After cooling to 50° C., 2.30 g of terephthaloyl dichloride was added. Temperature was elevated to 100° C., and stirring was conducted for 5 hours. After cooling to room temperature, the reaction solution was poured into 300 ml water, and after adjusting pH to 12 with 20% sodium hydroxide aqueous solution, stirring was conducted for 1 hour. A precipitated yellow solid was taken out by suction filtration, and washed with water. The solid obtained was vacuum dried at 70° C. for 20 hours, and purified with dispersion washing by a chloroform-methanol mixed solution to obtain 3.40 g (yield 58%) of PhpyOXDp. The product was identified with NMR analysis. The result of NMR analysis (CDCl3) was as follows. 8.45 ppm (4H), 8.29 ppm (2H), 8.16 ppm (4H), 7.93-8.02 ppm (4H), 7.50-7.59 ppm (6H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>[Pd].CCOC(C)=O.CO>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(C2=CCC3(CC2)OCCO3)cc1
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(C2CCC3(CC2)OCCO3)cc1
Yield: 92.9 %

Procedure:
A mixture of methyl 4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzoate (514 mg, 1.87 mmol) and 10% Pd/C (127 mg) in 15 mL of 1:2 v/v EtOAc/CH3OH was shaken for 6.5 h under 45 Psi of H2 using a Parr shaker. Catalyst was filtered off through a cake of Celite and washed with copious of EtOAc. The filtrate was concentrated to give 480 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[Cl-].[Li+].C([Mg+])(C)C.[Cl-].C(O[B:24]1[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]1)(C)C.[NH4+].[Cl-].Cl>O1CCCC1.C(OCC)(=O)C>[CH3:12][O:11][C:4]1[C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=[C:2]([B:24]2[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]2)[CH:3]=1
Reactant: COc1cc(Br)cc2c1OCO2
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg+]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)cc2c1OCO2
Temperature: 5 °C
Reaction time: 0.83 h
Yield: 33.2 %

Procedure:
6-Bromo-4-methoxybenzo[d][1,3]dioxole (1.5 g, 6.5 mmol, prepared according to Shirasaka, Tadashi; Takuma, Yuki; Imaki, Naoshi. Synthetic Communications 1990, 20, 1223-1232) was dissolved in dry tetrahydrofuran (25 mL), cooled to 5° C. and treated with isopropylmagnesium lithium chloride (1.3 M; 5.2 mL, 6.8 mmol). After 50 min at 10° C., the temperature was raised to 40° C. and stirred for 5 h. The mixture was cooled to 20° C., treated with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.3 g, 7.1 mmol) and stirred for 3 h. The mixture was treated with saturated NH4Cl (2 mL), followed by 1 M HCl (8 mL) and ethyl acetate (20 mL), and then was stirred for 10 min. The organic phase was washed with saturated NaCl (10 mL), dried (Na2SO4) and evaporated. The product was purified by flash chromatography with dichloromethane to give the title compound as a white solid (600 mg; 33%): mp 86-88° C.; 1H NMR (400 MHz, CDCl3) δ 7.01 (d, J=0.5 Hz, 1H), 6.97 (d, J=0.8 Hz, 1H), 5.98 (s, 2H), 3.93 (s, 4H), 1.33 (s, 12H); EIMS m/z 278.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].[F:15][CH2:16][CH:17]([OH:20])[CH2:18][F:19]>C1COCC1>[Cl:1][C:2]1[C:3]([O:20][CH:17]([CH2:18][F:19])[CH2:16][F:15])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: OC(CF)CF
Reactant: COC(=O)c1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cnc(OC(CF)CF)c(Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
Methyl 5,6-dichloronicotinate (1.5 g) and 60% sodium hydride (640 mg) were dissolved in THF (45 mL). 1,3-Difluoropropan-2-ol (1.5 g) was added thereto at 0° C., followed by stirring at 0° C. for 3 hours, and the reaction solution was quenched with aqueous NH4Cl. After extraction with EtOAc, the organic layer was dried over MgSO4 and then filtered, and the desiccant was removed. The vehicle was evaporated under reduced pressure, followed by purification by silica gel column chromatography (hexane:AcOEt=100:0 to 50:50) to obtain methyl 5-chloro-6-[(1,3-difluoropropan-2-yl)oxy]nicotinate (1.56 g) as a colorless liquid.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[CH:5]([N:9]=[N:10][C:11](Cl)([CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:12])([CH2:7][CH3:8])[CH3:6].O>CC(C)=O>[CH:5]([N:9]=[N:10][C:11]([N:3]=[C:2]=[O:1])([CH2:13][CH:14]([CH3:15])[CH3:16])[CH3:12])([CH2:7][CH3:8])[CH3:6]
Reactant: N#C[O-]
Reactant: CCC(C)N=NC(C)(Cl)CC(C)C
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCC(C)N=NC(C)(CC(C)C)N=C=O
Temperature: 25 °C

Procedure:
To a stirrred solution of 8.6 grams (0.105 moles) of potassium cyanate in 75 ml of 70% aqueous acetone in a 125 ml erlenmeyer flask was added 19 grams (0.093 moles) of 2-sec.-butylazo-2-chloro-4-methylpentane (from Example 3-23) over 10 minutes while holding the reaction temperature at 15°-20° C. with a cold water bath. After the addition was complete the reaction was stirred an additional hour at room temperature, poured into 200 ml water and the product extracted with 100 mls of pentane. The pentane solution was separated, washed with 50 ml portions of water and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure on a rotating evaporator. The product was a yellow liquid and weighed 13.1 grams (67% crude yield). The infrared spectrum of the product was in agreement with the structure of 2-sec.-butylazo-2-isocyanato-4-methylpentane (strong broad isocyanate band at 2125-2225 cm- 1).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[CH3:11][N:12]([CH3:17])[C:13](=[O:16])[CH2:14]Cl.C(=O)(O)[O-].[Na+].O1CCCC1>CO>[CH3:11][N:12]([CH3:17])[C:13](=[O:16])[CH2:14][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1
Reactant: CN(C)C(=O)CCl
Reactant: CNCCc1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CN(CCc1ccncc1)CC(=O)N(C)C

Procedure:
4-[2-(methylamino)ethyl]pyridine (34.4 g) and 29.18 g of chloroacetic acid-dimethylamide are dissolved in 200 ml of methanol. After the addition of 20 g of sodium bicarbonate the mixture is refluxed for 5 hours with stirring. For working up the mixture is combined with 1000 ml of tetrahydrofuran, decanted off from the precipitated salts and the solution is filtered through active charcoal. After the limination of the solvent, N,N-dimethyl-2-[methyl-(2-pyridine-4-yl-ethyl)-amino]-acetamide is obtained as a crude product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[N:19]3[CH:20]=[C:21]([O:24][C@H:25]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[C@@H:28]([NH:35][C:36]([NH:38][C:39]5[N:40]([C:48]6[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=6)[N:41]=[C:42]([C:44]([CH3:47])([CH3:46])[CH3:45])[CH:43]=5)=[O:37])[CH2:27][CH2:26]4)[CH:22]=[CH:23][C:18]3=[N:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:44]([C:42]1[CH:43]=[C:39]([NH:38][C:36]([NH:35][C@@H:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:25]([O:24][C:21]3[CH:22]=[CH:23][C:18]4[N:19]([C:15]([CH2:14][CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[N:16][N:17]=4)[CH:20]=3)[CH2:26][CH2:27]2)=[O:37])[N:40]([C:48]2[CH:49]=[CH:50][C:51]([CH3:54])=[CH:52][CH:53]=2)[N:41]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(CC5CCN(C(=O)OC(C)(C)C)CC5)n4c3)c3ccccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(CC5CCNCC5)n4c3)c3ccccc32)cc1

Procedure:
An orange solution of Intermediate 22c (155 mg, 0.211 mmol) and TFA (0.157 mL, 2.11 mmol) in DCM (3 mL) was stirred at RT for 3 h. The solution was concentrated in vacuo, redissolved in MeOH (1 mL), applied to an SCX-2 cartridge (2 g) and washed with MeOH (15 mL). The product was eluted with 2M NH3 in MeOH (15 mL); concentration in vacuo left the title compound as a pale brown solid (116 mg, 87%). LCMS (Method 3): Rt 2.90 min, m/z 633 [MH+].
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:4].O.[OH-].[Li+]>C1COCC1>[CH2:14]([O:13][C:11]([N:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C@H:5]1[C:3]([OH:4])=[O:2])=[O:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred solution of (S)-1-(benzyloxy-carbonyl)-2-piperidinecarboxylic acid methyl ester (2.00 g, 7.21 mmol) in THF (20 ml) at room temperature was treated with water (10 ml). Lithium hydroxide (190 mg, 7.93 mmol) was added and the resulting mixture stirred at room temperature for 3 hr. An additional quantity of lithium hydroxide (40 mg, 1.67 mmol) was added and the resulting mixture was stirred for 2 hr prior to the removal of the organic solvent. The resulting solution was washed with diethyl ether and the remaining aqueous layer was made acidic with 2 N HCl prior to a second extraction step with ethyl acetate. The organic layer was then recovered, dried (Na2SO4), filtered and concentrated to reveal a colorless oil (1.9927 g, 105%) which crystallized upon standing: 1H NMR (400 MHz, CDCl3) δ 1.30-1.88 (5H, m), 2.22-2.41 (1H, m), 3.00-3.21 (1H, m), 4.08-4.25 (1H, m), 4.91-5.30 (3H, m), 7.27-7.48 (5H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][CH2:12][CH2:13][C:14]1[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20]([OH:22])=O)=[CH:16][CH:15]=1)=[O:4].[Cl:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[CH2:28][NH:29][CH2:30][CH3:31].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[Cl:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[CH2:28][N:29]([CH2:30][CH3:31])[C:20](=[O:22])[CH2:19][O:18][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][S:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[CH:24][CH:23]=1
Reactant: CCNCc1ccccc1Cl
Reactant: COC(=O)c1ccccc1SCCc1ccc(OCC(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(Cc1ccccc1Cl)C(=O)COc1ccc(CCSc2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.5 %

Procedure:
[4-(2-{[2-(methoxycarbonyl)phenyl]thio}ethyl)phenoxy]acetic acid (0.250 g, 0.722 mmol) was dissolved in DCM (10 ml) and N-(2-chlorobenzyl)-N-ethylamine (0.116 g, 0.686 mmol) was added. N-[(1H-1,2,3-Benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.255 g, 0.0.794 mmol) and N-ethyl-N,N-diisopropylamine (0.187 g, 1.443 mmol) were added. The solution was stirred for 2 hours at room temperature. The crude was purified by flash chromatography (started with isocratic DCM 100% and then the MeOH concentration was increased from 0.5% to 20%, (silica gel 60 0.004-0.063 mm). The product containing fractions were pooled and the EtOAc was removed by evaporation. The substance needed to be purified once more and it was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. The ammonium acetate was removed by freeze drying the product overnight to give 0.111 g of methyl 2-{[2-(4-{2-[(2-chlorobenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)ethyl]thio}benzoate (yield 30.9%).
Reaction SMILES: CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].Br[CH2:16][C:17]1[N:21]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=2[Cl:33])[N:20]=[C:19]([C:34]#[N:35])[C:18]=1[S:36][C:37]([F:40])([F:39])[F:38].OO.O>C1COCC1.C(OCC)(=O)C>[C:34]([C:19]1[C:18]([S:36][C:37]([F:38])([F:40])[F:39])=[C:17]([CH3:16])[N:21]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:31])([F:32])[F:30])=[CH:24][C:23]=2[Cl:33])[N:20]=1)#[N:35]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(CBr)c1SC(F)(F)F
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
A solution of L-selectride (14.2 mL, 1 M in THF) was added to a solution of 5-bromomethyl-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole (6.75 g) in THF at −78° C. The reaction mixture was allowed to warm to room temperature with stirring over one hour, and then hydrogen peroxide (2.6 mL, 30% w/v) was added followed by water and ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography (SiO2, heptane/EA) to afford the title compound as a white solid (3.67 g, 65%). MS (ES): M/Z [M+NH4]=437. 1H NMR: (400 MHz, DMSO-d6): 2.30 (s, 3H) and 8.39 (s, 2H). 19F NMR (376 MHz, DMSO-d6): −44.03 (s, 3F) and −61.98 (s, 3F).
Reaction SMILES: [OH:1][CH:2]1[C:7](/[CH:8]=[CH:9]/[C:10]#[C:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)=[C:6]([CH3:23])[CH2:5][CH2:4][CH2:3]1.[C:24](Cl)(=[O:28])[CH:25]([CH3:27])[CH3:26]>>[C:24]([O:1][CH:2]1[C:7](/[CH:8]=[CH:9]/[C:10]#[C:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)=[C:6]([CH3:23])[CH2:5][CH2:4][CH2:3]1)(=[O:28])[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)C(=O)Cl
Reactant: CCOC(=O)c1ccc(C#C/C=C/C2=C(C)CCCC2O)cc1
Product: CCOC(=O)c1ccc(C#C/C=C/C2=C(C)CCCC2OC(=O)C(C)C)cc1

Procedure:
The title compound, a colorless oil, was prepared from ethyl (+)-(E)-4-(4-(6-hydroxy-2-methylcyclohex-1-enyl)but-3-en-1-ynyl)benzoate (Compound 1b, 25 mg, 0.081 mmol) and iso-butyryl chloride (0.084 mL, 0.81 mmol) as described in General Procedure C. [α]D=+138 (EtOAc), PNMR (300 MHz, CDCl3) δ 1.17 (d, 6 H, J=7.7 Hz), 1.39 (t, 3 H, J=7.1 Hz), 1.67 (m, 3 H), 1.92 (s, 3 H), 1.96 (m, 1 H), 2.21 (m, 2 H), 2.54 (m, 1 H, J=7.7 Hz), 4.3 7 (q, 2 H, J=7.1 Hz), 5.66 (s, 1 H), 5.67 (d, 1 H, J=16 Hz), 7.0 8 (d, 1 H, J=16 Hz), 7.48 (d, 2 H, J=8.3 Hz), 7.98 (d, 2 H, J=8.3 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C@@H:4]([NH2:10])[C@H:5]([OH:9])[CH:6]([CH3:8])[CH3:7].C(N(CC)CC)C.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>ClCCl>[CH3:1][O:2][C:3](=[O:11])[C@@H:4]([NH:10][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=1)(=[O:28])=[O:27])[C@H:5]([OH:9])[CH:6]([CH3:8])[CH3:7]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H](N)[C@H](O)C(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(C)cc1)[C@H](O)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (2S,3R)-2-amino-3-hydroxy-4-methyl-pentanoic acid methyl ester (0.50 g, 3.4 mmol) and triethylamine (0.69 g, 6.8 mmol) in dichloromethane (10 mL) was added 4-methyl-benzenesulfonyl chloride (0.71 g, 3.7 mmol) at 0° C. After stirring for 2 hours at room temperature, the mixture was washed with water and the organic layer was separated and then dried over sodium sulfate. After removal of solvent, the residue was used in next step without purification. MS: calc'd (MH+) 316, measured (MH+) 316.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][N:9]=1.C1C=C([Cl:24])C=C(C(OO)=O)C=1>CCOC(C)=O>[Cl:24][C:10]1[CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:13]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:9]=1
Reactant: FC(F)(F)c1ccnc(-c2ccccc2Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cc(Cl)nc(-c2ccccc2Cl)c1

Procedure:
To a solution of 2-(2-chlorophenyl)-4-(trifluoromethyl)pyridine (5.40 g, 21.0 mmol) in EtOAc (100 mL) was added mCPBA (7.25 g, 42.0 mmol) in EtOAc (100 mL) over 30 min and then the mixture was heated at reflux (caution: use shield) for 3 h. The reaction mixture was cooled and then washed twice with sat. aq. NaHCO3 and concentrated.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[NH:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:24]=2[N:23]=[CH:22]1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:30]([C:28]3[CH:27]=[CH:26][C:25]4[N:21]=[CH:22][NH:23][C:24]=4[CH:29]=3)=[O:31])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc2nc[nH]c2c1

Procedure:
3H-Benzoimidazole-5-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate D and 1H-benzimidazole-5-carboxylic acid. MS calcd. for C24H18ClN4O2 [(M+H)+] 429.1, obsd. 429.0.
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:27])[CH2:8][CH:9]([C:13]2[C:18]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:17]([CH3:23])[C:16]([CH3:24])=[C:15]([CH3:25])[C:14]=2[CH3:26])[CH2:10][C:11]=1[OH:12])(=O)[CH2:2][CH2:3][CH3:4].Cl.[CH2:29]([O:31][NH2:32])[CH3:30]>>[CH2:29]([O:31][N:32]=[C:1]([C:6]1[C:7](=[O:27])[CH2:8][CH:9]([C:13]2[C:18]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:17]([CH3:23])[C:16]([CH3:24])=[C:15]([CH3:25])[C:14]=2[CH3:26])[CH2:10][C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4])[CH3:30]
Reactant: CCON
Reactant: CCCC(=O)C1=C(O)CC(c2c(C)c(C)c(C)c(C)c2S(C)(=O)=O)CC1=O
Agent: Cl
Product: CCCC(=NOCC)C1=C(O)CC(c2c(C)c(C)c(C)c(C)c2S(C)(=O)=O)CC1=O

Procedure:
2-[1-(Ethoxyimino)butyl]-3-hydroxy-5-(6-methylsulfonyl-2,3,4,5-tetramethylphenyl)cyclohex-2-en-1-one (57) was prepared from 2-butyryl-3-hydroxy-5-(6-methylsulfonyl-2,3,4,5-tetramethylphenyl)cyclohex-2-en-1-one and ethoxyamine hydrochloride following essentially the same procedure as that described in Example 1, part (iv). The product was characterized by proton nuclear magnetic resonance spectroscopy and the spectroscopic data is reported in Table 5, Example 37.