Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH:8](O)(C)[CH3:9]>O>[C:1]([O:4][CH:5]([CH3:7])[CH3:6])([CH3:8])([CH3:3])[CH3:2].[C:1]([O:4][CH:5]([CH3:7])[CH3:6])([CH2:8][CH3:9])([CH3:3])[CH3:2]
Reactant: CC(C)O
Reactant: CC(C)OC(C)C
Solvent: O
Product: CC(C)OC(C)(C)C
Product: CCC(C)(C)OC(C)C

Procedure:
Aqueous alcohol stream 26 is passed to a drier 34 operated at 150° C. and 125 psig. A diisopropyl ether-containing stream 36 is also introduced into drier 34. The diisopropyl ether acts as an entrainer and draws water from the isopropyl alcohol into stream 38 so that stream 38 is a mixture of water and diisopropyl ether. Stream 38 enters a separator 40 where a diisopropyl ether enriched phase readily separates from a water enriched phase. The diisopropyl ether enriched phase is removed from the separator via line 44 and recycled to the drier. The water enriched phase is removed from the separator via line 42 and is combined with line 28. The dry isopropyl alcohol from drier 34 contains about 100 ppm water and is removed in line 46. A portion of the dry isopropyl alcohol stream 46 may be removed in line 48 and collected as high purity isopropyl alcohol product. The remainder of the dry isopropyl alcohol in line 46 and a 7.5 mass % isobutylene-12.5 mass % isoamylene feed 52 is passed to a second reaction zone 50. Second reaction zone 50 contains Amberlyst® 35 catalyst and is operated at 60° C. and 150 psig. In second reaction zone 50 the etherification of isobutylene and isoamylene with isopropyl alcohol is catalyzed and isopropyl tertiary butyl ether and isopropyl tertiary amyl ether are formed. Due to the lower operating temperature of second reaction zone 50, it is not expected that significant amounts of acid from the catalyst will enter the reaction mixture. Second reaction zone effluent 54 contains isobutylene, isoamylene, isopropyl alcohol, isopropyl tertiary butyl ether, and isopropyl tertiary amyl ether. Second reaction zone effluent 54 is directed to a second light ends fractionation zone 60 operating at 60° C. and 70 psig. Fractionation of second reaction zone effluent 54 in second light ends fractionation zone 60 results in an inert compounds, isobutylene, and isoamylene stream 62 and an isopropyl alcohol, isopropyl tertiary butyl ether, and isopropyl tertiary amyl ether stream 64.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:6][O:5][C:4]([C:7]2[O:11][N:10]=[C:9]([O:12][CH2:13][CH3:14])[C:8]=2[CH3:15])=[N:3]1.C1C(=O)N([Br:24])C(=O)C1>ClC(Cl)(Cl)Cl>[Br:24][CH2:15][C:8]1[C:9]([O:12][CH2:13][CH3:14])=[N:10][O:11][C:7]=1[C:4]1[O:5][CH2:6][C:2]([CH3:1])([CH3:16])[N:3]=1
Reactant: CCOc1noc(C2=NC(C)(C)CO2)c1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1noc(C2=NC(C)(C)CO2)c1CBr
Yield: 74.1 %

Procedure:
5-(4,5-Dihydro-4,4-dimethyl-1,3-oxazol-2-yl)-3-ethoxy-4-methylisoxazole (2.0 g, 8.9 mmol), NBS (1.75 g, 9.8 mmol) and tetrachloromethane (150 mL) was boiled under reflux for 5 h. The mixture was cooled, filtered and concentrated in vacuo. Flash chromatography (silica gel, eluent: toluene/EtOAc/triethylamine=100:10:1) gave the title compound as a yellow oil (2.0 g, 74%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]([OH:21])=[O:20])[CH2:14][CH2:13][N:12]([CH2:22][C:23]([OH:25])=[O:24])[CH2:11][CH2:10]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH-].[Na+].Br[CH2:29][C:30]([OH:32])=[O:31].Cl>O>[C:30]([CH2:29][N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][N:9]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]([OH:21])=[O:20])[CH2:14][CH2:13][N:12]([CH2:22][C:23]([OH:25])=[O:24])[CH2:11][CH2:10]2)[CH2:2][CH2:3]1)([OH:32])=[O:31]
Reactant: O=C(O)CBr
Reactant: O=C(O)CN1CCN(CCN2CCNCC2)CCN(CC(=O)O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CN1CCN(CCN2CCN(CC(=O)O)CCN(CC(=O)O)CC2)CC1
Reaction time: 15 h

Procedure:
A solution of 1-(2-piperazinoethyl)-4,7-bis-(carboxymethyl)-1,4,7-triazacyclononane (10.7 g, 0.03 mol) in 100 mL of deionized water is adjusted to pH 10 with 1N sodium hydroxide solution. Then bromoacetic acid (4.2 g, 0.03 mol) is added and the solution is heated at 50 C. for 15 hours, keeping the pH between 9 and 10 with 1N sodium hydroxide. After cooling the reaction mixture to 25 C., the pH is adjusted to 4 with 1N hydrochloric acid. The solvent is removed under reduced pressure to give 1-[2-(4-carboxymethylpiperazino)ethyl]-4,7-bis-(carboxymethyl)-1,4,7-triazacyclonane.
Reaction SMILES: [Br:1]CCC(C)(C)C.[C:8]1([P:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:27]1([CH3:33])[CH:32]=C[CH:30]=[CH:29][CH:28]=1>>[Br-:1].[CH3:32][CH:27]([CH3:33])[CH2:28][CH2:29][CH2:30][P+:14]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)CCBr
Reactant: Cc1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 190 °C
Reaction time: 72 h

Procedure:
Dissolve 1-bromo-3,3-dimethylbutane(9.6 g, 58.15 mmol) in toluene, add triphenyl-phosphine (13.8 g, 55.2 mmol) and stir at 80° C. for 4 days in a scewcapglass and 3 days in an autoklav at 4 bar and 190° C. Cool the reaction mixture down to room temperature and isolate the product by crystallization in ether as a white solid (9.8 g). MS (m/e): 347 (M+H).
Reaction SMILES: [F:1][CH:2]([CH:8](OC(SC)=S)[CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(OOC(C)(C)C)(C)(C)C.O1CCOCC1.O>C(OC(=O)C)C>[F:1][CH:2]([CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCCC1CCC(C(OC(=S)SC)C(F)C(=O)OCC)CC1
Agent: CC(C)(C)OOC(C)(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCCC1CCC(CC(F)C(=O)OCC)CC1
Yield: 75.1 %

Procedure:
To a reaction vessel under a nitrogen atmosphere, 2.1 g of ethyl 2-fluoro-3-(((methylthio)carbonothioyl)oxy)-3-(4-propylcyclohexyl)propanoate (e-10), 0.5 ml of di-tert-butylperoxide, 1.2 g of DPPO and 40 ml of dioxane were added, and the resultant mixture was subjected to heating reflux for 48 hours. After cooling the resultant reaction mixture to 25° C., 100 ml of water and 100 ml of ethyl-acetate were added to separate the mixture into an organic layer and an aqueous layer, and an extraction operation was performed. The resultant organic layer was isolated, and washed with water, and then the resultant solution was dried over anhydrous magnesium sulfate. The resultant solution was concentrated under reduced pressure, the resultant residue was purified by a preparative isolation operation by means of column chromatography using a mixed solvent of heptane and ethyl acetate (heptane:ethyl acetate=9:1 in a volume ratio) as an eluent and silica gel as a filler, the resultant product was dried, and thus 1.1 g of ethyl 2-fluoro-3-(4-propylcyclohexyl)propanoate (e-11) was obtained. A yield based on compound (e-10) was 74.5%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([OH:20])=O)=[N:12][CH:11]=[N:10][C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[NH2:24][CH2:25][C:26]#[N:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[C:25]([CH2:26][NH:27][C:18]([C:17]1[CH:16]=[C:15]([C:13]2[C:14]3[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][NH:8][C:9]=3[N:10]=[CH:11][N:12]=2)[CH:23]=[CH:22][CH:21]=1)=[O:20])#[N:24]
Reactant: N#CCN
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(C(=O)O)c3)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(C(=O)NCC#N)c3)c12
Temperature: 45 °C

Procedure:
To a mixture of crude 3-(5-(ethoxycarbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzoic acid 113 mg (theoretical mass 55 mg, 0.18 mmol), 2-aminoacetonitrile (49.5 mg, 0.883 mmol), HATU (101 mg, 0.265 mmol) in DMF (1.0 mL) was added DIPEA (62 μL, 0.35 mmol). The reaction mixture was heated to 45° C. for 2 hours and then diluted with ethyl acetate (5 mL). The reaction mixture was washed with 2 M aqueous sodium bicarbonate (5 mL) and brine (5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier to give ethyl 4-(3-(cyanomethylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C18H16N5O3[M+H]+: 350, found 350. 1H NMR (600 MHz, DMSO-D6) δ 9.19 (t, J=5.28 Hz 1H), 8.55 (s, 1H), 8.20 (s, 1H), 8.12 (s, 1H), 7.86 (d, J=8.21 Hz, 1H), 7.75 (d, J=7.63 Hz, 1H), 7.48 (t, J=7.63 Hz, 1H), 6.86 (bs, 1H), 4.30 (q, J=5.28 Hz, 2H), 3.76 (q, J=7.04 Hz, 2H), 0.83 (t, J=7.04 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[N:15][C:16]([CH:24]3[CH2:26][CH2:25]3)=[C:17]([O:19][C:20]([F:23])([F:22])[CH3:21])[CH:18]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH3:27][S:28]([NH2:31])(=[O:30])=[O:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[ClH:1].[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[N:15][C:16]([CH:24]3[CH2:26][CH2:25]3)=[C:17]([O:19][C:20]([F:23])([F:22])[CH3:21])[CH:18]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:31][S:28]([CH3:27])(=[O:30])=[O:29])=[O:8]
Reactant: CC(F)(F)Oc1cc(Oc2cc(F)c(C(=O)O)cc2Cl)cnc1C1CC1
Reactant: CS(N)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(F)(F)Oc1cc(Oc2cc(F)c(C(=O)NS(C)(=O)=O)cc2Cl)cnc1C1CC1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a dichloromethane (10 mL) solution of 5-chloro-4-(6-cyclopropyl-5-(1,1-difluoroethoxy)pyridin-3-yloxy)-2-fluorobenzoic acid (Preparation 271, 220 mg, 0.57 mmol) was added methanesulfonamide (64 mg, 0.68 mmol), HATU (259 mg, 0.68 mmol), and DIPEA (0.35 mL, 1.99 mmol). The reaction was left to stir at room temperature for 2 hours. The reaction was washed with a 2M aqueous solution of HCl (50 mL) and extracted into DCM (3×50 mL). The combined organics were dried over MgSO4, filtered and the solvent removed to leave an off white solid. The solid was triturated in a minimum of methanol, filtered and dried in air, to leave the title compound as a white solid as the HCl salt. (131 mg, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH2:7][CH2:6]2.Cl.Cl[CH2:23][C:24]1[CH:38]=[CH:37][C:27]([O:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:37][CH:38]=1)[CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH2:7][CH2:6]2
Reactant: COc1cccc(C2CCc3cc(OC)ccc3N2)c1
Reactant: ClCc1ccc(OCCN2CCCCC2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1cccc(C2CCc3cc(OC)ccc3N2Cc2ccc(OCCN3CCCCC3)cc2)c1
Temperature: 60 °C

Procedure:
To a solution of 6-methoxy-2-(3-methoxy-phenyl)-1,2,3,4-tetrahydro-quinoline (20 mg, 0.074 mmol) in THF (1.5 mL) at room temperature is added 1-[2-(4-chloromethyl-phenoxy)-ethyl]-piperidine hydrochloride (PCT Int. Appl. Publ. No. WO 99/19293) (43 mg, 0.149 mmol) followed by phosphazene P1 base (150 mg). The mixture is then heated to 60° C. for 18 h. The crude product is then loaded on a silica gel column and is eluted with 0–100% EtOAc/hexanes to yield 6-methoxy-2-(3-methoxy-phenyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1,2,3,4-tetrahydro-quinoline which is contaminated with an unidentified byproduct.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[CH3:22])=[CH:9][C:8]=1[CH3:23])[CH3:2].C(O)(=O)C.[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[CH3:22])=[CH:9][C:8]=1[CH3:23])[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(Oc2cc(OC)ccc2C)cc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)CCc1ccc(Oc2cc(OC)ccc2C)cc1C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
A solution of 3-[4-(5-methoxy-2-methyl-phenoxy)-2-methyl-phenyl]-acrylic acid ethyl ester (1.18 g, 3.63 mmol) and palladium under carbon (10%) (0.39 g, 0.36 mmol) in ethanol (20 mL) and acetic acid (2 mL) is stirred under 1 atm of hydrogen. After stirring overnight, the mixture is filtered off through Celite and washed with methanol. The mixture is concentrated under reduced pressure and purified by flash chromatography by eluting with hexane:ethyl acetate 5:1 to afford the title compound (1.02 g, 85%). Rf=0.42 (hexane:ethyl acetate 5:1). 1H NMR (300 MHz, CDCl3): δ1.26 (t, 3H, J=6.9 Hz), 2.16 (s, 3H), 2.28 (s, 3H), 2.56 (t, 2H, J=7.3 Hz), 2.90 (t, 2H, J=7.3 Hz), 3.72 (s, 3H), 4.17 (q, 2H, J=6.9 Hz), 6.45 (d, 1H, J=2.4 Hz), 6.62 (dd, 1H, J=2.8, 8.5 Hz), 6.67 (dd, 1H, J=2.4, 8.1 Hz), 6.74 (d, 1H, J=2.4 Hz), 7.06 (d, 1H, J=8.1 Hz), 7.13 (d, 1H, J=8.1 Hz).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:8][C:9]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2>C(Cl)(Cl)Cl>[N:1]1([CH2:8][C:9]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]3[C:10]=2[CH:11]=[CH:12][CH:13]=[N:14]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: Oc1ccc(CCl)c2cccnc12
Solvent: ClC(Cl)Cl
Product: Oc1ccc(CN2CCCCC2)c2cccnc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.8 %

Procedure:
Piperidine (2 ml; 20.26 mmol) was added to a solution of 5-chloromethyl-8-hydroxyquinoline (1.87 g; 8.13 mmol) in CHCl3 (50 ml) at 5° C. The mixture was stirred for two days at room temperature. Then the mixture was evaporated under vacuum to dryness. The residue was dissolved in CHCl3, washed with 5% NaHCO3 (2×50 ml), followed by brine (50 ml), dried over Na2SO4 and evaporated to dryness. The residue was crystallized from hexane to give 1.0 g of the title product (50%). M.p. 96° C. TLC (CHCl3; MeOH; NH3=8:2:0.5). Rf=0.63.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[N:21]([C:22](OC(C)(C)C)=[O:23])[CH2:20][CH:19]([CH2:29][Cl:30])[C:12]2=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH3:33][N:34]([CH3:49])[CH2:35][CH2:36][O:37][C:38]1[CH:48]=[CH:47][C:41](/[CH:42]=[CH:43]/C(O)=O)=[CH:40][CH:39]=1.CCN=C=NCCCN(C)C>CC(N(C)C)=O.O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[N:21]([C:22](=[O:23])/[CH:43]=[CH:42]/[C:41]3[CH:47]=[CH:48][C:38]([O:37][CH2:36][CH2:35][N:34]([CH3:49])[CH3:33])=[CH:39][CH:40]=3)[CH2:20][CH:19]([CH2:29][Cl:30])[C:12]2=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCOc1ccc(/C=C/C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc(OCc1ccccc1)c1ncccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: CN(C)CCOc1ccc(/C=C/C(=O)N2CC(CCl)c3c2cc(OCc2ccccc2)c2ncccc32)cc1
Temperature: 25 °C
Reaction time: 30 h
Yield: 70.7 %

Procedure:
A suspension of 14 (0.20 g, 0.47 mmol) in cooled (0° C.) dioxane (5 mL) was saturated with HCl, allowed to warm to r.t. over 1 h and evaporated. (E)-4-[2-(Dimethylamino)ethoxy]cinnamic acid hydrochloride (0.13 g, 0.47 mmol) [Atwell et al., J. Med. Chem., 1999, 42, 3400], EDCI (0.27 g, 1.42 mmol) and DMA (3 mL) were added to the remaining yellow solid, and the red mixture was stirred at r.t. for 30 h. The mixture was partitioned between CH2Cl2 and 5% NaHCO3 solution. The aqueous layer was extracted with CH2Cl2 (×3). The CH2Cl2 extracts were dried (brine, Na2SO4). Flash chromatography (Alumina, EtOAc/MeOH; 49:1, then 24:1) gave 2-(4-{(1E)-3-[5-(benzyloxy)-1-(chloromethyl)-1,2-dihydro-3H-pyrrolo[3,2-f]quinolin-3-yl]-3-oxo-1-propenyl}phenoxy)-N,N-dimethylethanamine (17c) (0.18 g, 70%) as a yellow solid: mp 172–175° C.; 1H NMR [(CD3)2SO]δ 8.76 (dd, J=4.1, 1.4, 1 H), 8.47 (bs, 1 H), 8.35 (dd, J=8.5, 1.4, 1 H), 7.76 (d, J=8.7, 2 H), 7.67 (d, J=15.3, 1 H), 7.58 (d, J=7.3, 2 H), 7.54 (dd, J=8.5, 4.1, 1 H), 7.44 (t, J=7.2, 2 H), 7.37 (t, J=7.2, 1 H), 7.08 (d, J=15.3, 1 H), 7.02 (d, J=8.7, 2 H), 5.31 (s, 2 H), 4.55 (dd, J=10.7, 9.5, 1 H), 4.44 (dd, J=10.9, 2.5, 1 H), 4.30 (m, 1 H), 4.11 (t, J=5.8, 2 H), 3.99 (dd, J=11.0, 3.0, 1 H), 3.91 (dd, J=11.2, 7.2, 1 H), 2.64 (t, J=5.7, 2 H), 2.23 (s, 6 H); 13C NMR [(CD3)2SO]δ 164.1, 160.1, 154.6, 147.1, 142.6, 142.2, 137.2, 136.7, 131.1, 130.1, 128.3, 127.83, 127 78, 127.3, 125.1, 122.3, 116.9, 115.7, 114.7, 101.6, 70.0, 65.9, 57.5, 52.9, 47.8, 45.4, 40.1.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:14]([Sn](CCCC)(CCCC)CCCC)[CH:15]=[CH2:16].[F-].[K+]>CN(C=O)C.C(OCC)(=O)C.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>[CH2:16]([C:2]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:3]=1[NH2:4])[CH:15]=[CH2:14]
Reactant: Nc1ccc(OC(F)(F)F)cc1Br
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCc1cc(OC(F)(F)F)ccc1N
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 2-bromo-4-(trifluoromethoxy)aniline (75 g, 293 mmol) in DMF (1000 ml) was added Pd(PPh3)4 (13.5 g, 11.7 mmol) and allyltributyltin (116 g, 351 mmol) and the reaction mixture was stirred at 80° C. for 16 h. The mixture was cooled to room temperature and saturated aqueous KF solution was added. The mixture was diluted with ethyl acetate (1500 mL) and washed with 1:1 H2O: saturated aqueous NaCl solution (2×750 mL) and saturated aqueous KF (1×). The aqueous layers were combined and extracted with ethyl acetate (250 mL). The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure to give the crude product, which was absorbed onto silica and purified by chromatography eluting with 1% ethyl acetate in petroleum ether to give the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Si:11]([O:18][C@H:19]1[CH2:23][CH2:22][N:21](/[N:24]=[CH:25]/[C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([Cl:34])[C:27]=2[CH3:35])[C@@H:20]1[CH2:36][OH:37])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>C(Cl)Cl>[Si:11]([O:18][C@H:19]1[CH2:23][CH2:22][N:21](/[N:24]=[CH:25]/[C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([Cl:34])[C:27]=2[CH3:35])[C@@H:20]1[CH:36]=[O:37])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: Cc1c(/C=N/N2CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]2CO)ccc(C#N)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1c(/C=N/N2CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]2C=O)ccc(C#N)c1Cl
Reaction time: 0.5 h

Procedure:
To a solution of oxalyl chloride (1.92 mL, 0.022 moles) in dry DCM (25 mL) at −78° C. was added DMSO (3.12 mL, 0.044 moles) and stirred for 30 min. Then to the reaction mixture at the same temperature was added a solution of 4-((E)-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(hydroxymethyl)pyrrolidin-1-ylimino)methyl)-2-chloro-3-methylbenzonitrile (IVa) (7.5 g, 0.0184 moles) in 100 mL DCM and continued stirring for 1 h. The reaction mixture was quenched with triethylamine (13 mL) at −30° C. and stirred for 1 h. Then it was diluted with DCM and washed with water, brine, dried over Na2SO4 and concentrated to get the title compound which was used in the next step without further purification.
Reaction SMILES: Br[CH:2]([CH3:13])[C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[CH:6]=1)=[O:4].C(#N)C.[CH2:17]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)C>[CH2:17]([CH:24]1[CH2:29][CH2:28][N:27]([CH:2]([CH3:13])[C:3]([C:5]2[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[CH:6]=2)=[O:4])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: Cc1cc(C)cc(C(=O)C(C)Br)c1
Solvent: CCOCC
Solvent: CC#N
Product: Cc1cc(C)cc(C(=O)C(C)N2CCC(Cc3ccccc3)CC2)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
21 g of 2-bromo-3'-,5'-dimethylpropiophenone are introduced into 50 ml of acetonitrile, the mixture is cooled to 0° C., 30.5 g of 4-benzylpiperidine are added and the mixture is stirred for 3 hours. It is diluted with 30 ml of diethyl ether, the precipitated hydrobromide is filtered off and 150 ml of diethyl ether are added to the filtrate, which produces a second crop of precipitate. This is filtered off and the filtrate is treated twice with 200 ml of 3N hydrochloric acid. The diethyl ether phase is separated off. The aqueous phase contains the hydrochloride of the propiophenone formed, as an emulsion. This aqueous phase is extracted with methylene chloride, the organic phase obtained is washed with water, dilute aqueous ammonia solution is added, the organic phase is decanted, washed with water, dried, filtered and treated with 100 g of silica, the mixture is filtered and the filtrate is evaporated. 14.4 g of an oil remain.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[N+:24]([O-])=O.C(N(CC)C(C)C)(C)C.[Cl:36][C:37]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:38]=1[C:39](Cl)=[O:40]>ClCCl>[Cl:36][C:37]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:38]=1[C:39]([NH:24][C:3]1[CH:4]=[C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)[CH:6]=[CH:7][C:2]=1[F:1])=[O:40]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c([N+](=O)[O-])c1)N2
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(NC(=O)c3ccc(F)cc3Cl)c1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To an ice-cold mixture of methyl 2-(4-fluoro-3-nitrophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (170 mg, 0.52 mmol) and N,N-diisopropylethylamine (140 mg, 1.03 mmol) in 5 mL of dichloromethane was dropwise added a solution of 2-chloro-4-fluorobenzoyl chloride (120 mg, 0.62 mmol) in 3 mL dichloromethane under nitrogen. Then the resulted mixture was stirred at R.T. for overnight. Thin layer chromatography and LC-MS indicated that the starting material was consumed completely. The solvent was removed by rotary evaporation. The residue was purified by silica gel (petroleum ether/ethyl acetate=3:1) to afford 189 mg of methyl 2-(3-(2-chloro-4-fluorobenzamido)-4-fluorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow solid; yield: 76%. MS (ESI+APCI) M+1=485.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([NH:8][CH:9](C)[C:10]2[N:14]([CH2:15][CH2:16][CH3:17])[CH:13]=[N:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.[CH2:21](O)C>[Pd]>[CH3:21][N:8]([CH2:9][C:10]1[N:14]([CH2:15][CH2:16][CH3:17])[CH:13]=[N:12][N:11]=1)[C:7]1[CH:19]=[CH:20][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: CCCn1cnnc1C(C)Nc1ccc([N+](=O)[O-])cc1
Reactant: CCO
Agent: [Pd]
Product: CCCn1cnnc1CN(C)c1ccc(N)cc1
Reaction time: 18 h

Procedure:
A mixture of 4-nitro[methyl(4-propyl-4H-1,2,4-triazol-3-ylmethyl)]aniline (1.0 g), and 10% Pd-C (0.3 g) in ethanol was stirred strongly for 18 hours under hydrogen atmosphere. Pd-C was removed by filtration, the reaction mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration. The crystals were washed with diethylether, to give 4-[methyl(4-propyl-4H-1,2,4-triazol-3-ylmethyl)amino]aniline (0.50 g) as brown crystals.