Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([CH2:16][O:17][CH:18]3[CH:23]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH:31]5[CH2:34][N:33]([C:35]6[S:36][CH:37]=[CH:38][N:39]=6)[CH2:32]5)=[CH:26][CH:25]=4)[CH2:22][CH2:21][N:20](C(OCC4C=CC=CC=4)=O)[CH2:19]3)[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH2:7]1.CO.[OH-].[K+]>O1CCOCC1.O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([CH2:16][O:17][CH:18]3[CH:23]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH:31]5[CH2:32][N:33]([C:35]6[S:36][CH:37]=[CH:38][N:39]=6)[CH2:34]5)=[CH:26][CH:25]=4)[CH2:22][CH2:21][NH:20][CH2:19]3)[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH2:7]1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OC4CN(c5nccs5)C4)cc3)cc21
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: COCCCN1CCOc2ccc(COC3CNCCC3c3ccc(OC4CN(c5nccs5)C4)cc3)cc21
Temperature: 100 °C
Reaction time: 5 h

Procedure:
0.190 g of benzyl 3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-[4-(1-thiazol-2-ylazetidin-3-yloxy)phenyl]piperidinecarboxylate is dissolved in 8 ml of dioxane. 8 ml each of methanol and 40% KOH are added and the reaction mixture is stirred at 100° C. in a sealed flask over 5 hours. The reaction mixture is subsequently cooled to room temperature, diluted with 40 ml of water and extracted with ethyl acetate (3×40 ml). The combined organic phases are washed with 40 ml of water, dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:17])[C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N:6][CH:7]=1.[CH2:18]([O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.O>[F:17][C:4]1[C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N:6][CH:7]=[C:2]([C:30]2[CH:31]=[CH:32][C:27]([O:26][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:28][CH:29]=2)[CH:3]=1
Reactant: CCCCCCCCOc1ncc(Br)cc1F
Reactant: CCCCCCCCOc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCCCCCCOc1ccc(-c2cnc(OCCCCCCCC)c(F)c2)cc1
Yield: 67.3 %

Procedure:
3.00 g (9.86 mmol) of 5-bromo-3-fluoro-2-octyloxypyridine, 2.47 g (9.86 mmol) of 4-octyloxybenzeneboronic acid, 0.11 g (0.10 mmol) of tetrakis(triphenylphospine)palladium(0) and 2.09 g (19.72 mmol) of sodium carbonate are heated at 80° C. for 3 hours in 90 ml of toluene, 60 ml of ethanol and 30 ml of water. The mixture is subsequently partitioned between aqueous sodium chloride solution and ether and the organic phase is washed with aqueous sodium chloride solution, dried over sodium sulfate, evaporated and purified by chromatography (silica gel/hexane: ethyl acetate 9:1), giving 2.85 g of 3-fluoro-2-octyloxy-5-(4-octyloxyphenyl)pyridine. ##STR24##
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([S:9][CH3:10])[N:6]=[C:5]([OH:11])[CH:4]=1.[Na+].[CH3:13][S:14]([O-:16])=[O:15].CN(C=O)C>C(#N)C>[CH3:10][S:9][C:7]1[N:6]=[C:5]([OH:11])[CH:4]=[C:3]([CH2:2][S:14]([CH3:13])(=[O:16])=[O:15])[N:8]=1
Reactant: CSc1nc(O)cc(CCl)n1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CSc1nc(O)cc(CS(C)(=O)=O)n1
Temperature: 100 °C

Procedure:
6-(Chloromethyl)-2-methylsulfanyl-pyrimidin-4-ol (19.07 g, 100 mmol) was suspended in acetonitrile (400 ml). To this stirring suspension was added methanesulphinic acid sodium salt (12.255 g, 120 mmol) and DMF (100 ml). The reaction was then heated to 100° C. to give a dark suspension and monitored by LCMS. Once complete, the solvents were removed and the resultant product added to 1:1 MeOH:DCM (200 ml) and acidified with acetic acid (10 ml). The resultant precipitate was collected, washed with water (200 ml) and MeOH (100 ml) and dried overnight in vacuo to afford the title compound as a white solid, 16.45 g.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH3:45])[C:18](=[O:44])[C:19]3[CH:30]=[C:29]([CH2:31][CH2:32][O:33][C:34]4[C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[N:37]=[CH:36][CH:35]=4)[CH:28]=[N:27][C:20]=3[N:21]([CH:24]3[CH2:26][CH2:25]3)[C:22]=2[N:23]=1>C(Cl)Cl.C1COCC1>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH3:45])[C:18](=[O:44])[C:19]3[CH:30]=[C:29]([CH2:31][CH2:32][O:33][C:34]4[C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[N+:37]([O-:9])=[CH:36][CH:35]=4)[CH:28]=[N:27][C:20]=3[N:21]([CH:24]3[CH2:26][CH2:25]3)[C:22]=2[N:23]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN1C(=O)c2cc(CCOc3ccnc4ccccc34)cnc2N(C2CC2)c2nc(Cl)ccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN1C(=O)c2cc(CCOc3cc[n+]([O-])c4ccccc34)cnc2N(C2CC2)c2nc(Cl)ccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 19.3 %

Procedure:
Solid mCPBA (177 mg, 0.82 mmol) was added to a solution of 2-chloro-11-cyclopropyl-5,11-dihydro-5-methyl-8-{2-(4-quinolinyloxy)ethyl}-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (143 mg, 0.30 mmol) in CH2Cl2 (3 mL) and THF (3 mL). The mixture was stirred at room temperature for 14 h then was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL), the solution was successively washed with aqueous 10% Na2S2O3 (3×10 mL), aqueous saturated NaHCO3 (3×10 mL) and brine (10 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was partially purified by flash chromatography (EtOAc:MeOH, 95:5 to CH2Cl2:MeOH, 9:1). The impure compound was further purified by reverse phase HPLC (CombiPrep ADS-AQ 50×20 mm, 5 μ, 120 A, 5-100% MeCN+0.10% TFA/water+0.10% TFA in 25 min). The pure fractions were treated with aqueous saturated NaHCO3, extracted with EtOAc and the solution was dried (MgSO4), filtered and concentrated under reduced pressure to give the title compound (28.3 mg, 19%) as a white solid: MS (ESI) m/z 488/490 (MH)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.CC(C)(O)[C:32]#[N:33]>O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)([C:32]#[N:33])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(O)C#N
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC1(Nc2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Temperature: 50 °C

Procedure:
Combine 1-benzyl-4-oxo-piperidine (100 mmol), 4-fluorophenylamine (110 mmol), and toluene (300 mL). Heat at reflux for 3 h with azeotropic removal of water. Cool to 50° C. Add acetone cyanohydrin (277 mmol). Slowly distill away the acetone. Concentrate the solvent in vacuo to obtain a residue. Chromatograph on silica gel to obtain the title compound.
Reaction SMILES: [CH:1]1([OH:7])[CH2:5][CH2:4][CH2:3][CH:2]1[OH:6].B(F)(F)F.CCOCC.[CH:17]12[O:22][CH:18]1[CH2:19][CH2:20][CH2:21]2.[OH-].[Na+]>>[OH:6][CH:2]1[CH2:3][CH2:4][CH2:5][CH:1]1[O:7][CH:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[OH:22]
Reactant: C1CC2OC2C1
Reactant: OC1CCCC1O
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: OC1CCCC1OC1CCCC1O

Procedure:
A 1-liter, three neck, round bottom flask equipped with magnetic stirrer, internal thermometer, addition funnel, condenser, argon supply, and heating mantle, is flushed with argon. Then 1,2-cyclopentanediol (about 306 g, about 3 moles, Aldrich) is added and boron trifluoride diethyl etherate (about 0.14 g, about 0.01 moles, cis-trans isomer mixture, Aldrich) is added. Then the reaction mixture is held at about 10°-40° C. as cyclopentene oxide (about 84 g. about 1 mole, Aldrich) is added dropwise with stirring until all the cyclopentene oxide has reacted. The reaction mixture is neutralized with sodium hydroxide, and the liquid is fractionally distilled under vacuum to recover the excess cyclopentanediol. The desired ether is obtained as a residue. Optionally, it is purified by further vacuum distillation.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:5](=[O:6])[CH2:4][C:3]1=[O:7].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH3:33])[CH:31]=2)[NH:26][CH:25]=1>>[CH3:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH3:33])[CH:31]=2)[NH:26][C:25]=1[CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]1[C:5](=[O:6])[C:2]([CH3:1])([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]=1[OH:7]
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc2[nH]cc(C)c2c1
Reactant: Cc1ccc(C2(C)C(=O)CC2=O)cc1
Product: Cc1ccc(C2(C)C(=O)C(C(c3ccccc3)c3[nH]c4ccc(C)cc4c3C)=C2O)cc1

Procedure:
Using general procedure C, 2-methyl-2-p-tolyl-cyclobutane-1,3-dione (from Example 4.1) was reacted with benzaldehyde and 3,5-dimethyl-1H-indole (Lit. 3) to give the title compound as a colorless solid. MS: 420.5 ([M−H]−).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13](=[O:20])[C:14]3[S:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:16][C:15]2[CH:17]=[CH:18][S:19][C:14]=2[C:13]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)=[O:20])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(N)cc1
Reactant: CC(C)(C)c1ccc(-c2nc3ccsc3c(=O)o2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(NC(=O)c2sccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 40.8 %

Procedure:
A solution of 2-[4-(tert-butyl)phenyl]-4-oxo-4H-thieno[3,2-d][1.3]oxazine (60 mg, 0.21 mmol) and p-anisidine (26 mg, 0.21 mmol) in toluene (1 mL) was treated with p-toluenesulfonic acid (4 mg) and the resulting mixture heated at relux for 30 h. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, hexanes/ethyl acetate) to yield 35 mg (41%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:22].CCCCCC>C(Cl)(Cl)Cl>[ClH:22].[Br:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(CCNC(=O)c2ccc(Br)cc2)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: COc1ccc2c(c1)CCN=C2c1ccc(Br)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
To a solution of 4-bromo-N-[2-(3-methoxyphenyl)ethyl]benzamide (5.00 g, 15.0 mmol) in CHCl3 (30 ml) was added phosphorous pentachloride (5.30 g, 25.0 mmol) and the mixture stirred for 18 hr at rt under N2. Hexane was added to the mixture and the liquid was then decanted off. EtOH (15 ml) was added to the residue and the mixture was triturated with diethyl ether to give 3.65 g (69% yield) of off-white solid.
Reaction SMILES: [OH-].[Na+].O.[SH2:4].[Na].Br[CH2:7][C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].[C:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])#[N:15].C(N(CC)CC)C>O.CCOC(C)=O>[CH3:20][O:19][C:17]([C:16]1[C:8]([OH:9])([C:10]([F:13])([F:12])[F:11])[CH2:7][S:4][C:14]=1[NH2:15])=[O:18]
Reactant: O=C(CBr)C(F)(F)F
Reactant: COC(=O)CC#N
Reactant: S
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(N)SCC1(O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 32.4 %

Procedure:
Aqueous NaOH solution (1M, 20 mL) was added slowly to a solution of sodium hydrogensulphide hydrate (4.1 g, 73 mmol) in water (16 mL) at 0° C. The reaction mixture was degassed and flushed with nitrogen before the addition of 1-bromo-3,3,3-trifluoroacetone (10 g, 52 mmol). After stirring at 0° C. for 50 minutes, methyl cyanoacetate (3.8 mL, 54 mmol) was added, followed by triethylamine (7.6 mL, 54 mmol), and the reaction mixture was allowed to warm to room temperature. The reaction mixture was then diluted with EtOAc and separated. The aqueous layer was washed with EtOAc and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford a brown solid. Recrystallisation from EtOAc/hexane gave the title compound (4.1 g) as a brown solid. LCMS (pH 10) RT 1.08 minutes; MS (m/z) 245 [M+H]+.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH:2]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=[CH2:1]
Reactant: C=Cc1ccccc1
Solvent: C1CCOC1
Product: C=CC1CCCCC1
Product: C=CCCCCC

Procedure:
The catalysts of the invention are effective and practical chiral catalysts for enantioselective metathesis. Examples of AROM/CM reactions catalyzed by chiral catalysts of the invention are shown in Table 1. As shown in Example 1, treatment of 19 with 5 equivalents of styrene in the presence of 10 mol % catalyst 9 in THF (50° C.) leads to the formation of 20a in 80% ee and 71% isolated yield (>98% trans). Ru-catalyzed AROM/CM is highly selective with aliphatic olefins. With aliphatic olefins such as 1-heptene and sterically bulky vinylcyclohexane (entries 2-3), 20b-c are obtained in >98% ee, >98% trans and 57-60% yield.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][CH:13]=2)=[N:3]1.[CH3:21][CH2:22][N:23]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN([CH:45]=[O:46])C>O>[CH3:45][O:46][CH2:21][CH2:22][NH:23][C:18]([C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([C:4]2[S:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2](=[O:1])[N:3]=2)[N:17]=1)=[O:20]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Product: COCCNC(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 80 °C
Reaction time: 17 h
Yield: 40 %

Procedure:
A mixture of 6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridinecarboxylic acid (350 mg, 1.2 mmol), WSC (471 mg, 2.4 mmol), HOBt (332 mg, 2.4 mmol) and DMF (10 ml) was stirred at 80° C. for 17 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated. The residue was subjected to a silica gel column chromatography, eluted with ethyl acetate-methanol (50:1, v/v) and recrystallized from tetrahydrofuran-hexane to give the titled compound (167 mg, 40%).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.[C:12](NC1C=CC=CC=1)([CH3:15])([CH3:14])[CH3:13].[CH:23]1[CH:24]=[CH:25][C:26]2[N:31](O)N=N[C:27]=2[CH:28]=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:12]([C:23]1[CH:28]=[CH:27][C:26]([NH:31][C:8](=[O:10])[C:7]2[CH:6]=[CH:5][C:4]([F:11])=[N:3][C:2]=2[F:1])=[CH:25][CH:24]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)Nc1ccccc1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc(F)nc1F
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(F)nc2F)cc1

Procedure:
A solution of 2,6-difluoropyridine-3-carboxylic acid (3.2 g, 20 mmol), t-butylaniline (3.0 g, 20 mmol), HOBt (2.6 g, 20 mmol), EDAC (8 g, 40 mmol), and DIEA (8 mL) in CH2Cl2 (80 mL) was stirred at RT for 1 h. The mixture was washed with aq. NaHCO3 and brine. The organic solution was dried over Na2SO4 and concentrated in vacuo. The residue was purified via flash chromatography on silica (Hex:EtOAc=4:1) to give a light yellow flaky crystal as desired product.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)[CH:9]=1)(O)=[O:6]>>[ClH:3].[Cl:3][C:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)[CH:9]=1)=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cn(-c2nccc3ccccc23)c2ccccc12
Product: Cl
Product: O=C(Cl)c1cn(-c2nccc3ccccc23)c2ccccc12

Procedure:
35 cm3 of thionyl chloride are added at 25° C. under an argon atmosphere to 1.2 g (4 mmol) of 3-carboxy-1-(isoquinol-1-yl)-1H-indole. After stirring at reflux for 4 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), successively triturated twice with 10 cm3 of dimethoxyethane and then concentrated to dryness under reduced pressure (2.7 kPa) to give 1.3 g of 3-chlorocarbonyl-1-(isoquinol-1-yl)-1H-indole hydrochloride in the form of a pale yellow solid which is used directly in the following step.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].[OH:9][C:10]1([CH:14]([O:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=5)=[CH:33][CH:32]=4)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]4[N:48]=[CH:49][N:50]=[C:24]34)[CH2:19][CH2:18]2)[CH3:15])[CH2:13][CH2:12][CH2:11]1>CS(C)=O.C(OCC)(=O)C>[OH:9][C:10]1([CH:14]([O:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:32]=[CH:33][C:34]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[C:43]5[NH:3][C:4](=[O:7])[O:5][N:44]=5)=[CH:35][CH:36]=4)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]4[N:48]=[CH:49][N:50]=[C:24]34)[CH2:19][CH2:18]2)[CH3:15])[CH2:11][CH2:12][CH2:13]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C3(O)CCC3)CC2)c2ncnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C3(O)CCC3)CC2)c2ncnn12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (2.67 g), sodium hydrogen carbonate (4.30 g) and dimethyl sulfoxide (7 mL) was stirred at 60° C. for 30 min, a solution of 4′-[(4-{trans-4-[1-(1-hydroxycyclobutyl)ethoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (1.45 g) in dimethyl sulfoxide (8 mL) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (503 mg) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (472 mg) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=50/50→35/65 (volume ratio)] to give the title compound as a colorless amorphous compound (890 mg, 56%).
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:13]=[C:12]([CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])[N:11]=[C:10]([NH:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)[N:9]=1.[C:32](Cl)(=[O:40])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>C(Cl)Cl>[Cl:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:15]=1[CH2:14][C:12]1[N:11]=[C:10]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]#[N:29])=[CH:30][CH:31]=2)[N:9]=[C:8]([NH:7][C:32](=[O:40])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:13]=1
Reactant: CCCCCCCC(=O)Cl
Reactant: N#Cc1ccc(Nc2nc(N)cc(Cc3c(Cl)cccc3Cl)n2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCC(=O)Nc1cc(Cc2c(Cl)cccc2Cl)nc(Nc2ccc(C#N)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
Pyridine (0.014 mol) was added to a mixture of 4-[[4-amino-6-[(2,6-dichlorophenyl)methyl]-2-pyrimidinyl]amino]benzonitrile (0.0013 mol) in CH2Cl2. A solution of octanoyl chloride (1.5 equiv) in CH2Cl2 (0.5 ml) was added dropwise. The mixture was stirred at room temperature for 2 hours. More octanoyl chloride (3.5 equiv) in CH2Cl2 was added dropwise. The mixture was stirred. The solvent was then evaporated. The residue was treated with a saturated aqueous NaHCO3 solution and the mixture was extracted with CH2Cl2. The separated organic layer was dried, filtered and the solvent was evaporated to give the crude product. The residue was recrystallized from CHCl3 and hexane, yielding 0.443 g (68.6%) of N-[6-[(2,6-dichloro-phenyl)methyl]-2-[(4-cyano-phenyl)amino]-4-pyrimidinyl]octanamide (comp. 17; mp. 135-137° C.).
Reaction SMILES: [N+](C1C=C[C:7]([C:8](Cl)=[O:9])=CC=1)([O-])=O.CC(CC)CN.[CH3:19][CH:20]([CH2:34][CH3:35])[CH2:21][NH:22][C:23](=[O:33])[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=1>>[CH3:19][CH:20]([CH2:34][CH3:35])[CH2:21][NH:22][C:23](=[O:33])[C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:8](=[O:9])[CH3:7])=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCC(C)CNC(=O)c1ccc([N+](=O)[O-])cc1
Agent: CCC(C)CN
Product: CCC(C)CNC(=O)c1ccc(NC(C)=O)cc1

Procedure:
The method of Example 3 is repeated using 4-nitrobenzoyl chloride and 2-methylbutyl amine in the amidation step. This yields N-2-methylbutyl-4-nitrobenzamide (CPI1146).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:15][C:14]=1[Cl:24].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[Cl:24][C:14]1[CH:15]=[C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:18][C:13]=1[NH:12][C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Fc1ccc2nc(Br)sc2c1
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Product: COC(=O)Cc1ccc(Nc2nc3ccc(F)cc3s2)c(Cl)c1
Yield: 31.7 %

Procedure:
In xylene (8 ml), 2-bromo-6-fluorobenzothiazole (330 mg, 1.42 mmol), methyl 4-amino-3-chlorophenylacetate (284 mg, 1.42 mmol), and pyridinium p-toluenesulfonate (PPTS) (107 mg, 0.43 mmol) were heated under reflux for 10 hours. After cooling, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (6:1, v/v) eluate fractions, methyl (3-chloro-4-(6-fluoro-2-benzothiazolyl)aminophenyl)acetate (158 mg, 32%) was obtained as a pale yellow solid.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([O:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C>[CH3:17][N:16]([CH3:18])[CH2:15][CH2:14][O:13][CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: CN(C)CCOC1CCN(Cc2ccccc2)C1
Reactant: [H][H]
Solvent: CCO
Product: CN(C)CCOC1CCNC1

Procedure:
A solution of 10.0 g. (0.0402 mole) of 1-benzyl-3-(2-dimethylaminoethoxy)pyrrolidine in ethanol containing 10% palladium on charcoal was shaken at 60° C. in about three atmospheres of hydrogen until the theoretical amount of hydrogen was used. The cooled filtered solution was concentrated at reduced pressure to give a quantitative yield of oily product. The structure was confirmed by its nuclear magnetic resonance spectrum.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:13]([O:20][CH3:21])(=[O:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16]>C1(C)C=CC=CC=1>[CH3:18][O:17][C:15]([CH:14]([CH:6]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:12][CH:11]=1)[CH2:7][N+:8]([O-:10])=[O:9])[C:13]([O:20][CH3:21])=[O:19])=[O:16]
Reactant: Cc1ccc(C=C[N+](=O)[O-])cc1
Reactant: COC(=O)CC(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)OC)C(C[N+](=O)[O-])c1ccc(C)cc1
Temperature: 30 °C
Reaction time: 24 h

Procedure:
[(S,S)-N-(4-tert-butylbenzenesulfonyl)-1,2-diphenylethylenediamine](hexamethylbenzene)ruthenium (12.9 mg, 0.02 mmol, S/C=50), 4-methyl-β-nitrostyrene (184 mg, 1.0 mmol), dimethyl malonate (114 μl, 1.0 mmol) and toluene (1 ml) were added into Schlenk (20 ml) under an argon atmosphere, and stirred at 30° C. for 24 hours. 1HNMR determination of the solution showed that the yield of the product was 51%. The reaction solution was purified by flash column chromatography (hexane/acetone=80/20, SiO2), and the optical purity was measured by HPLC (CHIRALPACK AD manufactured by Daicel Co., Ltd., hexane:2-propanol=90:10, flow rate 0.5 ml/min, detection by 210 nm), resulting to 82% ee.