Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][NH:20]C(=O)C1C(=CC=CC=1)C(N)=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccccc1C(=O)NCCCCBr
Reactant: Fc1ccc(-c2c[nH]cn2)cc1
Agent: [H-]
Agent: [Na+]
Product: NCCCCn1cnc(-c2ccc(F)cc2)c1
Yield: 81.8 %

Procedure:
Using the procedure of Stage A of Example 1, 10 g of the product of Stage A, 1.95 g of sodium hydride and 11.80 g of N-4-bromobutyl-phthalamide were reacted to obtain 7.53 g of the expected product melting at 138-140° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH3:13][N:14]([CH2:19][C:20]1[CH2:21][C:22]2[C:27]([C:28]=1[CH3:29])=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15](=[O:18])[CH:16]=[CH2:17].CCN(C(C)C)C(C)C>C(#N)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:13][N:14]([CH2:19][C:20]1[CH2:21][C:22]2[C:27]([C:28]=1[CH3:29])=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15](=[O:18])/[CH:16]=[CH:17]/[C:2]1[CH:11]=[N:10][C:9]2[NH:8][C:7](=[O:12])[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: O=C1CCc2cc(Br)cnc2N1
Reactant: C=CC(=O)N(C)CC1=C(C)c2ccccc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CC1=C(CN(C)C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)Cc2ccccc21
Reaction time: 18 h
Yield: 38.3 %

Procedure:
A mixture of 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (0.096 g, 0.42 mmole), from Preparation 15, and N-methyl-N-(3-methyl-1H-inden-2-ylmethyl)acrylamide (0.141 g, 0.62 mmole) in propionitrile (10 mL) was treated with (i-Pr)2NEt (0.15 mL, 0.08 mmole), palladium acetate (0.014 g, 0.062 mmole), and (o-tolyl)3P (0.025 g, 0.08 mmole), and the resulting mixture was heated at gentle reflux. After 18 hr, the reaction was cooled, filtered through Celite®, and concentrated. Flash chromatography on silica gel (2% MeOH/CH2Cl2) gave the title compound (0.06 g, 41%) as a glassy solid: MS (ES) m/e 374.2 (M+H)+. Anal. Calcd for C23H23N3O2.1.25H2O: C, 69.76; H, 6.41; N, 10.61. Found: C, 69.86; H, 6.67; N, 10.51.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[H-].[Na+].[C:12]1([C:22](Cl)=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.C([O:28][CH2:29][CH3:30])(=O)C>O1CCCC1>[CH3:1][C:2]1([CH3:9])[N:6]([C:22]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[O:23])[C:5](=[O:7])[N:4]([C:29]([C:30]2[C:21]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:17]=[CH:18][CH:19]=2)=[O:28])[C:3]1=[O:8]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)C(=O)N(C(=O)c2cccc3ccccc23)C(=O)N1C(=O)c1cccc2ccccc12
Reaction time: 0.5 h

Procedure:
5,5-Dimethylimidazolidine-2,4-dione (1.28 g) was dissolved in tetrahydrofuran (50 mL), and sodium hydride (60%, in oil) (0.80 g) was added at 0° C. under ice-cooling. After stirred for 30 minutes, 1-naphthoyl chloride (3.80 g) was added at 0° C., and the mixture was stirred at room temperature overnight. Ethyl acetate (200 mL) was added to the reaction solution, the mixture was washed with a saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. Further purification by silica gel chromatography (hexane:ethyl acetate=2:1) afforded 1.19 g of white crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[CH2:14](O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].CN(C1C=CC=CN=1)C>ClCCl>[N+:1]([C:4]1[CH:10]=[C:9]([C:11]([O:13][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCO
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCOC(=O)c1ccc(N)c([N+](=O)[O-])c1
Reaction time: 48 h

Procedure:
A mixture of 2-nitro-4-carboxyaniline (0.52 g), heptadecanol (0.7 g) and dimethylaminopyridine (20 mg) in dichloromethane (20 ml) was prepared and dicyclohexyldicarbodiimide (0.62 g) was added. The mixture was stirred for 48 hours and filtered. After separating between chloroform and 3% caustic soda solution the organic phase was washed with water, dried with magnesium sulphate and the solvent removed to leave a yellow solid. The solid was purified by chromatography to give a yellow solid which was recrystallised from 50:50 chloroform-hexane (yield: 0.85 g, m.p. 103°-105° C.).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:11][CH2:12][CH2:13][C:14]1[C:30]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:29][C:17]2[CH2:18][CH:19]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][C:16]=2[CH:15]=1.Cl>CN(C)C=O>[CH2:32]([O:31][C:30]1[C:14]([CH2:13][CH2:12][CH2:11][O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:15][C:16]2[O:20][CH:19]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][C:17]=2[CH:29]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Oc1ccccc1
Reactant: BrCCCc1cc2c(cc1OCc1ccccc1)CC(CCc1ccccc1)O2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(CCC2Cc3cc(OCc4ccccc4)c(CCCOc4ccccc4)cc3O2)cc1
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Dry phenol (14 gm, 152 mmoles) was added to 50% sodium hydride dispersion (7 gm; 145 mmoles) in dimethylformamide (200 mL) under nitrogen atmosphere. After stirring for 30 minutes, a solution of 6-(3-bromopropyl)-5-benzyloxy-2-(2-phenylethyl)-2,3-dihydrobenzofuran, E88, (8.7 gm; 16.9 mmoles) in dimethylformamide (25 mL). The mixture was stirred at room temperature for 3 hours, poured into excess 1N hydrochloric acid and extracted with diethylether. The ether layer was washed with 1N sodium hydroxide twice, dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel using 5% ethyl acetate in hexane to yield 6.3 g (82%) of 5-benzyloxy-2-(2-phenylethyl)-6-(3-phenoxypropyl)-2,3-dihydrobenzofuran, E38, as an oil.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11](OC(C)(C)C)=O)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.Cl.ClC[C@H:21]1[CH2:23][O:22]1.[OH-].[Na+]>ClCCl.O1CCOCC1>[CH:1]1([CH2:4][N:5]2[CH2:6][CH2:7][N:8]([CH2:11][C@@H:21]3[CH2:23][O:22]3)[CH2:9][CH2:10]2)[CH2:2][CH2:3]1
Reactant: ClC[C@H]1CO1
Reactant: CC(C)(C)OC(=O)N1CCN(CC2CC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: C1CC1CN1CCN(C[C@@H]2CO2)CC1
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
Tert-butyl 4-(cyclopropylmethyl)piperazine-1-carboxylate 31a (2 g, 8.30 mmol) was dissolved in 40 mL of dichloromethane followed by the addition of 20 mL of a 4 M solution of hydrogen chloride in dioxane. The reaction solution was stirred for 0.5 hours. The reaction solution was concentrated under reduced pressure followed by the addition of 40 mL of dichloromethane and dropwise with 20 mL of triethylamine to adjust pH to 10 to 11. The resulting solution was concentrated under reduced pressure. The residue was added with 50 mL of ethyl acetate and filtered. The filtrate was concentrated under reduced pressure, added with 50 mL of ethyl acetate and 20 mL of water, then added with (R)-2-chloromethyl-oxirane (0.92 g, 9.96 mmol) and sodium hydroxide (0.66 g, 16.60 mmol). The reaction solution was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, added with 50 mL of water and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 1-(cyclopropylmethyl)-4-[[(2R)-oxiran-2-yl]methyl]piperazine 31b (0.91 g, yield: 57.0%) as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].I[CH2:12][C:13]([NH2:15])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13]([NH2:15])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: NC(=O)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)COc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 74.7 %

Procedure:
A mixture of 4-nitrophenol (7.5 g), iodoacetamide (10 g), potassium carbonate (7.5 g) and dimethylformamide (50 ml) was stirred at 50° C. for 15 hours. The mixture was poured into ice-water, and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was recrystallized from acetone-diisopropyl ether to give the desired compound (7.9 g) as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH3:9])=[CH:7][C:6]([N+:10]([O-:12])=[O:11])=[CH:5][N:4]=1)#[N:2].[CH3:13][Mg]Br.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1>[C:1]([C:3]1[C:8]([CH3:9])=[C:7]([CH3:13])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][N:4]=1)#[N:2]
Reactant: Cc1cc([N+](=O)[O-])cnc1C#N
Reactant: C[Mg]Br
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Product: Cc1c([N+](=O)[O-])cnc(C#N)c1C
Temperature: -70 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
2-Cyano-3-methyl-5-nitropyridine (0.33g, 2 mmol) was dissolved in 10 mL of THF and cooled in a dry ice/acetone bath under nitrogen. Methylmagnesium bromide (1.33 mL, 4 mmol) was added via syringe over five mins. The reaction was stirred for 2 h at −70° C. DDQ (0.068g, 3 mmol) in 7 mL of THF was added and the mixture warmed to 25° C. The solvent was removed in vacuo and the residue was purified by silica gel chomatography using CH2Cl2 as the eluent to give compound 773A (0.15g, 42%) as a red oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.N1C=CC=CC=1>CN(C)C(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([N:4]2[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:2]([CH3:1])=[N:3]2)[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1c[nH]nc1C
Reactant: COc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: COC(=O)c1cn(-c2cccc(OC)c2)nc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
Methyl 3-methyl-1H-pyrazole-4-carboxylate (4.6 g) synthesized in Example 1(3) was dissolved in N,N-dimethylacetamide (50 mL), 3-methoxyphenylboronic acid (10.0 g), copper acetate (12.0 g) and pyridine (10.6 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1N hydrochloric acid (100 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (3.9 g, 48%) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH2:12]1[C:17](=[O:18])[N:16]([O:19][C:20](ON2C(=O)CCC2=O)=[O:21])[C:14](=[O:15])[CH2:13]1>C(#N)C>[CH2:12]1[C:17](=[O:18])[N:16]([O:19][C:20]([NH:1][C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][CH:6]=[CH:5][C:4]=3[CH:3]=2)=[O:21])[C:14](=[O:15])[CH2:13]1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: Nc1ccc2ncccc2c1
Solvent: CC#N
Product: O=C(Nc1ccc2ncccc2c1)ON1C(=O)CCC1=O

Procedure:
6-Aminoquinolyl-N-hydroxysuccinimidyl carbamate was synthesized according to the following procedure. Acetonitrile (500 ml, Baker analyzed HPLC grade) was distilled to azeotropically remove any water present. The first 50 ml of acetonitrile was discarded. 6-Aminoquinoline (1.5 g, 10 mmol, Aldrich Chemical Co.) was dissolved in 50 ml of acetonitrile and placed in an addition funnel. Di(N-succinimidyl) carbonate (DSC; 3 g., 12 mmol, Fluka Chemical Co.) was dissolved in 100 ml. of acetonitrile and heated to reflux with stirring. The aminoquinolino solution was added dropwise to the refluxing solution over a period of about 30 minutes.
Reaction SMILES: [CH2:1]([Si:4]([CH3:7])([CH3:6])[CH3:5])[CH:2]=[CH2:3].[C:8]([O:11][CH2:12][C:13](Cl)=[N:14][OH:15])(=O)[CH3:9].C(N(CC)CC)C.[OH2:24]>CCOCC>[CH3:5][Si:4]([CH2:1][CH:2]1[O:15][N:14]=[C:13]([C:12]([O:11][CH2:8][CH3:9])=[O:24])[CH2:3]1)([CH3:7])[CH3:6]
Reactant: CC(=O)OCC(Cl)=NO
Reactant: O
Reactant: C=CC[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)C1=NOC(C[Si](C)(C)C)C1

Procedure:
3.43 g of allyltrimethylsilane and 4.55 g of chloroximinoethyl acetate are introduced into 150 ml of ether. 3.03 g of triethylamine in 150 ml of ether are then slowly added dropwise. Water is subsequently added, and the mixture is extracted several times using ether. The ether phase is dried over MgSO4, and the ether is subsequently stripped off on a Rotavapor. Separation over a silica gel column (solvent: n-heptane:ether acetate=8:2) gives 4.2 g of the desired pure substance of a refractive index nD20 -1.462
Reaction SMILES: [NH2:1][C@@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.S(=O)(=O)(O)O.C(O)C.[CH:24](=O)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CO>[CH2:25]([CH:24]1[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]=2[CH2:3][C@H:2]([C:13]([OH:15])=[O:14])[NH:1]1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCC=O
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CCO
Product: CCCCCCCC1N[C@@H](C(=O)O)Cc2c1[nH]c1ccccc21
Temperature: 45 °C
Reaction time: 72 h

Procedure:
A mixture containing 147 mmol of D-tryptophan, 294 ml of 1 N sulfuric acid, 300 ml of ethanol and 294 mmol of octanal is stirred at 45° C. for 72 hours. The solution is concentrated and the residue is taken up in a water/methanol/ammonium hydroxide mixture. The methanol is evaporated at 45° C. and the precipitate is filtered off, washed with water and dried. The solid obtained is solubilized at high temperature in methanol. After cooling, the compound of preparation F crystallizes. It is then filtered and dried.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[CH2:8]([OH:10])[CH3:9].[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:8]([O:10][C:6](=[O:7])[NH:5][S:2]([O:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:4])=[O:3])[CH3:9]
Reactant: Oc1ccccc1
Reactant: CCO
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NS(=O)(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Chlorosulfonyl isocyanate (98%, 13.4 ml, 0.15 mole) was stirred in 40 ml of methylene chloride in an acetone-ice bath. Ethanol (8.8 ml, 0.15 mole) dissolved in 20 ml methylene chloride was added dropwise over 28 minutes. The reaction was stirred at room temperature for 15 minutes and then chilled in an ice bath. To the reaction was added a solution of phenol (11.3 g, 0.12 mole) and triethylamine (21 ml, 0.15 mole) in methylene chloride (20 ml) over 27 minutes. The reaction was stirred at ambient temperature for 4 hours and then extracted twice with dilute hydrochloric acid. The organic layer was dried over sodium sulfate and evaporated to 31 g oil. This oil was chromatographed on about 300 g silica gel eluted with 2% ethyl acetate/methylene chloride. The pure fractions were combined and concentrated to 15 g oil.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:19]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]2=[O:26])[CH2:18][N:5]2[CH2:6][CH2:7][C:8]3[C:13]([C@H:4]2[CH2:3]1)=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=3>CCCCCCC.C(O)C>[NH2:1][C@@H:2]1[C@@H:19]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]2=[O:26])[CH2:18][N:5]2[CH2:6][CH2:7][C:8]3[C:13]([C@@H:4]2[CH2:3]1)=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=3
Reactant: COc1cc2c(cc1OC)[C@H]1C[C@@H](N)[C@H](N3CCCCC3=O)CN1CC2
Solvent: CCO
Solvent: CCCCCCC
Product: COc1cc2c(cc1OC)[C@@H]1C[C@H](N)[C@@H](N3CCCCC3=O)CN1CC2

Procedure:
Light yellow semisolid, 220 mg (38%), tR=32.0 min (Chiralpak® AD 25×0.46 cm, heptane/ethanol 80:20, flow rate 1 mL/min). (+)-(R,R,R)-1-(2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-3-yl)-piperidin-2-one: Light yellow semisolid, 207 mg (36%), tR=55.4 min (Chiralpak® AD 25×0.46 cm, heptane/ethanol 80:20, flow rate 1 mL/min).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[O:3].[CH3:7][C:8]([CH:10]=[CH2:11])=[CH2:9]>C(=O)([O-])O.[Na+]>[CH3:6][O:5][C:1]([C@@H:2]1[O:3][CH2:11][CH:10]=[C:8]([CH3:9])[CH2:7]1)=[O:4]
Reactant: COC(=O)C=O
Reactant: C=CC(=C)C
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)[C@H]1CC(C)=CCO1
Temperature: -70 °C
Reaction time: 3 h
Yield: 22 %

Procedure:
In the same manner as in Example 1, a solution of an (R)-binaphthol-dichlorotitanium complex was obtained. This solution was cooled to -70° C. in a dry ice-acetone bath. To this solution were successively added 88 mg (1 mmole) of methyl glyoxylate and 136 mg (2 mmole) of 2-methyl-1,3-butadiene. Reaction was then allowed to proceed at -30° C. for 3 hours, and 10 ml of a sodiumhydrogen carbonate aqueous solution was added to the reaction mixture to terminate the reaction. The reaction mixture was filtered through Celite and then subjected to extraction once with a 20 ml of diethyl ether and twice with 20 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by evaporation, and the residue was purified by silica gel column chromatography (200 mesh; developing solvent: hexane/ethyl acetate=10/1), thereby obtaining 34 mg of desired optically active (6R)-6-methoxycarbonyl-4-methyl-5,6-dihydropyran (yield: 22%).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1.[OH:11][CH:12]([C@@H:17]1[CH2:22][CH2:21][C@H:20]([NH2:23])[CH2:19][CH2:18]1)[C:13]([F:16])([F:15])[F:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:8][C:7]1[C:2]([NH:23][C@H:20]2[CH2:21][CH2:22][C@@H:17]([CH:12]([OH:11])[C:13]([F:14])([F:15])[F:16])[CH2:18][CH2:19]2)=[N:3][CH:4]=[N:5][C:6]=1[CH2:9][CH3:10]
Reactant: CCc1ncnc(Cl)c1Cl
Reactant: N[C@H]1CC[C@@H](C(O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ncnc(N[C@H]2CC[C@@H](C(O)C(F)(F)F)CC2)c1Cl

Procedure:
1.3 g of 4,5-dichloro-6-ethylpyrimidine, 2.0 g of cis-4-(1-hydroxy-2,2,2-trifluoroethyl)cyclohexylamine and 1.5 g of potassium carbonate in 20 ml of dimethylformamide were stirred at 90° C. for 3 hours. For work-up, the mixture was concentrated, the residue was taken up in dichloromethane and water and the organic phase was dried and concentrated. Purification was carried out by silica gel chromatography (petroleum ether/ethyl acetate 1:1) to give the title product as a colourless solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][C:30](=O)[C:31](O)=[O:32])[CH:24]=1>C(O)C>[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][C:30]2[C:31](=[O:32])[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11](/[CH:15]=[CH:16]/[C:17]4[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=4)[CH:10]=3)[C:3]3[N:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[CH:24]=1
Reactant: O=C(O)C(=O)Cc1cccnc1
Reactant: Nc1cccnc1Nc1cccc(/C=C/c2ccncc2)c1
Solvent: CCO
Product: O=c1c(Cc2cccnc2)nc2cccnc2n1-c1cccc(/C=C/c2ccncc2)c1
Yield: 47.4 %

Procedure:
A mixture of 3-amino-2-[3-[(E)-2-(4-pyridyl)vinyl]phenylamino]pyridine (575 mg) and 3-(3-pyridyl)pyruvic acid (0.37 g) in ethanol (10.ml) was stirred under reflux for 1.5 hours. After evaporation of the solvent, the residue was chromatographed on silica gel column (chloroform-methanol, 9:1) and crystallized from ethanol to give 2-(3-pyridylmethyl)-4-[3-[(E)-2-(4-pyridyl)vinyl]phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (395 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@@H:24]1[CH2:28][NH:27][CH2:26][C@@H:25]1[NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[N:17]=[CH:16]2.[CH2:34]([N:36]=[C:37]=[O:38])[CH3:35]>ClCCl>[C:30]([NH:29][C@@H:25]1[C@H:24]([NH:23][C:18]2[N:17]=[CH:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:3]4[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=4[Cl:12])[CH:14]=3)[N:19]=2)[CH2:28][N:27]([C:37]([NH:36][CH2:34][CH3:35])=[O:38])[CH2:26]1)(=[O:33])[CH:31]=[CH2:32]
Reactant: C=CC(=O)N[C@H]1CNC[C@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ccc2n1
Reactant: CCN=C=O
Solvent: ClCCl
Product: C=CC(=O)N[C@H]1CN(C(=O)NCC)C[C@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ccc2n1
Reaction time: 0.75 h
Yield: 76.3 %

Procedure:
To a solution of N-((3S,4R)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)pyrrolidin-3-yl)acrylamide (0.040 g, 0.082 mmol) in dichloromethane (1.5 mL) at 0° C. was added TEA (0.014 mL, 0.098 mmol) and ethyl isocyanate (0.008 mL, 0.098 mmol) and the reaction was stirred for 45 mins. LC-MS indicated complete consumption of SM. The reaction mixture was purified by silica gel chromatography to yield (3S,4R)-3-acrylamido-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-N-ethylpyrrolidine-1-carboxamide (0.035 g, 76%). MS (ES+) C26H28Cl2N6O4 requires: 558, found: 559.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH3:14])=[N:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:20]Cl>CN(C)C=O>[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:20][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:13]=2)[C:9]([CH3:14])=[N:10]1
Reactant: COC(=O)c1ccc2c(C)n[nH]c2c1
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C)nn(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
6-(Methoxycarbonyl)-3-methyl-1H-indazole (0.40 g, 2.1 mmol) was dissolved in dimethylformamide (15 ml) and the mixture was ice-cooled. Sodium hydride (85 mg, 60% suspension in oil, 2.1 mmol as NaH) was added and the mixture was stirred at 0° C. for 30 min. 2,4-Dichlorobenzyl chloride (0.45 g, 2.3 mmol) was added and the mixture was stirred at room temperature for 18 hr. The reaction mixture was extracted with ethyl acetate/water. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained crystalline residue was separated and purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1) to give the objective compound (0.54 g, 74%) as colorless crystals.