Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]2[N:11]([CH2:23][CH2:24][S:25]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:12]=[C:13]3[C:18]=2[C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[N:14]3[CH3:22])[CH:9]=1)[C:5]#[N:6].[Cl:45][C:46]1[O:50][C:49]([CH:51]=O)=[CH:48][CH:47]=1.[O-]S(C(F)(F)F)(=O)=O.[Bi+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.CCCC(C)C>C1(C)C=CC=CC=1.CO.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]2[N:11]3[C:12]([CH:51]([C:49]4[O:50][C:46]([Cl:45])=[CH:47][CH:48]=4)[S:25][CH2:24][CH2:23]3)=[C:13]3[N:14]([CH3:22])[C:15](=[O:21])[N:16]([CH3:20])[C:17](=[O:19])[C:18]=23)[CH:9]=1)[C:5]#[N:6]
Reactant: Cn1c(=O)c2c(-c3cc(Cl)cc(C#N)c3)n(CCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(C)c1=O
Reactant: O=Cc1ccc(Cl)o1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Bi+3]
Solvent: CO
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cn1c(=O)c2c(-c3cc(Cl)cc(C#N)c3)n3c(c2n(C)c1=O)C(c1ccc(Cl)o1)SCC3
Temperature: 100 °C

Procedure:
3-Chloro-5-(1,3-dimethyl-2,4-dioxo-6-(2-(tritylthio)ethyl)-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (Intermediate GA) (146 mg, 0.237 mmol), 5-chlorofuran-2-carbaldehyde (34.0 mg, 0.260 mmol) and bismuth (III) triflate (31.0 mg, 0.047 mmol) were suspended in toluene (Volume: 2.5 ml). The reaction was then heated to 100° C. under microwave irradiation for 3 hr. The reaction mixture was suspended in MeOH (50 mL) and adsorbed onto silica. The residue was purified via ISCO SiO2 12 g Redisep Rf column eluting with 20% EtOAc/hexane. Fractions were combined and evaporated to afford a pale yellow gum. The gum was dissolved in Et2O (30 mL) and iso-hexane (30 mL) was added to afford a suspension. The solvent was evaporated to afford the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@H:4](/[CH:5]=[C:6](\[CH3:9])/[CH:7]=O)[C@H:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].Cl.[NH2:19][OH:20].N1C=CC=CC=1.O>C(OCC)(=O)C.O1CCOCC1>[OH:20][N:19]=[CH:7]/[C:6](/[CH3:9])=[CH:5]/[C@@H:4]1[C@@H:3]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:2]1([CH3:17])[CH3:1]
Reactant: NO
Reactant: C/C(C=O)=C\[C@@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C/C(C=NO)=C\[C@@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.2 %

Procedure:
Under nitrogen atmosphere, a mixture of 1.0 g of t-butyl (1R)-trans-2,2-dimethyl-3-[(E)-2-methyl-3-oxo-1-propenyl]cyclopropanecarboxylate, 0.29 g of hydroxylamine hydrochloride, 5 ml of pyridine, 5 ml of water and 30 ml of 1,4-dioxane was stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 1 mol/L hydrochloric acid and saturated brine respectively. The organic layer was dried over anhydrous magnesium sulfate, then, filtrated, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.71 g of t-butyl (1R)-trans-3-[(E)-3-hydroxyimino-2-methyl-1-propenyl]-2,2-dimethylcyclopropanecarboxylate:
Reaction SMILES: [CH:1]1([S:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(S(C1C2C(=CC=CC=2)NC=1)(=O)=O)C.[Cl:30][C:31]1[CH:48]=[CH:47][C:34]2[N:35]([CH2:40][CH2:41][CH2:42][S:43]([CH3:46])(=[O:45])=[O:44])[C:36]([CH2:38]Cl)=[N:37][C:33]=2[CH:32]=1>>[Cl:30][C:31]1[CH:48]=[CH:47][C:34]2[N:35]([CH2:40][CH2:41][CH2:42][S:43]([CH3:46])(=[O:44])=[O:45])[C:36]([CH2:38][N:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:7]([S:4]([CH:1]4[CH2:3][CH2:2]4)(=[O:6])=[O:5])=[CH:8]3)=[N:37][C:33]=2[CH:32]=1
Reactant: CS(=O)(=O)CCCn1c(CCl)nc2cc(Cl)ccc21
Reactant: O=S(=O)(c1c[nH]c2ccccc12)C1CC1
Agent: CCS(=O)(=O)c1c[nH]c2ccccc12
Product: CS(=O)(=O)CCCn1c(Cn2cc(S(=O)(=O)C3CC3)c3ccccc32)nc2cc(Cl)ccc21

Procedure:
The title compound was prepared in analogy to Example 1-2 by using 3-(cyclopropylsulfonyl)-1H-indole (prepared in an analogy to 3-ethanesulfonyl-1H-indole) and 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole instead of 3-(methylsulfonyl)-1H-indole and 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole.
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:2]1.F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1.C(=O)([O-])[O-].[Li+].[Li+]>>[CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][N:6]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:23])([F:25])[F:24])[CH:15]=3)[C@H:5]2[CH:9]([CH3:10])[CH3:11])[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC(C)[C@@H]1N(c2ccc(C#N)c(C(F)(F)F)c2)CC[C@@]1(O)C1CC1

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3R)-3-cyclopropyl-2-isopropylpyrrolidin-3-ol 0.5 oxalate (215 mg), 4-fluoro-2-(trifluoromethyl)benzonitrile (189 mg) and lithium carbonate (163 mg), the title compound was obtained as a pale-brown solid (yield: 227 mg, yield: 67%).
Reaction SMILES: [O:1]=[C:2]1CCC[C:8]2NC(=S)C(C#N)=C[C:3]1=2.[NH2:15][C:16]1[CH2:21][CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:19][C:18](=[O:28])[CH:17]=1.C(OCC)(=O)C#C>>[C:22]1([CH:20]2[CH2:21][C:16]3[NH:15][C:2](=[O:1])[CH:3]=[CH:8][C:17]=3[C:18](=[O:28])[CH2:19]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N#Cc1cc2c([nH]c1=S)CCCC2=O
Reactant: NC1=CC(=O)CC(c2ccccc2)C1
Agent: C#CC(=O)OCC
Product: O=C1CC(c2ccccc2)Cc2[nH]c(=O)ccc21

Procedure:
In analogy to (Pettit, G. R.; Fleming, W. C.; Paull, K. D. J. Org. Chem. 1968, 33 (3) 1089-1092), 3-amino-5-phenylcyclohex-2-en-1-one reacted with ethyl propiolate to give the title compound as a colorless solid.
Reaction SMILES: Cl.CC(O)=O.CO.[NH:8](C(OC(C)(C)C)=O)[C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[NH:16])[NH2:15].Cl>C(O)(C)C>[NH2:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[NH:15])[NH2:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Solvent: CC(=O)O
Product: N=C(N)NCCC[C@H](N)C(=O)O
Yield: 163 %

Procedure:
Into a mixture consisting of 1,093 ml of 2N HCl/AcOH and a small quantity of MeOH was dissolved 243.7 g (0.55 mole) of BOC-Arg-CHA.HCl, and the resulting solution was reacted at room temperature for one hour. After the reaction, 1,093 ml of isopropyl alcohol was added, and the product was re-precipitated in AcOEt. The deposited crystalline product was collected by filtration and dried to obtain 156.2 g (74.3%) of H-Arg-CHA.2HCl.
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]12.[CH3:8][S:9]([NH2:12])(=[O:11])=[O:10].C(O[K])(C)(C)C.Cl>O1CCCC1>[CH3:8][S:9]([NH:12][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]1[OH:1])(=[O:11])=[O:10]
Reactant: CS(N)(=O)=O
Reactant: C1CCC2OC2C1
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)NC1CCCCC1O

Procedure:
In a nitrogen atmosphere, a mixture of 108 g of 1,2-epoxycyclohexane, 95.1 g of methanesulfonamide, 11.2 g of t-butoxypotassium, and 1,000 g of tetrahydrofuran was heated under reflux for 100 hours. The reaction solution was neutralized with hydrochloric acid and then subjected to conventional aqueous work-up. Purification by column chromatography yielded an alcohol compound, 2-[(methylsulfonyl)amino]cyclohexanol. In a nitrogen atmosphere, the alcohol compound was combined with 111 g of triethylamine and 2,000 g of acetonitrile, to which 105 g of methacryloyl chloride was added dropwise at −20° C. The mixture was gradually warmed to room temperature and then stirred for 10 hours. The reaction mixture was subjected to conventional aqueous work-up and purified by column chromatography, obtaining 165 g of 2-[(methylsulfonyl)amino]-cyclohexyl methacrylate. The yield was 63% based on the methanesulfonamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:5]=1.[F:15][C:16]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[C:17]=1[NH2:18].N1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](=[O:12])(=[O:11])[NH:18][C:17]2[C:16]([F:15])=[CH:22][C:21]([F:23])=[CH:20][C:19]=2[F:24])[CH:5]=1
Reactant: COC(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1c(F)cc(F)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(S(=O)(=O)Nc2c(F)cc(F)cc2F)c1

Procedure:
2.35 g (10 mmol) of 3-chlorosulfonylbenzoic acid methyl ester is suspended in 30 ml of dichloromethane with exclusion of moisture, the suspension is cooled to -5° C and at this temperature a solution of 1.47 g (10 mmol) of 2,4,6-trifluoroaniline and 1 ml of pyridine in 20 ml of dichloromethane is instilled. When the instillation is completed, it is allowed to come to room temperature and is stirred for 12 more hours. The resulting precipitate is suctioned off and extracted with ether. The ether extract and filtrate together are concentrated by evaporation and the residue is dissolved in dichloroethane and chromatographed on silica gel 60 (Merck) with ethyl acetate/hexane. 2.8 g (8.12 mmol)= 81.2% of the theoretical yield is obtained as an amorphous product.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[O:3][CH2:2]1.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([NH:22][CH2:21][C:20]3[CH:23]=[CH:24][C:17]([F:16])=[CH:18][CH:19]=3)[CH2:11][CH2:10]2)[O:3][CH2:2]1
Reactant: NCc1ccc(F)cc1
Reactant: O=C1CCN(CCC2CCOCO2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Fc1ccc(CNC2CCN(CCC3CCOCO3)CC2)cc1
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a solution of 128NLS50 (1.73 g, 8.13 mmol) in methanol (100 mL) was added dropwise 4-fluorobenzylamine (0.93 mL, 8.13 mmol) and acetic acid. Sodium cyanoborohydride (2.15 g, 40 mmol) was added slowly to the mixture at 0° C. and stirring was continued at rt overnight. The reaction mixture was concentrated in vacuo and the residue partitioned between dichloromethane and 1M NaOH, the aqueous layer extracted twice with dichloromethane and the combined organic layers dried over Na2SO4, filtered and evaporated to dryness. Purification of the residue by a short silica gel column chromatography eluting with 0-30% methanol in dichloromethane gave the title compound (1.51 g, 58%) as a colourless solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=1)[CH3:27]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:28]([CH2:26][CH3:27])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=2)=[O:24])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CCNCc1cccc(C)n1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH2:6])C.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]=[C:19]=[S:20].Cl>C1(C)C=CC=CC=1>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:4][CH2:5][NH:6][C:19]1=[S:20]
Reactant: CCOC(CN)OCC
Reactant: COc1ccccc1N=C=S
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1ccccc1N1CCNC1=S
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
8.8 ml (0.065 mol) of aminoacetaldehyde-diethylacetal diluted in 15 ml of toluene are added, under nitrogen, to a solution of 10 g (0.065 mol) of 2-methoxyphenylisothiocyanate in 105 ml of toluene. The reaction mixture is stirred for 1 h 30 min at room temperature. 2.75 ml (0.030 mol) of hydrochloric acid at 35% are added and the mixture is stirred for 2 hours under reflux. The mixture is concentrated and water is added and the precipitate is triturated. The product is drained, washed with an ether/n-heptane mixture and dried over P2O5 overnight. 8.18 g of 1-(2-methoxyphenyl)imidazoline-2-thione are thus obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@H:9]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]([N:12]1[CH2:16][CH2:15][C:14]([F:19])([C:17]#[N:18])[CH2:13]1)=[O:11].Cl.N[C@H](C(C)(C)C)C(N1CCCC1)=O.[CH2:38]([N:40]1[CH:44]=[C:43]([C:45]2[N:50]=[C:49]3[C:51]([C:62](O)=[O:63])=[CH:52][N:53](COCC[Si](C)(C)C)[C:48]3=[N:47][CH:46]=2)[CH:42]=[N:41]1)[CH3:39]>>[C:17]([C:14]1([F:19])[CH2:15][CH2:16][N:12]([C:10]([C@H:9]([NH:8][C:62]([C:51]2[C:49]3[C:48](=[N:47][CH:46]=[C:45]([C:43]4[CH:42]=[N:41][N:40]([CH2:38][CH3:39])[CH:44]=4)[N:50]=3)[NH:53][CH:52]=2)=[O:63])[C:20]([CH3:23])([CH3:22])[CH3:21])=[O:11])[CH2:13]1)#[N:18]
Reactant: CC(C)(C)[C@@H](N)C(=O)N1CCC(F)(C#N)C1
Reactant: CCn1cc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)cn1
Agent: CC(C)(C)[C@@H](N)C(=O)N1CCCC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CCn1cc(-c2cnc3[nH]cc(C(=O)N[C@@H](C(=O)N4CCC(F)(C#N)C4)C(C)(C)C)c3n2)cn1

Procedure:
Prepared according to the procedure outlined in Example 1, steps 3-4 substituting 1-((R)-2-amino-3,3-dimethylbutanoyl)-3-fluoropyrrolidine-3-carbonitrile trifluoroacetate for (R)-2-amino-3,3-dimethyl-1-(pyrrolidin-1-yl)butan-1-one hydrochloride and 2-(1-ethyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid for 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2, 3-1)]pyrazine-7-carboxylic acid. MS: (M+H)+=467.
Reaction SMILES: C([O:9][CH2:10]/[CH:11]=[CH:12]/[C:13]1[N:21]([CH3:22])[C:20]2[C:19](OC3C=CC=CC=3)=[N:18][CH:17]=[N:16][C:15]=2[CH:14]=1)(=O)C1C=CC=CC=1.[Cl:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][C:37]=1[O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=1)[NH2:34].Cl.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>CN1CCCC1=O>[Cl:30][C:31]1[CH:32]=[C:33]([NH:34][C:19]2[C:20]3[N:21]([CH3:22])[C:13](/[CH:12]=[CH:11]/[CH2:10][OH:9])=[CH:14][C:15]=3[N:16]=[CH:17][N:18]=2)[CH:35]=[CH:36][C:37]=1[O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=1
Reactant: Cn1c(/C=C/COC(=O)c2ccccc2)cc2ncnc(Oc3ccccc3)c21
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Product: Cn1c(/C=C/CO)cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c21
Temperature: 140 °C
Yield: 39.5 %

Procedure:
A mixture of (2E)-3-(5-methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)-2-propenyl benzoate (100 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (130 mg), pyridine hydrochloride (36 mg) and 1-methyl-2-pyrrolidone (0.518 mL) was stirred with heating at 140° C. for 4 hrs. After cooling to room temperature, aqueous sodium hydrogen carbonate (20 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate (100 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (0.518 mL)/ethanol (0.518 mL), 1N aqueous sodium hydroxide solution (0.518 mL) was added, and the mixture was stirred at room temperature for 2 hrs. Tetrahydrofuran/ethyl acetate (1:1, 50 mL) and saturated brine (30 mL) were added, and the mixture was extracted. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate:methanol=100:0→85:15) to give the title compound (45 mg) as crystals.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.I[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[CH3:23].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:23][C:22]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=2)[C:9]1=[O:13]
Reactant: O=C1NCCc2cc(C(F)(F)F)ccc21
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2cc(C(F)(F)F)ccc2C1=O
Yield: 9.4 %

Procedure:
Using analogous reaction conditions as described in Example 1, 6-trifluoromethyl-3,4-dihydro-2H-isoquinolin-1-one (I-17c: 150 mg, 0.698 mmol) was reacted with 3-iodo-4-methyl-pyridine (152.8 mg, 0.698 mmol), 1,4-dioxane (10 mL), copper iodide (13.3 mg, 0.0698 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (29.73 mg, 0.209 mmol) and potassium phosphate (369.94 mg, 1.745 mmol) to afford the crude product. Purification by column chromatography on silica gel (1.5% methanol in DCM) afforded 20 mg of the product (9.38% yield).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Na].Cl.[CH2:14]([N:21]1[CH:25]=[CH:24][N:23]=[C:22]1[CH2:26]Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[C:1]([CH:2]([CH2:26][C:22]1[N:21]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:25]=[CH:24][N:23]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])([O:9][CH2:10][CH3:11])=[O:8]
Reactant: ClCc1nccn1Cc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(Cc1nccn1Cc1ccccc1)C(=O)OCC
Temperature: 0 °C

Procedure:
Diethyl malonate (52.45 g) in ethanol (50 ml) was added dropwise to a solution of sodium (11.3 g) in dry ethanol (300 ml) with stirring. The mixture was cooled to 0° C. and a solution of 1-benzyl-2-chloromethylimidazole hydrochloride (40.0 g, prepared as described in J.A.C.S. 1949, 383) in dry ethanol (250 ml) was added over 30 minutes with stirring. The mixture was stirred at ambient temperature for 2 hours and then the ethanol removed under reduced pressure. Ice cold 2M hydrochloric acid (400 ml) was added to the residue and the mixture was washed with ether. The aqueous layer was basified with solid sodium carbonate and then extracted with dichloromethane to give ethyl 2-carbethoxy-3-(1-benzyl-1H-imidazol-2-yl)propanoate as an oil.
Reaction SMILES: [CH:1]1([N:4]=[C:5]=[O:6])[CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([NH:13][NH2:14])=[O:12]>C1COCC1>[CH:1]1([NH:4][C:5]([NH:14][NH:13][C:11](=[O:12])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[O:8][CH3:7])=[O:6])[CH2:3][CH2:2]1
Reactant: O=C=NC1CC1
Reactant: COc1ccccc1C(=O)NN
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)NNC(=O)NC1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
250 mg (3.01 mmol) of cyclopropyl isocyanate, dissolved in 3 ml THF, are added dropwise to 500 mg (3.01 mmol) of 2-methoxybenzoic acid hydrazide, dissolved in 7 ml THF, and the mixture stirred overnight at room temperature. The resulting precipitate is filtered off, washed with diethyl ether and dried in vacuo. 709 mg (94% of theory) of the target compound are thus obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([O:26]C)=[O:25])[CH:14]=3)[N:9]=2)=[C:4]([CH3:28])[CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([OH:26])=[O:25])[CH:14]=3)[N:9]=2)=[C:4]([CH3:28])[CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3C)c(N3CCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(F)ccc1-c1nc2ccc(C(=O)O)cc2nc1N1CCC[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To a solution of (S)-methyl 2-(4-fluoro-2-methylphenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (120 mg, 0.32 mmol) in methanol (20 mL) and water (1 mL) was added sodium hydroxide (50.7 mg, 1.27 mmol,) and the reaction was stirred overnight at room temperature. The resulting mixture was concentrated in vacuo, adjusted to pH 6 with aqueous HCl (3N), collected by filtration to afford (S)-2-(4-fluoro-2-methylphenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid (85.7 mg, 74%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[N:19]=3)[N:14]=[CH:13][C:12]=2[F:23])[OH:10])[CH2:4]1.[O:24]=[C:25]1[CH2:30][S:29][C:28]2[CH:31]=[CH:32][C:33]([CH:35]=O)=[N:34][C:27]=2[NH:26]1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH4-].[Na+]>C(Cl)Cl.CCO>[F:23][C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:11]=1[C@@H:9]([OH:10])[CH2:8][N:5]1[CH2:6][CH2:7][C@@H:3]([CH2:2][NH:1][CH2:35][C:33]3[CH:32]=[CH:31][C:28]4[S:29][CH2:30][C:25](=[O:24])[NH:26][C:27]=4[N:34]=3)[CH2:4]1)=[N:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2
Reactant: COc1ccc2ncc(F)c([C@@H](O)CN3CC[C@@H](CN)C3)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2ncc(F)c([C@@H](O)CN3CC[C@@H](CNCc4ccc5c(n4)NC(=O)CS5)C3)c2n1
Reaction time: 18 h
Yield: 3.6 %

Procedure:
To a stirred solution of (1R)-2-[(3S)-3-(aminomethyl)-1-pyrrolidinyl]-1-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethanol (90 mg, 0.28 mmol) in dry CH2Cl2 (2 mL) and dry EtOH (2 mL) was added 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde (55 mg, 0.28 mmol) along with Na2SO4 (350 mg, 2.46 mmol). After 18 h at room temperature, NaBH4 (24 mg, 0.56 mmol) was added. After 2 h, the solution wa partitioned between ethyl acetate and the aqueous solution of sodium bicarbonate. The aqueous solution was extreacted several times with ethyl acetate. The organic fraction were pooled, concentrated and purified with column chromatography (silica, 0-8% MeOH in DCM (1% NH4OH)) affording a light yellow solid, which was completed with chiral purification. The title compound (5 mg, 3.6%) was provided as a white solid: LC/MS (ES) m/e 499 (M+H)+; 1H NMR (400 MHz, CD3OD): δ 8.56 (s, 1H), 8.14 (d, J=9.0 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.10 (d, J=9.2 Hz, 1H), 6.89 (d, J=7.6 Hz, 1H), 5.82-5.84 (m, 1H), 4.03 (s, 3H), 3.64 (s, 2H), 3.39-3.41 (m, 1H), 3.09-3.12 (m, 1H), 2.87-3.07 (m, 2H), 2.59-2.67 (m, 2H), 2.48-2.52 (m, 2H), 2.28-2.36 (m, 2H), 1.86-1.97 (m, 1H), 1.37-1.46 (m, 1H), 1.16-1.18 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][O:10][CH2:11][O:12][CH3:13])=[C:7]([C:14]([CH2:18][CH3:19])=[CH:15][CH2:16][OH:17])[CH:6]=[CH:5][N:4]=1.C([C@@](C([O-])=O)(O)[C@@](CC)(O)C([O-])=[O:25])C.C(OO)(C)(C)C>C(Cl)Cl.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH2:18]([C@:14]1([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[C:8]=2[CH2:9][O:10][CH2:11][O:12][CH3:13])[O:25][CH:15]1[CH2:16][OH:17])[CH3:19]
Reactant: CC[C@](O)(C(=O)[O-])[C@](O)(CC)C(=O)[O-]
Reactant: CCC(=CCO)c1ccnc(OC)c1COCOC
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: CC(C)(C)OO
Solvent: ClCCl
Product: CC[C@]1(c2ccnc(OC)c2COCOC)OC1CO
Yield: 88.7 %

Procedure:
Following the procedure in Example 5, the reaction was carried out with 5b (0.80 g, 3 mmol), Ti(OiPr)4 (0.71 mL, 2.4 mmol), diethyl-L(+)-tartrate (0.51 mL, 3 mmol), tBuOOH (0.95 mL, 5.0-6.0M in decane) and 4 Å molecular sieves (241 mg) in dry CH2Cl2 for 24 h to afford 6b as a yellow oil (754 mg, 89%) with 96% ee. The crude product was sufficiently pure for the subsequent reaction. Epoxide 6b was analyzed for enantiomeric purity using a Chiralcel OD-H column with 98:2 hexane/iPrOH as the eluent with the racemate as the standard. IR (CH2Cl2, NaCl,cm−1) 3408, 2980, 1765, 1607, 1457, 1410, 1393, 1266, 1040, 742, 546; 1H NMR (300 MHz, CDCl3) δ0.92 (t, J=7.6 Hz, 3H), 1.82 (m, 1H), 1.99 (m, 1H), 3.24 (t, J=5.8 Hz, 1H), 3.46 (s, 3H), 3.90 (m, 2H), 3.99 (s, 3H), 4.71 (s, 2H), 4.73 (s, 2H), 6.93 (d,J=5.2 Hz, 1H), 8.12 (d, J=5.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ9.41, 25.73, 25.98, 54.06, 55.82, 60.80, 61.33, 63.72, 64.72, 96.70, 116.46, 116.83, 146.60, 150.98, 163.10; HRMS (EI) m/z calcd for C14H22NO5 (M+H) 284.1498, found 284.1507; LRMS (EI) m/z 284(M+H, 58), 190(100), 178(73), 162(27), 148(27), 77(13); [α]D23=+65.6(c=0.25, CH2Cl2).