Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[S:10]([O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH2:30][C:31](=O)[CH:32]([CH3:34])[CH3:33])(=[O:29])=[O:28])=[CH:23][CH:22]=1)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11]>C(OCC)C>[CH:32]([C:31]1[C:30]([S:27]([C:24]2[CH:25]=[CH:26][C:21]([O:20][S:10]([C:13]3[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=3)(=[O:12])=[O:11])=[CH:22][CH:23]=2)(=[O:28])=[O:29])=[CH:4][C:3]2[C:2](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)([CH3:34])[CH3:33]
Reactant: Nc1ccccc1C=O
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(S(=O)(=O)CC(=O)C(C)C)cc2)cc1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)Oc2ccc(S(=O)(=O)c3cc4ccccc4nc3C(C)C)cc2)cc1
Temperature: 185 °C

Procedure:
In a sealed tube a mixture of 0.02 mol of 2-aminobenzaldehyde and 0.02 mol of 1-(4-tosyloxybenzenesulphonyl)-3-methyl-butan-2-one was heated at 185° C. for 2 hours. The mixture was then taken up in dry ethyl ether and filtered. M.P. of the hydrochloride: about 90° C.
Reaction SMILES: C([N:3]([CH2:6]C)[CH2:4][CH3:5])C.NC1C=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[OH:18].CI>CO>[CH3:6][NH:3][C:4]1[CH:5]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[OH:18]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: CCN(CC)CC
Solvent: CI
Solvent: CO
Product: CNc1cc([N+](=O)[O-])ccc1O
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Triethylamine (2 ml, 14.4 mmol) was added to a solution of 2-amino-4-nitrophenol (1) (1.54 g, 10 mmol) and methyl iodide (1 ml, 16 mmol) in methanol (10 ml). After 1 hour at 40° C., further methyl iodide (1 ml) and triethylamine (1 ml) were added and the mixture was stirred at 40° C. for a further 2 hours. The reaction mixture was concentrated to dryness in vacuo, the residue was added to aqueous 2N sodium acetate solution and the mixture was extracted with ethyl acetate. The organic phase was dried with sodium sulfate and chromatographed on silica gel (eluent dichloromethane/methanol 95/5). Yield 880 mg (52%).
Reaction SMILES: [C:1]([C:5]1[O:6][C:7](=[O:20])[CH:8]=[C:9]2[C:13]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=3[O:11][C:10]=12)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:22]([NH:24][CH2:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:23].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:28][C:27]([CH3:30])([CH3:29])[CH2:26][CH2:25][N:24]([CH2:22][CH3:23])[C:7](=[O:20])[CH2:8][C:9]1[C:13]2[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=2[O:11][C:10]=1[C:5](=[O:6])[C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc2oc3c(C(C)(C)C)oc(=O)cc3c2c1
Reactant: CCNCCC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CCC(C)(C)C)C(=O)Cc1c(C(=O)C(C)(C)C)oc2ccc(OC)cc12
Temperature: 45 °C

Procedure:
To a mixture containing 21.8 mg 1-tert-butyl-6-methoxy-3H-pyrano[3,4-b][1]benzofuran-3-one from the Step B above and 21.6 mg N-Ethyl-3,3-dimethylbutan-1-amine hydrochloride from the Step A above in 0.75 mL DMF was 26 μL DIEA. The mixture was heated in 45° C. oil bath over night. It was purified directly on RP-HPLC using 65˜85% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound. LC-MS: 4.38 min. (m/Z=318.2, 402.3, 424.3). Alternative preparation of N-(3,3-dimethylbutyl)-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N-ethylacetamide
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]([OH:15])([CH2:13][CH3:14])[CH2:11][CH3:12].[CH3:16][C:17]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:21])[CH2:18][CH:19]=O>>[CH2:11]([C:10]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[NH:1][CH2:19][CH2:18][C:17]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:21])[CH3:16])([OH:15])[CH2:13][CH3:14])[CH3:12]
Reactant: CCC(O)(CC)c1cccc(OC)c1N
Reactant: CC(C)(CC=O)NC(=O)OC(C)(C)C
Product: CCC(O)(CC)c1cccc(OC)c1NCCC(C)(C)NC(=O)OC(C)(C)C

Procedure:
The product is obtained analogously to intermediate product 1b starting from 3-(2-amino-3-methoxyphenyl)pentan-3-ol and tert-butyl (1,1-dimethyl-3-oxopropyl)carbamate. The crude product is purified by column chromatography (silica gel, cyclohexane/EtOAc, 4:1). Yield: 4.60 g (47%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([NH:14][CH3:15])[CH:8]=[N:7]2.Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=1.O>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([N:14]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([C:25]([F:28])([F:26])[F:27])[CH:19]=1)[CH3:15])[CH:8]=[N:7]2
Reactant: CNc1cnc2cc(Br)ccc2n1
Reactant: Fc1ccc(CBr)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1ccc(F)c(C(F)(F)F)c1)c1cnc2cc(Br)ccc2n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67.3 %

Procedure:
To a suspension of sodium hydride (0.08 g, 1.5 eq, 3.37 mmol) in DMF (15 mL) was added (6-Bromo-quinoxalin-2-yl)-methyl-amine (0.6 g, 1.0 eq, 2.51 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes. A mixture of 4-(bromomethyl)-1-fluoro-2-(trifluoromethyl)benzene (0.7 g, 1.2 eq. 2.72 mmol) in DMF (15 mL) was added at room temperature and the reaction mixture was stirred for 2.0 hours at 0° C. After completion of the reaction, cold water (180 mL) was added and the reaction mixture was stirred for 15 minutes then filtered. The solid was dried under vacuum to afford the title compound (0.7 g, 67%).
Reaction SMILES: [N+:1]([C:4]1[CH:42]=[CH:41][CH:40]=[CH:39][C:5]=1[CH2:6][O:7][C:8]([CH2:10][P:11]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[N:12]1[CH:15]([CH2:16][C:17](O)=[O:18])[CH2:14][C:13]1=[O:20])=[O:9])([O-:3])=[O:2].C(Cl)(=O)C([Cl:46])=O>C(Cl)Cl.CN(C=O)C>[N+:1]([C:4]1[CH:42]=[CH:41][CH:40]=[CH:39][C:5]=1[CH2:6][O:7][C:8]([CH2:10][P:11]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[N:12]1[CH:15]([CH2:16][C:17]([Cl:46])=[O:18])[CH2:14][C:13]1=[O:20])=[O:9])([O-:3])=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CC1CC(=O)N1P(CC(=O)OCc1ccccc1[N+](=O)[O-])(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CC1CC(=O)N1P(CC(=O)OCc1ccccc1[N+](=O)[O-])(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
From Step A, 1-(o-nitrobenzyloxycarbonylmethyltriphenylphosphoranyl)-4-(carboxymethyl)-2-azetidinone (0.851 g) is dissolved in 20 ml CH2Cl2 and cooled to 0° C. under N2. Oxalyl chloride (0.8 ml) is added dropwise over 5 min and then 1 drop of DMF is added. The mixture is stirred at 0° C. for 5 min and then at 25° C. for 15 min. The solvent and excess oxalyl chloride are evaporated under reduced pressure. The residue is the desired acid chloride which is used without purification in the next step.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.[N:35]1([C:41]2[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][CH:42]=2)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(#N)CC>[O:17]=[C:7]1[NH:6][C:5]2[CH:4]=[C:3]([CH2:2][N:38]3[CH2:37][CH2:36][N:35]([C:41]4[CH:42]=[CH:43][C:44]([C:45]#[N:46])=[CH:47][CH:48]=4)[CH2:40][CH2:39]3)[CH:12]=[N:11][C:10]=2[N:9]2[CH2:13][CH2:14][CH2:15][CH2:16][C@@H:8]12
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 20 %

Procedure:
(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (86.0 mg, 0.369 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (108.0 mg, 0.442 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (193 ul, 1.1 mmol). To the stirred mixture was then added 4-(piperazin-1-yl)benzonitrile (76 mg, 0.406 mmol). The reaction was heated to 90° C. with stirring for 16 h. The crude reaction was cooled to room temperature and concentrated to a residue, then taken up in 3 mL DMSO and purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer). The fractions were combined and concentrated until a white solid precipitated. The precipitate was filtered off and dried in vacuum to afford the title compound (29.7 mg, 20.0%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.48 (s, 1H), 7.65 (s, 1H), 7.57 (d, J=8.8 Hz, 2H), 6.94-7.04 (m, 3H), 4.44-4.55 (m, 1H), 3.79-3.88 (m, 1H), 3.35 (br. s., 2H), 3.30 (br. s., 4H), 2.54-2.69 (m, 1H), 2.45 (br. s., 4H), 1.97-2.09 (m, 1H), 1.80-1.90 (m, 1H), 1.57-1.69 (m, 1H), 1.32-1.56 (m, 3H). [M+H] calc'd for C23H26N6O, 403; found, 403. MP: 212.2° C.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)[N:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:27]1[CH:28]=[CH:29][N:30]2[CH2:35][CH2:34][NH:33][CH2:32][C:31]=12.C(N(CC)CC)C.CN(C)C(=O)C>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:1]([S:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)[N:12]=[C:11]([N:33]2[CH2:34][CH2:35][N:30]3[CH:29]=[CH:28][N:27]=[C:31]3[CH2:32]2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(SCc2ccccc2)nc(Cl)nc1N1CCC(O)CC1
Reactant: c1cn2c(n1)CNCC2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COC(=O)c1c(SCc2ccccc2)nc(N2CCn3ccnc3C2)nc1N1CCC(O)CC1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
A mixture of 4-benzylthio-5-methoxycarbonyl-6-(4-hydroxypiperidine-1-yl)-2-chloropyrimidine (prepared in the above (4)) 120 mg, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine 70 mg, triethylamine 57 mg and N,N-dimethylacetamide 3 ml is stirred at 10° C. for 3 hours. The reaction mixture is diluted with an aqueous citric acid solution and extracted with ethyl acetate. The water layer is made basic with an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo to give 4-benzylthio-5-methoxycarbonyl-6-(4-hydroxypiperidin-1-yl)-2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)pyrimidine as a colorless foam, 105 mg.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH:21](O)[CH2:20][CH2:19]2>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH:21]([O:1][C:2]1[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=1)[CH2:20][CH2:19]2
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OC1CCc2cc(Cl)ccc21
Product: N#Cc1ccnc(-n2nccc2OC2CCc3cc(Cl)ccc32)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and 5-chloro-2,3-dihydro-1H-inden-1-ol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.36-2.44 (1H, m), 2.57-2.66 (1H, m), 2.90-2.98 (1H, m), 3.12-3.20 (1H, m), 5.73-5.75 (1H, m), 5.85 (1H, d, J=2.0 Hz), 7.20 (1H, d, J=8.0 Hz), 7.29 (1H, s), 7.32 (1H, d, J=8.0 Hz), 7.36 (1H, dd, J=1.8 Hz, 4.8 Hz), 7.63 (1H, d, J=2.0 Hz), 7.87 (1H, s), 8.65 (1H, d, J=4.8 Hz). [M+H] Calc'd for C18H13ClN4O, 337; Found, 337.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][N:8]=1.N1C=CC=CC=1.Cl>O>[NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][N:8]=1
Reactant: Brc1ccc(Br)nc1
Reactant: NCCCN
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: NCCCNc1ccc(Br)cn1

Procedure:
A mixture of 1,3-diaminopropane (17.6 ml), 2,5-dibromopyridine (10 g) and pyridine (5 ml) was heated under reflux for 4 hr. After stripping off the excess of 1,3-diaminopropane, the residue was taken up in water, the pH adjusted to 7 (conc. hydrochloric acid) and the solution extracted with chloroform. The pH was raised to 14 and extracted with chloroform. After drying (K2CO3), the final extract was evaporated to give 2-(3-aminopropylamino)-5-bromopyridine (9.1 g) as an oil which was used without further purification. (ii) To a suspension of sodium hydride (0.3 g) in DMSO (20 ml) was added 2-(3-aminopropylamino)-5-bromopyridine (2.88 g). The mixture was stirred and heated slowly to 85° C. After the evolution of hydrogen had ceased the mixture was cooled to room temperature and methyl iodide (1.77 g) in DMSO (5 ml) added dropwise maintaining the temperature below 30° C. After a further 15 min water (150 ml) was added and the mixture extracted with chloroform. The chloroform extract was washed with water and extracted with 1N hydrochloric acid. The acid extract was washed with chloroform, the pH adjusted to 13 (2N NaOH) and extracted again with chloroform. The final extract was stripped and the residue chromatographed (silica gel, 5% ammoniacal methanol/dichloromethane) to give 2-[N-(3-aminopropyl)-N-methylamino]-5-bromopyridine (1.44 g) as an oil which was used without further purification. (iii) 2-[N-(3-aminopropyl)-N-methylamino]-5-bromopyridine (1.4 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one (1.25 g) were heated together under reflux in pyridine (10 ml) for 20 hr. After stripping, the residue was triturated with wet ether and recrystallised from isopropanol/water to give 2-[3-[N-methyl-N-(5-bromopyrimid-2-yl)amino]propylamino]-5-(6-methylpyrid-3-yl-methyl)pyrimid-4-one, 1.5 g (71%) mp 137°-40° C.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]([N:12]2[C:15](=[O:16])[C@H:14]([S:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=3)[C@H:13]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[Sn](Cl)(Cl)(Cl)Cl>C(OCC)(=O)C>[C:1]1([C@H:7]([NH:9][C:10]([N:12]2[C:15](=[O:16])[C@H:14]([S:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=3)[C@H:13]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:11])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)[C@@H]1[C@@H](Sc2cccc([N+](=O)[O-])c2)C(=O)N1C(=O)N[C@H](C)c1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1[C@@H](Sc2cccc(N)c2)C(=O)N1C(=O)N[C@H](C)c1ccccc1
Temperature: 50 °C
Yield: 70.8 %

Procedure:
To a solution of compound 85a (18 mg, 41 umol) in ethyl acetate (1 mL) was added tin chloride monohydrate (2.5 eq.) and the solution was heated to 50° C. After 1 h the solution was concentrated in vacuo. The residue was purified by column chromatography using a gradient of hexane/ethyl acetate 20-100% as eluent to yield 86 (12 mg, 72%). Product MS: 414.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([O:9][CH3:10])([CH3:8])[C:4](OC)=[O:5].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCCCCC>[CH2:11]([NH:18][C:4](=[O:5])[C:3]([O:9][CH3:10])([O:2][CH3:1])[CH3:8])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C(C)(OC)OC
Reactant: NCc1ccccc1
Solvent: CCCCCC
Product: COC(C)(OC)C(=O)NCc1ccccc1
Temperature: 55 °C
Reaction time: 288 h

Procedure:
A mixture of methyl 2,2-dimethoxypropionate (2.33 g, 15.7 mmol) and benzylamine (1.68 g, 15.7 mmol) in a 20 mL screw-capped vial was stirred at 55° C. for 12 d. To the reaction mixture, which mostly solidified upon cooling to ambient temperature was added hexane (5 mL), and the mixture was sonicated and stirred vigorously. The solid was filtered off, washed with hexanes, and dried in vacuo to give the title compound as off-white solid. 1H NMR (400 MHz, CDCl3): δ=7.38-7.25 (m, 5H), 7.08 (brs, 1H), 4.49 (d, J=5.6 Hz, 2H), 3.25 (s, 6H), 1.52 (s, 3H). MS(ES+): m/z=246.07 (58) [MNa+], 224.11 (58) [MH+], 192.12 (100) [MH+-MeOH], 160.11 (33) [MH+-2 MeOH]. HPLC: tR=2.78 min (polar—5 min, ZQ3).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][CH2:17][O:18][C:19]([C:21]1[C:22]([C:31]2[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=2[C:33]([OH:35])=[O:34])=[CH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:20].FC(F)(F)S(OC1C(C(OCOC)=O)=CC2C(=CC=CC=2)C=1)(=O)=O>CN(C)C=O.O>[CH3:15][O:16][CH2:17][O:18][C:19]([C:21]1[C:22]([C:31]2[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=2[C:33]([O:35][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:34])=[CH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:20]
Reactant: COCOC(=O)c1cc2ccccc2cc1-c1ccccc1C(=O)O
Reactant: BrCc1ccccc1
Agent: COCOC(=O)c1cc2ccccc2cc1OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOC(=O)c1cc2ccccc2cc1-c1ccccc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
Benzyl bromide (160 μl) and potassium carbonate (202 mg) were added to a solution of 2-(3-(methoxymethoxycarbonyl)naphthalen-2-yl)benzoic acid (410 mg) which was prepared by the same procedure as a series of reaction of Reference Example 4→Reference Example 5 using methoxymethyl 2-trifluoromethylsulfonyloxy-3-naphthalenecarboxylate, in dimethylformamid (5 ml). The mixture was stirred for 22 hours at room temperature. Water was added to the reaction mixture, and the solution was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=8:2) to give the title compound (498 mg) having the following physical data.
Reaction SMILES: O.P([O-])([O-])([O-])=O.[CH2:7]([O:9][C:10]([CH:12]1[CH2:17][CH2:16][C:15]2[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=2[O:13]1)=[O:11])[CH3:8].[OH-]>O1CCCC1>[CH2:7]([O:9][C:10]([C@H:12]1[CH2:17][CH2:16][C:15]2[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=2[O:13]1)=[O:11])[CH3:8]
Reactant: CCOC(=O)C1CCc2ccc(O)cc2O1
Agent: O=P([O-])([O-])[O-]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@H]1CCc2ccc(O)cc2O1
Yield: 45.5 %

Procedure:
A 250 mL 3-necked, round-bottomed flask equipped with a mechanical stirrer, a pH electrode connected to a pH control unit and an addition tube connected to a peristaltic pump, was charged with 60 mL of deionized water, 15 mL of 0.05M phosphate buffer (pH 7.0) and 2.2 g racemic 3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylic acid ethyl ester dissolved in 7.5 mL of tetrahydrofuran. The pH was adjusted to 8.0 with 0.1N aqueous hydroxide solution, and 0.4 g of Pseudomonas lipase enzyme (P-30, Amano International Enzyme Co., Inc., Troy, Va.) was added while the mixture was stirred at a fast rate. The reaction flask was stoppered to avoid loss of the co-solvent by evaporation and the stirring was continued at the same rate. The pH was maintained at 8.0 by adding 0.1N aqueous sodium hydroxide solution via the peristaltic pump. The reaction was discontinued when 55 mL of 0.1N aqueous sodium hydroxide had been consumed (at about the 10 hour mark) and the tetrahydrofuran was removed by evaporation at 35° C. under 10 mm Hg of vacuum. The remaining mixture was extracted 3 times with 50 mL (for a total of 150 mL) of ethyl acetate. The combined organic layers were washed with 50 mL of saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The solution was filtered and concentrated at 40° C. under 10 mm Hg of vacuum, to obtain 1.0 g (45% yield, 100% of theory) of (R)-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylic acid ethyl ester as an off-white solid; m.p. 77°-78° C., (α)D25 -20.2° (c 1.0, CHCl3), 99.6% e.e.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][N:20](CC2C=CC(Cl)=CC=2)[CH2:19]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)=O>[OH-].[OH-].[Pd+2].CO>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=CO
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCNC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
A mixture of (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]-1-(4-chlorobenzyl)pyrrolidine (6.3 g, 11.4 mmol), Pd(OH)2 (1.68 g), HCO2H (3.7 mL), and methanol (80 mL) was stirred at 50° C. overnight. After the mixture was cooled to room temperature, the Pd catalyst was filtered off through Celite and the filtrate was concentrated. Column chromatography (SiO2, AcOEt, AcOEt/MeOH=5/1-4/1) gave (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (4.42 g, 90%) as a white solid:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH2:8][CH2:7][CH2:6]2.Cl.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23]N)=[CH:19][CH:18]=1.Cl.O>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:9]3[NH:23][C:20]4[C:21]([C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=1)=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=4
Reactant: COc1ccc(NN)cc1
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)CCc1c-2[nH]c2ccc(OC)cc12
Yield: 74 %

Procedure:
10.0 g (57 mmol) of 6-methoxy-1-tetralone in 125 ml of ethanol is added in drops within 35 minutes to a boiling solution of 10.0 g (57 mmol) of p-methoxyphenylhydrazine-hydrochloride and 5.0 ml of concentrated hydrochloric acid in 180 ml of ethanol. Then, it is refluxed for 5 hours. After 370 ml of hot water is added, it is allowed to cool. The almost colorless reaction product is suctioned off and recrystallized from ethanol. Yield 74%, melting point 189-191° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[CH:5]1([CH2:11]Br)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>>[CH:5]1([CH2:11][NH:4][CH2:3][CH2:2][OH:1])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: NCCO
Reactant: BrCC1CCCCC1
Product: OCCNCC1CCCCC1

Procedure:
2-Hydroxyethylamine was reacted with cyclohexylmethyl bromide according to Method B2a to give N-cyclohexylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclohexylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methoxy4-nitrophenyl isothiocyanate to give 2-(2-methoxy-4-nitrophenylimino)-3-(cyclohexylmethyl)-1,3-thiazolidine.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([SH:9])[CH3:8].Cl[CH2:11][C:12]1[N:13]=[C:14]([CH:17]2[CH2:22][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH3:30])=[CH:25][CH:24]=3)[CH2:20][N:19]([C:31]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[O:32])[CH2:18]2)[S:15][CH:16]=1>O1CCOCC1>[CH2:29]([C:26]1[CH:27]=[CH:28][C:23]([CH:21]2[CH2:22][CH:17]([C:14]3[S:15][CH:16]=[C:12]([CH2:11][S:9][CH2:7][CH3:8])[N:13]=3)[CH2:18][N:19]([C:31]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[O:32])[CH2:20]2)=[CH:24][CH:25]=1)[CH3:30]
Reactant: CCS
Reactant: CCc1ccc(C2CC(c3nc(CCl)cs3)CN(C(=O)N3CCOCC3)C2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCSCc1csc(C2CC(c3ccc(CC)cc3)CN(C(=O)N3CCOCC3)C2)n1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
73 mg (0.221 mmol) of caesium carbonate and 36 μl (0.442 mmol) of ethanethiol were added to a solution of 100 mg (about 0.184 mmol) of the compound from Example 141A in 1.5 ml of dioxane. The reaction mixture was stirred at 70° C. for 4 hours. Without any further work-up, the mixture was purified by preparative HPLC. Yield: 40 mg (47% of theory).