Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:44][O:45][C:46]1[C:47]2[N:60]=[C:59]([NH2:61])[S:58][C:48]=2[C:49]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)=[N:50][CH:51]=1>C1COCC1>[CH3:44][O:45][C:46]1[C:47]2[N:60]=[C:59]([NH:61][C:1]([C:2]3[CH:10]=[CH:9][C:8]4[O:7][CH2:6][O:5][C:4]=4[CH:3]=3)=[O:12])[S:58][C:48]=2[C:49]([N:52]2[CH2:53][CH2:54][O:55][CH2:56][CH2:57]2)=[N:50][CH:51]=1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3ccc4c(c3)OCO4)nc12

Procedure:
From piperonylic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 415 (M+H+, 100).
Reaction SMILES: [N:1]([CH:4]([C:6]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:14]2[C:9]([CH:10]=[CH:11][N:12]=[N:13]2)=[C:8]([Cl:23])[CH:7]=1)[CH3:5])=[N+]=[N-].O.CP(C)C>O1CCCC1>[Cl:23][C:8]1[CH:7]=[C:6]([CH:4]([NH2:1])[CH3:5])[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:14]2[C:9]=1[CH:10]=[CH:11][N:12]=[N:13]2
Reactant: CC(N=[N+]=[N-])c1cc(Cl)c2ccnnc2c1-c1cccc(F)c1
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(N)c1cc(Cl)c2ccnnc2c1-c1cccc(F)c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A solution of peak 1 of 7-(1-azidoethyl)-5-chloro-8-(3-fluorophenyl)cinnoline (0.57 g, 1.7 mmol), from step A, in tetrahydrofuran (9.3 mL) and water (1.8 mL) was treated with 1 M of trimethylphosphine in tetrahydrofuran (2.1 mL, 2.1 mmol) and stirred at 20° C. for 30 minutes.
Reaction SMILES: Cl/[CH:2]=[CH:3]\Cl.[C:5]1([S-:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Na+]>CN(P(N(C)C)(N(C)C)=O)C>[C:5]1([S:11]/[CH:6]=[CH:5]\[S:11][C:3]2[CH:2]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: [S-]c1ccccc1
Reactant: Cl/C=C\Cl
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C(=C\Sc1ccccc1)\Sc1ccccc1

Procedure:
A solution of (Z)-1,2-dichloroethene (0.49 g, 5.04 mmol) and compound 43 (2.0 g, 15.15 mmol) in HMPA (10 mL) was stirred under nitrogen for 1 h. The solvent was removed under reduced pressure to give the crude product that was then purified by column chromatography using 100% hexane as a solvent to give control (1.04 g, 85%). 1H NMR (400 MHz, CDCl3) δ 6.55 (s, 2H), 7.29 (m, 2H), 7.35 (t, J=7.7 Hz, 4H), 7.43 (s, 2H), 7.44 (m, 2H). HRMS ESI (m/z): Calculated for C14H12S2 [M]+: 244.0380. found: 244.0377.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=1[NH2:15])(C)(C)C.CC1(C)O[C:22](=[O:24])[CH:21]=[C:20]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:20]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[CH2:21][C:22](=[O:24])[NH:15][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccs2)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccs2)=Nc2ccc(I)cc2N1

Procedure:
Prepared from (2-amino-4-iodo-phenyl)-carbamic acid tert.-butyl ester (Example G1) and 2,2-dimethyl-6-thiophen-2-yl-[1,3]dioxin-4-one (Example J1) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (30 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.[CH2:17]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]1[C:33]([NH:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:30]2[CH2:31][CH2:32][N:27]([C:25]([O:24][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:26])[C@H:28]([C:33]([NH:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29]2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: CC(C)(C)NC(=O)[C@@H]1CNCCN1C(=O)OCc1ccccc1
Solvent: CC(C)O
Product: COc1cc2nc(N3CCN(C(=O)OCc4ccccc4)[C@H](C(=O)NC(C)(C)C)C3)nc(N)c2cc1OC

Procedure:
A solution of 4-amino-2-chloro-6,7-dimethoxyquinazoline (0.78 g, 3.2535 mmol) and (S)-4-[(benzyloxy)carbonyl]-3-(1,1-dimethylethylamino) carbonyl piperazine (see Askin, D. et al., Tetrahedron Letters 1994, 35, 673-676) (1.04 g, 3.2535 mmol) in 2-propanol (6 mL) was heated at 90° C. (24 h). The solvent was removed in vacuo and the residue subjected to SGC (SiO2, 40 mm×240 mm, 0-10% MeOH/CH2Cl2) which afforded (S)-1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-4-[(benzyloxy)carbonyl]-3-(1,1-dimethylethylamino)carbonyl piperazine.
Reaction SMILES: [N:1]1[N:5]2[C:6]3[C:11]([C:12](O)=[CH:13][C:4]2=[N:3][N:2]=1)=[CH:10][CH:9]=[N:8][CH:7]=3.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:12]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[N:5]2[N:1]=[N:2][N:3]=[C:4]2[CH:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc2nnnn2c2cnccc12
Product: Clc1cc2nnnn2c2cnccc12
Temperature: 90 °C

Procedure:
A suspension of tetrazolo[1,5-a][1,7]naphthyridin-5-ol (3.5 g) in phosphorous oxychloride (15 mL) was heated at 90° C. for 2 hours. The reaction mixture was concentrated under vacuum. The residue was poured into ice water, dichloromethane was added followed by the addition of 10% sodium hydroxide to neutral pH. The product was partitioned into dichloromethane. The dichloromethane layer was separated, dried over magnesium sulfate then concentrated under vacuum to provide 3.8 g of 5-chlorotetrazolo[1,5-a][1,7]naphthyridine as a solid, m.p. 176-177° C. Analysis: Calculated for C8H4ClN5: %C, 46.73; %H, 1.96; %N, 34.06. Found: %C, 46.80; %H, 2.16; %N, 34.45.
Reaction SMILES: CS(C)=O.[Cl:5][C:6]1[N:7]=[N:8][C:9](Cl)=[CH:10][CH:11]=1.[F:13][C:14]([F:23])([F:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21].C(=O)([O-])[O-].[K+].[K+]>O>[Cl:5][C:6]1[N:7]=[N:8][C:9]([O:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([F:13])([F:22])[F:23])=[CH:10][CH:11]=1
Reactant: Oc1ccccc1C(F)(F)F
Reactant: Clc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: FC(F)(F)c1ccccc1Oc1ccc(Cl)nn1
Yield: 92.4 %

Procedure:
80 ml of a dimethylsulfoxide solution containing 3.50 g of 3,6-dichloropyridazine, 6.44 g of 2-trifluoromethylphenol and 3.58 g of potassium carbonate, was reacted at 100° C. for 2.5 hours under stirring. After the completion of the reaction, the product was poured into water, and extracted with ethyl acetate. The extract layer was dried over anhydrous sodium sulfate, and then ethyl acetate was distilled off. The residue was purified by silica gel column chromatography, whereby 5.96 g of 3-chloro-6-(2-trifluoromethylphenoxy) pyridazine was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1.C(=O)([O-])O.[Na+].BrC1C=CC(S(O[CH2:31][CH2:32][CH:33]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[OH:34])(=O)=O)=CC=1>COCCOC>[CH:35]1([CH:33]([OH:34])[CH2:32][CH2:31][N:12]2[CH2:13][CH2:14][CH:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=3)[CH2:10][CH2:11]2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: Cc1ccc(NC2CCNCC2)nc1
Reactant: O=S(=O)(OCCC(O)C1CCCCC1)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(NC2CCN(CCC(O)C3CCCCC3)CC2)nc1
Yield: 61.1 %

Procedure:
A mixture of 4-(5-methylpyridin-2-yl)aminopiperidine (394 mg, 2 mmol), sodium hydrogencarbonate (277 mg, 3.2 mmol) and 3-cyclohexyl-3-hydroxypropyl 4-bromobenzenesulfonate (932 mg, 2.4 mmol) in 1,2-dimethoxyethane (10 mL) was refluxed for 8 hours. After then adding 5 g of NH silica Chromatorex DM1020 to the reaction mixture, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60 g NH silica Chromatorex DM2035, hexane:ethyl acetate=1:1) to obtain the title compound as a light yellow solid (405 mg) (59.6% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][C:20]#[N:21]>CC(C)=O>[C:20]([CH2:19][O:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1)#[N:21]
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Nc1cccc(OCC#N)c1
Temperature: 100 °C

Procedure:
To a solution of N-(3-hydroxy-phenyl)-acetamide (5 g, 33.1 mmol) in acetone (50 ml) were added K2CO3 (5.49 g, 39.8 mmol) and bromo-acetonitrile (4.37 g, 36.4 mmol). The reaction mixture was heated to 100° C. for 3 h, filtered and the acetone layer evaporated in vacuo. This residue was dissolved in EtOAc (100 ml) and washed with 1M NaOH (10 ml×2). The organic layer was dried (Na2SO4), filtered and the solvent removed in vacuo. The crude residue was purified by column chromatography eluting with 80% EtOAc in heptane to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[CH:31]=[CH:30][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27](O)=[O:28])=[O:20])=[CH:17][CH:16]=1.C(N(CC)CC)C.ClC(OCC)=O.[NH2:45][OH:46]>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[CH:31]=[CH:30][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([NH:45][OH:46])=[O:28])=[O:20])=[CH:17][CH:16]=1
Reactant: O=C(O)CCCCCNC(=O)c1ccc(C=NN=C2C(=O)Nc3ccc(F)cc32)cc1
Reactant: NO
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(CCCCCNC(=O)c1ccc(C=NN=C2C(=O)Nc3ccc(F)cc32)cc1)NO
Temperature: 0 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
6-(4-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)benzamido)hexanoic acid (424 mg, 1 mmol), triethylamine (151 mg, 1.5 mmol) and 20 ml of DMF were stirred at 0° C. while ethyl chloroformate (163 mg, 1.5 mmol) was added. The mixture was stirred at 0° C. for 2 hours, and then 50% aqueous solution of hydroxylamine (1.32 g, 20 mmol) was added. The mixture was stirred for 3 hours at room temperature, and then diluted with 1000 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (224 mg, 51%) as a brown solid. LC-MS (m/z) 440 (M+1).
Reaction SMILES: CC[O-].[Na+].Cl.[CH:6]([NH2:8])=[NH:7].C[CH2:10][CH:11]([C:16](OCC)=[O:17])[C:12](OC)=[O:13]>C(O)C>[OH:13][C:12]1[C:11]([CH3:10])=[C:16]([OH:17])[N:8]=[CH:6][N:7]=1
Reactant: N=CN
Reactant: CCOC(=O)C(CC)C(=O)OC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1c(O)ncnc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
102 ml (282 mmoles) of a solution of sodium ethylate at 21% in ethanol is added to a solution of 7.5 g (94 mmoles) of formamidine hydrochloride in 250 ml of ethanol cooled down to 0° C. and the mixture is stirred for 30 minutes; then a solution of 13 ml (94 mmoles) of diethyl methyl malonate in 50 ml of ethanol is added followed by stirring overnight at ambient temperature. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate, water and acetic acid in order to adjust the pH to 6. The precipitate is filtered then washed successively with water, isopropanol, diethyl ether and finally with pentane. 7 g (Yield=60%) of expected product is obtained in the form of a beige solid.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[C:7]([NH2:15])=[N:6]1)=[O:4]>N1C=CC=CC=1>[NH2:15][C:7]1[C:8]2[C:13](=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[NH:5][N:6]=1.[CH3:1][N:2]=[C:3]=[O:4]
Reactant: CNC(=O)n1nc(N)c2ccc(Cl)cc21
Solvent: c1ccncc1
Product: CN=C=O
Product: Nc1n[nH]c2cc(Cl)ccc12

Procedure:
Analogously to Example 46, 0.1 mol of 3-amino-6-chloroindazole and 0.1 mol of methyl isocyanate in 100 ml of pyridine give 3-amino-6-chloroindazole-1-carboxylic acid methylamide (melting point: 148°-150° C; 50% of theory) in 30 minutes at 10°-15° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](C)[CH:5]=[CH:6][C:7]=1[N+]([O-])=O.[NH2:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>>[C:2]1([NH:12][C:13]2[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15]([OH:17])=[O:16])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: Cc1ccc([N+](=O)[O-])c(Br)c1
Product: O=C(O)c1ccccc1Nc1ccccc1

Procedure:
As shown in Scheme 7, coupling of 3-bromo-4-nitrotoluene with 2-amino-benzoic acid via an Ullmann reaction yields an N-phenyl-anthranilic acid. After protection of the acid with 2-amino-2-methyl-1-propanol, oxidation affords the corresponding aldehyde. Addition of vinyl magnesium bromide and deprotection provides the N-phenyl-anthranilic acid containing a latent Michael acceptor. ##STR15##
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[N:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1.CCN(CC)CC.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:25][S:26]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:11][CH2:12][C:13](=[O:17])[NH:14][C:15]=2[N:16]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CCc2ccc(OCCCCO)nc2N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCOc1ccc2c(n1)NC(=O)CC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.6 %

Procedure:
A mixture of intermediate 11 (140 mg, 0.593 mmol), Et3N (240 mg, 2.37 mmol) and methylsulfonyl chloride (102 mg, 0.89 mmol) was dissolved in DCM and the solution was stirred for 6 h at rt. The solution was then washed with water, brine, and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo to give 4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yloxy)butyl methanesulfonate (intermediate 12) (180 mg, 96%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:18][C:19]2[N:27]=[C:26](Cl)[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[C@@H:29]2[CH2:33][C@H:32]([NH:34][C:35](=[O:38])[CH2:36][CH3:37])[C@@H:31]([OH:39])[C@H:30]2[OH:40])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.O.[NH2:42][NH2:43].C(O)(C)C>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:18][C:19]2[N:27]=[C:26]([NH:42][NH2:43])[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[C@@H:29]2[CH2:33][C@H:32]([NH:34][C:35](=[O:38])[CH2:36][CH3:37])[C@@H:31]([OH:39])[C@H:30]2[OH:40])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NC(c4ccc(OC)cc4)c4ccc(OC)cc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NC(c4ccc(OC)cc4)c4ccc(OC)cc4)nc(NN)nc32)[C@H](O)[C@@H]1O
Reaction time: 12 h

Procedure:
A mixture comprising N-[(1S,2R,3S,4R)-4-(6-{[Bis-(4-methoxy-phenyl)-methyl]-amino}-2-chloro-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-propionamide (1.6 g, 2.82 mmol), and hydrazine monohydrate (14 ml) is stirred at room temperature for 72 h. Then isopropyl alcohol (10 ml) is added and the solvent was decanted off to afford a gummy mixture. It is dissolved in water (10 ml) and stirred for 12 h. The fine solid obtained is filtered, washed with water and dried in vacuo to afford the title product which is used in the next step without further purification. LC-MS (0.1% formic acid, acetonitrile): (MH+ 563).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([O:34][CH3:35])=[C:26]([CH2:36][C:37]2[S:38][C:39](Br)=[CH:40][CH:41]=2)[CH:25]=1)(=O)C.C([Sn](CCCC)(CCCC)[C:48]1[N:53]=[CH:52][CH:51]=[CH:50][N:49]=1)CCC.BrC1C=CC(=O)N(CC2C=CC(CC)=CC=2)C=1>>[C@@H:6]1([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([O:34][CH3:35])=[C:26]([CH2:36][C:37]3[S:38][C:39]([C:48]4[N:53]=[CH:52][CH:51]=[CH:50][N:49]=4)=[CH:40][CH:41]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: COc1c(Cc2ccc(Br)s2)cc([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)c2ccccc12
Agent: CCc1ccc(Cn2cc(Br)ccc2=O)cc1
Product: COc1c(Cc2ccc(-c3ncccn3)s2)cc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c2ccccc12

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methoxynaphthalene obtained in Example 265-(3) and 2-tributylstannylpyrimidine were treated in a manner similar to Example 128-(5) and (6) to give 1-(β-D-glucopyranosyl)-3-(5-(2-pyrimidinyl)-2-thienylmethyl)-4-methoxynaphthalene. APCI-Mass m/Z 495 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([NH2:17])=[CH:13][N:12]([CH2:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])[C:11]1=[O:27])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:42][CH2:43][C:44](Cl)=[O:45]>ClCCl>[C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([NH:17][C:44](=[O:45])[CH2:43][Cl:42])=[CH:13][N:12]([CH2:18][C:19]2[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=2[F:25])[C:11]1=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c(N)cn(Cc2c(F)cccc2F)c1=O)c1ccccc1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c(NC(=O)CCl)cn(Cc2c(F)cccc2F)c1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a solution of {(R)-2-[5-amino-3-(2,6-difluoro-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester (50 mg, 0.11 mmol) in dichloromethane (2 mL) were added triethylamine (29 μl, 0.22 mmol) and chloro-acetyl chloride (9.3 μl, 0.12 mmol) in that order, followed by stirring at room temperature for 2 hrs. Again, chloro-acetyl chloride (5.0 μl, 0.06 mmol) was added to the solution which was then stirred at room temperature for 1 hr. The solution was washed with an aqueous saturated sodium bicarbonate solution to separate an organic layer which was then concentrated. The residue was purified using silica gel chromatography (eluent: hexane/ethyl acetate, 2/1) and dried in a vacuum to afford 44 mg of the compound as a colorless oil (yield 76%).
Reaction SMILES: [CH:1]1([C:6]2[C:7]([OH:28])=[CH:8][C:9]([N+:25]([O-:27])=[O:26])=[C:10]([C:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=3)[CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:37]([O:39][CH3:40])=[O:38]>ClCCl>[CH:1]1([C:6]2[C:7]([O:28][C:37]([O:39][CH3:40])=[O:38])=[CH:8][C:9]([N+:25]([O-:27])=[O:26])=[C:10]([C:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=3)[CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C3CCCC3)c(O)cc2[N+](=O)[O-])CC1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Oc1cc([N+](=O)[O-])c(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1C1CCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.5 %

Procedure:
Tert-butyl 4-(5-cyclopentyl-4-hydroxy-2-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (596 mg, 1.53 mmol) was dissolved in dichloromethane (5 mL) and triethylamine (388 mg, 535 μL, 3.84 mmol) then treated dropwise with methyl chloroformate (178 μL, 2.301 mmol). The reaction was stirred for 5 min at room temperature and then concentrated in vacuo to tert-butyl 4-(5-cyclopentyl-4-(methoxycarbonyloxy)-2-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (680 mg, 99% yield). The material was used without purification. LC/MS m/z 447.4 [M+H]+.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.Cl.[Cl:13][C:14]1[CH:15]=[C:16]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH2:27][NH:26][CH2:25][CH2:24]3)[CH:17]=[C:18]([Cl:20])[CH:19]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:13][C:14]1[CH:15]=[C:16]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH2:27][N:26]([CH2:3][C:4]2[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=2)[CH2:25][CH2:24]3)[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: Clc1cc(Cl)cc(-c2ccc3c(c2)CCNC3)c1
Reactant: Cc1ncc(CCl)c(N)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ncc(CN2CCc3cc(-c4cc(Cl)cc(Cl)c4)ccc3C2)c(N)n1
Temperature: 25 °C
Reaction time: 65 h
Yield: 38.1 %

Procedure:
A suspension of 1.85 g (0.0095 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride in 105 ml of dimethylformamide was treated with 250 g (0.00795 mol) of 6-(3,5-dichlorophenyl)-1,2,3,4-tetrahydro-isoquinoline hydrochloride and 3.66 ml (0.026 mol) of triethylamine and stirred at room temperature under argon for 65 hours. The mixture was completely freed from the solvents. The residue was partitioned between dichloromethane and water. 30 ml of a 1N aqueous sodium hydroxide solution were added dropwise thereto, the mixture was extracted and chromatographed over silica gel with ethyl acetate/isopropyl alcohol 9:1 as the eluent. Crystallization was then carried out, firstly from methanol/ethyl acetate/n-hexane and then from hot ethyl acetate. 1.21 g (38%) of 5-[6-(3,5-dichlorophenyl)-3,4-dihydro-1H-isoquinolin-2-ylmethyl]-2-methyl-pyrimidin-4-ylamine were obtained as white crystals; m.p. 205°-211°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([CH:14]2[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]2)[CH:3]=1.[CH:22](=O)[CH2:23][CH2:24][CH3:25].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:10][CH2:9]2)=[C:4]([CH:14]2[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]2)[CH:3]=1
Reactant: CCCC=O
Reactant: CC1(C)CCC(c2cc(Br)ccc2N2CCNCC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCN1CCN(c2ccc(Br)cc2C2CCC(C)(C)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.2 %

Procedure:
To a mixture of the crude product of 1-[4-bromo-2-(4,4-dimethylcyclohexyl)phenyl]piperazine produced in Example (57a) (1.21 g), butyraldehyde (0.35 mL, 3.98 mmol), acetic acid (0.1 mL, 3.32 mmol) and tetrahydrofuran (8 mL) was added sodium triacetoxyborohydride (1.1 g, 4.98 mmol), followed by stirring for 2 hours and 10 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was washed with water and brine in that order and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 901 mg of the title compound as a yellow oil.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:7]=[C:8](/[C:15](/[C:23]2[NH:28][C:27](=[O:29])[C:26]([CH:30]3[CH2:32][CH2:31]3)=[CH:25][CH:24]=2)=[CH:16]\[C@H:17]2[CH2:21][CH2:20][C:19](=[O:22])[NH:18]2)[CH:9]=[CH:10][C:11]=1[O:12]CC.O>CCCCCC.C(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8](/[C:15](/[C:23]2[NH:28][C:27](=[O:29])[C:26]([CH:30]3[CH2:32][CH2:31]3)=[CH:25][CH:24]=2)=[CH:16]\[C@H:17]2[CH2:21][CH2:20][C:19](=[O:22])[NH:18]2)[CH:9]=[CH:10][C:11]=1[OH:12]
Reactant: CCOc1ccc(/C(=C\[C@H]2CCC(=O)N2)c2ccc(C3CC3)c(=O)[nH]2)cc1Cl
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: O
Product: O=C1CC[C@H](/C=C(\c2ccc(O)c(Cl)c2)c2ccc(C3CC3)c(=O)[nH]2)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1 M solution of boron tribromide in hexane (0.8 mL) was added to a solution of 6-{(E)-1-(3-chloro-4-ethoxyphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-cyclopropylpyridin-2(1H)-one obtained in Example 4-10 (110 mg) in chloroform (2 mL), and the mixture was stirred at room temperature for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:0→90:10) to give the title compound as a colorless amorphous (17.5 mg).