Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([Cl:19])[C:10]=1[N+:20]([O-:22])=[O:21])C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>S(=O)(=O)(O)O>[Cl:19][C:11]1[C:10]([N+:20]([O-:22])=[O:21])=[C:9]([NH2:8])[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[N:12]=1
Reactant: O=[N+]([O-])c1c(NCc2ccccc2)cc(C(F)(F)F)nc1Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Nc1cc(C(F)(F)F)nc(Cl)c1[N+](=O)[O-]
Yield: 97.9 %

Procedure:
Benzyl-(2-chloro-3-nitro-6-trifluoromethyl-pyridin-4-yl)-amine (3.1 g, 9.3 mmol) was stirred in 5 ml concentrated sulphuric acid for 0.5 h before cautiously pouring the solution into a beaker of crushed ice. Solid K2CO3 was added portion-wise until a basic pH was achieved and the aqueous extracted with 2×50 ml EtOAc. The combined organics were dried over MgSO4 and concentrated in vacuo to afford 2.2 g of the title compound as a pale yellow solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]([O:15]C2CCCCO2)[CH3:14])(=O)=O)=CC=1.CC1C=CC(S(OC[C@@H](OC2CCCCO2)C)(=O)=O)=CC=1.[F:43][C:44]1([F:88])[CH2:49][CH2:48][CH:47]([C:50]2[C:59]3[CH:58]([OH:60])[CH2:57][C:56]([CH3:62])([CH3:61])[CH2:55][C:54]=3[N:53]=[C:52]([CH:63]3[CH2:68][CH2:67][N:66]([C:69]4[N:74]=[CH:73][C:72]([OH:75])=[CH:71][N:70]=4)[CH2:65][CH2:64]3)[C:51]=2[CH:76]([F:87])[C:77]2[CH:82]=[CH:81][C:80]([C:83]([F:86])([F:85])[F:84])=[CH:79][CH:78]=2)[CH2:46][CH2:45]1>>[F:88][C:44]1([F:43])[CH2:45][CH2:46][CH:47]([C:50]2[C:59]3[CH:58]([OH:60])[CH2:57][C:56]([CH3:61])([CH3:62])[CH2:55][C:54]=3[N:53]=[C:52]([CH:63]3[CH2:64][CH2:65][N:66]([C:69]4[N:74]=[CH:73][C:72]([O:75][CH2:12][C@H:13]([OH:15])[CH3:14])=[CH:71][N:70]=4)[CH2:67][CH2:68]3)[C:51]=2[CH:76]([F:87])[C:77]2[CH:78]=[CH:79][C:80]([C:83]([F:85])([F:84])[F:86])=[CH:81][CH:82]=2)[CH2:48][CH2:49]1
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](C)OC2CCCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)OC[C@H](C)OC2CCCCO2)cc1
Product: C[C@@H](O)COc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1

Procedure:
Reactions similar to those of Example 37 were performed except for using (2R)-2-(tetrahydro-2H-pyran-2-yloxy)propyl 4-methylbenzenesulfonate, which was synthesized by the method described in B. A. Jones et al., Journal of Heterocyclic Chemistry, 1982, Vol. 19, pp. 551-556, instead of (2S)-2-(tetrahydro-2H-pyran-2-yloxy)propyl 4-methylbenzenesulfonate, and from 50 mg (77 μmol) of 4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxy pyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Example 4, 39 mg of the title compound was obtained as a white solid (yield: 71%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23].O1CCOCC1>ClCCl>[ClH:23].[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2F)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(c1ccccc1F)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(2-fluoro-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (16.3 g, 53 mmol) in dichloromethane (100 mL), add a solution of 4 M HCl in 1,4-dioxane (40 mL, 159 mmol) and stir the reaction mixture at room temperature overnight. Add Et2O to the resultant white suspension and evaporate solvents under reduced pressure to give 12.6 g of (2-fluoro-phenyl)-piperazin-1-yl-methanone hydrochloride. ES+ (m/z) 209[M+H]).
Reaction SMILES: [C:1]([C:9]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:10]=1[NH:11][C:12](=[O:17])C(Cl)(Cl)Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.C([O-])(=O)C.[NH4+:34]>O>[C:2]1([C:1]2[C:9]3[C:10](=[CH:18][CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=3)[NH:11][C:12](=[O:17])[N:34]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C(c1ccccc1)c1cc(C(F)(F)F)ccc1NC(=O)C(Cl)(Cl)Cl
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Solvent: O
Product: O=c1nc(-c2ccccc2)c2cc(C(F)(F)F)ccc2[nH]1
Temperature: 75 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
A mixture of 1.08 g of 2′-benzoyl-2,2,2-trichloro-4′-trifluoromethylacetanilide, 10 ml of DMSO and 1.18 g of ammonium acetate was stirred at 75° C. for 1 hour. After cooling, 100 ml of water was added to the mixture. Precipitated crystals were collected by filtration. The collected substance was dissolved in a mixture of hexane:ethyl acetate=1:1, dehydrated using anhydrous magnesium sulfate, and then concentrated to obtain 765 mg of the titled compound. 1H NMR (CDCl3): 7.58-7.68 (3H, m), 7.75 (1H, d, J=8.8 Hz), 7.79-7.83 (2H, m), 7.93 (1H, dd, J=8.8, 1.7 Hz), 8.17 (1H, br. s), 13.37 (1H, br. s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][CH2:9][CH:10](O)[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)=[CH:5][CH:4]=1.S(=O)(=O)(O)O.C(Cl)(Cl)Cl.CO>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:23]=[C:22]2[C:6](=[CH:5][CH:4]=1)[CH2:7][NH:8][CH2:9][CH:10]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1
Reactant: COc1ccc(CNCC(O)c2ccc(OC)c(OC)c2)cc1
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)C(c1ccc(OC)c(OC)c1)CNC2
Yield: 88.2 %

Procedure:
α-[[(4-methoxybenzyl)amino]methyl]-3,4-dimethoxybenzyl alcohol (950 mg) was dissolved in 7.2 ml of trifluoroacetic acid, and after adding thereto 0.22 ml of conc. sulfuric acid under ice cooling, the reaction was allowed to react for 45 minutes. The reaction solution was concentrated, and subjected to azeotropic distillation with toluene 2 times. After adding chloroform, the mixture was basified by addition of 28% aqueous ammonia under ice cooling. By a separating procedure, the chloroform layer was collected, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue obtained was subjected to silica gel column chromatography (chloroform-methanol-28% aqueous ammonia=15:1:0.1), giving 790 mg of 6-methoxy-4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline as oily matter.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:48]=[CH:47][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][Si](C(C)(C)C)(C4C=CC=CC=4)C4C=CC=CC=4)=[CH:24][C:23]=3[F:46])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:66][C:67]1[CH:72]=[CH:71][C:70]([O:73][CH2:74][CH:75]2[CH2:77][O:76]2)=[CH:69][CH:68]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[F:46][C:23]1[CH:24]=[C:25]([OH:28])[CH:26]=[CH:27][C:22]=1[CH2:21][NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:47]=[CH:48][C:7]([CH2:6][CH2:5][NH:4][CH2:77][CH:75]([OH:76])[CH2:74][O:73][C:70]3[CH:71]=[CH:72][C:67]([OH:66])=[CH:68][CH:69]=3)=[CH:8][CH:9]=2)[CH2:13][CH2:14]1)=[O:19]
Reactant: CC(C)(C)[Si](Oc1ccc(CNC(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)c(F)c1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Product: O=C(NCc1ccc(O)cc1F)N1CCC(Nc2ccc(CCNCC(O)COc3ccc(O)cc3)cc2)CC1

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(4-{[tert-butyl(diphenyl)silyl]oxy}-2-fluorobenzyl)-1-piperidinecarboxamide formate (0.855 g, 1.3 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane according to Procedure G to give the title compound (0.24 g, 0.2 mmol).
Reaction SMILES: [CH2:1]([C:8]1[N:9]([CH2:16][CH2:17][O:18]C(=O)C)[CH:10]=[CH:11][C:12](=[O:15])[C:13]=1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>[OH-].[Na+].C(O)C>[CH2:1]([C:8]1[N:9]([CH2:16][CH2:17][OH:18])[CH:10]=[CH:11][C:12](=[O:15])[C:13]=1[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OCCn1ccc(=O)c(O)c1Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=c1ccn(CCO)c(Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.915 g of 2-benzyl-3-hydroxy-1-(2-acetoxy-ethyl)-1H-pyridin-4-one (Example 42) are stirred at room temperature in a mixture of 2 ml of 2N NaOH and 10 ml of ethanol for 24 hours. Then 2 ml of 2N HCl are added and the reaction mixture is stirred at room temperature for one hour, filtered and washed with cold ethanol. Drying yields 2-benzyl-3-hydroxy-1-(2-hydroxy-ethyl)-1H-pyridin-4-one.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:15](O)=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[O:6]CC1C=CC=CC=1.[NH2:28][C@H:29]([C:34]([NH:36][C@H:37]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:35])[C@H:30]([CH2:32][CH3:33])[CH3:31].Cl.C1CCC(N=C=NC2CCCCC2)CC1.C(N1CCOCC1)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.CCOCC>[NH2:1][C@H:2]([C:15]([NH:28][C@H:29]([C:34]([NH:36][C@H:37]([C:45]([O:47][C:48]([CH3:49])([CH3:51])[CH3:50])=[O:46])[CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:35])[C@H:30]([CH2:32][CH3:33])[CH3:31])=[O:16])[CH2:3][CH2:4][C:5](=[O:6])[OH:14]
Reactant: O=C(CC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CC[C@H](C)[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](N)CCC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C

Procedure:
1.85 g of Z-Glu(OBzl)-OH, 1.85 g of H-Ile-Phe-OBut.HCl and 1.1 g of DCC are reacted, analogously to Example 21 (C), in the presence of 0.65 ml of N-ethylmorpholine and 0.7 g of HOBt in dimethylformamide, the product is subjected to catalytic hydrogenation and 2.4 g of the compound insoluble in ether are isolated.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=O)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32]/[C:33](=[N:36]/[H])/[NH:34]O.[O-]CC.[Na+]>CCO>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][C:19]2[O:21][N:36]=[C:33]([CH2:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[Cl:25])[N:34]=2)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: [H]/N=C(/Cc1ccccc1Cl)NO
Reactant: CCCCn1c(=O)n(CCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCn1c(=O)n(CCCc2nc(Cc3ccccc3Cl)no2)c(=O)c2[nH]c(Cl)nc21
Yield: 48.6 %

Procedure:
Ethyl 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate (53 mg, 0.15 mmol) and (1Z)-2-(2-chlorophenyl)-N-hydroxyethanimidamide (30 mg, 0.18 mmol; Entry 1, table 7) were heated in EtOH (0.75 ml) with 21% ethanolic sodium ethoxide (0.083 ml, 0.22 mmol) at 140° C. for 10 min. The mixture was then partitioned between EtOAc and 2M HCl and the organic phase evaporated. The product was purified by MDAP to yield the title compound as a solid (34.8 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH2:15][S:16][C:17]1[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=1)[C:7]([C:23]([O:25]CC)=[O:24])=[C:6]2[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH2:15][S:16][C:17]1[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=1)[C:7]([C:23]([OH:25])=[O:24])=[C:6]2[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1
Reactant: CCOC(=O)c1c(CSc2nccn2C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2c(C(=O)O)c(CSc3nccn3C)nc3cc(OC)c(OC)cc23)cc1OC
Yield: 52.8 %

Procedure:
A mixture of ethyl 6,7-dimethoxy-4-(3,4-dimethoxy- phenyl)-2-[(1-methylimidazol-2-yl)thiomethyl]quinoline-3-carboxylate (0.6 g), 2N NaOH (1.7 ml) and ethanol (12 ml) was refluxed for 6 hours. The reaction mixture was concentrated in vacuo. The residue was diluted with H2O, washed with ethyl acetate, acidified with 2N HCl and extracted with ethyl acetate. The extract was washed with H2O, dried over MgSO4, and concentrated in vacuo to give crystals. Recrystallization from ethanol-ethyl ether gave 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-[(1-methylimidazol-2-yl)thiomethyl]quinoline-3-carboxylic acid (0.3 g, 53%) as colorless prisms, mp 213-214° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:9]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[OH:10])=[N:5][CH:6]=[CH:7][CH:8]=1>C(O)C.[Pd]>[NH2:17][C:14]1[CH:13]=[CH:12][C:11]([CH:9]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][N:5]=2)[OH:10])=[CH:16][CH:15]=1
Reactant: COc1cccnc1C(O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: COc1cccnc1C(O)c1ccc(N)cc1
Reaction time: 3 h
Yield: 91 %

Procedure:
A mixture of (3-methoxypyridin-2-yl)-(4-nitrophenyl)methanol (600 mg) and 5% Pd-C (0.06 g) in ethanol (20 ml)was vigorously stirred under hydrogen atmosphere for 3 hours, and the Pd-C was filtered off. The filtrate was concentrated under reduced pressure to give (4-aminophenyl)-(3-methoxypyridin-2-yl)-methanol (483 mg) as pale yellow crystals.
Reaction SMILES: CN1C(=O)CCC1.Br[C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[N:13][CH:14]=1.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20].C(N(CC)C(C)C)(C)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.O>[N+:15]([C:12]1[CH:11]=[CH:10][C:9]([C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])=[CH:14][N:13]=1)([O-:17])=[O:16]
Reactant: C#C[Si](C)(C)C
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[Si](C)(C)C#Cc1ccc([N+](=O)[O-])nc1
Temperature: 65 °C
Reaction time: 4 h

Procedure:
To a NMP solution (20 mL) of 5-bromo-2-nitropyridine (1.00 g, 4.93 mmol) were added trimethylsilyl acetylene (1.4 mL), tetrakis(triphenylphosphine)palladium(0) (110 mg), copper(I) iodide (38 mg), and N,N-diisopropylethylamine (1.7 mL) at room temperature, which was stirred under a nitrogen atmosphere for 4 hours at 65° C. Water was added at 0° C. to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered, after which the solvent was evaporated from the filtrate under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=6:1) to obtain the titled compound (490 mg).
Reaction SMILES: C(NC1S[C@H]2[O:12][C@H](CN3C=C(C4C=CC=CN=4)N=N3)[C@@H](O)[C@H](O)[C@H]2N=1)C.[CH2:27]([NH:29][C:30]1[S:31][C@H:32]2[O:38][C@H:37]([CH2:39][OH:40])[C@@H:36]([OH:41])[C@H:35]([OH:42])[C@H:33]2[N:34]=1)[CH3:28].CC1(C)N([O])C(C)(C)CCC1.[Br-].[K+].Cl[O-].[Na+]>C1COCC1>[CH2:27]([NH:29][C:30]1[S:31][C@H:32]2[O:38][C@H:37]([C:39]([OH:12])=[O:40])[C@@H:36]([OH:41])[C@H:35]([OH:42])[C@H:33]2[N:34]=1)[CH3:28]
Reactant: CCNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Reactant: CCNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](Cn3cc(-c4ccccn4)nn3)O[C@@H]2S1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](C(=O)O)O[C@@H]2S1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The carboxylic acid intermediate of Schemes 1 to 3 was synthesized as follows: To a suspension of (3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (23 g, 93 mmol) in 1:1 THF/aqueous NaHCO3 (1200 mL) was added TEMPO (3.2 g, 20 mmol) and potassium bromide (3.5 g, 30 mmol). The mixture was then cooled to 0° C. and a solution of sodium hypochlorite (190 mL, 9% active chlorine basis) was added, dropwise. After 1 h, additional amounts of sodium hypochlorite solution (95 mL) and TEMPO (1.6 g, 10 mmol) were added. After TLC analysis indicated the reaction was complete, the reaction solution was extracted with diethyl ether (2×250 mL). The aqueous layer was acidified with 5N HCl to pH 5-6, and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of methanol/dichloromethane (1% to 50%) to afford the title compound (23 g).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]3=2)[C@H:7]([NH2:18])[CH2:6][C@@H:5]1[CH3:19])(=[O:3])[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.N1C=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]3=2)[C@H:7]([NH:18][C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=2)[CH2:6][C@@H:5]1[CH3:19])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2c(ccc3ccccc23)[C@H](N)C[C@@H]1C
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)N1c2c(ccc3ccccc23)[C@H](Nc2ccc(Cl)cc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.1 %

Procedure:
[Step 5] 91 mg of the cis-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydrobenzo[h]quinoline and 84 mg of 4-chlorophenylboronic acid were dissolved in 2.5 mL of DMF followed by adding 130 mg of divalent copper acetate and 87 μL of pyridine and stirring for 30 minutes at room temperature in the presence of air. Following completion of the reaction, the solution was filtered with celite followed by the addition of water and extracting three times with ethyl acetate. After washing with saturated brine and dehydrating with anhydrous sodium sulfate, the solution was concentrated under reduced pressure and the resulting residue was purified using silica gel chromatography (ethyl acetate:hexane=1:1) to obtain 25 mg of the target compound in the form of a yellow solid (19%).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Si:9]([O:26][CH:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CS(C)=O.O>[C:22]([Si:9]([O:26][CH:27]1[CH2:32][CH2:31][C:30]2([O:33][CH2:4]2)[CH2:29][CH2:28]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)[Si](OC1CCC(=O)CC1)(c1ccccc1)c1ccccc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)[Si](OC1CCC2(CC1)CO2)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of sodium hydride (60% in mineral oil, 441 mg, 11.0 mmol) in dimethylsulfoxide (7 mL) was added trimethylsulfoxonium iodide (2.53 g, 11.5 mmol) at room temperature, and the mixture was stirred at room temperature for 30 min. To this mixture was added a solution of 4-{[tert-butyl(diphenyl)silyl]oxy}cyclohexanone (3.53 g, 10.0 mmol, Okamura, William H. et al., J. Org. Chem., 1993, 58, 600) in dimethylsulfoxide (35 mL) dropwise at room temperature, and the mixture was stirred at room temperature for 2 h. Then the mixture was diluted with water (600 mL), and extracted with diethyl ether (200 mL×4). The combined organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with ethyl acetate/n-hexane (1:10), and then purified with plate TLC eluting with ethyl acetate/n-hexane (1:15) to give 459 mg (13%, trans) and 390 mg (11%, cis) of the title compound as a colorless oil respectively.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.[Cl:43][C:44]1C(CCl)=[N:46][C:47]([Cl:50])=[CH:48][CH:49]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:44]([Cl:43])=[CH:49][CH:48]=[C:47]([Cl:50])[N:46]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: ClCc1nc(Cl)ccc1Cl
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3nc(Cl)ccc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3,6-dichloro-2-(chloromethyl)pyridine and isolated as light brown gum. MS (m/e): 442.3 (MH+).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[CH:7](=O)[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10].B.[Na]>[OH-].[Na+]>[OH:10][C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[CH2:7][NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3]
Reactant: C[C@H](N)C(=O)O
Reactant: O=Cc1ccccc1O
Agent: B
Agent: [Na+]
Agent: [Na]
Product: C[C@H](NCc1ccccc1O)C(=O)O
Reaction time: 1 h

Procedure:
L-alanine (2.9 g) was dissolved in 20 ml of a 2N sodium hydroxide aqueous solution. To the solution were then added 3.5 ml of salicylaldehyde and 0.4 g of sodium boron hydride in this order. After the mixture was stirred for 1 hour, 3.5 ml of salicylaldehyde and 0.4 g of sodium boron hydride were added thereto again. After the resulting mixture was stirred at room temperature for 1 hour, the insoluble matter was separated by filtration, and the filtrate was extracted with diethyl ether. The extract was adjusted to a pH of 6 with hydrochloric acid to obtain 5.8 g of N-(2-hydroxybenzyl)-L-alanine. The resulting N-(2-hydroxybenzyl) -L-alantne ( 4.6 g) and 8.8 g of 1-dodecanol were added to 150 ml of toluene. A hydrogen chloride gas was then added thereto to saturation. Ten grams of molecular sieves were added thereto, and the mixture was stirred overnight. The insoluble matter was separated by filtration, and the filtrate was then concentrated. The resulting oil was dissolved in methylene chloride, and washed with a saturated aqueous solution of sodium chloride. The product was dried over magnesium sulfate, and then concentrated under reduced pressure to obtain 8g of N-(2-hydroxybenzyl)-L-alanine lauryl ester.
Reaction SMILES: [F:1][C:2]1[C:7]2[NH:8]C(=O)O[C:11](=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O1CCOCC1.C(=O)=O.[NH3:23]>>[NH2:8][C:7]1[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=1[C:11]([NH2:23])=[O:12]
Reactant: O=c1[nH]c2c(F)cccc2c(=O)o1
Reactant: N
Agent: O=C=O
Solvent: C1COCCO1
Product: NC(=O)c1cccc(F)c1N

Procedure:
A mixture of 8-Fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (2.00 g, 0.0110 mol) in 1,4-Dioxane (25 mL, 0.32 mol) was treated with ammonia (20 mL, 0.5 M in dioxane) and warmed to 60° C. for 2 h (dry ice cold finger). Additional ammonia (20 mL) was added and after 1 h at 60° C., solvent was evaporated to afford title compound.
Reaction SMILES: C(O[C:4]1[C:5](=[O:14])[C:6](=[O:13])[C:7]=1[NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])C.[Cl:15][C:16]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([CH3:25])[C:17]=1[CH2:18][NH2:19]>C(O)C>[C:9]([NH:8][C:7]1[C:6](=[O:13])[C:5](=[O:14])[C:4]=1[NH:19][CH2:18][C:17]1[C:20]([CH3:25])=[CH:21][C:22]([Cl:24])=[CH:23][C:16]=1[Cl:15])([CH3:10])([CH3:11])[CH3:12]
Reactant: CCOc1c(NC(C)(C)C)c(=O)c1=O
Reactant: Cc1cc(Cl)cc(Cl)c1CN
Solvent: CCO
Product: Cc1cc(Cl)cc(Cl)c1CNc1c(NC(C)(C)C)c(=O)c1=O
Yield: 89 %

Procedure:
This compound was prepared in a procedure similar to the one described in Example 4. From 3-ethoxy-4-tert-butylamino-cyclobut-3-ene-1,2-dione (0.22 g, 1.1 mmol) and 2,4-dichloro-6-methylbenzylamine (0.22 g, 1.2 mmol, containing approximately 5% of a compound which is regioisomeric with respect to the substitution on the aryl ring) in absolute ethanol (5.5 mL) there was obtained 0.34 g (89%) of 3-tert-butylamino-4-(2,4-dichloro-6-methyl-benzylamino)-cyclobut-3-ene-1,2-dione as a white solid, which contains approximately 5% of a compound which is regioisomeric with respect to substitution on the aryl ring: mp 264°-268° C.; 1H NMR (DMSO-d6) δ 7.54 (d, 1H), 7.46 (s, 1H), 7.43 (br t, 1H), 7.39 (d, 1H), 4.89 (d, 2H), 4.72 (d, minor isomer), 2.40 (s, 3H), 2.31 (s, minor isomer), 1.34 (s, 9H) ppm. IR (KBr): 3200, 2950, 1800, 1650 cm-1 ; MS (m/z) 340/342/344 (M+).