Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][N:17](C(OCC2C=CC=CC=2)=O)[CH2:16][CH2:15]3)[CH2:7]1)(=[O:3])[CH3:2]>CO.C1COCC1.[OH-].[OH-].[Pd+2]>[CH2:18]1[C:19]2[C:14](=[CH:13][C:12]([N:8]3[CH2:7][C@H:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])[O:10][C:9]3=[O:11])=[CH:21][CH:20]=2)[CH2:15][CH2:16][NH:17]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CCN(C(=O)OCc2ccccc2)C3)C(=O)O1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CCNC3)C(=O)O1
Reaction time: 1 h

Procedure:
A mixture of phenylmethyl 6-[(5S)-5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Step 5, 1.71 g, 4.04 mmol) and 20% Pd(OH)2/C (567 mg) in MeOH (40 mL) in a Parr bottle is shaken under 20 psi H2 for 1 hr. The resulting slurry is then diluted with MeOH (100 mL) and THF (100 mL), filtered through Celite to remove the catalyst, and concentrated under reduced pressure to give a quantitative yield of the title compound as an amorphous solid which is used without further purification. 1H NMR (400 MHz, CD3OD) δ 7.36 (bd, 1H), 7.31 (s, 1H), 7.08 (d, 1H), 4.78 (m, 1H), 4.14 (t, 1H), 3.98 (s, 2H), 3.82 (dd, 1H), 3.57 (m, 2H), 3.13 (m, 2H), 2.88 (m, 2H), 1.98 (s, 3H); MS (ESI+) for C15H19N3O3 m/z 290 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10]Br)[C:5]([CH2:8]Br)=[N:6][CH:7]=1.[C:12]([NH2:31])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:10][N:31]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:8][C:5]2=[N:6][CH:7]=1
Reactant: BrCc1cc(Br)cnc1CBr
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Brc1cnc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
To a solution of 5-bromo-2,3-bis(bromomethyl)pyridine (Step 2 above, 5.6 g, approximately 16.3 mmol) in DMF (40 mL) was added trityl amine (5.3 g, 20.6 mmol) followed by diisopropylethylamine (8.6 mL, 49 mmol). The resulting solution was warmed to 60° C. and stirred at this temperature for 2.5 hr. The mixture was then concentrated under reduced pressure and the residue was purified by silica chromatography (50 g silica, eluted with 10-100% dichloromethane in hexanes) to give the title compound as a foam.
Reaction SMILES: [CH2:1]([CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:12](O)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(Cl)(=O)C([Cl:30])=O.Cl>C1COCC1.CN(C)C=O>[CH2:1]([CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:12]([Cl:30])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCCCC(CCCCCCCCCC)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCC(CCCCCCCCCC)C(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 100 mL round bottom flask is charged with 1.15 g (3.13 mmol) of 2-decyltetradecanoic acid (available as ISOCARB 24 from Sasol America), which is dissolved in 20 mL of THF with stirring under inert atmosphere. The solution is cooled to 0° C. and 1.1 mL (12.6 mmol) oxalyl chloride is added dropwise. Upon addition of N,N-dimethylformamide (DMF, 2-3 drops as catalyst), gaseous HCl is observed to evolve from the reaction mixture, after which the mixture is allowed to slowly warm to room temperature. Gas evolution ceases after 30 min, and the reaction is allowed to stir for an additional 30 min before removing solvent by rotary evaporation. The crude acid chloride is redissolved in 10 mL of fresh dry THF and then added dropwise and slowly to the appropriate amine solution, as described below.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=1[CH3:10])=[S:3].Br[CH:16](C)[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O.[CH3:26]N(C=O)C>>[CH3:14][O:13][C:11]([C:7]1[S:8][C:9]([CH3:10])=[C:5]([NH:4][C:2]2[S:3][CH:16]=[C:17]([C:19]3[CH:20]=[C:21]([CH3:26])[CH:22]=[CH:23][CH:24]=3)[N:1]=2)[CH:6]=1)=[S:12]
Reactant: COC(=S)c1cc(NC(N)=S)c(C)s1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: CN(C)C=O
Product: COC(=S)c1cc(Nc2nc(-c3cccc(C)c3)cs2)c(C)s1
Yield: 100 %

Procedure:
Methyl-4-[(5-methyl-4-phenyl(1,3-thiazol-2-yl)amino]-5-methylthiothiophene-2-carboxylate: Using a procedure similar to Example 204, step (a), 51 mg (0.19 mmol) of methyl 4-[(aminothioxomethyl)amino]-5-methylthiothiophene-2-carboxylate was allowed to react with 41.4 mg (0.38 mmol) of 2-bromopropiophenone (Aldrich Chemical Co., Milwaukee, Wis.) in 2 mL of DMF for 4 h. Concentration in vacuo of the reaction mixture afforded 73 mg (100%) of methyl-4-[(5-methyl-4-phenyl(1,3-thiazol-2-yl))amino]-5-methylthiothiophene-2-carboxylate. Mass spectrum (ESI, m/z): Calcd. for C17H16N2O2S3, 377.05 (M+H), found 377.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=2)[N:10]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:55][C:56]([F:68])([F:67])[C:57]1[CH:62]=[CH:61][C:60]([C:63]2([NH2:66])[CH2:65][CH2:64]2)=[CH:59][CH:58]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([NH:66][C:63]3([C:60]4[CH:61]=[CH:62][C:57]([C:56]([F:55])([F:67])[F:68])=[CH:58][CH:59]=4)[CH2:65][CH2:64]3)=[O:21])=[CH:22][CH:23]=2)[N:10]=1
Reactant: O=C(O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Reactant: NC1(c2ccc(C(F)(F)F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NC1(c2ccc(C(F)(F)F)cc2)CC1)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Yield: 20 %

Procedure:
The title compound was prepared according to the procedure described in Example-17 by using 4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoic acid (Intermediate-9, 0.100 g, 0.290 mmol), THF (5 mL), di-isopropyl ethyl amine (2.0 mL), TBTU (0.193 g, 0.590 mmol) and 1-[4-(trifluoromethyl)phenyl]cyclopropanamine (Intermediate-13, 0.073 g, 0.350 mmol) to afford 0.030 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.35 (s, 4H), 7.36 (d, J=7.8 Hz, 2H), 7.46-7.70 (m, 5H), 8.01 (s, 4H), 9.30 (s, 1H), 12-13 (br s, 1H); MS (m/z): 515.23 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][CH2:17][C:18]1([CH2:23][OH:24])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[OH:24][CH2:23][C:18]1([CH2:17][NH:16][C:8]([C:5]2[CH:4]=[C:3]([O:11][CH2:12][CH:13]3[CH2:15][CH2:14]3)[C:2]([Cl:1])=[CH:7][N:6]=2)=[O:10])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Reactant: NCC1(CO)CCCC1
Product: O=C(NCC1(CO)CCCC1)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 12d, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and 1-(aminomethyl)-cyclopentanemethanol (CAN 2239-31-8) as starting materials and isolated (35 mg, quant.) as colorless oil; LC-MS (UV peak area, m/z) 100%, 339.1470 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([N:12]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:13][C@H:14]([OH:23])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][OH:11])=[CH:4][CH:3]=1.[C:31]1([N:37]=[C:38]=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl.N>[CH2:24]([N:12]([C@H:9]([CH2:10][OH:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:38]([NH:37][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:39])=[CH:3][CH:4]=1)[CH2:13][C@H:14]([OH:23])[CH2:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccccc2)cc1
Agent: N
Solvent: ClCCl
Product: O=C(Nc1ccccc1)Nc1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To an ice-cooled solution of (2S)-3-(4-aminophenyl)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-1-propanol (76 mg) in dichloromethane (0.8 ml) was added dropwise phenyl isocyanate (0.022 ml), and the mixture was stirred at the same temperature for 40 minutes. One drop of 28% ammonia solution was added to the mixture, the mixture was concentrated, and the residue was purified by column chromatography (silica gel, chloroform/methanol) to give N-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]-amino]-3-hydroxypropyl]phenyl]-N′-phenylurea (89 mg) as a white amorphous powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]2[N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:15]=[CH:16][C:3]=12.Cl.C([OH:26])C>>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[F:13])[NH:5][C:4]1[N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:15]=[CH:16][C:3]=1[C:2]2=[O:26]
Reactant: CCO
Reactant: Fc1cc2nc3c(cnn3-c3ccccn3)c(Cl)c2cc1F
Agent: Cl
Product: O=c1c2cc(F)c(F)cc2[nH]c2c1cnn2-c1ccccn1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a solution of 4-chloro-6,7-difluoro-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (3.17 g, 10.0 mmol) in ethanol (160 mL) was added 6 N hydrochloric acid (8 mL, 48.0 mmol), and the mixture was heated under reflux for 6 hours. The solution was allowed to cool to room temperature, and the resulting crystals were collected by filtration. The crystals were washed with ethanol, air dried, and subsequently recrystallized from ethanol to give the title compound (2.47 g, 83% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C@@H:14]2[CH2:16][C@H:15]2[C:17]([N:19]2[CH2:24][CH2:23][CH:22]([CH2:25][NH2:26])[CH2:21][CH2:20]2)=[O:18])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:27][C:28]1[CH:29]=[N:30][C:31](Cl)=[N:32][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Br:27][C:28]1[CH:29]=[N:30][C:31]([NH:26][CH2:25][CH:22]2[CH2:21][CH2:20][N:19]([C:17]([C@@H:15]3[CH2:16][C@H:14]3[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[O:18])[CH2:24][CH2:23]2)=[N:32][CH:33]=1
Reactant: Clc1ncc(Br)cn1
Reactant: NCC1CCN(C(=O)[C@@H]2C[C@H]2c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C([C@@H]1C[C@H]1c1ccccc1)N1CCC(CNc2ncc(Br)cn2)CC1
Temperature: 100 °C

Procedure:
A mixture of (1-{[(1R,2R)-2-phenylcyclopropyl]carbonyl}piperidin-4-yl)methylamine trifluoroacetate salt (1.00 g, 2.69 mmol), 5-bromo-2-chloro-pyrimidine ([32779-36-5 ], 0.519 g, 2.69 mmol) and cesium carbonate (1.75 g, 5.37 mmol) in DMF (7 mL) was heated at 100° C. for 1.5 h. The reaction mixture was cooled to RT, diluted with ethyl acetate (200 mL), washed with water (5×20 mL), and brine (10 mL), then dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel 60, eluting with 10:1–20:89–70 CH2Cl2:2-propanol:hexane to give the title compound. (0.31 g, 28.1%). M.S. (M+1): 416.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]([O:14][CH3:15])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.[Cu][C:17]#[N:18]>CN1CCCC1=O>[C:17]([C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]([O:14][CH3:15])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1)#[N:18]
Reactant: N#C[Cu]
Reactant: COC(=O)N1CCc2ccc(Br)cc2C1
Solvent: CN1CCCC1=O
Product: COC(=O)N1CCc2ccc(C#N)cc2C1
Yield: 82.9 %

Procedure:
A mixture of 7-bromo-2-methoxycarbonyl-1,2,3,4-tetrahydroisoquinoline (12.0 g, 0.044 mol), copper (I) cyanide (8.7 g, 0.097 mol) and N-methyl-2-pyrrolidinone (100 ml) was heated at reflux for 4 h, cooled, then partitioned between dilute aqueous ammonia (500 ml) and ethyl acetate (300 ml). Organic phase was washed with dilute aqueous ammonia (100 ml), water (4×100 ml), then dried (Na2SO4) and evaporated in vacuo to give the title compound as an oil (7.89 g, 83%).
Reaction SMILES: [CH:1]1([C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)O)[CH2:3][CH2:2]1.[BrH:20].O.[OH-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:20][CH2:3][CH2:2][CH:1]=[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: COc1cccc(C(O)(c2cccnc2)C2CC2)c1
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc(C(=CCCBr)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of the product of step 1 (470 mg) in acetic acid (5 ml) was added 48% aqueous HBr (3 ml) at 10° C. The reaction mixture was warmed to room temperature, and stirred for 12 hours. Water and ethyl acetate were added to the reaction mixture and neutralized with dilute NaOH solution. The organic layer was separated and washed with saturated aqueous sodium chloride, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1:4) to give 4-bromo-1-(3-methoxyphenyl)-1-(3-pyridinyl)-1-butene (560 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[N:4][O:5][C:6]=1[N:7]([C:16]([O:18]CC(Cl)(Cl)Cl)=O)C(OCC(Cl)(Cl)Cl)=O.[C:25]1([C:31]2[N:32]=[C:33]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[S:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[Cl:1][C:2]1[C:3]([CH3:24])=[N:4][O:5][C:6]=1[NH:7][C:16]([N:39]1[CH2:40][CH2:41][N:36]([C:33]2[S:34][CH:35]=[C:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:32]=2)[CH2:37][CH2:38]1)=[O:18]
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: Cc1noc(N(C(=O)OCC(Cl)(Cl)Cl)C(=O)OCC(Cl)(Cl)Cl)c1Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4ccccc4)cs3)CC2)c1Cl

Procedure:
A solution of bis(2,2,2-trichloroethyl) (4-chloro-3-methylisoxazol-5-yl)imidodicarbonate (200 mg, 0.418 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (204 mg, 0.836 mmol), diisopropylethylamine (0.144 ml, 0.836 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (123 mg, 73.2%) as a solid.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]#C)[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].[CH3:15]N(C)C=O>>[CH3:1][N:2]1[C:7]2[CH:15]=[C:9]([CH3:10])[NH:8][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14]
Reactant: CN(C)C=O
Reactant: C#CCNc1cn(C)c(=O)n(C)c1=O
Product: Cc1cc2c([nH]1)c(=O)n(C)c(=O)n2C

Procedure:
A solution of Step 2 intermediate (500 mg, 2.587 mmol) in dry N,N-dimethylformamide (20 mL) was refluxed for 40 h under nitrogen atmosphere. The excess of solvent was evaporated and the residue obtained was purified by silica gel column chromatography by using 5% methanol in chloroform to obtain 200 mg of the product as a yellow solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 2.26 (s, 3H), 3.21 (s, 3H), 3.33 (s, 3H), 5.91 (s, 1H), 11.84 (br s, 1H); ESI-MS (m/z) 194.28 (M+H)+.
Reaction SMILES: C[C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])O1.[O:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[CH2:22]C(Cl)=O>>[O:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[CH2:22][C:4](=[O:9])[CH2:5][C:6]([O:7][CH2:2][CH3:10])=[O:8]
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Reactant: CC1(C)OC(=O)CC(=O)O1
Product: CCOC(=O)CC(=O)CN1C(=O)c2ccccc2C1=O

Procedure:
The title compound was prepared in a manner analogous to Intermediate 123 starting from 2,2-dimethyl-1,3-dioxane-4,6-dione and (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH:14]=[CH:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]3)[C:9](=[O:23])[NH:8][C:5]2=[CH:6][CH:7]=1>C1COCC1.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:11]3)[C:9](=[O:23])[NH:8][C:5]2=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C=CCC2(C1)C(=O)Nc1ccc(F)cc12
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)Nc1ccc(F)cc12
Yield: 93.6 %

Procedure:
A solution of tert-butyl 5-fluoro-2-oxo-2′,4′-dihydro-1′H-spiro[indoline-3,3′-pyridine]-1′-carboxylate (4.0 g, 13 mmol) in THF (50 mL) was hydrogenated at 50 psi in the presence of 5% Pd/C (1.3 g) overnight. The mixture was filtered. Evaporation of the solvent gave tert-butyl 5-fluoro-2-oxospiro[indoline-3,3′-piperidine]-1′-carboxylate (3.9 g, 97%) as an oil. LCMS (APCI+) m/z 221 [M+H−Boc]+; Rt=3.21 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](Cl)(Cl)Cl)=[CH:4][CH:3]=1.Cl.[NH2:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[OH:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:23][C:15]3[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:14]=3[N:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C(Cl)(Cl)Cl)cc1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Agent: Cl
Product: O=[N+]([O-])c1ccc2oc(-c3ccc(Cl)cc3)nc2c1

Procedure:
Compound XV was prepared as in Example 12 at 180°-200° C from p-chlorobenzotrichloride and 2-amino-4-nitrophenol hydrochloride, and purified through a preheated Al2O3 column: 3.4 g of raw product melting at 205°-210° C (12% of the theory). After recrystallization from benzene: melting point 217°-218° C.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:4]=2[CH2:3]1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(Cl)(Cl)Cl>[CH3:18][C:16]1[CH:15]=[CH:14][C:5]2[O:6][C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=3[CH:2]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[CH2:3][C:4]=2[CH:17]=1
Reactant: Cc1ccc2c(c1)CC(Cl)c1cc(C)ccc1O2
Reactant: CN1CCNCC1
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(c1)CC(N1CCN(C)CC1)c1cc(C)ccc1O2

Procedure:
0.8 G. of 10-chloro-10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin and 0.58 g. of 1-methyl-piperazine are dissolved in 4 ml. of chloroform and heated at reflux for 21 hours. Then, the chloroform is evaporated in vacuo. The residue is partitioned between benzene and aqueous sodium carbonate solution. The benzene solution is extracted with dilute hydrochloric acid. The hydrochloric acid extract is made alkaline with sodium carbonate and extracted with benzene. Thereafter, the benzene extract is washed several times with water, dried over sodium sulfate, evaporated in vacuo, and there is obtained 1-[10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-4-methyl-piperazine, the dihydrochloride of which melts at 197°-198° C. (with decomposition).
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9].[C:12]([O-:15])(=[O:14])[CH3:13].[Na+].P([O-])([O-])([O-])=O>CN(C)C=O>[C:12]([O:15][CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9])(=[O:14])[CH3:13]
Reactant: COC(=O)c1sccc1CBr
Reactant: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sccc1COC(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 79 %

Procedure:
To a solution of methyl 3-(bromomethyl)-2-thenoate (described in Tetrahedron Lett., 22, 5097-5100, (1981); 6.80 g, 28.9 mmol) in N,N-dimethylformamide (80 ml) was added sodium acetate (7.12 g, 86.8 mmol). The mixture was stirred at room temperature for 24 hours, and then stirred at 40° C. for 1 hour. A phosphate buffer solution (pH 7, 100 ml) was added to the reaction mixture, and the product was extracted with ethyl acetate. The organic layer was washed three times with water, and the solvent was distilled off under reduced pressure. The residue was subjected to chromatography on a silica gel (150 g) column (eluent; ethyl acetate:hexane=1:10˜1:1) to afford the title compound (4.89 g, 79% yield) as a colorless solid (mp. 42-43° C.).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[S:52][C:18]2[N:19]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]4[C:45]([C:50]#[N:51])=[CH:46][CH:47]=[CH:48][CH:49]=4)=[CH:40][CH:39]=3)[C:20](=[O:36])[N:21]([CH2:24][C:25]3([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[CH2:27][CH2:26]3)[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]>C(Cl)(Cl)Cl>[CH2:13]([C:15]1[S:52][C:18]2[N:19]([CH2:37][C:38]3[CH:39]=[CH:40][C:41]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=4[C:50]4[NH:3][C:4](=[O:7])[O:5][N:51]=4)=[CH:42][CH:43]=3)[C:20](=[O:36])[N:21]([CH2:24][C:25]3([C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)[CH2:27][CH2:26]3)[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCc1cc2c(=O)n(CC3(c4ccc(OC)cc4)CC3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: CCc1cc2c(=O)n(CC3(c4ccc(OC)cc4)CC3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 38.1 %

Procedure:
A mixture of hydroxylammonium chloride (1.44 g), sodium hydrogencarbonate (2.2 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[6-ethyl-3-{[1-(4-methoxyphenyl)cyclopropyl]methyl}-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.71 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in methylene chloride (20 mL), N,N′-carbonyldiimidazole (0.21 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.3 g, 38%).
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([C:14]2[O:18][N:17]=[C:16]([Br:19])[CH:15]=2)[O:7][C@H:6]1[N:20]1[CH:28]=[N:27][C:26]2[C:21]1=[N:22][CH:23]=[N:24][C:25]=2[NH:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[F:37])(=O)C.C(N)(C)(C)C>CO>[Br:19][C:16]1[CH:15]=[C:14]([C@@H:8]2[C@@H:9]([OH:10])[C@@H:5]([OH:4])[C@H:6]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][CH:23]=[N:24][C:25]=4[NH:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[F:37])[O:7]2)[O:18][N:17]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](c2cc(Br)no2)O[C@H]1n1cnc2c(Nc3ccc(Cl)cc3F)ncnc21
Solvent: CO
Solvent: CC(C)(C)N
Product: O[C@@H]1[C@H](O)[C@@H](c2cc(Br)no2)O[C@H]1n1cnc2c(Nc3ccc(Cl)cc3F)ncnc21
Yield: 110.9 %

Procedure:
(2R,3R,4R,5S)-4-(acetyloxy)-5-(3-bromoisoxazol-5-yl)-2-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]tetrahydrofuran-3-yl acetate (16.8 mg) was treated with t-butylamine (0.08 ml) in methanol (0.8 ml) at 0° C. for 1.5 h, and the mixture was evaporated to dryness to give the title compound (16 mg).