Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][N:2]=1.[Br:7][C:8]1[C:9]([F:16])=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12].[Li]N1C(C)(C)CCCC1(C)C.Cl.CCO.C1COCC1.C([O-])(O)=O.[Na+]>C1COCC1>[Br:7][C:8]1[C:9]([F:16])=[C:10]([CH:11]([C:6]2[N:1]=[N:2][CH:3]=[CH:4][CH:5]=2)[OH:12])[CH:13]=[CH:14][CH:15]=1
Reactant: c1ccnnc1
Reactant: O=Cc1cccc(Br)c1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Li]N1C(C)(C)CCCC1(C)C
Solvent: C1CCOC1
Solvent: CCO
Product: OC(c1cccnn1)c1cccc(Br)c1F
Temperature: -78 °C
Reaction time: 4 h
Yield: 91.1 %

Procedure:
A solution of pyridazine (0.078 mL, 1.075 mmol) in THF (2.0 mL) and a solution of 3-bromo-2-fluorobenzaldehyde (0.200 g, 0.985 mmol) in THF (2.0 mL) were added simultaneously to a cold solution of LTMP at −78° C. The mixture was stirred at −78° C. for 4 h, followed by the addition of excess of HCl/EtOH/THF. The solution was allowed to warm to room temperature, then treated with a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (3×). The organic phases were combined, dried over Na2SO4, filtered, and concentrated to afford the title compound (0.254 g, 0.897 mmol, 100% yield) as a yellow residue.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17](I)=[N:18][C:19]=3[Cl:23])[O:7][C@@H:6]1[CH2:25][O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2].[Cu](C#N)[C:31]#[N:32]>CN(C)C=O>[C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:31]#[N:32])=[N:18][C:19]=3[Cl:23])[O:7][C@@H:6]1[CH2:25][O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 115 °C
Yield: 54 %

Procedure:
A mixture of (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-chloro-2-iodo-9H-purin-9-yl)tetrahydro-3-furanyl acetate (J. Med. Chem., 1992, 35, 248) (0.5 g, 0.93 mmol) and copper (II) cyanide (0.11 g, 1.23 mmol) in N,N-dimethylformamide was heated at 115° C. for 90 minutes. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with dichloromethane:ethyl acetate (4:1 by volume) to give a product which was then azeotroped sequentially with dichloromethane and diethyl ether to afford the title compound as a solid (0.22 g).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]([F:42])([F:41])[O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](O)=[O:39])=[CH:33][CH:32]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C.CCCCCC.CCOC(C)=O>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]([C:38](=[O:39])[CH2:37][C:34]2[CH:35]=[CH:36][C:31]([O:30][C:29]([F:41])([F:28])[F:42])=[CH:32][CH:33]=2)[CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Reactant: CCCCOC(=O)c1ccc2c(c1)CCC2N[C@H]1CC[C@H](C(C)(C)C)CC1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCCCOC(=O)c1ccc2c(c1)CCC2N(C(=O)Cc1ccc(OC(F)(F)F)cc1)[C@H]1CC[C@H](C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of butyl 1-[(trans-4-tert-butylcyclohexyl)amino]indane-5-carboxylate (0.30 g, 0.81 mmol) in DMF/CH2CL2 (1:1, 10 mL) was added [4-(trifluoromethoxy)phenyl]acetic acid (0.21 g, 0.97 mmol), EDC (0.20 g, 1.05 mmol), HOBt (0.11 g, 0.81 mmol) and DIEA (0.45 mL, 2.43 mmol). After stirring at room temperature for 18 h, the reaction mixture was poured into saturated aqueous NaHCO3 (20 mL) and extracted with EtOAc (30 mL). The organic layer was washed with brine (2×10 mL), dried over Na2SO4, filtered and concentrated. Chromatography (10% to 20% EtOAc in Hexane) gave 0.39 g (84% yield) of butyl 1-((trans-4-tert-butylcyclohexyl){[4-(trifluoromethoxy)phenyl]acetyl}amino)indane-5-carboxylate. HPLC/MS: m/z=574.2 (M+1), Rt=3.19 min. The racemic compound was then resolved on chiral HPLC (ChiralPak AD column, 5% EtOH in n-Heptane) to give enantiomer A (+) (Rt=8.65 min) and B (−) (Rt=12.0 min).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:12]([O:11][C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7][CH:6]=1)=[O:10])[CH3:13]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCNc1ccc(CC(=O)OCC)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 74.4 %

Procedure:
A mixture of ethyl 4-aminophenylacetate (2.0 g, 11 mmols), ethyl 4-bromobutanoate (8.7 g, 45 mmols), potassium carbonate (2.3 g, 17 mmols) and N,N-dimethylformamide (50 ml) was stirred at 60° C. for 24 hours. The reaction mixture was cooled, then poured into water, and extracted with ethyl acetate. The extract was washed with water and brine, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an oil of ethyl 4-[4-(ethoxycarbonylmethyl)phenyl]aminobutanoate (2.4 g, 74%).
Reaction SMILES: [CH2:1]([N:4]1[S:9](=[O:11])(=[O:10])[NH:8][C:7]([O:12][CH2:13][CH3:14])=[N:6][C:5]1=[O:15])CC.[Na]>>[CH3:1][N:4]1[S:9](=[O:11])(=[O:10])[NH:8][C:7]([O:12][CH2:13][CH3:14])=[N:6][C:5]1=[O:15]
Reactant: CCCN1C(=O)N=C(OCC)NS1(=O)=O
Agent: [Na]
Product: CCOC1=NC(=O)N(C)S(=O)(=O)N1

Procedure:
6-n-propyl-3-ethoxy-5,6-dihydro-1,2,4,6-thiatriazin-5-one-1,1-dioxide, sodium salt
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:9][C:8]2([CH3:18])[CH3:17])([O-:3])=[O:2].[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]([C:19](=[O:21])[CH3:20])[C:8]2([CH3:18])[CH3:17])([O-:3])=[O:2]
Reactant: CC1(C)Nc2ccccc2-c2c([N+](=O)[O-])cnn21
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1c2ccccc2-c2c([N+](=O)[O-])cnn2C1(C)C
Yield: 69 %

Procedure:
1-Nitro-5,5-dimethyl-5,6-dihydropyrazolo[1,5-c]quinazoline is treated with acetic anhydride to give 1-nitro-5,5-dimethyl-6-acetyl-5,6-dihydropyrazolo[1,5-c]quinazoline with a yield of 69%. M.p.: 182°-183° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([NH:13][CH3:14])=[CH:6][C:5]=1[N:15]1[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]1>[Ni].CO>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH:13][CH3:14])=[CH:6][C:5]=1[N:15]1[CH2:16][CH2:17][CH:18]([C:21]([F:22])([F:24])[F:23])[CH2:19][CH2:20]1
Reactant: CNc1cc(N2CCC(C(F)(F)F)CC2)c(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CNc1cc(N2CCC(C(F)(F)F)CC2)c(C(=O)OC)cc1N
Reaction time: 5 h

Procedure:
A mixture of methyl-2-[4-trifluoromethyl-piperidinyl]-4-methylamino-5-nitro-benzoate (1.80 g, 4.19 mmol), Ra—Ni (200 mg) and MeOH (100 mL) is stirred for 5 h under 3 bar H2-atmosphere. The mixture is filtered, and the filtrate is concentrated.
Reaction SMILES: [CH3:1][S:2]([O-:4])=[O:3].[Na+].CS(O[CH2:11][C:12]([CH3:25])([CH3:24])[CH2:13][O:14][C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([Br:22])=[C:17]([CH3:23])[CH:16]=1)(=O)=O>CN1CCCC1=O.C(OCC)C>[Br:22][C:18]1[C:17]([CH3:23])=[CH:16][C:15]([O:14][CH2:13][C:12]([CH3:25])([CH3:24])[CH2:11][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:20][C:19]=1[CH3:21]
Reactant: Cc1cc(OCC(C)(C)COS(C)(=O)=O)cc(C)c1Br
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: Cc1cc(OCC(C)(C)CS(C)(=O)=O)cc(C)c1Br
Temperature: 180 °C

Procedure:
In a microwave vial sodium methanesulfinate (720 mg) is added to a solution of 3-(4-bromo-3,5-dimethylphenoxy)-2,2-dimethylpropyl methanesulfonate (271 mg) in N-methyl-2-pyrrolidinon (NMP) (8 mL). The mixture is heated to 180° C. for 30 minutes. Then the mixture is diluted with diethylether, washed with water and brine and dried (MgSO4). The solvent is evaporated and the residue is purified by HPLC on reversed phase to give the title compound. Yield: 32 mg; LC (method 8): tR=0.47 min; Mass spectrum (ESI+): m/z=349 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18](Cl)=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[NH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][NH2:30]>C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>[C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([NH:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][NH:30][C:18](=[O:19])[CH2:17][CH2:16][C:7]2[CH:8]=[C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[C:10]([OH:11])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=2)=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(CCC(=O)Cl)cc(C(C)(C)C)c1O
Reactant: NCCNCCNCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)c1cc(CCC(=O)NCCNCCNCCNC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Reaction time: 2 h

Procedure:
0.02 moles β-(3,5-di-t-butyl-4-hydroxy phenyl) propionyl chloride in 25 ml methylene chloride was added to a stirred mixture containing a solution of 0.02 mol triethylene tetramine in 125 ml methylene chloride and 25 ml 10% sodium carbonate. The mixture was stirred for two hours and then separated. The methylene chloride layer was washed with 5% sodium carbonate solution and then with water, subsequently dried over anhydrous magnesium sulfate and finally evaporated to dryness. A resinous material of 1,8-bis[β-(3,5-di-t-butyl-4-hydroxy phenyl) propionamido]-3,6-diazaoctane resulted which was pulverized to give a light brown solid having a melting point of 80°-110° C.
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:17]([CH2:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:16]([CH2:25][O:26][CH2:27][CH3:28])=[N:15][C:9]=3[C:10]([NH2:14])=[N:11][C:12]=2[CH:13]=1.C(N(CC)CC)C.[N:36]1([C:42](Cl)=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>C(Cl)(Cl)Cl>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:17]([CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([C:42]([N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[O:43])[CH2:21][CH2:20]4)[C:16]([CH2:25][O:26][CH2:27][CH3:28])=[N:15][C:9]=3[C:10]([NH2:14])=[N:11][C:12]=2[CH:13]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CC1CCN(C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
A solution of 7-bromo-2-ethoxymethyl-1-(piperidin-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine dihydrochloride (4.0 g, 8.1 mmol) and triethylamine (5.67 mL, 40.7 mmol) in chloroform (300 mL) was cooled to 0° C., and 4-morpholinecarbonyl chloride (0.95 mL, 8.1 mmol) was added dropwise. The reaction was allowed to warm to ambient temperature and stirred overnight before it was diluted with chloroform (200 mL); washed sequentially with water (200 mL), 2 M sodium carbonate (2×200 mL), water (200 mL), and brine (200 mL); and concentrated under reduced pressure. The residue was triturated with ethyl acetate and subsequently recrystallized from acetonitrile to provide 3.64 g of 7-bromo-2-ethoxymethyl-1-{[1-(morpholin-4-ylcarbonyl)piperidin-4-yl]methyl}-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 198-199° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C1(OC)C=CC=CC=1.[F:16][C:17]1[CH:18]=[CH:19][C:20]2[NH:26][C:25]3=[CH:27][S:28][CH:29]=[C:24]3[NH:23][C:22](=O)[C:21]=2[CH:31]=1>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[F:16][C:17]1[CH:18]=[CH:19][C:20]2[NH:26][C:25]3=[CH:27][S:28][CH:29]=[C:24]3[N:23]=[C:22]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[C:21]=2[CH:31]=1
Reactant: CN1CCNCC1
Reactant: O=C1Nc2cscc2Nc2ccc(F)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: COc1ccccc1
Product: CN1CCN(C2=Nc3cscc3Nc3ccc(F)cc32)CC1

Procedure:
To a stirred mixture of 14.0 g. of N-methylpiperazine, 3.4 ml. of titanium tetrachloride and 6 ml. of anisole in 60 ml. of toluene is added a mixture of 6.7 g. of N-methylpiperazine and 5.6 g. of 7-fluoro-4H-thieno[3,4-b][1,4]benzodiazepin-9(10H)-one in 6 ml. of toluene. The mixture is treated as described in Example 1, giving the desired product as a tan solid, m.p. 224°-227° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([CH:20](I)[CH3:21])[C:3]=1[OH:23].[NH:24]([CH3:26])[CH3:25]>C(Cl)Cl.CCO>[CH3:25][N:24]([CH3:26])[CH:20]([C:4]1[C:3]([OH:23])=[C:2]([F:1])[CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH3:21]
Reactant: CNC
Reactant: CC(I)c1c(O)c(F)cc2c1ccn2S(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: CCO
Product: CC(c1c(O)c(F)cc2c1ccn2S(=O)(=O)c1ccccc1)N(C)C
Yield: 62 %

Procedure:
A solution of crude 6-fluoro-4-(1-iodoethyl)-1-(phenylsulfonyl)-1H-indol-5-ol (ca. 44.5 μmol; Intermediate 104) in CH2Cl2 (1 mL) was treated with Me2NH (159 μL of a 5.6 M solution in EtOH, 890 μmol) at rt for 1.5 h. The reaction mixture was concentrated in vacuo, the obtained residue taken up with MeOH and purified by prep. HPLC (25-55% MeCN, 50 mM NH4HCO3) to yield the title compound as an off-white solid (10.0 mg, 62% over two steps). MS (ESI+) for C18H19FN2O3S m/z 363 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[C:11]2[CH:12]=[C:13]([N:16]3[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]([CH3:27])[C:17]3=[O:28])[CH:14]=[CH:15][C:10]=2[S:9][N:8]=1.[Br:29]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:29][CH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[C:11]2[CH:12]=[C:13]([N:16]3[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]([CH3:27])[C:17]3=[O:28])[CH:14]=[CH:15][C:10]=2[S:9][N:8]=1
Reactant: Cc1ccsc1-c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(-c4sccc4CBr)c3c2)c1=O
Yield: 68.2 %

Procedure:
To a mixture of 3-[3-[3-(methyl)-2-thienyl]-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)uracil(0.420 g, 0.993 mmol) and carbon tetrachloride is added N-bromosuccinimide (0.200 g, 1.12 mmol) and benzoyl peroxide (10.0 mg). The resultant mixture is stirred overnight at reflux, cooled and filtered. The filtrate is concentrated in vacuo and the residue partitioned between water and methylene chloride. The organic layer is washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel with methylene chloride-diethyl ether to afford a pale yellow oil, which is crystallized in diethyl ether to afford the title compound as a cream-colored solid (0.340 g, 68.1%, mp 169° C.(dec)) which is identified by NMR spectral analysis.
Reaction SMILES: C[S:2]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[O:15][CH2:14][CH2:13][CH2:12][O:11]2)=[CH:6][CH:5]=1)=O.N1C(C)=CC=CC=1C.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(#N)C>[O:11]1[CH2:12][CH2:13][CH2:14][O:15][CH:10]1[C:7]1[CH:8]=[CH:9][C:4]([SH:2])=[CH:5][CH:6]=1
Reactant: CS(=O)c1ccc(C2OCCCO2)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: Sc1ccc(C2OCCCO2)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
2-(4-Methanesulfinyl-phenyl)-[1,3]dioxane (400 mg, 1.76 mmol) is dissolved in acetonitrile (20 mL). 2,6-Lutidine (0.64 mL, 5.5 mmol) is added and the solution is cooled to −10° C. TFAA (0.75 mL, 5.3 mmol) is added dropwise via syringe. The reaction is stirred for 1 h at −10 to 0° C. All volatile materials are evaporated while keeping the reaction mixture at 0° C. A mixture of MeOH and triethyl amine (50 mL, 1:1 v/v) that has been pre-cooled to 0° C. is added. The resulting mixture is allowed to warm and stir at room temperature for 30 min. All volatile materials are evaporated. The obtained residue is dissolved in diethyl ether and washed with saturated aqueous NH4Cl. The organic layer is separated, dried over Na2SO4, and concentrated to give crude 4-[1,3]dioxan-2-yl-benzenethiol as a yellow oil, which is used immediately in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]O)=[N:6][CH:5]=1.S(Cl)([Cl:15])=O>ClCCl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Cl:15])=[N:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccc(CO)nc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CCl)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 122 %

Procedure:
Add 6-hydroxymethyl-nicotinic acid methyl ester (9.6 g, 57.4 mmol) and dichloromethane (200 mL) to a flask and cool to 0° C. Add thionyl chloride (10.25 g, 86.14 mmol). Stir the mixture at room temperature for 1 hr. Concentrate the reaction mixture under reduce pressure to give the crude 6-chloromethyl-nicotinic acid methyl ester (13 g, 102% yield) as a yellow solid. MS (m/z): 223 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[Br:19]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1([CH2:12][C:13]2[CH:18]=[N:17][CH:16]=[N:15][CH:14]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Br:19])[CH:9]=2)[NH:4][C:3]1=[O:11]
Reactant: CC1(Cc2cncnc2)C(=O)Nc2ccccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(Cc2cncnc2)C(=O)Nc2ccc(Br)cc21

Procedure:
3-Methyl-3-(pyrimidin-5-ylmethyl)-1,3-dihydro-2H-indol-2-one (900 mg, 3.76 mmol) and N-bromosuccinimide (669 mg, 3.76 mmol) in N,N-dimethylformamide (20 mL) were stirred at room temperature for 3 days. The mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC on Chiralpak AS, eluting with 25% isopropyl alcohol/CO2, to afford the enantiomers of 3-methyl-3-(pyrimidin-5-ylmethyl)-5-bromo-1,3-dihydro-2H-indol-2-one. Enantiomer A was isolated as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:29])[CH2:10][N:11]1[C:20](=[O:21])[C:19]2[N:18]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[C:17]([Cl:27])=[N:16][C:15]=2[N:14]([CH3:28])[C:12]1=[O:13].B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:29])[CH2:10][N:11]1[C:20](=[O:21])[C:19]2[N:18]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[C:17]([Cl:27])=[N:16][C:15]=2[N:14]([CH3:28])[C:12]1=[O:13]
Reactant: COc1ccccc1C(=O)Cn1c(=O)c2c(nc(Cl)n2CC=C(C)C)n(C)c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)=CCn1c(Cl)nc2c1c(=O)n(CC(=O)c1ccccc1O)c(=O)n2C

Procedure:
Prepared by treating 1-[2-(2-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-chloro-xanthine with boron tribromide in methylene chloride. The desired product is contaminated with approx. 20% 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-bromo-3-methyl-butyl)-8-chloro-xanthine.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5](N)=[CH:4][C:3]=1[S:9][CH2:10][C:11]([F:14])([F:13])[F:12].N([O-])=[O:16].[Na+].CCCCCC.C(OCC)(=O)C>O.S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([OH:16])=[CH:4][C:3]=1[S:9][CH2:10][C:11]([F:14])([F:13])[F:12]
Reactant: Cc1ccc(N)cc1SCC(F)(F)F
Reactant: O=N[O-]
Agent: [Cu+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: Cc1ccc(O)cc1SCC(F)(F)F
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
49.7 g (225 mmol) of 4-methyl-3-(2,2,2-trifluoroethylthio)aniline was suspended in 500 ml of a 15% aqueous sulfuric acid solution. Thereinto was dropwise added an aqueous solution obtained by dissolving 18.6 g (270 mmol) of sodium nitrite in 100 ml of water, at 0 to 5° C. with ice-cooling. After the completion of the dropwise addition, the mixture was stirred for 1 hour with the temperature being kept. The reaction mixture was gradually dropped at 120° C. into a solution obtained by dissolving 71.8 g (450 mmol) of anhydrous copper sulfate in 400 ml of 60% sulfuric acid. The mixture was allowed to cool to room temperature and subjected to extraction with ethyl acetate. The organic phase obtained was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was purified by column chromatography (developing solvent: a mixed solvent of n-hexane:ethyl acetate=10:1), to obtain 19 g (yield: 38%) of an intended product.
Reaction SMILES: C(O[C:4](=[O:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])C.[CH3:11][C:12]([CH3:14])=[O:13].[Na:15]>C(O)C>[OH:10][C:4](=[CH:11][C:12](=[O:13])[CH3:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Na:15]
Reactant: CC(C)=O
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(O)=CC(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.6 %

Procedure:
To a mixture of diethyloxalate (81 mL, 0.66 mol) and acetone (45 mL, 0.66 mol) was slowly added over 2-3 hours a solution of sodium metal (15.0 g, 0.66 mol) in absolute ethanol (330 mL) and condensation was allowed to occur with stirring at room temperature for 4 hours. The precipitate thus formed was filtered, washed with ethanol and dried to afford the title compound as a bright yellow solid (103.5 g, 87%).
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][C:9]([NH:11][CH:12]2[CH2:16][C:15](=[O:17])[O:14][CH:13]2[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:10])[C:6](=[O:26])[C:5]([NH:27][C:28](=[O:37])[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:4][CH:3]=1.[K+].[Br-]>>[O:26]=[C:6]1[C:5]([NH:27][C:28](=[O:37])[CH2:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:4][CH:3]=[C:2]([C:1]2[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=2)[N:7]1[CH2:8][C:9]([NH:11][CH:12]1[CH2:16][C:15](=[O:17])[O:14][CH:13]1[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:10]
Reactant: Cc1ccc(NC(=O)CCc2ccccc2)c(=O)n1CC(=O)NC1CC(=O)OC1OCc1ccccc1
Agent: [Br-]
Agent: [K+]
Product: O=C(CCc1ccccc1)Nc1ccc(-c2ccccc2)n(CC(=O)NC2CC(=O)OC2OCc2ccccc2)c1=O
Yield: 53 %

Procedure:
N(3(S)) 2[1,2-Dihydro-6-methyl-2-oxo-3-(3-phenylpropionyl)amino-1-pyridyl]-N-(2-benzyloxy-5-oxotetrahydrofuran-3-yl)acetamide (53e), was obtained (67%) as a mixture of anomers: IR (KBr) 3282, 1774, 1667, 1651, 1596, 1561, 1556, 1498, 1265, 1254, 1236, 1199, 1143; 1H NMR (d6-DMSO) δ 9.17 and 9.15 (1H, 2×s), 8.89 (0.5H, d, J=6.5), 8.73 (0.5H, d, J=7.4), 7.25 (10H, m), 6.13 (1H, t), 5.64 (0.5H, d, J=5.0), 5.45 (0.5H, s), 4.89-4.61 (4.5H, m), 4.26 (0.5H, m), 3.17-2.36 (6H, m), 2.23 and 2.15 (3H, 2s). N(3(S)) 2-[1,2-Dihydro-2-oxo-6-phenyl-3(3-phenylpropionyl)amino-1-pyridyl]-N-(2-benzyloxy-5-oxotetrahydrofuran-3-yl)acetamide (53%), was obtained (73%) as a mixture of anomers: IR (KBr) 3296, 1792, 1691, 1643, 1595, 1561, 1514, 1489, 1453, 1420, 1373, 1230, 1118; 1H NMR (d6-DMSO) δ 9.40, 9.36 (1H, 2s), 8.70 (0.5H, d, J=7.6), 8.52 (0.5H, d, J=7.5), 8.29 (1H, dd), 7.25 (15H, m), 6.20 (1H, d, J=7.6), 5.61 (0.5H, d, J=5.0), 5.28 (0.5H, s), 4.78-4.20 (5H, m), 3.12-2.24 (6H, m). N(3(S)) 2-[1,2-Dihydro-2-oxo-3-(3-phenylpropionyl) amino-1-pyridyl]-N-(2-benzyloxy-5-oxotetrahydrofuran-3-yl)acetamide (53g), was obtained (70%) as a mixture of anomers: IR (KBr) 3336, 3290, 1791, 1691, 1646, 1595, 1582, 1556, 1518, 1454, 1376, 1351, 1150, 1122; 1H NMR (d6-DMSO) δ 9.26 (1H, 2s), 8.86 (0.5H, d, J=6.4), 8.67 (0.5H, d, J=7.5), 8.23 (1H, m), 7.40-7.13 (11H, m), 6.24 (1H, 2t, J=7.2), 5.61 (0.5H, d, J=5.0), 5.44 (0.5H, s), 4.83-4.59 (2.5H, m), 4.25 (0.5H, m), 3.15-2.34 (2H, m), 2.91-2.70 (4H, m). Anal. Calc. for C27H27N3O6 H2O: C, 63.90; H, 5.76; N, 8.28. Found: C 63.70; H, 5.68; N, 8.22. MS FAB M+=490 (M +1). 2(R,S), N(3(S)) 2-[6-Benzyl-1,2-dihydro-2-oxo-3-(3-phenylpropionyl)amino-1-pyridyl]-N(2-benzyloxy-5-oxotetrahydrofuran-3-yl)propionamide (53h), was obtained (89%) as a mixture of diastereomers. Data is given for a single diastereomer: IR (film) 3356, 1788, 1677, 1645, 1602, 1517, 1455, 1377, 1203, 1167, 1120;