Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:27]([O-])=O)[C:5]([O:8][CH2:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:14][C@H:13]2[CH3:26])=[O:11])=[N:6][CH:7]=1.[H][H]>C(O)C.[Pt](=O)=O>[NH2:27][C:4]1[C:5]([O:8][CH2:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:14][C@H:13]2[CH3:26])=[O:11])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ncc(Cl)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ncc(Cl)cc1N
Yield: 86.3 %

Procedure:
To a solution of 2-(5-chloro-3-nitro-pyridin-2-yloxy)-1-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-ethanone (0.96 g, 2.3 mmol) in ethanol (25 mL) was added platinum dioxide on carbon (0.90 mg, 5% on carbon). The reaction was subject to 35 psi hydrogen gas for 20 minutes. The reaction was filtered through celite, concentrated in vacuo and chromatographed on silica gel to give the title compound (0.78 g).
Reaction SMILES: [Br-].[N:2]1([C:7]2[CH:25]=[CH:24][C:10]([C:11](=[O:23])[CH2:12][N+:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.BrCC(C1C=C[C:33]([N:36]2CCCC2)=[CH:32][CH:31]=1)=O.N1C2C(=CC=CC=2)C=CC=1>C(#N)C>[C:33]([C:32]1[CH:31]=[C:12]([C:11](=[O:23])[C:10]2[CH:9]=[CH:8][C:7]([N:2]3[CH2:6][CH2:5][CH2:4][CH2:3]3)=[CH:25][CH:24]=2)[N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][C:14]=12)#[N:36]
Reactant: O=C(CBr)c1ccc(N2CCCC2)cc1
Reactant: O=C(C[n+]1cccc2ccccc21)c1ccc(N2CCCC2)cc1
Agent: [Br-]
Solvent: c1ccc2ncccc2c1
Solvent: CC#N
Product: N#Cc1cc(C(=O)c2ccc(N3CCCC3)cc2)n2c1ccc1ccccc12
Yield: 96 %

Procedure:
1-(4-Pyrrolidin-1-yl-phenacyl)-quinolinium bromide: A stirred solution of 2-bromo-1-(4-pyrrolidin-1-yl-phenyl)-ethanone (689 mg, 2.57 mmol), quinoline (250 μL, 2.11 mmol) and acetonitrile (5.0 mL) was refluxed at 96° C. for 7 h under argon. The solution was equilibrated to room temperature and the precipitate was filtered on a Buchner funnel. The solid was dried in vacuo to yield 812 mg (96%) of the title compound. 1H NMR (DMSO-d6): 9.49 (d, J=4.67 Hz, 1H), 9.42 (d, J=8.25 Hz, 1H), 8.54 (d, J=8.24 Hz, 1H), 8.30 (m, 2H), 8.22 (td, J=7.92, 1.31 Hz, 1H), 8.06 (t, J=7.41 Hz, 1H), 7.96 (d, J=8.79 Hz, 2H), 6.84 (s, 2H), 6.72 (d, J=9.07 Hz, 2H), 3.40 (t, J=6.31 Hz, 4H), 2.02 (t, J=6.46 Hz, 4H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([C:21]1[O:26][C:25](=[O:27])[C:24]2[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=2[N:22]=1)[C:10]1[O:15][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N:11]=1.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH:5]1[CH:6]=[CH:7][C:2]([CH:1]=[C:9]([C:10]2[O:15][C:14](=[O:16])[C:13]3[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:11]=2)[C:21]2[O:26][C:25](=[O:27])[C:24]3[C:23](=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:22]=2)=[CH:3][CH:4]=1
Reactant: O=Cc1ccccc1
Reactant: O=c1oc(Cc2nc3ccccc3c(=O)o2)nc2ccccc12
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=c1oc(C(=Cc2ccccc2)c2nc3ccccc3c(=O)o2)nc2ccccc12

Procedure:
Benzaldehyde (259 mg, 2.45 mmol), Compound (2,2'-methylenebis(3,1-benzoxazine-4-one) (500 mg, 1.63 mmol), and BF3.(C2H5)2O (0.045 ml, 0.163 mmol) were heated under reflux in dry toluene (20 ml) for 20 hours. After the reaction, the solvent was removed under reduced pressure from the reaction mixture, the residue was treated with water, extracted with benzene, and the organic layer was separated, washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in the developing solvent and adsorbed on silica gel, and was purified by column chromatography to give the desired compound 52. The obtained product was crystallized from isopropylether to give the desired compound 52 in white solid in a good yield. m.p., IR, and NMR spectra of the product fully agreed with those of the one obtained in Example 19.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>CS(C)=O.O>[ClH:15].[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH3:29])[N:19]=[CH:18][CH:17]=[C:16]2[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(O)c1cccc2cc(O)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A slurry of 6-hydroxy-naphthalene-1-carboxylic acid (0.100 g, 0.531 mmol), 4-chloro-6,7-dimethoxy-quinoline (0.143 g, 0.638 mmol) and Cs2CO3 (0.519 g, 1.59 mmol) in 2.66 mL of DMSO under argon was stirred for 15 min at RT. The mixture was heated to 140° C. in a microwave. After 1 h, the reaction was diluted with ca. 2.7 mL of water. 6N HCl was added dropwise until the solution was at pH 3-4. The resulting precipitate was filtered and washed with acetone to afford the titled compound as a tan solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]([C:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][CH:8](Br)[C:7]=1O)=[O:5])[CH3:2].[F:17][CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(O)C.[Cl-].[Zn+2].[Cl-]>[CH2:1]([N:3]([CH2:15][CH3:16])[C:4]([CH:6]1[C:7]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:19][CH2:18][F:17])[C:8]=2[CH2:9][CH:10]([CH3:12])[CH2:11]1)=[O:5])[CH3:2]
Reactant: FCCNc1ccccc1
Reactant: CCN(CC)C(=O)C1=C(O)C(Br)CC(C)C1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)O
Product: CCN(CC)C(=O)C1CC(C)Cc2c1c1ccccc1n2CCF
Temperature: 50 °C
Reaction time: 3 h
Yield: 17.3 %

Procedure:
A mixture of 3-bromo-2-hydroxy-5-methyl-cyclohex-1-enecarboxylic acid diethylamide (47; prepared according to Example 11(d)) (2.0 g, 7 mmol) and (2-fluoro-ethyl)-phenyl-amine (24; prepared according to Example 4(a)) (1.9 g, 14 mmol) was stirred under N2 at 50° C. for 3 h and the reaction turned brown. The resulting mixture was dissolved in propan-2-ol (7 mL) and dry zinc chloride (2.86 g, 21 mmol) was added. The mixture was heated to reflux under N2 for 16 h and then concentrated in vacuo. The residue was dissolved in ethyl acetate (100 mL) and washed with 2 N HCl (30 mL), water (2×30 mL) and aqueous potassium carbonate solution (2×30 mL) then dried and concentrated in vacuo. The crude mixture was purified by SCX cartridge (40 mL) and then silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (0-100% B, 100 g, 12 CV, 85 mL/min) to afford 400 mg (17%) of 9-(2-fluoro-ethyl)-2-methyl-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (non-radioactive imaging agent 11) as a white solid. The structure was confirmed by 1H NMR (300 MHz, CDCl3) δH 1.10-1.35 (9H, m, CH3 and N(CH2CH3)2), 1.95-2.10 (2H, m, 3-CH2), 2.30-2.50 (1H, m, 2-CH), 2.70-2.80 (2H, m, 1-CH2), 3.40-3.70 (4H, m, N(CH2CH3)2), 4.05-4.15 (1H, m, 4-CH), 4.30 (2H, dm, J=21 Hz, NCH2CH2F), 4.65 (2H, dm, J=41 Hz, NCH2CH2F), and 7.00-7.30 (4H, m, NCCHCHCHCH.
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:13])[CH2:4][C:5]([NH:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:6].[BH4-].[Na+]>C(COC)OC>[Br:1][CH2:2][CH:3]([OH:13])[CH2:4][C:5]([NH:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:6]
Reactant: COC(=O)CNC(=O)CC(=O)CBr
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)CNC(=O)CC(O)CBr
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
1.5g Methyl 2-(4-bromo-3-oxobutanamido)acetate is dissolved in 15 ml dimethoxyethane. The solution is cooled to 0° C. and 60 mg NaBH4 is added. After 5 min, the solvent is evaporated in vacuo and the residue is chromatographed on silica, eluting with ethyl acetate. The title compound is obtained as a white powder, m.p. 60°-61° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([C:19]#[CH:20])[CH2:16][CH:17]=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[N:32]=[C:31]([CH3:33])[O:30][N:29]=2)[CH:23]=1>C(N(CC)CC)C.[Cu]I>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([C:19]#[C:20][C:26]3[CH:27]=[CH:22][CH:23]=[C:24]([C:28]4[N:32]=[C:31]([CH3:33])[O:30][N:29]=4)[CH:25]=3)[CH2:16][CH:17]=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1nc(-c2cccc(I)c2)no1
Reactant: C#CC(CC=O)c1ccc(OC)c(OC2CCCC2)c1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1ccc(C(C#Cc2cccc(-c3noc(C)n3)c2)CC=O)cc1OC1CCCC1
Temperature: 80 °C
Yield: 70 %

Procedure:
A mixture (+/-)-3-(3-cyclopentyloxy-4-methoxyphenyl)pent-4-ynal (0.20 g, 0.73 mmol) and 1-iodo-3-(5-methyl-[1,2,4]oxadiazol-3-yl)benzene (0.21 g, 0.73 mmol) and trace tetrakistriphenylphosphine palladium (0) and trace copper(I)iodide in triethylamine (5 mL)under an argon atmosphere was heated at 80° C. for 0.25 h. The mixture was cooled to room temperature and was evaporated. The residue was purified by flash chromatography (silica gel, 35% EtOAc/Hex) to provide the title compound as a yellow oil (0.22 g, 71%).1H NMR (250 Mhz, CDCl3) δ 9.86 (t, J=1.7 Hz, 1 H), 8.15, (d, J=1.4 Hz, 1 H), 8.01 (dt, J=7.8 and 1.4 Hz, 1 H), 7.54 (dt, J=7.8 and 1.4 Hz, 1 H), 7.42 (t, J=7.8 Hz),lH), 6.95 (m. 2 H), 6.84 (d, J=8.5 Hz, 1 H), 4.8 (m, 1 H), 4.40 (t, J=7 Hz, 1 H), 3.85 (s, 3 H), 2.86-3.10 (m, 2 H), 2.66 (s, 3 H), 1.80-2.05 (m, 6 H), 1.60-1.69 (m, 2 H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8](Cl)[C:7](O)=[C:6](Cl)[CH:5]=1)=[O:3].[OH2:13]>>[OH:13][CH2:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: O
Reactant: CC(=O)c1cc(Cl)c(O)c(Cl)c1
Product: O=C(CO)c1ccccc1

Procedure:
As a stock solution (5/5), 0.2 mM solution of 3,5-dichloro-4-hydroxyacetophenone was used. The solution was diluted with purified water to prepare 5-stage serial dilutions. To 0.02 ml of the solution in each concentration was mixed with 0.38 ml each of 0.1M citrate buffer solution (pH 5.4) containing 0.1% Triton X-100 and a buffer solution further supplemented with 0.3% BSA. Each absorbance was measured at 340 nm with a spectrophotometer to prepare the standard curve (FIG. 2).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH2:17]([SH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCO>[CH2:17]([S:24][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: SCc1ccccc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cccnc1SCc1ccccc1
Yield: 95.9 %

Procedure:
In a similar fashion using route 38 general procedure 92, 2-chloro-3-nitro-pyridine(2 g, 12.7 mmol), Na2CO3 (1.75 g, 16.6 mmol), benzylmercaptan (1.87 g, 15.1 mmol) and EtOH (20 ml) at 90° C. for 4 h gave the title compound (3 g, 96%) which was used in the next step without further purification. The structure was confirmed by 1H NMR.
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([CH2:9][NH2:10])=[O:8].C(=O)(O)[O-].[Na+].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:16]([NH:10][CH2:9][C:7]([C:3]1[O:2][CH:6]=[CH:5][CH:4]=1)=[O:8])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCC(=O)c1ccco1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(NCC(=O)c1ccco1)c1ccccc1
Yield: 82.9 %

Procedure:
3.4 g of (2-furylcarbonyl)methylamine hydrochloride, 4.4 g of sodium bicarbonate and 3.3 g of benzoyl chloride are treated in the same manner as described in Preparation 1-(1). 4.0 g of N-benzoyl-(2-furylcarbonyl)methylamine are thereby obtained. Yield: 83.3%
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:4][CH2:3]1.[Li+].[OH-].[H][H]>C1COCC1.O>[CH3:1][C:2]1([CH3:29])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=3)=[CH:7][C:6]=2[C:5]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C(C)(C)C)=CCC3(C)C)cc1
Reactant: [H][H]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
A solution of 24.0 mg (0.06 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl]benzoate (Compound 71) and 6.5 mg (0.16 mmol) of LiOH-H2 0 in 3 mL THF/water (3:1, v/v) was stirred overnight (22 hours) at room temperature. The reaction mixture was extracted with Et2O and the layers were separated. The aqueous layer was acidified with HCl (1M aqueous solution) and then extracted with EtOAc. The organic phase was dried over Na2 SO4 and concentrated in vacuo to give the title compound as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N:20]2[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]2)=[CH:11][C:12]2[CH2:13][CH2:14][CH:15]([OH:19])[CH2:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:28]([N:23]1[C:22](=[O:27])[CH2:21][N:20]([C:10]2[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:18][C:17]3[CH2:16][CH:15]([OH:19])[CH2:14][CH2:13][C:12]=3[CH:11]=2)[S:24]1(=[O:26])=[O:25])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CN(c2cc3c(cc2OCc2ccccc2)CC(O)CC3)S(=O)(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CN(c2cc3c(cc2OCc2ccccc2)CC(O)CC3)S(=O)(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5-(3-benzyloxy-6-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (90 mg, 0.23 mmol) from preparing Example 45, benzyl bromide (0.033 mL, 0.28 mmol) and potassium carbonate (63 mg, 0.46 mmol) in DMF (2 mL) is stirred at RT for 18 h. The mixture is partitioned between EtOAc and 1 N HCl solution. The organic extract is dried with MgSO4 and concentrated. The residue is purified to give the title compound as an oil: (M+NH4)+=478.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([F:19])[F:18])=[CH:12][CH:11]=2)[CH2:7][CH:6]([C:20](O)=[O:21])[CH2:5]1)(=[O:3])[CH3:2].O[NH:24][C:25](=[NH:30])[CH2:26][CH2:27][O:28][CH3:29]>>[F:18][CH:17]([F:19])[CH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH:8]2[CH2:7][CH:6]([C:20]3[O:21][N:30]=[C:25]([CH2:26][CH2:27][O:28][CH3:29])[N:24]=3)[CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9]2)=[CH:15][CH:14]=1
Reactant: COCCC(=N)NO
Reactant: CC(=O)N1CC(C(=O)O)CC(c2ccc(CC(F)F)cc2)C1
Product: COCCc1noc(C2CC(c3ccc(CC(F)F)cc3)CN(C(C)=O)C2)n1

Procedure:
According to General Method 6A, 153 mg (0.270 mmol, purity 50%) of the compound from Example 59A and 41.3 mg (0.297 mmol, purity 85%) of N-hydroxy-3-methoxypropanimidamide were reacted Yield: 46.6 mg (32% of theory, purity 72%)
Reaction SMILES: [F:1][C:2]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[NH3:28]>>[F:1][C:2]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[NH:28])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccc(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)c1F
Reactant: N
Product: Cc1cccc(COc2cccnc2NC(=N)Nc2ccc(Cl)cc2)c1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of yellow mercuric oxide (1.29 g, 0.0059 mol), N-[3-(2-fluoro-3-methylbenzyloxy)pyrid-2-yl]-N'-4-chlorophenylthiourea (2.0g, 0.0049 mol) and methanolic ammonia solution (40 ml) was stirred for 2 days at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent followed by trituration with ether and recrystallisation from acetonitrile gave the desired product. Yield 1.59g, (84.5%), m.p. 179°-181 ° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH:14][CH2:15][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24]CC3C=CC=CC=3)=[C:20]([CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:19]=2)[OH:17])[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]>C(O)C.[Pd]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH:12]([NH:14][CH2:15][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH2:32][S:33]([CH3:36])(=[O:34])=[O:35])[CH:19]=2)[OH:17])[CH3:13])=[CH:9][CH:10]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(CC(C)NCC(O)c2ccc(OCc3ccccc3)c(CS(C)(=O)=O)c2)cc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(CC(C)NCC(O)c2ccc(O)c(CS(C)(=O)=O)c2)cc1

Procedure:
N-(2-[4-Carbomethoxyphenyl]-1-methylethyl)-2-(4-benzyloxy-3-methylsulphonylmethylphenyl)-2-hydroxyethanamine(2.3 g) was converted to the hydrochloride salt and hydrogenated in ethanol (200 ml) in a Parr hydrogenerator at 50 psi and 25° for 2 hours in the presence of 10% palladium on charcoal (0.5 g). The catalyst was removed and the product was isolated as a mixture of diastereoisomers, mp 145°-148° (methanol:ether). τ(d6DMSO) 8.90 (3H, d, J=6 Hz), 7.2 (3H, s), 6.20-7.10 (6H, m), 6.20 (3H, s), 5.70 (2H, s), 5.00 (1H, m), 390 (1H, b), 2.40-3.10 (5H, m), 2.08 (2H, d, J=8 Hz)., 0.70 (1H, br),-0.10 (1H, br).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH2:5]1[C:12]2[N:8]([CH:9]=[CH:10][CH:11]=2)[CH2:7][CH2:6]1>C1(C)C=CC=CC=1.CCOCC>[CH2:11]1[C:12]2[N:8]([C:7]([C:1]([Cl:4])=[O:2])=[CH:6][CH:5]=2)[CH2:9][CH2:10]1
Reactant: O=C(Cl)Cl
Reactant: c1cc2n(c1)CCC2
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C(Cl)c1ccc2n1CCC2
Temperature: 25 °C

Procedure:
To a stirred, ice-bath cooled portion (30 ml) of 12.5% phosgene in toluene was added a solution of 2,3-dihydro-1H-pyrrolizine (0.80 g, 0.0074 m) in ether (30 ml) dropwise over ca two minutes. After stirring cold for ca 2.5 hr, the reaction mixture is allowed to warm to room temperature, the volatiles are removed in vacuo, and the resultant crystalline 2,3-dihydro-1H-pyrrolizine-5-carbonyl chloride used as is in the next step.
Reaction SMILES: [S:1]1[C:5]([C:6](O)=[O:7])=[CH:4][C:3]2[CH2:9][CH2:10][CH2:11][C:2]1=2.S(Cl)([Cl:14])=O>>[S:1]1[C:5]([C:6]([Cl:14])=[O:7])=[CH:4][C:3]2[CH2:9][CH2:10][CH2:11][C:2]1=2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc2c(s1)CCC2
Product: O=C(Cl)c1cc2c(s1)CCC2

Procedure:
1.0 g of 5,6-dihydro-4H-cyclopenta[b]thiophene-2-carboxylic acid was reacted with 4 ml of thionyl chloride for 3.5 hours under reflux. Then, excess thionyl chloride was distilled off under reduced pressure to obtain 5,6-dihydro-4H-cyclopenta[b]thiophene-2-carbonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:20])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1.[C:21](=O)([O-])[O-].[K+].[K+].CI>CO>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH3:21])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:20])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccc(F)cc1
Agent: [K+]
Solvent: CO
Solvent: CI
Product: CSc1nc(N)c2nc(O)n(Cc3ccc(F)cc3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
6-amino-9-(4-fluorobenzyl)-8-hydroxy-2-mercaptopurine (200 mg, 0.687 mmol) was suspended in methanol (20 ml). To the suspension were added potassium carbonate (190 mg, 1.37 mmol) and methyl iodide (975 mg, 6.87 mmol) in order. The mixture was stirred at room temperature for 30 minutes. The reaction mixture were evaporated in vacuo to dryness and extracted with chloroform. The organic layer was dried on sodium sulfate. After removal of the solvent in vacuo, the residue was purified by silica gel chromatography (3% methanol/chloroform) to give the subject compound (63 mg, yield 30%).
Reaction SMILES: [C@@H:1]1([N:9]2[C:13]3=[N:14][CH:15]=[N:16][C:17]([O:18][CH3:19])=[C:12]3[C:11]([I:20])=[N:10]2)[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1.[C:21]([Si:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)Cl)([CH3:24])([CH3:23])[CH3:22]>N1C=CC=CC=1>[Si:25]([CH:7]([OH:8])[C@H:5]1[O:6][C@@H:1]([N:9]2[C:13]3=[N:14][CH:15]=[N:16][C:17]([O:18][CH3:19])=[C:12]3[C:11]([I:20])=[N:10]2)[CH2:2][C@@H:3]1[OH:4])([C:21]([CH3:24])([CH3:23])[CH3:22])([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COc1ncnc2c1c(I)nn2[C@H]1C[C@H](O)[C@@H](CO)O1
Solvent: c1ccncc1
Product: COc1ncnc2c1c(I)nn2[C@H]1C[C@H](O)[C@@H](C(O)[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O1
Reaction time: 72 h
Yield: 89.6 %

Procedure:
In a 500 mL flask was suspended 2 (3.6 g, 9.2 mmol) in anhydrous pyridine (60 mL), then tert-butyldiphenylchlorosilane (2.78 g, 10 mmol) was added and the mixture stirred for 72 hours. The suspension was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with 10% citric acid, brine, dried over MgSO4, and concentrated to a white foam. The crude product was purified by flash chromatography with 25-33% ethyl acetate in hexanes to obtain 3 as a white foam (5.2 g, 90% yield).
Reaction SMILES: Cl.[CH3:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:10]2=[O:31])[CH:4]=1.[CH2:32]([O:34][C:35]1[C:44]([O:45][CH3:46])=[CH:43][C:42]2[C:41]([C:47]3[CH:55]=[CH:54][C:50]([C:51](O)=[O:52])=[CH:49][CH:48]=3)=[N:40][C@@H:39]3[CH2:56][CH2:57][S:58][CH2:59][C@@H:38]3[C:37]=2[CH:36]=1)[CH3:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:32]([O:34][C:35]1[C:44]([O:45][CH3:46])=[CH:43][C:42]2[C:41]([C:47]3[CH:48]=[CH:49][C:50]([C:51]([N:28]4[CH2:29][CH2:30][CH:25]([N:11]5[C:12](=[O:24])[C:13]6[S:17][C:16]([C:18]7[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=7)=[CH:15][C:14]=6[N:9]([CH2:8][C:5]6[CH:4]=[C:3]([CH3:2])[O:7][N:6]=6)[C:10]5=[O:31])[CH2:26][CH2:27]4)=[O:52])=[CH:54][CH:55]=3)=[N:40][C@@H:39]3[CH2:56][CH2:57][S:58][CH2:59][C@@H:38]3[C:37]=2[CH:36]=1)[CH3:33]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: Cc1cc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)no1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5cc(C)on5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(5-methylisoxazol-3-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (250 mg; compound B31) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (238 mg; compound C10) and HBTU (246 mg) in DCM (15 ml) in the presence of DIPEA (0.38 ml) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [silica gel, eluation gradient: DCM/MeOH, 1/0 to 3/2 (v/v)] and preparative HPLC as a solid.