Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH2:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:10][C:11]1([S:14]([O:17]C(C)C)(=[O:16])=[O:15])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([S-])#N.[K+].O>C1COCC1>[CH2:1]([O:8][C@@H:9]([CH2:21][O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:10][C:11]1([S:14]([OH:17])(=[O:16])=[O:15])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OS(=O)(=O)C1(C[C@H](COCc2ccccc2)OCc2ccccc2)CC1
Agent: N#C[S-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(O)C1(C[C@H](COCc2ccccc2)OCc2ccccc2)CC1
Temperature: 90 °C
Yield: 64 %

Procedure:
A mixture of (R)-isopropyl 1-(2,3-bis(benzyloxy)propyl)cyclopropane-1-sulfonate (460 g) and KSCN (170 g) in THF 2.2 L) and water (2.2 L) at 25° C. was refluxed for approximately 24 hours at 90° C. until HPLC analysis showed that the reaction had gone to completion. The reaction mixture was concentrated to about 2 L at 40° C. and extracted with MTBE (1.5 L (×3)). The organic layer was discarded and the aqueous layer was neutralized to pH 14 with KOH (30 g) in water (100 mL) and cooled to −5° C. The mixture was neutralized to a pH of between 2 and 3 with concentrated HCl (205 mL) and extracted with ETOAc (2 L (×2)). The combined organic layers was dried over Na2SO4 for approximately 16 hours, filtered and concentrated to dryness to give the product as a deep red oil (265 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH3:25][CH:26]1[CH2:30][CH2:29][CH2:28][NH:27]1>>[CH3:25][CH:26]1[CH2:30][CH2:29][CH2:28][N:27]1[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1
Reactant: CC1CCCN1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Product: CC1CCCN1CCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1

Procedure:
The product from Example 1C and 2-methyl-pyrrolidine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.88 (m, 1H), 7.80 (m, 4H), 7.60 (m, 2H), 6.82 (s, 1H), 3.8-3.9 (m, 2H), 3.58 (m, 1H), 3.25-3.5 (m, 4H), 2.48 (m, 1H), 2.05-2.2 (m, 2H), 1.75 (m, 1H), 1.50 (d, 3H, J=6 Hz); MS (DCI) m/z 331 (M+H)+;
Reaction SMILES: [CH3:1][N:2]1[CH:9]([CH3:10])[CH2:8][C:7]2([CH3:12])[CH2:11][CH:3]1[CH2:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=12.BrC#[N:19]>C(Cl)Cl>[CH3:10][CH:9]1[N:2]([C:1]#[N:19])[CH:3]2[CH2:11][C:7]([CH3:12])([C:6]3[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=3[CH2:4]2)[CH2:8]1
Reactant: CC1CC2(C)CC(Cc3ccccc32)N1C
Reactant: N#CBr
Solvent: ClCCl
Product: CC1CC2(C)CC(Cc3ccccc32)N1C#N
Temperature: 45 °C
Reaction time: 2 h

Procedure:
3,4,6-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine (from Example LVI, 1.7 g) dissolved in CH2Cl2 (40 mL) is added to a solution of BrCN (1.17 g) in CH2Cl2 (10 mL) chilled in an ice bath. The cooling bath is removed and the mixture is stirred at ambient temperature for 1 h and at 45° C. for 2 h. After cooling to ambient temperature, the solution is washed with water, 2 M hydrochloric acid, and 10% aqueous K2CO3 solution. The solution is dried (MgSO4), the solvent is removed, and the residue is triturated with little acetone to give the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH2:38][C:39](Cl)=[O:40])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]>C(Cl)Cl>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH2:38][C:39]([N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]2[CH2:8][CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:40])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Reactant: c1ccc(C(CC2CCCCN2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CC(=O)N2CCCCC2CC(c2ccccc2)c2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2.65 g (0.01M) of 2-(2,2-diphenylethyl)piperidine in 25 ml of methylene chloride containing 1.5 ml of triethylamine was cooled in ice and a solution of 2.35 g (0.011M) of 3,4-di-methoxyphenylacetyl chloride in 25 ml of methylene chloride was added dropwise. The cooling bath was removed and the mixture was stirred at room temperature overnight. The mixture was then washed with dilute hydrochloric acid, water, dilute sodium hydroxide and saturated sodium chloride solution. Removal of the solvent left an oil which was purified by chromatography on silica gel. The solid thus obtained melted at 113°-114° C. after recrystallization from cyclohexane-ethyl acetate.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[C:8]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]1[CH:13]=[N:12][CH:11]=[CH:10][C:9]2=1)=[O:5])C.[CH3:19][NH:20][CH3:21]>C=C>[CH3:19][N:20]([CH3:21])[C:4]([C:6]1[CH:7]=[C:8]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]1[CH:13]=[N:12][CH:11]=[CH:10][C:9]2=1)=[O:5]
Reactant: CNC
Reactant: CCOC(=O)c1ccc2[nH]c3cnccc3c2c1
Agent: C=C
Product: CN(C)C(=O)c1ccc2[nH]c3cnccc3c2c1

Procedure:
150 mg of 6-ethoxycarbonyl-β-carboline are heated in 5 ml of ethylene gylcol with 2 ml of dimethylamine solution for 20 hours to 100° C. After cooling, it is placed on ice, extracted with ethyl acetate and the organic phase is dried, filtered and concentrated. 50 mg of 6-dimethylaminocarbonyl-β-carboline are obtained as oil after chromatography on silica gel with methylene chloride/ethanol=10:1.
Reaction SMILES: [CH3:1][NH2:2].C[Al](C)C.[CH3:7][S:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][N:19]3[CH:23]=[C:22]([C:24]([O-:26])=O)[N:21]=[CH:20]3)[CH:15]=[CH:14][C:12]=2[N:13]=1>C1COCC1.C1(C)C=CC=CC=1.ClCCCl>[CH3:1][NH:2][C:24]([C:22]1[N:21]=[CH:20][N:19]([CH2:18][C:16]2[CH:15]=[CH:14][C:12]3[N:13]=[C:9]([S:8][CH3:7])[S:10][C:11]=3[CH:17]=2)[CH:23]=1)=[O:26]
Reactant: CSc1nc2ccc(Cn3cnc(C(=O)[O-])c3)cc2s1
Reactant: CN
Agent: C[Al](C)C
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: Cc1ccccc1
Product: CNC(=O)c1cn(Cc2ccc3nc(SC)sc3c2)cn1
Temperature: 70 °C
Reaction time: 0.03 h
Yield: 58 %

Procedure:
To a stirred solution of methylamine (623 μL of a 2 M solution in THF, 1.3 mmol) at 0° C. was added trimethylaluminum (623 μL of a 2 M solution in toluene, 1.2 mmol). The mixture was stirred for 2 min and then a solution of 1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-1H-imidazole-4-carboxylate (80 mg, 0.25 mmol) from Step 1 of this Example in DCE (1 mL) was added dropwise. The reaction vessel was sealed and the mixture was heated at 70° C. for 20 h. The mixture was then concentrated under reduced pressure and the residue was purified by silica gel flash chromatography eluting with 5% MeOH in EtOAc to afford N-methyl-1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-1H-imidazole-4-carboxamide (46 mg, 58%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.98 (d, J=1.3 Hz, 1H), 7.81-7.94 (m, 3H), 7.71 (d, J=1.1 Hz, 1H), 7.42 (dd, J=1.6, 8.4 Hz, 1H), 5.33 (s, 2H), 2.78 (s, 3H), 2.70 (d, J=4.9 Hz, 3H). LCMS (ESI) m/z 319 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[C:3]=1[CH3:10].[N+:11]([O-])([OH:13])=[O:12]>C(O)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([N+:11]([O-:13])=[O:12])=[C:4]([OH:9])[C:3]=1[CH3:10]
Reactant: Cc1c(O)cc(O)nc1Cl
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Cc1c(Cl)nc(O)c([N+](=O)[O-])c1O
Temperature: 0 °C
Yield: 28 %

Procedure:
6-Chloro-2,4-dihydroxy-5-methyl-pyridine (500 mg, 3.1 mmol) was taken up in acetic acid (1 mL), cooled to 0° C. and nitric acid added (4 mL) dropwise with stirring. After the addition was complete, the ice bath was removed, and the reaction mixture was allowed to warm to room temperature over 16 h. Ice was added to the mixture to provide a precipitate, which was collected by filtration and dried in vacuo to give the title compound as a yellow solid (180 mg, 28%).
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6](=[O:16])[N:5](COCCOC)[C:4]=2[N:3]=1.Cl>O1CCOCC1.O>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6](=[O:16])[NH:5][C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(C)c(=O)n2COCCOC
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: C=CCn1c(Cl)nc2[nH]c(=O)n(C)c(=O)c21
Temperature: 100 °C
Yield: 67.8 %

Procedure:
To a solution of 8-chloro-1-methyl-3-({[2-(methyloxy)ethyl]oxy}methyl)-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (2.9 g, 6.37 mmol) in dioxan (20 ml) and water (20 ml) was added 5M HCl (20 ml). The resulting mixture was heated at 100° C. under nitrogen for 18 hours. The reaction mixture was then concentrated in vacuo, the residue was dissolved in EtOAc (100 ml) and washed with water. The organic extract was dried (MgSO4) filtered and evaporated. Purification by SPE (Si, 20 g) eluting 2:3 EtOAc/cyclohexane afforded the title compound as a white solid (1.04 g, 68%). m/z 241.1[MH+].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[C:9]([C@@H:13]1[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15][CH2:14]1)([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:9]([C@@H:13]1[CH2:14][CH2:15][C@H:16]([NH:19][C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=2)[CH2:17][CH2:18]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)[C@H]1CC[C@@H](N)CC1
Reactant: Clc1cc(Cl)ncn1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)[C@H]1CC[C@@H](Nc2cc(Cl)ncn2)CC1

Procedure:
58.6 g (0.39 mol) of 4,6-dichloropyrimidine were placed in 400 ml of toluene, and a mixture of 61.0 g (0.39 mol) of cis-4-tert-butylcyclohexylamine and 50.0 g (0.50 mol) of triethylamine in 100 ml of toluene was added dropwise at from 70° to 80° C. The mixture was subsequently stirred at reflux for 4 hours. After cooling, it was extracted by stirring with water, the organic phase was dried and concentrated, to give a colorless oil which crystallized after trituration with petroleum ether. Filtration with suction left 70.5 g (67.0% of theory) of colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C@H:3]1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[O:22][CH2:23][C:24]([O:26]CC)=[O:25].[OH-].[Na+]>C1COCC1.CO>[CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C@H:3]1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[O:22][CH2:23][C:24]([OH:26])=[O:25]
Reactant: CCOC(=O)CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](OCC(=O)O)CC[C@H]4[C@@H]3CC[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To ethyl 4-methyl-5α-4-azaandrostan-3-on-17β-yloxyacetate (275 mg) in THF (10 ml) and MeOH (5 ml) under N2 was added 2N NaOH (3.0 ml). The mixture was stirred at room temperature for 2 hours, then concentrated in vacuo. The aqueous residue was extracted with CH2 Cl2. The aqueous layer was then acidified with 3.0N HCl (ca. 2.1 ml) to pH 2, and extracted with CH2Cl2. The organic layer was washed with brine and dried (Na2SO4). The solvent was removed, and the crude product recrystallized from CH2Cl2 /hexane to give the title compound. M.p. 180.5°-184° C.
Reaction SMILES: [CH2:1]([S:4]([C:7]1[CH:8]=[C:9]([C@H:23]2[CH2:27][CH2:26][C@H:25]([C:28]3[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=3)[O:24]2)[CH:10]=[C:11]([O:21][CH3:22])[C:12]=1[O:13]CC1C=CC=CC=1)(=[O:6])=[O:5])[CH2:2][CH3:3]>C(OCC)(=O)C>[CH2:1]([S:4]([C:7]1[CH:8]=[C:9]([C@H:23]2[CH2:27][CH2:26][C@H:25]([C:28]3[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=3)[O:24]2)[CH:10]=[C:11]([O:21][CH3:22])[C:12]=1[OH:13])(=[O:6])=[O:5])[CH2:2][CH3:3]
Reactant: CCCS(=O)(=O)c1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(OC)c1OCc1ccccc1
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)c1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(OC)c1O

Procedure:
A solution of trans-2-(3-n-propylsulfonyl-4-benzyloxy-5-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl) tetrahydrofuran (5.0 g) in ethyl acetate (100 mL) was hydrogenated over 10% palladium-over-charcoal (250 mg) for 1 h. The catalyst was filtered off and the filtrate was concentrated to a crystalline mass. Recrystallization from ethyl ether gave pure product: mp 168°-169° C.; NMR (CDCl3) δ 1.0 (t, CH2CH2CH3), 1.7 (m, CH2CH2CH3), 2.0 & 2.49 (2 m, H-3 & H-4), 3.4 (m, CH2CH2CH3), 3.84, 3.89 & 3.93 (3 s, 4 OCH3), 5.20 (m, H-2 & H-5), 6.62 (s, C5ArH), 7.24 & 7.47 (2 d, J=1.5 Hz, C2ArH).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[CH:30]1([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:32][CH2:31]1>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:36]4[CH2:37][CH2:38][N:33]([CH:30]5[CH2:32][CH2:31]5)[CH2:34][CH2:35]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)cn1
Reactant: C1CN(C2CC2)CCN1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCN(C6CC6)CC5)c34)cc2Cl)cn1
Yield: 28 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 16) and N-cyclopropylpiperazine to give the title compound in 28% yield; NMR Spectrum: 0.23-0.25 (m, 2H), 0.35-0.38 (m, 2H), 1.51-1.55 (m, 1H), 2.45 (s, 3H), 2.50 (hidden by DMSO, 8H), 2.78 (t, 2H), 4.44 (t, 2H), 7.20 (d, 1H), 7.25 (br s, 2H), 7.73 (d, 1H), 8.11 (s, 1H), 8.21 (s, 1H), 8.36 (s, 1H), 8.62 (br s, 1H); Mass Spectrum: 521 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([I:16])[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:17]#[N:18].N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C=O)C>[C:27]([Si:24]([CH3:26])([CH3:25])[O:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([I:16])[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:17]#[N:18])([CH3:30])([CH3:29])[CH3:28]
Reactant: N#Cc1cnc2ccc(I)cc2c1SCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCSc1c(C#N)cnc2ccc(I)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
To the solution of 4-(3-hydroxy-propylsulfanyl)-6-iodo-quinoline-3-carbonitrile (example 50a, 3.0 g, 8.1 mmol) and imidazole (2.2 g, 32.4 mmol) in DMF (10 mL) was added dropwisely the solution of tert-butyldimethylsilyl chloride (TBDMS-Cl, 2.94 g, 19.4 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature overnight. The product was extracted with ethylacetate. The combined organic layers were successively washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 5%-30% ethyl acetate in hexanes in 50 min) afforded 4-[3-(tert-butyl-dimethyl-silanyloxy)-propylsulfanyl]-6-iodo-quinoline-3-carbonitrile (3.41 g, 87%) as a yellow solid. LC-MS m/e 485 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]23[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=4)[C:13](=[O:25])[N:12]2[CH2:11][CH2:10][NH:9][CH2:8]3)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:47][N:48]([CH3:53])[CH2:49][C:50](O)=[O:51]>C1COCC1.C(Cl)CCl>[CH3:47][N:48]([CH2:49][C:50]([N:9]1[CH2:8][C:7]2([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Br:1])=[CH:3][CH:4]=3)[N:12]([C:13](=[O:25])[N:14]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)[C:15]2=[O:16])[CH2:11][CH2:10]1)=[O:51])[CH3:53]
Reactant: CN(C)CC(=O)O
Reactant: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(Br)cc3)CNCCN12
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N1CCN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)C2(Cc2ccc(Br)cc2)C1
Reaction time: 8 h

Procedure:
To a solution of 6-(4-bromobenzyl)-8-(3,5-dichlorophenyl)-1,4,8-triazabicyclo[4.3.0]nonane-7,9-dione (0.085 g) in THF (5 mL) was added DIEA (0.1 mL), HOBt (0.57 g), EDC (0.054 g) and N,N-dimethylglycine (0.037 g). After stirring overnight, the reaction was concentrated and the residue was diluted with EtOAc and washed with water, NaHCO3, and brine, dried (Na2SO4), filtered, and concentrated. Purification by chromatography (Silica gel: 2% MeOH/CH2Cl2, Chromatotron) afforded the titled compound. (0.093 g). MS (m/z) 553 (MH+). mp 73.5° C.
Reaction SMILES: [C:1]([O:4][CH:5]1[O:18][C@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:11]([N:24]=[N+:25]=[N-:26])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2].[C:27]([O:31][CH3:32])(=[O:30])[C:28]#[CH:29].C(N(C(C)C)CC)(C)C>[Cu](I)I.C1(C)C=CC=CC=1>[C:1]([O:4][CH:5]1[O:18][C@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:11]([N:24]2[CH:29]=[C:28]([C:27]([O:31][CH3:32])=[O:30])[N:26]=[N:25]2)[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](OC(C)=O)[C@@H](N=[N+]=[N-])[C@H]1OC(C)=O
Reactant: C#CC(=O)OC
Agent: I[Cu]I
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cn([C@H]2[C@@H](OC(C)=O)[C@@H](COC(C)=O)OC(OC(C)=O)[C@@H]2OC(C)=O)nn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93 %

Procedure:
A mixture of 1,2,4,6-tetra-O-acetyl-3-azido-3-deoxy-D-galactopyranose 22 (Lowary and Hindsgaul, 1994) (10 mg, 0.027 mmol), methyl propiolate (2.4 μL, 1 eq.), copper iodide (0.6 mg, 0.1 eq.), diisopropylethylamine (1 eq.), and toluene (1 mL) were stirred together for 12 h at r.t. The solvent was evaporated and the product was purified by column chromatography (SiO2, heptane:EtOAc 2:1) to give 23 (12.2 mg, 93%).
Reaction SMILES: [F:1][C:2]1([F:26])[CH:12]2[N:13](S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH:8]([CH2:9][O:10][CH2:11]2)[C:7]2[CH:6]=[N:5]N[C:3]1=2.[Li+].[OH-].SCC(O)=[O:32]>CN(C=O)C>[F:1][C:2]1([F:26])[CH:12]2[NH:13][CH:8]([CH2:9][O:10][CH2:11]2)[C:7]2[CH:6]=[N:5][O:32][C:3]1=2
Reactant: O=C(O)CS
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N1C2COCC1C(F)(F)c1[nH]ncc12
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: FC1(F)c2oncc2C2COCC1N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of compound 107e (100 mg, 0.26 mmol, 1.0 eq) and LiOH (33 mg, 0.78 mmol, 3.0 eq) in DMF (5 mL) was added mercaptoacetic acid (36 mg, 0.4 mmol, 1.5 eq) slowly, the mixture was stirred at room temperature for 3 h. The solvent was removed in vacuo to give 7,7-difluoro-5,10-dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene 107a as an oil, used in next step without further purification. MS: calc'd (MH+) 202, measured (MH+) 202.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH2:11][C:12](=[CH2:17])[CH2:13][C:14](=[CH2:16])[CH:15]=1)[CH3:2].C1(C)C(S(O[CH2:31][CH:32]2[CH2:36][CH:35]=[CH:34][CH2:33]2)(=O)=O)=CC=CC=1>>[CH:32]1([CH2:31][N:7]2[C:8]([C:9](=[O:18])[C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]2=[O:19])[CH2:36][CH:35]=[CH:34][CH2:33]1
Reactant: Cc1ccccc1S(=O)(=O)OCC1CC=CC1
Reactant: C=C1C=C(C(=O)c2[nH]c(=O)[nH]c(=O)c2CC)CC(=C)C1
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(CC2CC=CC2)c(=O)[nH]c1=O
Yield: 59.6 %

Procedure:
5-Ethyl-6-(3,5-dimethlylbenzoyl)-2,4-pyrimidinedione and (cyclopent-3-en-1-yl)methyl toluenesulfonate were reacted by the same method with the example 1 to obtain the titled compound (84 mg).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=1>>[C:12]([C:11]1[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[C:16]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:15]=1)(=[O:13])[NH2:14]
Reactant: COc1ccc(C(N)=O)cc1
Reactant: O=S(=O)(O)Cl
Product: COc1ccc(C(N)=O)cc1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 92.8 %

Procedure:
To 1733 g of chlorosulfonic acid was added in small portions 150 g of 4-methoxybenzamide under ice-cooling with stirring during 15 minutes, and the mixture was stirred at room temperature for 14 hours. After being stirred at 50° C. for additional 1.5 hours, the reaction mixture was dropped into 7 kg of ice. The precipitate was collected by filtration, washed with water and hexane to give 230 g of 5-carbamoyl-2-methoxybenzenesulfonyl chloride.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([CH2:14][N:15]2[C:24](=[O:25])[C:23]3[N:22]([CH2:26][C:27]#[C:28][CH3:29])[C:21]([N:30]4[CH2:35][CH2:34][CH2:33][C@@H:32]([NH2:36])[CH2:31]4)=[N:20][C:19]=3[N:18]([CH2:37][C:38]([O:40]C)=[O:39])[C:16]2=[O:17])[N:5]=1.Cl>O1CCCC1.O.CO>[CH3:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([CH2:14][N:15]2[C:24](=[O:25])[C:23]3[N:22]([CH2:26][C:27]#[C:28][CH3:29])[C:21]([N:30]4[CH2:35][CH2:34][CH2:33][C@@H:32]([NH2:36])[CH2:31]4)=[N:20][C:19]=3[N:18]([CH2:37][C:38]([OH:40])=[O:39])[C:16]2=[O:17])[N:5]=1
Reactant: CC#CCn1c(N2CCC[C@@H](N)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2CC(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC#CCn1c(N2CCC[C@@H](N)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2CC(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2 ml of 1 M sodium hydroxide solution are added to a solution of 150 mg of (R)-1-(4-methyl-quinazolin-2-ylmethyl)-3-(methoxycarbonylmethyl )-7-(but-2-ynyl)-8-(3-amino-piperidin-1-yl)-xanthine in 6 ml of tetrahydrofuran/water/methanol (1:1:1). The solution is stirred for 1 h at ambient temperature and then neutralised with 1 M hydrochloric acid. The solution is evaporated to dryness and purified by HPLC (YMC-C18) with water/acetonitrile (70:30).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8]([CH3:15])([CH3:14])[C:7](=[O:16])[CH2:6][CH2:5]2.[CH3:17][CH:18](C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C[Si](C#C)(C)C>C(#N)C.C(OCC)(=O)C>[C:17]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8]([CH3:15])([CH3:14])[C:7](=[O:16])[CH2:6][CH2:5]2)#[CH:18]
Reactant: COc1cc2c(cc1Br)CCC(=O)C2(C)C
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: C#C[Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C#Cc1cc2c(cc1OC)C(C)(C)C(=O)CC2
Temperature: 85 °C
Reaction time: 2 h
Yield: 430.1 %

Procedure:
6-Bromo-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (1 g) was dissolved in acetonitrile (50 ml), added with PdCl2(CH3CN)2 (45 mg), X-phos (168 mg), CsCO3 (1.2 g) and trimethylsilylacetylene (0.9 ml), and the mixture was stirred at 85° C. for 2 hrs. The reaction mixture was diluted with ethyl acetate (100 ml). The organic layer was washed twice with 10% brine and concentrated under reduced pressure. The resulting residues were dissolved in THF (10 ml), added with the THF solution (4 ml) comprising tetrabutylammonium fluoride and stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate (100 ml). The organic layer was washed twice with 10% brine and concentrated under reduced pressure. The resulting residues were purified by silica gel column (n-hexane/ethyl acetate=9/1) to obtain the title compound (346 mg, two step yield 43%).