Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:23][C:24]([C:26]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[OH:22])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([CH:14]([NH:23][C:24]([C:26]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(Cc2ccccc2O)NC(=O)c2cc(OC)c3ccccc3n2)CC1
Reactant: CCOC(=O)CBr
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccccc1CC(NC(=O)c1cc(OC)c2ccccc2n1)C(=O)N1CCN(C(=O)OCC)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 60.6 %

Procedure:
To a solution of 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(2-hydroxyphenyl)ethyl]aminocarbonyl-4-methoxyquinoline (200 mg, 0.39 mmol) in DMF (5 mL) was added CsCO3 (260 mg, 0.8 mmol) and ethyl bromoacetate (120 mg, 0.7 mmol) and the reaction mixture was stirred at ambient temperature for 6 hours. The reaction mixture was partitioned in water and ethyl acetate and extracted with ethyl acetate. Combined organic layers were washed with water, brine, dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC to afford 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(2-(ethoxycarbonyl)methoxyphenyl)ethyl]aminocarbonyl-4-methoxyquinoline as a white solid 140 mg (60%); NMR (DMSO-d6), 1.18 (m, 6), 3.26 (m, 10), 4.00 (q, 2), 4.04 (s, 3), 4.84 (s, 2), 5.26 (m, 1), 6.82 (q, 1), 7.88 (d, 1), 7.48 (s, 1), 7.64 (t, 1), 7.82 (t, 1), 8.06 (d, 1), 8.16 (d, 1), 8.86 (d, 1) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH3:30][N:31]([CH3:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:36]2[CH:37]=[CH:38][C:33]([CH2:32][N:31]([CH3:48])[CH3:30])=[CH:34][CH:35]=2)[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Reactant: CN(C)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN(C)C)cc3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 9 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)benzamide (1 equiv.) and N,N-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3.6 equiv.) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.1 equiv.) was added and argon was purged again for 10 min. The solution was heated at 100° C. for 4 h. The reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the title compound (0.01 g, 9%). LCMS: 517.30 (M+1)+; HPLC % 98.12 (@ 254 nm) (Rt; 3.972; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% Bin 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.16 (t, 1H), 7.58 (d, 2H, J=8 Hz), 7.34-7.36 (m, 2H), 7.18 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=4 Hz), 3.84 (d, 2H, J=10.8 Hz), 3.42 (s, 2H), 3.02 (m, 2H), 2.66 (m, 1H), 2.63 (s, 3H), 2.50 (3H merged in solvent peak), 2.23 (s, 3H), 2.20 (s, 3H), 2.16 (s, 3H), 2.10 (s, 3H), 1.60 (m, 4H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:1][C@@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:7]1
Reactant: C[C@H]1CN(c2ccccn2)CCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CN(c2ccccn2)CCN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To a solution of (S)-tert-butyl 2-methyl-4-(pyridin-2-yl)piperazine-1-carboxylate (5.2 g, 18.75 mmol,) in dichloromethane (30 ml) was added trifluoroacetic acid (5 ml). After stirring overnight at room temperature, the pH was adjusted to 8 with an aqueous sodium carbonate solution, extracted with dichloromethane (3×150 ml), dried over anhydrous magnesium sulfate and concentrated under vacuum to afford (S)-3-methyl-1-(pyridin-2-yl)piperazine as yellow oil (3.1 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:27])[N:10]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:13]=1.[CH3:28][N:29]([CH2:31][CH2:32]Cl)[CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:27])[N:10]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:32][CH2:31][N:29]([CH3:30])[CH3:28])=[CH:24][CH:25]=2)[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:13]=1
Reactant: CN(C)CCCl
Reactant: O=c1c(-c2ccccc2Cl)cc(-c2ccccn2)cn1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCOc1ccc(-n2cc(-c3ccccn3)cc(-c3ccccc3Cl)c2=O)cc1
Temperature: 60 °C
Yield: 27.7 %

Procedure:
3-(2-Chlorophenyl)-5-(2-pyridyl)-1-(4-hydroxyphenyl)-1,2-dihydropyridin-2-one (82 mg) and 57 mg of N,N-dimethylaminoethyl chloride were dissolved in 2 ml of dimethylformamide, 55 mg of potassium carbonate were added thereto at 60° C. and the mixture was stirred for one night. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated in vacuo and purified by an NH silica gel column chromatography (hexane-ethyl acetate system) to give 27 mg of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([NH2:8])=[N:5][N:4]=1)[CH3:2].N1C=CC=CC=1.[C:15]1([O:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[C:15]1([O:21][C:22](=[O:23])[NH:8][C:6]2[S:7][C:3]([CH2:1][CH3:2])=[N:4][N:5]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCc1nnc(N)s1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1nnc(NC(=O)Oc2ccccc2)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5-Ethyl-[1,3,4]thiadiazol-2-ylamine (2.5 g, 19.4 mmol) and pyridine (1.72 ml, 21.3 mmol) in dichloromethane (70 ml) is cooled to −70° C. and treated with a solution of phenylchloroformate (2.45 ml, 19.6 mmol) in dichloromethane (10 ml) dropwise. The reaction mixture is allowed to warm to ambient temperature and stirred for 3 hours during which a precipitate forms. The precipitate is collected by filtration, and dried under vacuum to afford (5-Ethyl-[1,3,4]thiadiazol-2-yl)-carbamic acid phenyl ester as white solid. [M+H] 250.15
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[N:18]=1>>[N:20]1[CH:21]=[CH:22][N:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:13]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[S:25][C:15]=2[N:16]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: O=[N+]([O-])c1cccc(CNc2nc(-c3cnccn3)nc3sc([N+](=O)[O-])cc23)c1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyrazin-2-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3-nitrobenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]2[CH3:14])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:26][CH2:27][CH:28]=[C:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]=2[CH2:33][O:32][C:31]2[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:26][CH2:27][CH:28]=[C:29]3[C:35]4[CH:36]=[CH:37][CH:38]=[N:39][C:34]=4[CH2:33][O:32][C:31]4[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]3=4)[CH2:10][C@@H:9]2[CH3:14])=[CH:6][CH:7]=1
Reactant: C[C@H]1CNCCN1c1ccc(Cl)cc1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: C[C@H]1CN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CCN1c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 17.6 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-3-(S)-methyl-piperazine (0.56 g, 2.6 mmol) in isopropanol (20 mL) was added 2,6-lutidine (0.305 mL, 2.6 mmol) and catalytic potassium iodide. This mixture was heated to 80° C., and then treated with 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.64 g, 1.7 mmol), added in portions over 2 h. The solution was then stirred at 80° C. for an additional 20 h. The reaction was concentrated in vacuo and purified by flash chromatography (100% dichloromethane to 2% methanol/dichloromethane) to yield the title compound (0.151 g, 18%). 1H-NMR (CDCl3) δ: 1.0 (3H, d), 1.57 (6H, s), 1.79 (s, 1H), 2.25–2.52 (7H, m), 2.66–2.69 (1H, m), 2.98–3.12 (2H, m), 3.68–3.73 (1H, m), 5.32 (2H, br s), 6.17 (1H, t), 6.82 (3H, d), 7.18–7.31 (4H, m), 7.44 (1H, d), 7.56–7.60 (1H, m), 8.50 (1H, dd). ESI-MS m/z: 504 (M), UV retention time: 1.49 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[N:18][C:17]([C:20]#[N:21])=[C:16](Cl)[N:15]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][NH2:25]>CC(O)C.O>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:15]=[C:16]3[NH:24][N:25]=[C:20]([NH2:21])[C:17]3=[N:18][CH:19]=2)=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cnc(C#N)c(Cl)n2)cc1
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cnc3c(N)n[nH]c3n2)cc1
Temperature: 120 °C

Procedure:
[4-(6-Chloro-5-cyano-pyrazin-2-yl)-phenyl]carbamic acid tert-butyl ester (1.0 g) was suspended in a mixture of 10 ml iPrOH and 10 ml 35% hydrazine in water at RT and heated to 120° C. by microwave irradiation for 70 min under stirring in a sealed vessel. The reaction mixture was left to cool to RT, and the precipitate was filtered off and washed with water to afford [4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-carbamic acid tert-butyl ester as a yellow solid after drying under vacuum. Yield: 815 mg (83%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[NH:12][CH3:13])[CH3:2].[Cl:15]N1C(C)(C)C(=O)N(Cl)C1=O>C(O)(=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([Cl:15])[CH:8]=[C:7]([F:11])[C:6]=1[NH:12][CH3:13])[CH3:2]
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Reactant: CCOC(=O)c1cccc(F)c1NC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(Cl)cc(F)c1NC
Temperature: 25 °C
Reaction time: 3 h
Yield: 124 %

Procedure:
To a solution of 3-fluoro-2-methylaminobenzoic acid ethyl ester (124 mg, 0.63 mmol) in acetic acid (4 ml) was added 1,3-dichloro-5,5-dimethylhydantoin (93 mg, 0.47 mmol). The reaction mixture was stirred at RT for 3 h. The mixture was diluted with ethyl acetate and then washed with sat. NaHCO3. The organic phase was then washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give a residue which was purified by flash column chromatography to give 5-chloro-3-fluoro-2-methylaminobenzoic acid ethyl ester (135 mg, 93%) as a yellow oil. 1H NMR (CDCl3, 300 MHz): 7.67 (dd, J=2.5, 1.5 Hz, 1H), 7.52 (brds, 1H), 7.09 (dd, J=13.5, 2.5 Hz, 1H), 4.31 (q, J=7.0 Hz, 2H), 3.11 (m, 3H), 1.38 (t, J=7.0 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][S:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:45])[C:27]([CH3:44])([C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1)[CH3:28]>>[CH3:24][O:25][C:26](=[O:45])[C:27]([CH3:28])([C:29]1[CH:30]=[CH:31][C:32]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH2:14][S:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:33][CH:34]=1)[CH3:44]
Reactant: COC(=O)C(C)(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CSCCc1ccccc1
Product: COC(=O)C(C)(C)c1ccc(-c2ccc(-c3onc(C)c3CSCCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 5-(4-bromo-phenyl)-3-methyl-4-phenethylsulfanylmethyl-isoxazole and 2-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13](Cl)=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:20][C:21]1[N:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24].C(N(CC)CC)C.CS(Cl)(=O)=O>C(#N)C>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:14][C:23](=[O:24])[C:22]4[CH:26]=[CH:27][CH:28]=[N:29][C:21]=4[N:20]=3)=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncccc1C(=O)O
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2ncccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
5-Trifluoromethyl-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid chloride (example 2, step 3) (800 mg) was added to a mixture of 2-aminonicotinic acid (356 mg) in acetonitrile (20 mL). The mixture was stirred for 10 minutes at room temperature and triethylamine (360 μL) was added and stirred for 15 minutes, before a second portion of triethylamine (720 μL) was added. After the mixture was stirred for further 15 minutes at room temperature, methanesulfonyl chloride (220 μL) was added. After stirring for 1.5 hours at room temperature, the reaction was quenched with water and extracted 2× with ethyl acetate, washed with brine, dried over MgSO4 and concentrated in vacuum. The residue was purified by column chromatography (silica 60, chloroform/ethyl acetate=1:1, Rf=0.40) to afford 660 mg of the title compound of the formula
Reaction SMILES: [CH:1]1([S:7][C:8]2[CH:15]=[CH:14][C:11](C=O)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][O:17][CH:18](OC)[O:19][CH3:20].C[O-].[Na+]>CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:8]1([S:7][C:1]2[CH:6]=[CH:5][C:4]([CH:18]([O:19][CH3:20])[O:17][CH3:16])=[CH:3][CH:2]=2)[CH2:15][CH2:14][CH2:11][CH2:10][CH2:9]1
Reactant: COC(OC)OC
Reactant: O=Cc1ccc(SC2CCCCC2)cc1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1ccc(SC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 101.9 %

Procedure:
To a solution of 4-(cyclohexylthio)benzaldehyde (215 mg, 0.976 mmol) in methanol (4 mL) was added trimethylorthoformate (130 μL, 1.19 mmol) and p-toluenesulfonic acid (15 mg, 0.079 mmol), and the resulting solution stirred at room temperature for 72 hours. Sodium methoxide solution (25 wt %, 18 μL) was then added to the solution, and the volatiles removed in vacuo to afford crude cyclohexyl(4-(dimethoxymethyl)phenyl)sulfane (˜265 mg, quantitative yield) which was used directly without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1.CO.[BH4-].[Na+]>O1CCCC1>[OH:16][CH2:15][C:11]1[CH:10]=[C:9]([C:5]2[C:4]([CH3:17])=[CH:3][C:2]([OH:1])=[CH:7][C:6]=2[CH3:8])[CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(O)cc(C)c1-c1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(O)cc(C)c1-c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 93.6 %

Procedure:
A solution of 4′-hydroxy-2′,6′-dimethylbiphenyl-3-carbaldehyde (6.95 g, 30.7 mmol) in a mixed solvent of methanol (30 mL) and tetrahydrofuran (60 mL) was ice-cooled, sodium borohydride (90%, 1.29 g, 30.7 mmol) was added, and the mixture was stirred for 20 hr under nitrogen atmosphere, during which the mixture was allowed to gradually warm to room temperature. The reaction mixture was concentrated under reduced pressure, the residue was treated with diluted hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (6.56 g, yield 93%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([F:24])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.Cl[C:35]([O:37][CH3:38])=[O:36]>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:35]([O:37][CH3:38])=[O:36])[CH2:9]2)=[N:4][C:3]=1[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([F:24])[CH:15]=1
Reactant: COC(=O)c1ccc(-c2nc(C3CCCNC3)cnc2N)cc1F
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nc(C3CCCN(C(=O)OC)C3)cnc2N)cc1F
Reaction time: 0.5 h

Procedure:
To methyl 4-(3-amino-6-(piperidin-3-yl)pyrazin-2-yl)-2-fluorobenzoate (55 mg, 0.166 mmol) (for synthesis, see Example 34, Step 7) in DCM (3 mL) in ice bath was added DIEA (0.116 mL, 0.666 mmol) and methyl chloroformate (0.013 mL, 0.166 mmol). The reaction mixture was stirred at in ice bath for 30 min. The reaction mixture was partitioned between DCM and water. The DCM layer was separated, washed with brine, dried over sodium sulfate, filtered and evaporated. The residue (50 mg, 77%) was taken to the next step without further purification. LCMS (m/z): 389.2 (MH+), 0.785 min.
Reaction SMILES: [CH3:1][N:2]([CH3:4])[NH2:3].C([O:8][C@@H:9]1[C@H:13]([O:14]C(=O)C)[C@@H:12]([CH2:18][O:19]C(=O)C)[O:11][C@H:10]1[N:23]1[CH:31]=[N:30][C:29]2[C:24]1=[N:25][C:26]([NH2:33])=[N:27][C:28]=2Cl)(=O)C.N>>[NH2:33][C:26]1[N:27]=[C:28]([NH:3][N:2]([CH3:4])[CH3:1])[C:29]2[N:30]=[CH:31][N:23]([C:24]=2[N:25]=1)[C@@H:10]1[O:11][C@H:12]([CH2:18][OH:19])[C@@H:13]([OH:14])[C@H:9]1[OH:8]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CN(C)N
Agent: N
Product: CN(C)Nc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 18.4 %

Procedure:
The title compound was prepared according to method A as described in example 4 by reacting 1,1-dimethylhydrazine (0.79 g, 13.1 mmol) with 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2-amino-6-chloro-9H-purine (4.0 g, 9.35 mmol) and debenzoylating the purified product using methanolic ammonia to provide the title 2-amino-N-(dimethylamino)adenosine (after column chromatography) as an amorphous foam (0.56 g, 45%), 1H NMR (DMSO-d6)γ 2.54 (6H, s, 2×--CH3), 3.50-3.57 (1H, m, H-5'b), 3.61-3.68 (1H, m, H-5'b), 3.93 (1H, q, H-4'), 4.12 (1H, q, H-3'), 4.51 (1H, q, H-2'), 5.12, 5.38 (2H, 2d, 2'- and 3'-OH), 5.42 (1H, t, 5'-OH), 5.76 (1H, d, H-1'), 5.95 (2H, s, --NH2), 7.93 (1H, s, H-8), 8.20 (1H, s, N-H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.[F:10][C:11]1[CH:34]=[CH:33][C:14]([O:15][C:16]2[C:17](=[O:32])[NH:18][N:19]=[CH:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:13][CH:12]=1.N>O>[F:9][C:4]1[CH:3]=[C:2]([N:18]2[C:17](=[O:32])[C:16]([O:15][C:14]3[CH:33]=[CH:34][C:11]([F:10])=[CH:12][CH:13]=3)=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:24][CH:23]=3)[CH:20]=[N:19]2)[CH:7]=[CH:6][C:5]=1[F:8]
Reactant: Fc1ccc(Br)cc1F
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2Oc2ccc(F)cc2)cc1
Agent: N
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to Example 93, substituting 1-bromo-3,4-difluorobenzene in place of 4-bromothioanisole and 4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 108A) in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 185 mg, 39%). mp 178–180° C. 1H NMR (300 MHz, CDCl3) δ 3.11 (s, 3H), 6.89–7.04 (m, 4H), 7.45–7.52 (m, 1H), 7.45–7.52 (m, 1H), 7.61 (dt, J=6 Hz, 3 Hz, 1H), 7.82 (d, J=9 Hz, 2H), 8,07 (d, J=9 Hz, 2H), 8.08 (s, 1H). MS (DCI/NH3) m/z 473 (M+H)+, 490 (M+NH4)+. Anal. calc. for C23H15F3N2O4S.0.5 H2O: C, 57.38; H, 3.33; N, 5.83. Found: C, 57.17; H, 3.13; N, 5.62.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([OH:14])=[C:8]([O:15][CH3:16])[CH:7]=1)=O.[CH2:25]1[C:30](=[O:31])[O:29][CH2:28][C:26]1=O>S(=O)(=O)(O)O.C(O)(=O)C>[CH3:22][O:21][C:19]1[C:18]([O:23][CH3:24])=[CH:17][C:3]2[C:4]([C:6]3[CH:11]=[C:10]([O:12][CH3:13])[C:9]([OH:14])=[C:8]([O:15][CH3:16])[CH:7]=3)=[C:25]3[C:30](=[O:31])[O:29][CH2:28][C:26]3=[N:1][C:2]=2[CH:20]=1
Reactant: O=C1COC(=O)C1
Reactant: COc1cc(N)c(C(=O)c2cc(OC)c(O)c(OC)c2)cc1OC
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1cc2nc3c(c(-c4cc(OC)c(O)c(OC)c4)c2cc1OC)C(=O)OC3
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 87.9 %

Procedure:
One drop of conc. sulfuric acid was added to a mixture of 2-amino-4,5,3',5'-tetramethoxy-4'-hydroxybenzophenone (0.333 g), tetronic acid (tetrahydrofuran-2,4-dione) (0.11 g) and acetic acid (10 ml), and the mixture was stirred at 100° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residual oil was poured into water, neutralized with an aqueous saturated sodium bicarbonate solution and extracted with chloroform. The chloroform layer was washed with water and dried over magnesium sulfate. Evaporation of the solvent gave 6,7-dimethoxy-9-(4-hydroxy-3,5-dimethoxyphenyl)furo[3,4-b]quinoline -1(3H)-one (0.349 g, 88%) which was then recrystallized from methanol. Pale yellow needles. mp. 247°-248° C.