Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17](=O)[CH:18]=[CH:19][NH:20]2)=[CH:15][C:14]=1[C:24]([O:26][CH3:27])=[O:25])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O>[CH2:5]([O:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17]([Cl:3])=[CH:18][CH:19]=[N:20]2)=[CH:15][C:14]=1[C:24]([O:26][CH3:27])=[O:25])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)c1cc2c(=O)cc[nH]c2cc1OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(Cl)ccnc2cc1OCc1ccccc1

Procedure:
After adding thionyl chloride (70 ml) and a catalytic amount of dimethylformamide to methyl 7-(benzyloxy)-4-oxo-1,4-dihydro-6-quinolinecarboxylate (7.19 g, 23.2 mmol), the mixture was heated to reflux for 3 hours while stirring. The reaction solution was concentrated under reduced pressure, a 2N sodium hydroxide solution was gradually added for neutralization, extraction was performed with ethyl acetate, and the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, diethyl ether was added for crystallization, and the crystals were filtered out and blow-dried to obtain the title compound (4.067 g, 12.4 mmol) as light brown crystals.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH2:27][NH:28][CH3:29]>O1CCOCC1>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N:28]([CH2:27][C:21]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:20]=2[Cl:19])[CH3:29])=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: CNCc1ccc(Cl)cc1Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(CC(=O)c1ccc(Br)cc1)Cc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-bromo-1-(4-bromophenyl)ethanone (9.3 g, 33.45 mmol, 1.00 equiv) in dioxane (100 mL), triethylamine (5.0 g, 1.50 equiv), and (2,4-dichlorophenyl)-N-methylmethanamine (6.4 g, 33.68 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at 25° C. The solids were filtered out. The filtrate was used for next step directly.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:10])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(N)c(S(N)(=O)=O)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Temperature: 23 °C
Reaction time: 48 h
Yield: 73.7 %

Procedure:
2,5-Diamino-benzenesulfonamide (4.20 kg, 22.4 mol) was dissolved in dichloromethane (120 L) and pyridine (8.00 kg, 89.9 mol), and the resulting solution was cooled to 0° C. Methanesulfonyl chloride (2.80 kg, 24.4 mol) was added slowly, and the resulting mixture was allowed to warm to 23° C. and stirred for 2 days. The mixture was filtered and the resulting solid was washed with dichloromethane (2×20 L). The solid was diluted with water (100 L) and 1.0 M aqueous hydrochloric acid solution (25 L), and was then stirred at 23° C. for 1 h. The mixture was filtered and the resulting solid was washed with water (20 L) and then with methyl-tert-butyl ether (2×10 L). The solid was further dried in vacuo at 45° C. to afford the desired product, 2-amino-5-methanesulfonylamino-benzenesulfonamide (4.39 kg, 16.5 mol, 73%) as a pale pink solid. 1H NMR (400 MHz, CD3OD) δ: 2.89 (3H, s), 6.82 (1H, d, J=8.5 Hz), 7.20 (1H, dd, J1=8.5 Hz, J2=2.5 Hz), 7.58 (1H, d, J=2.5 Hz). LC-MS (ESI) calcd for C7H11N3O4S2 265.02, found 266.0 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.O=[C:18]([CH3:31])[CH2:19][C:20]([O:22][C@@H:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:21].[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(O)C.C(OCC)C>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:18]([CH3:31])[C:19]([C:20]([O:22][C@@H:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:21])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)CC(=O)O[C@H](C)c1ccccc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCO
Solvent: CCOCC
Product: Cc1nc2ccc(Cl)cc2c(-c2ccccc2)c1C(=O)O[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.2 %

Procedure:
To a solution of (2-amino-5-chlorophenyl)(phenyl)methanone (1.16 g, 5.0 mmol) in ethanol (20 ml) was added (R)-1-phenylethyl 3-oxobutanoate (1.3 g, 6.5 mmol) followed by ytterbium triflate (294 mg, 0.5 mmol). The mixture was stirred at room temperature for 12 hours, then the ethanol was removed under reduced pressure, and the residual viscous oil dissolved in ethyl acetate. The organic phase was poured into a separatory funnel and washed with 1M aqueous hydrochloric acid, water, then brine. The organic phase was seoarated, and the solvent was removed under reduced pressure to provide a viscous oil. This was dissolved in a small amount of diethyl ether, and the solution allowed to stand at room temperature overnight. The white precipitate formed was filtered, washed with cold diethyl ether, and dried under reduced pressure, to provide (R)-1-phenylethyl 6-chloro-2-methyl-4-phenylquinoline-3-carboxylate (1.33 g, 67%) as a white powder. Rf=0.26 using 80:20 hexanes:ethyl acetate eluent on glass backed silica gel plates. 1H NMR (CDCl3, 400 MHz) δ 8.98 (d, 1H, J=8.9 Hz); 7.96 (d, 1H, J=7.4 Hz); 7.72 (d, 1H, J=1.95 Hz); 7.6-7.1 (m, 10H); 5.88 (q, 1H, J=6.6 Hz); 3.05 (s, 3H); 1.3 (d, 3H, J=6.6 Hz). LC MS (CI) shows M+H 402.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9](=[O:16])[NH:8][N:7]=1.[CH3:20][C:21]1([C:24](O)=[O:25])[CH2:23][CH2:22]1.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CC(N(C)C)=O>[CH3:20][C:21]1([C:24]([NH:1][C:2]2[CH:19]=[CH:18][CH:17]=[C:4]([CH2:5][C:6]3[C:15]4[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=4[C:9](=[O:16])[NH:8][N:7]=3)[CH:3]=2)=[O:25])[CH2:23][CH2:22]1
Reactant: Nc1cccc(Cc2n[nH]c(=O)c3c2CCCC3)c1
Reactant: CC1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC1(C(=O)Nc2cccc(Cc3n[nH]c(=O)c4c3CCCC4)c2)CC1

Procedure:
A solution of EXAMPLE 89 (20 mg, 0.08 mmol), 1-methylcyclopropanecarboxylic acid (10 mg, 0.096 mmol), HATU (2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium) (38 mg, 0.1 mmol) and triethylamine (20 mg, 0.2 mmol) in dimethylacetamide (2.5 mL) was stirred at room temperature for 18 hours, and concentrated. The residue was dissolved in a 1:1 mixture of dimethylsulfoxide/methanol, and separated by HPLC (Waters Sunfire® C-8 analytical column [Milford, Mass.], 0.1% trifluoroacetic acid/water/CH3CN) to provide the title compound. MS (DCI/NH3) m/z 338 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 0.57-0.69 (m, 2H), 1.02-1.10 (m, 2H), 1.38 (s, 3H), 1.57-1.65 (m, 4H), 2.29-2.44 (m, 4H), 3.87 (s, 2H), 6.89 (d, J=7.63 Hz, 1H), 7.23 (t, J=7.93 Hz, 1H), 7.42 (s, 1H), 7.46 (d, J=8.24 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=2[S:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:20][C:21]1[CH:26]=[C:25]([C:2]2[C:11]3[O:10][CH:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=3[S:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC1CN(C(=O)OC(C)(C)C)Cc2scc(Br)c2O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC1CN(C(=O)OC(C)(C)C)Cc2scc(-c3cccc(F)c3)c2O1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
A mixed solution of tert-butyl 8-bromo-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (348 mg) obtained in Example 6, steps 1-6, (3-fluorophenyl)boronic acid (182 mg), dichlorobis(triphenylphosphine)palladium (35 mg) and potassium carbonate (415 mg) in DME-water (1:1, 10 ml) was stirred at 85° C. for 2 hr under a nitrogen stream. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 5-12% ethyl acetate/hexane) to give the title compound (281 mg, 77%) as a colorless oil.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11]CCCCCCCCC)=[N+:2]=[N-:3].[N:22](CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7]([C:8]1[NH:22][CH:11]=[CH:10][CH:9]=1)=[O:21])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCN
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [N-]=[N+]=NCCNC(=O)c1ccc[nH]1
Yield: 65.4 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, (0.249 g, 1.17 mmol) was reacted with 2-azidoethanamine (0.101 g, 1.17 mmol) and triethylamine (0.237 g, 2.34 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-1H-pyrrole-2-carboxamide (0.137 g, 66%). 1H NMR (300 MHz, CD3OD) δ 6.88 (d, 1H), δ 6.77 (d, 1H), δ 6.14 (t, 1H), δ 3.46 (t, 2H), δ 3.37 (q, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 162.9, 125.6, 122.2, 121.9, 110.9, 109.2, 50.6, 38.9 ppm; HRMS (ESI) calcd for C7H9N5O (M+) 179.0807. found 179.0803.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=3[S:14][CH:15]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(Cl)Cl.[Br:23]Br.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:23][C:15]1[S:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: CS(=O)(=O)c1ccc(-c2csc3ccccc23)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2c(Br)sc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(4-(methanesulfonyl)phenyl)benzo[b]thiophene (1 g) from Step 2 in CH2Cl2 (70 mL) one equivalent of a 1M Br2 solution in CCl4 was added. The mixture was stirred at 25° C. for 2 hrs, then a 10% Na2S2O3 solution was added. After extraction with EtOAc, the organic layers were washed with a saturated solution of NaHCO3 (3×), brine, and dried over MgSO4, filtered and the solvent evaporated under vacuum. Purification by column chromatography using 5% EtOAc in toluene afforded the title compound.
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]1[N:12]=[C:11]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:10]([C:18]2[CH:23]=[CH:22][C:21](=[O:24])[NH:20][CH:19]=2)=[CH:9][C:6]=1[C:7]#[N:8].I[CH2:26][CH3:27]>CO>[NH2:4][C:5]1[N:12]=[C:11]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:10]([C:18]2[CH:23]=[CH:22][C:21](=[O:24])[N:20]([CH2:26][CH3:27])[CH:19]=2)=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: N#Cc1cc(-c2ccc(=O)[nH]c2)c(-c2ccco2)nc1N
Reactant: CCI
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCn1cc(-c2cc(C#N)c(N)nc2-c2ccco2)ccc1=O
Reaction time: 0.25 h
Yield: 33.8 %

Procedure:
Sodium methoxide (155 mg, 2.87 mmol) was added to a suspension of 2-amino-6-(2-furyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinonitrile (400 mg, 1.44 mmol) in methanol (8 ml) at room temperature in a nitrogen atmosphere, followed by stirring. After 15 minutes, iodoethane (0.35 ml, 4.38 mmol) was added thereto, followed by stirring as it was. After 15 hours, additional iodoethane (0.35 ml, 4.38 mmol) was added thereto, and the mixture was further stirred. After 24 hours, the reaction solution was concentrated. The residue was subjected to silica gel column chromatography (elution solvent; hexane, hexane:ethyl acetate=2:1, 1:2, 1:5). The resulting crude objective compound was suspended in diethyl ether, and then the solid was collected by filtration and washed with diethyl ether, to give the title compound (149 mg, 34%) as a pale yellow solid.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:23])[C:13]2[C:8](=[N:9][C:10]([Cl:24])=[CH:11][N:12]=2)[N:7]=1)[CH:3]([CH3:5])[CH3:4].[C:25]([O:29][C:30](=[O:37])[NH:31][C:32]([CH3:36])([CH3:35])[CH:33]=O)([CH3:28])([CH3:27])[CH3:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:25]([O:29][C:30](=[O:37])[NH:31][C:32]([CH3:36])([CH3:35])[CH2:33][NH:1][CH:2]([C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:23])[C:13]2[C:8](=[N:9][C:10]([Cl:24])=[CH:11][N:12]=2)[N:7]=1)[CH:3]([CH3:4])[CH3:5])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)C(N)c1nc2nc(Cl)cnc2c(=O)n1Cc1ccccc1
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C(NCC(C)(C)NC(=O)OC(C)(C)C)c1nc2nc(Cl)cnc2c(=O)n1Cc1ccccc1
Reaction time: 0.17 h

Procedure:
Formula 201 where R2 is H; R3 is Cl; R5 is Benzyl; R6 is Isopropyl; R6′ is H; Ra and Rb are Methyl: W and Z are —N═: X and Y are —C═: To a solution of 2-(1-amino-2-methyl-propyl)-3-benzyl-7-chloro-3H-pteridin-4-one (1.10 g, 3.19 mmol) and (1,1-dimethyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (Seki et. al. Chem. Pharm. Bull. 1996, 44, 2061) (0.59 g, 3.19 mmol) in dichloromethane (80 mL) is added sodium triacetoxyborohydride (1.01 g, 4.79 mmol). The resultant mixture is maintained at ambient temperature for 4 hours, at which time it is quenched with brine (75 mL) and stirred vigorously for 10 minutes. The aqueous layer is extracted with dichloromethane (50 mL) and the combined extracts are dried over magnesium sulfate, filtered and concentrated under reduced pressure to give (±)-{2-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-pteridin-2-yl)-2-methyl-propylamino]-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester which is used in the subsequent step without purification.
Reaction SMILES: [C:1]([O:4][CH3:5])(=[O:3])[CH3:2].[Li+].CC([N-]C(C)C)C.CN(C)P(=O)(N(C)C)N(C)C.Br[CH2:26][C:27]([CH:29]([N:31]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:30])=[O:28]>C1COCC1>[CH3:5][O:4][C:1](=[O:3])[CH2:2][CH2:26][C:27](=[O:28])[C@@H:29]([N:31]([CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH3:30]
Reactant: CC(C(=O)CBr)N(Cc1ccccc1)Cc1ccccc1
Reactant: COC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)CCC(=O)[C@H](C)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.75 h
Yield: 62 %

Procedure:
Methyl acetate (1.0 mmol, 0.08 mL) was added dropwise to a solution of LDA (1.05 mmol) in 2.0 mL THF at -78° C., and the resulting solution was stirred for 45 minutes. Hexamethyl phosphoric triamide (1.0 mmol, 0.18 mL) was then added, and after 15 minutes a solution of α-(N,N-dibenzylamino)ethyl bromomethyl ketone (crude from the previous reaction, assumed to be 1.0 mmol) in 2.0 mL was added via syringe. The resulting solution was stirred at -78° C. for 45 minutes and then quenched with saturated solution of NaHCO3. After a work-up as described in Example 8, 0.39 g of crude product was obtained. The product was further purified by column chromatography on silica gel with 8:1 hexanes-ethyl acetate as the solvent system (Rf=0.33) to yield 0.21 g (62%) of methyl-(5S)-5-(N,N-dibenzylamino)-4-oxo-hexanoate as a colorless viscous oil. Analytical data: 1H NMR (300.15 MHz) δ 0.95 (d, J=6.6 Hz, 3H), 2.62-2.30 (m, 4H), 3.36 (q, J=6.2 Hz, 1H), 3.60 (ABq, δA =3.41, δB =3.82, J=13.5 Hz, 4H), 3.49 (s, 3H), 7.23-7.37 (m, 10H); 13C NMR 5.1, 38.9, 48.8, 51.4, 54.4, 57.5, 126.9, 128.2, 128.8, 129.2, 139.4, 170.4, 208.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[C:9]([SH:12])[NH:10][N:11]=2)[CH:2]=1.C(N(CC)CC)C.Cl[CH2:21][C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1)=[O:23]>CN(C=O)C>[Cl:31][C:27]1[CH:26]=[C:25]([NH:24][C:22](=[O:23])[CH2:21][S:12][C:9]2[NH:10][N:11]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[N:8]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: O=C(CCl)Nc1cccc(Cl)c1
Reactant: Sc1nc(-c2cccnc2)n[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CSc1nc(-c2cccnc2)n[nH]1)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
The thiol intermediate prepared in Step B (101 mg, 0.567 mmol) was dissolved in DMF (2 ml) and triethylamine (0.24 ml, 1.7 mmol). 2,3′-dichloroacetanilide (116 mg, 0.567 mmol) was added and allowed to stir at room temperature overnight. The mixture was loaded directly onto an HPLC reverse phase column and purified by water to acetonitrile gradient in the presence of 0.1% trifluoroacetic acid. The aqueous phase was evaporated by lyophilization to yield the title compound as a fluffy white solid (166 mg, 85% yield). MS (ES) 346.5 (M+H)+
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[N:11]([CH3:12])[C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3Cl)[CH:14]=2)=[N:9][CH:8]=1.[F:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=1[OH:33].C([O-])(O)=O.[Na+]>O(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[N:11]([CH3:12])[C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:33][C:25]3[CH:26]=[CH:27][C:28]([N+:30]([O-:32])=[O:31])=[CH:29][C:24]=3[F:23])[CH:14]=2)=[N:9][CH:8]=1
Reactant: Cn1c(C2OCCCO2)cnc1-c1cc2nccc(Cl)c2s1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cn1c(C2OCCCO2)cnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 180 °C
Yield: 31.2 %

Procedure:
A mixture of 40 (5.9 g, 17.57 mmol), 2-fluoro-4-nitrophenol (5.52 g, 35.1 mmol) and NaHCO3 (1.346 g, 16.02 mmol) in Ph2O (7 mL) was heated to 180° C. for 4 hours. The reaction mixture was cooled to RT and diluted with DCM, filtered and concentrated. Purification of the residue by column chromatography (eluent EtOAc) afforded 41 (2.5 g, 31% yield) as a yellow solid. MS (m/z): 457.1 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:21])[N:4]=1.[N:22]1[C:30]([NH2:31])=[C:29]2[C:25]([N:26]=[CH:27][NH:28]2)=[N:24][CH:23]=1>CN(C=O)C>[NH2:31][C:30]1[N:22]=[CH:23][N:24]=[C:25]2[C:29]=1[N:28]=[CH:27][N:26]2[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:21])[N:4]=1
Reactant: Nc1ncnc2nc[nH]c12
Reactant: O=c1c2c(F)cccc2nc(CCl)n1-c1ccccc1Cl
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2Cc1nc2cccc(F)c2c(=O)n1-c1ccccc1Cl
Yield: 64.3 %

Procedure:
Prepared according to Procedure C using Intermediate 2e (200 mg, 0.619 mmol), adenine (92 mg, 0.681 mmol), L2CO3 (94 mg, 0.680 mmol), and DMF (4 mL). The crude product was chromatographed in MeOH/CH2Cl2 to provide 168 mg of an off-white solid (64%), mp 159-172° C. (gradually decomposes). 1H NMR (DMSO-d6) δ: 8.10 (s, 1H); 8.08 (s, 1H); 7.73-7.89 (m, 3H); 7.57-7.71 (m, 2H); 7.37-7.48 (m, 2H); 7.34 (d, J=11 Hz, 1H); 7.30 (d, J=8.3 Hz, 1H); 5.14 (d, J=17 Hz, 1H); 4.94 (d, J=17 Hz, 1H). 13C NMR (DMSO-d6) ppm: 160.8 (d, J=264 Hz), 157.5 (d, J=4.2 Hz), 155.8, 152.4, 152.4, 150.0, 148.7, 142.1, 136.4 (d, J=11 Hz), 133.0, 132.2, 132.1, 131.2, 130.9, 129.4, 123.8 (d, J=3.6 Hz), 118.4, 114.5 (d, J=20 Hz), 110.2 (d, J=6.0 Hz), 44.9. MS (ES): m/z 422.0 (M+). Anal. calcd. for C20H13ClFN7O: C, 56.95; H, 3.11; Cl, 8.40; N, 23.24. Found: C, 54.62; H, 3.32; Cl, 9.40; N, 21.29.
Reaction SMILES: F[C:2]1[C:7]([C:8](=O)[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][NH2:12].C(Cl)Cl>C(O)CO>[CH3:9][C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[NH:12][N:11]=1
Reactant: NN
Reactant: CC(=O)c1cccnc1F
Solvent: OCCO
Solvent: ClCCl
Product: Cc1n[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 1.10 g (7.91 mmol) of 1-(2-fluoropyridin-3-yl)ethanone in 5 mL of ethylene glycol under nitrogen was treated with 265 μL (8.31 mmol) of hydrazine. This solution was stirred for 2 hours at room temperature and then heated at 165° C. for 1.5 hours. The solution was cooled to room temperature, poured into CH2Cl2 (25 mL), and extracted with H2O (2×50 mL). The organic portions were combined, dried (MgSO4), filtered and concentrated in vacuo to give the title product as a fluffy off-white solid. 1H NMR (CDCl3): 2.61 (s, 3H), 7.14 (m, 1H), 8.06 (dd, 1H), 8.58 (dd, 1H), 11.18 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([CH3:26])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[CH:25]=[C:24]([CH3:26])[S:23][C:13]=2[N:14]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: Cc1cc2c(NCc3ccc(F)cc3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-2-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(4-fluorobenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:26]12[CH2:34][C:30]([CH2:35]O)([CH2:31][CH2:32][CH2:33]1)[CH2:29][CH2:28][CH2:27]2.C([Li])CCC.CCCCCC>O1CCCC1>[N:26]12[CH2:34][C:30]([CH2:35][O:7][C:6](=[O:8])[C:5]3[CH:9]=[C:10]([Cl:11])[C:2]([NH2:1])=[CH:3][C:4]=3[O:12][CH3:13])([CH2:31][CH2:32][CH2:33]1)[CH2:29][CH2:28][CH2:27]2
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: OCC12CCCN(CCC1)C2
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(N)c(Cl)cc1C(=O)OCC12CCCN(CCC1)C2
Reaction time: 1 h
Yield: 57.3 %

Procedure:
A solution of 4-amino-5-chloro-2-methoxybenzoic acid (2.02 g, 10 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.70 g, 10.5 mmol), stirred for one hour, then degassed with a stream of nitrogen over 10 minutes. Meanwhile, a cooled (-10° C.) solution of 1-azabicyclo[3.3.1]nonane-5-methanol (1.71 g, 11 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated (via syringe) with 2.5N n-butyllithium/hexane (10.7 mmol), stirred for 30 minutes, concentrated in vacuo, and taken up in anhydrous tetrahydrofuran (10 mL) under nitrogen. The above prepared suspension was transferred into this solution, and the mixture was stirred overnight (18 hours) and concentrated in vacuo. The residue was partitioned between methylene chloride (100 mL) containing a little 2-propanol and saturated aqueous sodium carbonate (50 mL), and the organic layer was separated. The aqueous solution was extracted with methylene chloride (2×50 mL), and the combined organic solution was dried (Na2SO4), concentrated in vacuo and recrystallized from acetonitrile (2 crops) to afford 1.94 g (57%) of pale yellow solid; mp 152.5°-154.5° C.