Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.N1C=CC=CC=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>CN(C=O)C>[O:20]([C:18]([NH:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1)=[O:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1nc2cnccc2s1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Nc1nc2cnccc2s1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 71.1 %

Procedure:
To a mixture of 2-aminothiazolo[4,5-c]pyridine (302 mg, 2 mmoles) and pyridine (0.2 ml) in 5 ml of DMF was added phenyl chloroformate (400 mg, 2.5 mmoles), and the mixture was stirred at room temperature for 1.5 days. The crystalline precipitate was collected by filtration to afford 386 mg (71%) of the title compound. Mp. >290° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:18][C:17]3[C:12](=[CH:13][C:14]([N+:19]([O-])=O)=[CH:15][CH:16]=3)[C:11](=[O:22])[N:10]2[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:5][CH:4]=1)#[N:2].[H][H]>CO.[Pd]>[NH2:19][C:14]1[CH:13]=[C:12]2[C:17]([CH2:18][CH:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[N:10]([CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:11]2=[O:22])=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCCCN1C(=O)c2cc([N+](=O)[O-])ccc2CC1c1ccc(C#N)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCN1C(=O)c2cc(N)ccc2CC1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of Intermediate 1 (350 mg, 0.78 mmol) in 20 mL of MeOH was added 10% Pd/C (40 mg). A balloon filled with hydrogen gas was attached, and the reaction was stirred at 25° C. for 12 hrs. The mixture was filtered through Celite pad and the solvent was evaporated. The residue was purified by medium pressure liquid chromatography on silica gel using ethyl acetate:hexane (8:2) to yield Intermediate 13 as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]2[NH:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.O1CCOCC1.Br[C:39]1[S:40][C:41]2[C:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:46][CH:45]=[CH:44][C:42]=2[N:43]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15]([C:39]3[S:40][C:41]4[C:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:46][CH:45]=[CH:44][C:42]=4[N:43]=3)[CH2:14][C@H:13]2[NH:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NC(CC)CC)nc1Cl
Reactant: CCOC(=O)c1cccc2nc(Br)sc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc2nc(N3CC[C@@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](NC(CC)CC)C3)sc12
Yield: 55.8 %

Procedure:
The same operation as in Example (196c) was performed using tert-butyl trans(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-[(1-ethylpropyl)amino]piperidine-1-carboxylate obtained in Example (215a) (16.0 mg, 0.036 mmol), 4 N hydrochloric acid/1,4-dioxane (1 mL), ethyl 2-bromo-1,3-benzothiazole-7-carboxylate obtained in Example (1f) (11 mg, 0.040 mmol) and sodium carbonate (38 mg, 0.362 mmol), to obtain 11 mg of the title compound (56%) as a pale yellow oily substance.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([O:7][CH:8]2[CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>ClCCCl>[NH:10]1[CH2:11][CH:8]([O:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccncc2)C1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc(OC2CNC2)ccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.4 %

Procedure:
tert-Butyl 3-(pyridin-4-yloxy)azetidine-1-carboxylate (494 mg) was mixed with DCE (5 ml), and TFA (2 ml) was added thereto, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (CHCl3/MeOH) to obtain 4-(azetidin-3-yloxy)pyridine (268 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([NH:15][CH3:16])=[O:14].C(N(C(C)C)C(C)C)C>CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([NH:15][CH3:16])=[O:14])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CNC(=O)c1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CNC(=O)c1cccc(Nc2ccnc(Cl)n2)c1
Temperature: 60 °C
Reaction time: 23 h
Yield: 88.2 %

Procedure:
To 2,4-dichloropyrimidine (250.0 mg, 1.678 mmol) and 3-amino-N-methylbenzamide (252 mg, 1.678 mmol) in 2-propanol (8390 μL) in a disposable sealed tube at RT was added N-ethyl-N-isopropylpropan-2-amine (585 μL, 3.36 mmol). The resulting reaction mixture was heated at 60° C. for 22 h, then to 70° C. for 23 h, then 80° C. for 3 days, cooled to RT, concentrated, purified using MPLC (5 g cartridge, 12 g column, 0 to 60% 90/10 CH2Cl2-MeOH in CH2Cl2) giving 3-(2-chloropyrimidin-4-ylamino)-N-methylbenzamide (389.0 mg).
Reaction SMILES: C[N:2]([CH:4]=[C:5]([N:11]1[CH:15]=[C:14]([C:16]#[N:17])[N:13]=[CH:12]1)[C:6]([O:8]CC)=O)C.[NH:18]([C:20]1[N:25]=[CH:24][N:23]=[C:22]([N:26]2[CH2:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:21]=1)N.FC(F)(F)C(O)=O>O>[O:29]1[CH2:30][CH2:31][CH2:32][N:26]([C:22]2[N:23]=[CH:24][N:25]=[C:20]([N:18]3[C:6](=[O:8])[C:5]([N:11]4[CH:15]=[C:14]([C:16]#[N:17])[N:13]=[CH:12]4)=[CH:4][NH:2]3)[CH:21]=2)[CH2:27][CH2:28]1
Reactant: NNc1cc(N2CCCOCC2)ncn1
Reactant: CCOC(=O)C(=CN(C)C)n1cnc(C#N)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cn(-c2c[nH]n(-c3cc(N4CCCOCC4)ncn3)c2=O)cn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 200 mg (0.9 mmol) of the compound from Example 6A, 178 mg (0.9 mmol) of the compound from Example 14A and 33 μl (49 mg, 0.4 mmol) of trifluoroacetic acid in 3 ml of water is stirred at 100° C. for 16 h. The precipitated solid is filtered off and washed first with water and then with diethyl ether. The product is dried under reduced pressure. Yield: 120 mg (40% of theory)
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:16][C:7]([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[CH3:1])=[O:9])=[CH:13][CH:12]=1
Reactant: Cc1ccsc1C(=O)O
Reactant: NCc1ccc(F)cc1
Product: Cc1ccsc1C(=O)NCc1ccc(F)cc1
Yield: 94 %

Procedure:
Following the procedure as described in Preparation 18, making variations only as required to use 3-methylthiophene-2-carboxylic acid in place of 3-methylfuran-2-carboxylic acid to react with 4-fluorobenzylamine in place of benzylamine, N-(4-fluorobenzyl)-3-methylthiophene-2-carboxamide was obtained as a colorless solid in 94% yield: 1H NMR (300 MHz, CDCl3) δ 7.37-7.26 (m, 3H), 7.08-7.00 (m, 2H), 6.90 (d, J=5.0 Hz, 1H), 6.09 (br s, 1H), 4.57 (d, J=5.8 Hz, 2H), 2.52 (s, 3H); MS (ES+) m/z 250.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:9]2[S:8][C:7]([NH:10]C(=O)OC(C)(C)C)=[N:6][C:5]=2[C:4](=[O:18])[O:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:10][C:7]1[S:8][C:9]2[C:2]([CH3:1])([CH3:19])[O:3][C:4](=[O:18])[C:5]=2[N:6]=1
Reactant: CC(C)(C)OC(=O)Nc1nc2c(s1)C(C)(C)OC2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OC(=O)c2nc(N)sc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Example 249A (7.4 g, 26.0 mmol) in CH2Cl2 (20 mL) was added trifluoroacetic acid (20.0 mL, 260 mmol) slowly at 0° C. The reaction mixture was stirred at room temperature for 3 hours, and then concentrated under vacuum. The residue was diluted with ethyl acetate (100 mL) and neutralized with saturated aqueous NaHCO3 solution. The layers were separated and the aqueous phase was extracted with ethyl acetate (5×100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to afford the title compound. MS (ESI+) m/z 185 (M+H)+
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:10]([C:11]2[NH:15][CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:12]=2[F:26])=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4].C1OCCOCCOCCOCCOC1.[C:42]([C:44]1[CH:45]=[C:46]([S:50](Cl)(=[O:52])=[O:51])[CH:47]=[CH:48][CH:49]=1)#[N:43]>O1CCCC1.O>[C:42]([C:44]1[CH:45]=[C:46]([S:50]([N:15]2[C:11]([C:10]3[C:5]([C:3]#[N:4])=[N:6][CH:7]=[CH:8][CH:9]=3)=[C:12]([F:26])[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[CH:14]2)(=[O:52])=[O:51])[CH:47]=[CH:48][CH:49]=1)#[N:43]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CN(Cc1c[nH]c(-c2cccnc2C#N)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2cccc(C#N)c2)c(-c2cccnc2C#N)c1F)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) were added dropwise a solution (5 mL) of tert-butyl {[5-(2-cyanopyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (330 mg) in tetrahydrofuran, 15-crown-5 (330 mg) and 3-cyanobenzenesulfonyl chloride (302 mg) under ice-cooling and the mixture was stirred for 15 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→2:1) to give the title compound as a pale-yellow oil (yield 401 mg, 81%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[H-].[Na+].Cl[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].O>CN(C)C=O>[OH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:6]1[C:5]2[CH:9]=[C:10]([CH3:11])[C:2]([CH3:1])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: Cc1cc2nc[nH]c2cc1C
Reactant: OCCCCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2ncn(CCCCCCO)c2cc1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1.46 g of 5,6-dimethylbenzimidazole dissolved in 50 ml of dry N,N-dimethylformamide was added 0.84 g of NaH, and further, 8.2 ml of 6-chloro-1-hexanol. After the reaction was carried out by stirring the mixture at room temperature for one day, the reaction was stopped by an addition of water. Subsequently, according to the same processes as in Example 1, crude 1-(6-hydroxyhexyl)-5,6-dimethylbenzimidazole was obtained. The conversion to this compound from 5,6-dimethylbenzimidazole was found to be 95% or higher.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:15]2[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
p-Chlorophenol (7 g), p-nitrobromobenzene (11.0 g) and potassium carbonate (9.02 g) in dimethylsufoxide (35 ml) were heated with stirring at 120° C. for 24 hours and cooled, and the mixture was poured into water. The resulting precipitate was collected by filtration and washed with water. The resultant was heated in a mixed solvent of methanol/water [4:1,(v/v)], and allowed to cool. The resulting product was collected by filtration to give 4-(4-chlorophenoxy)nitrobenzene (12.92 g).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[C:8]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([CH3:39])[CH:31]=2)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:25][CH:24]([N:26]([CH3:28])[CH3:27])[CH2:23]3)=[C:16]([NH2:29])[CH:15]=2)=[N:11][CH:12]=1>C(Cl)Cl>[Cl:6][C:7]1[C:8]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([CH3:39])[CH:31]=2)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:23][CH:24]([N:26]([CH3:28])[CH3:27])[CH2:25]3)=[C:16]([NH:29][C:1](=[O:4])[CH:2]=[CH2:3])[CH:15]=2)=[N:11][CH:12]=1
Reactant: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3cn(C)c4ccccc34)n2)c(OC)cc1N1CC(N(C)C)C1
Reaction time: 1 h
Yield: 74.5 %

Procedure:
A solution of acryloyl chloride (0.049 mL, 0.60 mmol) in CH2Cl2 (0.5 mL) was added dropwise to a mixture of N-[5-chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-4-(3-dimethylaminoazetidin-1-yl)-6-methoxybenzene-1,3-diamine (Intermediate 112, 260 mg, 0.54 mmol) in CH2Cl2 (9 mL). This mixture was stirred for 1 h and then loaded onto a SCX column. The column was washed with CH3OH and the desired product was then eluted from the column using 2M methanolic ammonia. Appropriate fractions were concentrated in vacuo to give a brown gum. Purification by FCC, eluting with 1-10% CH3OH in CH2Cl2 (containing 1% concentrated aqueous ammonia) gave the title compound (214 mg, 74%) as a yellow solid after trituration with CH3OH (0.5 mL) using an ultrasound bath for 2 mins; 1H NMR: 2.10 (6H, s), 3.03-3.14 (1H, m), 3.59 (2H, t), 3.77 (3H, s), 3.90 (3H, s), 3.97 (2H, t), 5.66 (1H, dd), 6.16 (1H, dd), 6.23 (1H, s), 6.46 (1H, dd), 7.12 (1H, t), 7.23 (1H, t), 7.44-7.54 (2H, m), 8.20-8.38 (3H, m), 8.51 (1H, s), 9.21 (1H, s); m/z: ES+ MH+ 532.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([C:25]1([C:28](O)=[O:29])[CH2:27][CH2:26]1)#[N:24]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([NH:20][C:28]([C:25]2([C:23]#[N:24])[CH2:27][CH2:26]2)=[O:29])=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(CCCCCCCOCc2ccccc2)cc1
Reactant: N#CC1(C(=O)O)CC1
Product: N#CC1(C(=O)Nc2ccc(CCCCCCCOCc3ccccc3)cc2)CC1
Yield: 98.1 %

Procedure:
General procedure E was used to convert 1.05 mmol of 13a and 1.575 mmol of 1-cyanocyclopropanecarboxylic acid to 1.03 mmol (98%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][CH2:13][S:14](Cl)(=[O:16])=[O:15].CN(C1C=CC=CN=1)C>ClCCl.N1C=CC=CC=1>[Cl:12][CH2:13][S:14]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)(=[O:16])=[O:15]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=S(=O)(Cl)CCl
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(NS(=O)(=O)CCl)ccc1F
Reaction time: 3 h
Yield: 93.1 %

Procedure:
20 g of 4-fluoro-3-nitroaniline (128 mmol) was dissolved in a mixture of 200 mL of dichloromethane and 40 mL of pyridine. To this solution was added 21 g (140 mmol) of chloromethylsulfonyl chloride dropwise at 20-30° C., followed by the addition of 3.21 g of dimethylaminopyridine. The solution was stirred for an additional 3 hours. The reaction mixture was transferred into a separatory funnel and washed sequentially with water (twice with 25 mL), 5% HCl (twice with 25 mL), and water (25 mL). The organic phase was separated, dried (MgSO4), filtered and concentrated under reduced pressure to yield 32 g (93%) of the title compound as a solid melting at 112-113° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33]>C1COCC1.C(OCC)(=O)C>[C:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][C:4]([C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[C:29]([CH3:28])[CH:30]=2)([C:3]([O:2][CH3:1])=[O:17])[CH2:5][CH2:6]1)=[O:11])([CH3:14])([CH3:16])[CH3:15]
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1(C(=O)c2cccc(C)c2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
To a cold (−78° C.) solution of methyl N-tert-butoxycarbonyl-piperidine-4-carboxylate (0.25 g, 1.03 mmol; Example 3, Step B) in anhydrous THF (10 mL), a solution of sodium bis(trimethylsilyl)amide (1.2 mL, 1M, 1.2 mmol) was added over a period of 5 min. The resultant mixture was stirred at −78° C. for 1 h., and 3-methylbenzoyl chloride (135 μL, 1.02 mmol) was added. The reacting mixture was allowed to warm up to room temp. and stirred overnight. The product mixture was diluted with ethyl acetate and washed with brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 8-10% ethyl acetate in hexane gradient. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[S:28][C:27]2[C:26](=[O:29])[N:25]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])=[CH:32][CH:31]=3)[CH:24]=[N:23][C:22]=2[CH:21]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:40][N:39]([CH3:41])[CH2:38][CH2:37][O:36][C:33]1[CH:34]=[CH:35][C:30]([N:25]2[C:26](=[O:29])[C:27]3[S:28][C:20]([CH2:19][OH:18])=[CH:21][C:22]=3[N:23]=[CH:24]2)=[CH:31][CH:32]=1
Reactant: CN(C)CCOc1ccc(-n2cnc3cc(CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)sc3c2=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(-n2cnc3cc(CO)sc3c2=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-(tert-butyldiphenylsilanyloxymethyl)-3-[4-(2-dimethylaminoethoxy)phenyl]-3H-thieno[3,2-d]pyrimidin-4-one (1.6 g), tetra-N-butylammonium fluoride (3.2 mL) in THF (23 mL) was stirred at room temperature for 3 h. The solvent was removed in vacuo. The crude product was purified by preparative HPLC. The product with the molecular weight of 345.42 (C17H19N3O3S) was obtained in this way; MS (ESI): 346 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=[CH:12][C:11]=2[CH2:19][C:20]([OH:22])=O)=[C:7]([CH2:25][CH2:26][CH3:27])[CH:6]=1)([O:3][CH3:4])=[O:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[C:40]([C:44]1[CH:49]=[CH:48][C:47]([S:50]([NH2:53])(=[O:52])=[O:51])=[CH:46][CH:45]=1)([CH3:43])([CH3:42])[CH3:41].C1CCN2C(=NCCC2)CC1>C1COCC1>[C:40]([C:44]1[CH:49]=[CH:48][C:47]([S:50]([NH:53][C:20](=[O:22])[CH2:19][C:11]2[CH:12]=[CH:13][C:14]3[O:18][CH2:17][O:16][C:15]=3[C:10]=2[O:9][C:8]2[CH:23]=[CH:24][C:5]([C:1]([O:3][CH3:4])=[O:2])=[CH:6][C:7]=2[CH2:25][CH2:26][CH3:27])(=[O:51])=[O:52])=[CH:46][CH:45]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)c1ccc(S(N)(=O)=O)cc1
Reactant: CCCc1cc(C(=O)OC)ccc1Oc1c(CC(=O)O)ccc2c1OCO2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCCc1cc(C(=O)OC)ccc1Oc1c(CC(=O)NS(=O)(=O)c2ccc(C(C)(C)C)cc2)ccc2c1OCO2
Temperature: 50 °C

Procedure:
To the product of Step A (57.2 mg, 0.154 mmol) in dry THF (0.75 mL) was added CDI (76.0 mg, 0.469 mmol) and the reaction heated to 50° C. for 2.5 hr. To this solution was added a solution of p-t-butylphenyl-sulfonamide (131.7 mg, 0.618 mmol) and DBU (92.1 μL, 0.594 mmol) in dry THF (0.75 mL). The reaction continued to be stirred at 50° C. monitoring by thin layer chromatography until all of the mono-acid was consumed (approx. 3 hr). The reaction was concentrated in vacuo and the residue was taken up in 50:50/Et2O:EtOAc. The organic phase was washed with 10% citric acid (2×), water and brine then dried over MgSO4, filtered and the solvent removed. Purification was accomplished by radial chromatography eluting with 3:2/Hex:EtOAc. Yield=74.3 mg (0.131 mmol, 85%) rf=0.32 (80:10:1/CHCl3 :MeOH:NH4OH) FAB mass spectrum, m/e 590.0 (M+Na calculated for C30H33 NSO8 590). See Drummond, J. T.; Johnson, G. Tetrahedron Lett., 1988, 29, 1653.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]([OH:17])=O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:20])=O>>[CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]([Cl:20])=[O:17])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c2ccccc2cc2ccccc12
Product: O=C(Cl)c1c2ccccc2cc2ccccc12

Procedure:
A mixture of 18.85 g of 9-anthroic acid and 60 ml of thionyl chloride is heated under reflux for 1 hour. The excess thionyl chloride is removed under vacuum (30 mm; 90° bath temperature); 50 ml of toluene is added and the mixture is concentrated again. This operation is repeated once more to give 20.6 g of 9-anthroyl chloride as a very moisture-sensitive, yellow solid.
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[N:4][CH:3]=1.CCCCCC.C([Li])CCC.CON(C)[C:21](=[O:23])[CH3:22]>O1CCCC1>[CH3:1][C:2]1[S:6][C:5]([C:21](=[O:23])[CH3:22])=[N:4][CH:3]=1
Reactant: CON(C)C(C)=O
Reactant: Cc1cncs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)c1ncc(C)s1
Temperature: -78 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
Commercially available 5-methyl-1,3-thiazole (218 mg) was dissolved in tetrahydrofuran (5 ml) to prepare a solution which was then cooled to −78° C. A hexane solution (1.56 M) (1.4 ml) of n-butyllithium was slowly added to the cooled solution over a period of 10 min, and the mixture was stirred at −78° C. for 2 hr. N-Methoxy-N-methylacetamide (206 mg) was dissolved in tetrahydrofuran (2 ml) to prepare a solution which was then slowly added thereto over a period of 10 min, followed by stirring at −78° C. for 2 hr. The cooling bath was removed, an aqueous saturated ammonium chloride solution (5 ml) was added, and the mixture was stirred for 30 min. Further, water (5 ml) was added thereto, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated brine and was dried over sodium sulfate. The solvent was removed, and the residue was purified by chromatography on silica gel using hexane/ethyl acetate for development to give the title compound (267 mg, 86%).
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]([CH2:26][CH3:27])[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]([CH2:26][CH3:27])[S:23][C:13]=2[N:14]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: CCc1cc2c(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-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(4-fluorobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.Br[C:13](C)(C)[C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+].O>CC#N>[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][CH:6]=1)(=[O:11])[CH3:10]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)COc1ccc(NC(C)=O)cc1

Procedure:
To a solution of N-(4-hydroxyphenyl)acetamide (500 mg, 3.31 mmol) in CH3CN (10 mL) was added ethyl 2-bromo-2-methylpropanoate (663 mg, 3.97 mmol) and K2CO3 (3 g, 21.7 mmol) at 25° C. The mixture was heated at reflux for 16 h. The mixture had water (100 mL) added and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the title compound which was used in next step without further purification.