Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][Si:7]([CH3:13])([CH3:12])[CH2:8][CH2:9][CH2:10][OH:11].S(=O)(O)[O-:15].[Na+].[Cr](O)(O)(=O)=O>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6].O>[CH3:6][Si:7]([CH3:13])([CH3:12])[CH2:8][CH2:9][C:10]([OH:15])=[O:11]
Reactant: C[Si](C)(C)CCCO
Reactant: O=S([O-])O
Agent: O=[Cr](=O)(O)O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: C[Si](C)(C)CCC(=O)O
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To 12.5 mL of water was added 8.73 g (0.0873 mole) of chromium trioxide which was mixed until all solid had dissolved. This solution was immersed in an ice/water bath, and 13.4 g (7.3 mL, 0.137 mole) of concentrated sulfuric acid (18M) was added cautiously. This was followed by the addition of 25 mL of water. The solution was then cooled to 0°-5° C. and added to a stirred solution of 16.5 g (0.125 mole) of 4,4-dimethyl-4-silapentanol in 800 mL of acetone which had been cooled to 0°-10° C. in an ice/water bath. During the addition the temperature was maintained at 20° C., and stirring was continued for three hours after the addition was complete. At the conclusion of this period sodium bisulfite was added to the reaction mixture in small portions until the brown color of chromic acid had disappeared from the upper layer. The two layers were separated, and the dense, green lower layer was extracted with 200 mL of petroleum ether. The layers were separated, and the upper layer was added to the upper layer which had been previously separated. This caused two phases to form. The layers were separated, and the lower layer was added to the lower layer from the reaction mixture. The combined lower layers were extracted three times with 200 mL of petroleum ether. The extracts were combined with the previously separated petroleum ether extract, and this mixture was successively washed twice with a saturated aqueous solution of sodium chloride, twice with a saturated aqueous solution of sodium bicarbonate, and finally with a saturated aqueous solution of sodium chloride. After being dried over anhydrous magnesium sulfate, the solvent was evaporated from the combined extracts under reduced pressure, leaving 4,4-dimethyl-4-silapentanoic acid as a residue. The NMR spectrum was consistent with the proposed structure. This is the method described in Organic Synthesis, Vol. V, p 866.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:28][CH:29]([F:31])[F:30])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[F:27])[C:10]([CH2:17][CH3:18])=[N:11]2.[OH-].[Li+]>O1CCCC1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][C:9]2[C:10]([CH2:17][CH3:18])=[N:11][C:12]3[C:7]([C:8]=2[O:28][CH:29]([F:30])[F:31])=[C:6]([O:5][CH2:4][C:3]([OH:32])=[O:2])[CH:15]=[CH:14][C:13]=3[F:16])=[C:21]([F:27])[CH:22]=1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(Cl)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of [3-(4-chloro-2-fluorobenzyl)-4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy]acetic acid methyl ester (0.071 g), tetrahydrofuran (5.0 mL) and 1.0 M aqueous lithium hydroxide solution (0.30 mL) was stirred at room temperature for 2 hour. The solvent was removed under reduced pressure and the residue was diluted with water. The pH of mixture was adjusted to 4 by the addition of sodium dihydrogenphosphate and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure to afford title compound, 0.064 g.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[C:19](I)=[CH:18][N:17]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH:29][S:30]([CH:33]2[CH2:35][CH2:34]2)(=[O:32])=[O:31])[CH2:4]1)[CH3:2].[C-:36]#[N:37].[K+]>CN(C=O)C.[Cu]I.C1OCCOCCOCCOCCOCCOC1>[C:36]([C:19]1[C:13]2[N:12]3[C:8]([C@@H:7]4[C@H:3]([CH2:1][CH3:2])[CH2:4][C@H:5]([NH:29][S:30]([CH:33]5[CH2:35][CH2:34]5)(=[O:32])=[O:31])[CH2:6]4)=[N:9][N:10]=[C:11]3[CH:16]=[N:15][C:14]=2[N:17]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])[CH:18]=1)#[N:37]
Reactant: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1c1nnc2cnc3c(c(I)cn3COCC[Si](C)(C)C)n12
Reactant: [C-]#N
Agent: [Cu]I
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1c1nnc2cnc3c(c(C#N)cn3COCC[Si](C)(C)C)n12
Temperature: 110 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
To a solution of N-((1S,3R,4S)-3-ethyl-4-(8-iodo-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide (0.1 g, 0.16 mmol, prepared using KK from Preparation #GGG.1) in DMF (1.2 mL) was added potassium cyanide (0.03 g, 0.40 mmol), copper(I) iodide (0.076 g, 0.40 mmol), tetrakis(triphenyl-phosphine)palladium(0) (0.002 g, 0.002 mmol) and 18-crown-6 (0.003 g, 0.01 mmol). The reaction mixture was stirred at about 110° C. for about 4 h and cooled to ambient temperature. The solvent was removed under reduced pressure. The residue was partitioned between EtOAc (15 mL) and water (8 mL). The aqueous layer was further extracted with EtOAc (15 mL). The combined organic layers were dried with MgSO4, filtered, and concd under reduced pressure to give N-((1S,3S,4R)-3-(8-cyano-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-4-ethylcyclopentyl)cyclopropanesulfonamide (0.069 g, 82%): LC/MS (Table 1, Method b) Rt=2.50 min; MS m/z: 530 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:18]([CH2:19][N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.C([BH3-])#N.[Na+].C(O)(=O)C.[NH:39]1[CH:43]=[CH:42][N:41]=[C:40]1[CH:44]=O>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:19][N:20]([CH2:21][CH2:22][CH3:23])[CH2:24][CH2:25][CH3:26])=[CH:27][CH:28]=2)=[CH:11][CH:10]=1)[CH2:44][C:40]1[NH:39][CH:43]=[CH:42][N:41]=1
Reactant: CCCN(CCC)Cc1ccc(OCc2ccc(CNCc3ncc[nH]3)cc2)cc1
Reactant: O=Cc1ncc[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)Cc1ccc(OCc2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)cc1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
The compound (20.4 mg) obtained in Example 35-5 was dissolved in anhydrous methanol (2.0 ml) and added with sodium cyanoborohydride (9.50 mg), acetic acid (2.0 ml), and 2-imidazole carboxaldehyde (9.60 mg), followed by stirring at room temperature under a nitrogen atmosphere for 6.5 hours and a half. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and added with a saturated aqueous sodium bicarbonate solution, followed by stirring. The solution was subjected to extraction with chloroform and the extract was then washed with a saturated aqueous sodium bicarbonate solution and saturated saline solution. Subsequently, the organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off, and the residue was treated with hydrochloric acid and then purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (4.50 mg) of the subject compound as a white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:11][NH:12][C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17]Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[Si:1]([O:8][CH2:9][C@@H:10]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC(=O)CCCCCl)CO[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)CN1CCCCC1=O
Reaction time: 4 h

Procedure:
Upon cooling a solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-3-(5-chloropentanamido)propan-2-ylcarbamate (500 mg, 1.18 mmol) in DMF (10 mL) to 0° C., NaH (52 mg, 1.30 mmol) was added. The reaction mixture was stirred for 4 h. The mixture was taken up in EtOAc, washed with saturated NaCl solution, dried over Na2SO4, concentrated under reduced pressure and the crude (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-3-(2-oxopiperidin-1-yl)propan-2-ylcarbamate was used in next step without purification (370 mg, 81%). 1H NMR (CDCl3, 300 MHz) δ 5.25 (d, 1H), 4.04-3.81 (m, 2H), 3.67-3.20 (m, 4H), 2.36 (m, 2H), 1.78 (m, 4H), 1.41 (s, 9H), 0.88 (s, 9H), 0.0 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.[CH3:11][C:12](=[CH:14][CH3:15])[CH3:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:11][C:12]([N:4]1[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:2]([CH3:1])=[N:3]1)([CH3:13])[CH2:14][CH3:15]
Reactant: COC(=O)c1c[nH]nc1C
Reactant: CC=C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCC(C)(C)n1cc(C(=O)OC)c(C)n1
Temperature: 120 °C
Reaction time: 4 h
Yield: 29 %

Procedure:
Methyl 3-methyl-1H-pyrazole-4-carboxylate (10.8 g) synthesized in Example 1(3) was dissolved in acetonitrile (100 mL), 2-methyl-2-butene (16.3 mL) and p-toluenesulfonic acid monohydrate (4.4 g) were added, and the mixture was stirred in a sealed tube at 120° C. for 4 hr. The reaction mixture was poured into aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (4.6 g, 29%) as an oil.
Reaction SMILES: CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[CH:15]1([C@@H:19]([CH3:28])[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])[CH2:18][CH2:17][CH2:16]1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C1COCC1>[C:22]1([C@H:20]([OH:21])[C@@H:19]([CH:15]2[CH2:18][CH2:17][CH2:16]2)[CH3:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[C@@H](C(=O)c1ccccc1)C1CCC1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](C1CCC1)[C@@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A dry flask was charged with 25 mL THF and a solution of L-Selectride® (12.6 mL, 1 M in THF, 12.6 mmol) was added. The solution was cooled to −78 C and a solution of (R)-Cyclobutylpropiophenone (2.38 grams, 12.6 mmol, from Step E) in 5 mL THF was added. After stirring at −78 C for 1 h the was warmed to room temperature gradually overnight. Sat'd sodium bicarbonate was added and the mixture was extrated with ethyl acetate. The organic portion was washed with water and sat'd NaCl. The solvent was removed and the residue was dissolved in methanol (100 mL). Concentrated HCl (1 mL) was added and the mixture was stirred at 50 C for 15 hours. After removal of the solvent the product was purified by flash chromatography (100/1 hexane/ethyl acetate →20/1 hexane ethyl acetate) to afford 1.4 grams (58%/o) of product. 1H NMR (500 MHz, CDCl3). δ 0.68 (d, 3H), 1.64-1.98 (m, 6H), 2.02-2.09 (m, 1H), 2.11-2.19 (m, 1H), 4.58 (d, 1H), 7.23-7.38 (m, 5H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[F:15][C:16]([F:26])([F:25])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][NH2:21].Cl.N>O>[CH3:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=[C:2]([NH:21][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([C:16]([F:15])([F:25])[F:26])[CH:18]=2)[CH:7]=1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: NCc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: N
Solvent: O
Product: Cc1cc(NCc2cccc(C(F)(F)F)c2)nc(-c2ccccn2)n1
Yield: 24.7 %

Procedure:
A mixture of 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (82.3 mg, 0.4 mmol), 3-trifluoromethylbenzylamine (70.1 mg, 0.4 mmol), water (5 ml) and 2N HCl (300 μl) was refluxed for two days. The resulting solution was basified to pH˜11 with ammonia and extracted with ethyl acetate (10 ml×3). The combined ethyl acetate extracts were dried with sodium sulfate, and evaporated under vacuum. The residue was purified by column chromatography (hexane/ethyl acetate: 1/1) to give the title compound as a solid (34 mg, 25%). 1H NMR (CD3OD): 8.59 (d, J=4.2 Hz, 1H), 8.27 (m, 2H), 7.86 (m, 2 H), 7.43 (m, 2H), 6.18 (s, 2H), 4.76 (s, 2H), 2.26 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([CH3:22])=[C:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:14][CH2:13]3)[O:9]2)=[CH:4][CH:3]=1.[CH2:24](Br)[CH:25]=[CH2:26].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:26]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([CH3:22])=[C:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:14][CH2:13]3)[O:9]2)=[CH:4][CH:3]=1)[CH:25]=[CH2:24]
Reactant: CCC(=O)N1CCC(c2oc3cc(O)ccc3c(=O)c2C)CC1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCOc1ccc2c(=O)c(C)c(C3CCN(C(=O)CC)CC3)oc2c1
Temperature: 55 °C
Reaction time: 20 h
Yield: 84.1 %

Procedure:
A solution of 7-hydroxy-3-methyl-2-(1-propanoylpiperidin-4-yl)-4H-chromen-4-one (1.00 g, 3.17 mmol) obtained in Example 31-2, allyl bromide (560 μL, 6.34 mmol), and potassium carbonate (613 mg, 4.44 mmol) in acetone (20 mL) was heated with stirring at a bath temperature of 55° C. for 20 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate. The desiccant was filtered off, and then the filtrate was concentrated under reduced pressure to obtain 947 mg of the title compound (yield: 84%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([C@H:19]([C:23]([O:25][CH3:26])=[O:24])[CH2:20][CH:21]=O)[CH2:13][C@H:12]1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:29]1[C:31]2([CH2:36][CH2:35][NH:34][CH2:33][C@H:32]2[OH:37])[CH2:30]1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([C@H:19]([C:23]([O:25][CH3:26])=[O:24])[CH2:20][CH2:21][N:34]2[CH2:35][CH2:36][C:31]3([CH2:30][CH2:29]3)[C@H:32]([OH:37])[CH2:33]2)[CH2:13][C@H:12]1[CH3:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CC=O)N1C[C@@H](C)N(C(=O)OCc2ccccc2)CCC1=O
Reactant: O[C@@H]1CNCCC12CC2
Agent: Cl
Product: COC(=O)[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1C[C@@H](C)N(C(=O)OCc2ccccc2)CCC1=O
Yield: 42 %

Procedure:
In analogy to the procedure described for example 58D, (R)-4-((S)-1-methoxycarbonyl-3-oxo-propyl)-2-methyl-5-oxo-[1,4]diazepane-1-carboxylic acid benzyl ester and (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2) gave the title compound in 42% yield as yellow oil. MS: 488.4 (MH+).
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17][C:18]([C:20]2[NH:21][N:22]=[N:23][CH:24]=2)=[O:19])[CH2:9][C@:10]([CH2:15][OH:16])([CH3:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH2:52]1[C:60]2[C:55](=[CH:56][C:57](O)=[CH:58][CH:59]=2)[CH2:54][CH2:53]1.CN1CCOCC1>C(Cl)Cl>[CH2:52]1[C:60]2[C:55](=[CH:56][C:57]([O:12][C:11](=[O:13])[C@@:10]([CH2:15][OH:16])([CH3:14])[CH2:9][C@H:8]([NH:17][C:18]([C:20]3[NH:21][N:22]=[N:23][CH:24]=3)=[O:19])[CH2:7][C:4]3[CH:5]=[CH:6][C:1]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:2][CH:3]=3)=[CH:58][CH:59]=2)[CH2:54][CH2:53]1
Reactant: C[C@@](CO)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1)C(=O)O
Reactant: Oc1ccc2c(c1)CCC2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@@](CO)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1)C(=O)Oc1ccc2c(c1)CCC2
Reaction time: 0.25 h
Yield: 0.9 %

Procedure:
(2S,4R)-5-Biphenyl-4-yl-2-hydroxymethyl-2-methyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid (118 mg, 290 μmol), HOBt (118 mg, 871 μmol), and EDCI (154 μL, 871 μmol) were dissolved into DCM and stirred for 15 minutes. 5-Indanol (310 mg, 2.3 mmol) and 4-methylmorpholine (128 μL, 1.2 mmol) were added and the resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with water and the DCM layer was separated and concentrated. AcOH was added and the product was purified by preparative HPLC to yield the title compound (1.4 mg; purity 95%). MS m/z [M+H]+ calc'd for C31H32N4O4, 525.24. found 5254.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:20][C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cccc(Cl)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2cccc(Cl)n2)sc2ccccc12
Yield: 36.4 %

Procedure:
A mixture of methyl thiosalicylate (0.65 g, 3.9 mmol), 2-cyano-6-chloropyridine (0.54 g, 3.9 mmol), triethylamine (1.00 ml, 7.2 mmol) and toluene (2.0 ml) was refluxed for 6.5 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol to give the titled compound (0.39 g, 37%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]([CH2:18]O)=[C:15]([CH3:17])[N:16]=2)=[CH:8][CH:7]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][C:21]1=[O:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[S:13][C:14]([CH2:18][N:20]3[CH2:24][CH2:23][CH2:22][C:21]3=[O:25])=[C:15]([CH3:17])[N:16]=2)=[CH:10][CH:11]=1
Reactant: Cc1nc(-c2ccc(OCCCCl)cc2)sc1CO
Reactant: O=C1CCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1nc(-c2ccc(OCCCCl)cc2)sc1CN1CCCC1=O
Yield: 100 %

Procedure:
In a flask fitted with a magnetic stirrer and a reflux condenser, {2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-thiazol-5-yl}methanol i109 (0.67 mmol, 1 eq, 0.2 g), pyrrolidinone (0.8 mmol, 1.2 eq, 0.069 g) and p-toluenesulfonic acid (0.067 mmol, 0.1 eq, 0.013 g) are dissolved in toluene (5 ml) and the mixture is brought to reflux overnight. After this time, the mixture is concentrated, taken up in ethyl acetate and washed with a saturated solution of sodium bicarbonate. The organic layer is dried over magnesium sulfate and concentrated to dryness to give 0.295 g of 1-({2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-thiazol-5-yl}methyl)pyrrolidin-2-one i110. This crude product is used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1.Cl[C:13]1[C:14]2[C:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:20][S:19][C:15]=2[N:16]=[CH:17][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.[Cu]I>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][NH:1][C:13]2[C:14]3[C:21]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[CH:20][S:19][C:15]=3[N:16]=[CH:17][N:18]=2)=[CH:11][CH:10]=1
Reactant: Fc1ccc(-c2csc3ncnc(Cl)c23)cc1
Reactant: NCCCc1ccc(N)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1ccc(CCCNc2ncnc3scc(-c4ccc(F)cc4)c23)cc1
Yield: 30 %

Procedure:
4-(3-aminopropyl)aniline (0.034 g, 0.23 mmol) was added to a solution of 4-chloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine (0.04 g, 0.15 mmol), copper(I) iodide (0.009 g, 0.04 mmol) and potassium carbonate (0.0626 g, 0.453 mmol) in N,N-dimethylacetamide (3 mL) and the resulting mixture was subjected to microwave radiation at 140° C. for 4 hours. The solvent was then removed by evaporation, and the residue was dissolved in ethyl acetate (50 mL), filtered, and the organics were washed with a saturated solution of sodium bicarbonate (30 mL). Concentration and purification by silica gel column chromatography (using 1-3% methanol, 0.06% ammonia in 1:1 ethyl acetate/hexane) afforded N-[3-(4-aminophenyl)propyl]-5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-amine as a white solid in 30% yield.
Reaction SMILES: [H-].[Na+].[CH2:3]1[CH2:7][O:6][CH2:5][CH2:4]1.[CH3:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OCCBr)C>C(OCC)(=O)C.O>[CH2:5]([O:6][CH2:7][CH2:3][N:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:8])[CH3:4]
Reactant: CNCc1ccccc1
Reactant: C1CCOC1
Agent: CCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOCCN(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Process 1) NaH (washed with hexane in advance, 8.78 g, 0.305×1.2 mol) was added to a dry THF (300 mL) solution of N-methylbenzylamine (39 mL, 0.305 mol) under an argon atmosphere at room temperature. After stirring at room temperature for 30 minutes, a dry THF (100 mL) solution of bromoethyl ethyl ether (51 mL, 0.305×1.5 mol) was added dropwise, and further heated under reflux under an argon atmosphere for 24 hours. After cooling to room temperature, water (350 mL) was carefully added for dissolution of insoluble materials, followed by adding ethyl acetate (350 mL). The organic layer was separated, further washed with brine (200 mL) and then concentrated to dryness. Since insoluble materials precipitated in the residual fraction, they were filtered off and washed with ethyl acetate, and the filtrate was again concentrated to dryness. The residue was purified by vacuum distillation (fraction at 1.0 to 1.1 kpa and 95° C. to 110° C. collected), and BnEO (49.73 g, 0.257 mol, 84%) was obtained as a colorless transparent liquid.
Reaction SMILES: C([O:8][CH:9](O)[C@:10]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])([OH:31])[C@@:11]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])([OH:22])[CH:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[OH:13])C1C=CC=CC=1>CCOC(C)=O.[Pd]>[Si:15]([O:14][CH:12]([OH:13])[C@@:11]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])([C@:10]([O:32][Si:33]([C:36]([CH3:37])([CH3:38])[CH3:39])([CH3:35])[CH3:34])([CH2:9][OH:8])[OH:31])[OH:22])([C:18]([CH3:21])([CH3:19])[CH3:20])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)OC(O)[C@@](O)(O[Si](C)(C)C(C)(C)C)[C@](O)(O[Si](C)(C)C(C)(C)C)C(O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC(O)[C@@](O)(O[Si](C)(C)C(C)(C)C)[C@@](O)(CO)O[Si](C)(C)C(C)(C)C
Yield: 38.6 %

Procedure:
4-Benzyloxy-1,2,3-tri(tert-butyldimethylsilyloxy)-L-threitol (5.9 g, 10.6 mmol) dissolved in EtOAc (70 mL) was hydrogenated (balloon as H2 container) in the presence of 10% Pd/C (1 g) until no more starting material could be detected on TLC plate (about 5 h). The catalyst was removed by filtration through a Celite pad, with rinsing the solid with EtOAc. The filtrate was evaporated to dryness, and the residue was purified by silica gel flash chromatography (eluting with 10% ether in hexanes) to give 1,2,3-tri(tert-butyldimethylsilyloxy)-L-threitol (2.1 g, 41% yield).