Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4](=[O:22])[C:5]([CH3:21])([C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][N:14]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH:24]([Mg]Br)=[CH2:25].Cl>O1CCCC1>[CH3:21][C:5]([C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][N:14]=1)([CH2:6][CH:7]1[CH2:8][CH2:9][O:10][CH2:11][CH2:12]1)[C:4](=[O:22])[CH:24]=[CH2:25]
Reactant: CON(C)C(=O)C(C)(CC1CCOCC1)c1ccc(SC)cn1
Reactant: C=C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)C(C)(CC1CCOCC1)c1ccc(SC)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
A solution of N-methoxy-N,2-dimethyl-2-[5-(methylsulfanyl)pyridin-2-yl]-3-(tetrahydro-2H-pyran-4-yl)propanamide (401 mg) in tetrahydrofuran (4.8 mL) was cooled to 0° C., and vinylmagnesium bromide (1.0M tetrahydrofuran solution, 4.76 mL) was added dropwise thereto. The reaction mixture was stirred at room temperature for 3 hr, and poured into 1M hydrochloric acid, and the mixture was stirred for 30 min. The reaction mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (250 mg, yield 69%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([OH:6])=[O:5].[Si:8]([O:25][CH:26]([CH3:30])[C:27](=[S:29])[NH2:28])([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[Si:8]([O:25][CH:26]([C:27]1[S:29][CH:2]=[C:3]([C:4]([OH:6])=[O:5])[N:28]=1)[CH3:30])([C:21]([CH3:22])([CH3:23])[CH3:24])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)C(=O)CBr
Reactant: CC(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(N)=S
Solvent: C1CCOC1
Product: CC(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1nc(C(=O)O)cs1
Temperature: 25 °C

Procedure:
A flask containing 3-bromopyruvic acid (317 mg, 1.901 mmol) was put under nitrogen atmosphere. 2-(tert-butyldiphenylsilyloxy)propanethioamide (653 mg, 1.901 mmol) was dissolved in dry THF (8 ml) and added through a septum. The following mixture was refluxed for two hours and then allowed to cool to RT. The solvent was evaporated and extracted with DCM/water and the combined organic phases were evaporated. 1H-NMR (400 MHz; DMSO-d6): δ 1.07 (s, 9H), 1.35 (d, 3H), 5.14 (q, 1H), 7.39-7.54 (m, 2H), 7.57-7.61 (m, 2H), 7.26-7.69 (m, 2H), 8.38 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:15][CH3:16])=[C:8]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])[CH:9]=1)(=[O:3])[CH3:2].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[OH-].[Na+]>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:15][CH3:16])=[C:8]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])[CH:9]=1)(=[O:3])[CH:2]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(C(C)=O)cc1C=CC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C(=O)C=Cc2ccccc2)cc1C=CC(=O)O

Procedure:
Using 10 g (0.045 mole) of the acid obtained in step (c), 80 ml of 20% sodium hydroxide and 5 g (0.045 mole) of benzaldehyde and according to a modus operandi similar to the one described in step (c) of preparation I, 11.5 g of the desired pure product are obtained, m.p.=204° C.
Reaction SMILES: [Li]CCCC.[O:6]([C:13]1[CH:18]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:16]=[C:15]([S:26][CH3:27])[N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:28](=[O:30])=[O:29].Cl>C1COCC1>[O:6]([C:13]1[C:18]([C:28]([OH:30])=[O:29])=[C:17]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:16]=[C:15]([S:26][CH3:27])[N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C=O
Reactant: CSc1nc(Oc2ccccc2)cc(Oc2ccccc2)n1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1nc(Oc2ccccc2)c(C(=O)O)c(Oc2ccccc2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
n-BuLi (1.0M, 1.2 mmol) was added to a stirred solution of 4,6-diphenoxy-2-(methylthio)pyrimidine (298 mg, 1.0 mmol) in THF (2 ml) at −78° C. The reaction mixture was stirred for 2 hours and warmed up to 0° C. Dry ice (5 pieces) was added in small pieces over 10 minutes and the reaction was warmed to room temperature for 30 minutes. Dilute HCl was added and the mixture was extracted with EtOAc. The combined organic extract was dried over MgSO4, filtered and evaporated in vacuo to give a yellow solid that was recrystallized from ethyl acetate/hexanes to give a yellow solid (243 mg, 71% yield), m.p. 97-98° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:13])[C:8]=2[CH3:12])[NH:3]1.C(O[CH:17]=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:13])[C:8]=2[CH3:12])[N:3]1[CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: Cc1c(F)ccc2c1CCC(C)N2
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CN1c2ccc(F)c(C)c2CCC1C)C(=O)OCC
Temperature: 110 °C

Procedure:
3350 g (18.7 mole) of 2,5-dimethyl-6-fluoro-1,2,3,4-tetrahydroquinoline and 4445.7 g (20.6 mole) of diethyl ethoxymethylenemalonate were combined and heated to 110° C. The ethanol was removed by atmospheric distillation initially and then through vacuum distillation when the reaction temperature reached 150° C. The resulting material, diethyl (2,5-dimethyl-6-fluoro-1,2,3,4-tetrahydro-1-quinolinyl)methylenemalonate, was used directly in the next step.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.[NH2:15][C:16]1[S:17][C:18]([C:24]2[N:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:25]=2)=[CH:19][C:20]=1[C:21]([NH2:23])=[O:22].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:9]1([CH2:8][C:4]2[N:3]=[C:2]([NH:15][C:16]3[S:17][C:18]([C:24]4[N:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:25]=4)=[CH:19][C:20]=3[C:21]([NH2:23])=[O:22])[CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: Clc1ccnc(CN2CCOCC2)n1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2cc(C(N)=O)c(N)s2)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: C[Si](C)(C)CCOCn1cnc(-c2cc(C(N)=O)c(Nc3ccnc(CN4CCOCC4)n3)s2)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
4-[(4-Chloropyrimidin-2-yl)methyl]morpholine (Example 529 Step 1) (85 mg, 0.40 mmol), 2-amino-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)thiophene-3-carboxamide (Intermediate 40) (142 mg, 0.42 mmol), Pd2 dba3 (36 mg, 0.040 mmol), X-Phos (95 mg, 0.20 mmol), and K2CO3 (61 mg, 0.44 mmol) were combined in a vial, sealed, and evacuated/backfilled with nitrogen. Degassed t-amyl alcohol (1.0 mL) was added, and the reaction was vigorously stirred at 100° C. overnight. The reaction mixture was then diluted with MeOH, combined with silica, and evaporated. Flash chromatography (dry load, 0-15% MeOH/EtOAc) afforded the title compound as an orange solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][C:18]([CH3:21])([CH3:20])[C:17](=[O:22])[C:16]=2[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[O:19][C:18]([CH3:20])([CH3:21])[C:17](=[O:22])[C:16]=2[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:13][CH:14]=1
Reactant: CC1(C)OC(c2ccc(OCc3ccccc3)cc2)=C(c2ccncc2)C1=O
Solvent: CO
Product: CC1(C)OC(c2ccc(O)cc2)=C(c2ccncc2)C1=O
Reaction time: 1 h
Yield: 99535.8 %

Procedure:
To a stirred solution of 5-(4-(benzyloxy)phenyl)-2,2-dimethyl-4-(pyridin-4-yl) furan-3(2H)-one (620 mg, 0.001 mmol) in MeOH (15 mL) was added Pd (OH)2 (120 mg, 0.85 mmol) at RT under an inert atmosphere. The reaction mixture was stirred under a hydrogen atmosphere for 1 h. The reaction mixture was then filtered through a pad of Celite® and the filtrate was concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(4-hydroxyphenyl)-2,2-dimethyl-4-(pyridin-4-yl) furan-3(2H)-one (280 mg, 60%) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20]Br)[CH:9]=[CH:8][C:7]=1[Cl:22])[CH3:2].[CH3:24][C@@H:25]1[C@H:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:28][C:27](=[O:36])[NH:26]1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20][N:26]2[C@@H:25]([CH3:24])[C@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:28][C:27]2=[O:36])[CH:9]=[CH:8][C:7]=1[Cl:22])[CH3:2]
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: CCOC(=O)Cc1cc(Oc2ccc(Br)cc2CBr)ccc1Cl
Product: CCOC(=O)Cc1cc(Oc2ccc(Br)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@@H]2C)ccc1Cl

Procedure:
Prepared according to the procedure described in Example 24, Step 7, using the following starting materials: [5-(4-bromo-2-bromomethyl-phenoxy)-2-chloro-phenyl]acetic acid ethyl ester and (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:7][CH:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:9][Cl:10].S(=O)(=O)(O)O>C(Cl)(Cl)Cl>[CH:1]1([C:15]2[CH:16]=[CH:17][C:12]([CH2:11][CH:8]([CH3:7])[CH2:9][Cl:10])=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(CCl)Cc1ccccc1
Reactant: C1=CCCCC1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CC(CCl)Cc1ccc(C2CCCCC2)cc1
Reaction time: 14 h
Yield: 70 %

Procedure:
33 parts by weight of cyclohexene are added dropwise to a mixture of 67 parts by weight of 2-methyl-3-phenylpropyl chloride and 40 parts by weight of 96% strength sulfuric acid at 10° C. Stirring is continued for 14 hours at room temperature. The crude product is dissolved in CHCl3 and the solution is thoroughly washed with ice water, dried over Na2CO3 and distilled. 70 parts by weight of 3-(4-cyclohexylphenyl)-2-methylpropyl chloride are obtained; boiling point 130°-2° C./0.1 mm Hg, yield 70% (based on 2-meythyl-3-phenylpropyl chloride).
Reaction SMILES: [Na].[N+](C(C)C)([O-])=[O:3].Br[CH2:9][C:10]1[CH:19]=[C:18]([Br:20])[CH:17]=[C:16]2[C:11]=1[N:12]=[C:13]([O:23][CH3:24])[C:14]([O:21][CH3:22])=[N:15]2.O>CO>[Br:20][C:18]1[CH:17]=[C:16]2[C:11]([N:12]=[C:13]([O:23][CH3:24])[C:14]([O:21][CH3:22])=[N:15]2)=[C:10]([CH:9]=[O:3])[CH:19]=1
Reactant: CC(C)[N+](=O)[O-]
Reactant: COc1nc2cc(Br)cc(CBr)c2nc1OC
Agent: [Na]
Solvent: O
Solvent: CO
Product: COc1nc2cc(Br)cc(C=O)c2nc1OC
Reaction time: 1 h

Procedure:
1.38 g (60 mmol) of sodium are dissolved in portions, at 0° C. under N2, in 200 ml of methanol. At 0° C., 5.85 ml (65 mmol) of 2-nitropropane are added dropwise. 18.1 g (50 mmol) of 5-(bromomethyl)-7-bromo-2,3-dimethoxy-quinoxaline are then added. The beige suspension is heated to reflux and stirred for 1 hour. The reaction mixture is poured onto 600 ml of water and the methanol is distilled off. The residue is extracted twice with ethyl acetate, and the organic phases are dried over sodium sulfate and filtered with suction. The filtrate is concentrated and the residue is dried under a high vacuum. 7-Bromo-5-formyl-2,3-dimethoxy-quinoxaline is obtained in the form of beige crystals having a melting point of 179-182° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[CH2:4].[Mg].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[C@@H:20]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[Cl-].[NH4+]>C1COCC1>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][C@:21]([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH2:4])([OH:25])[C@@H:20]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: C=C(CBr)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)[C@@H]1c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C(C[C@]1(O)CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1)c1ccccc1
Temperature: -30 °C
Reaction time: 16 h
Yield: 22.4 %

Procedure:
A Grignard reagent was prepared from 3-bromo-2-phenylprop-1-ene (Description 93, 150 mg, 0.76 mmol) and magnesium metal (24 mg, 1 mmol) in THF (4 mL). The solution was cooled to -30° C. and a solution of (2S)-1-tert-butoxycarbonyl-2-phenylpiperidin-3-one (Description 1, 161 mg, 0.59 mmol) in THF (1 mL) was added. The mixture was stirred at ambient temperature for 16 h., then saturated aqueous ammonium chloride (10 mL) was added. The mixture was extracted with ethyl acetate (2×20 mL) and the combined organic fractions were dried (Na2SO4). The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with hexane/ethyl acetate (85:15) to give the title compound as an oil (52 mg). 1H NMR (360 MHz, CDCl3) δ7.44-7.20 (10 H, m), 5.43 (1 H, s), 5.25 (1 H, s), 5.12 (1 H, s), 4.06-4.03 (1 H, m), 3.34-3.30 (1 H, m), 3.08-2.94 (3 H, m), 2.47-2.43 (1 H, m), 1.93-1.86 (2 H, m), 1.70-1.64 (2 H, m), and 1.38 (9 H, s). m/z (ES+) 394 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH2:6][C:5](=[O:7])[NH:4][N:3]=1.[CH3:8][O:9][C:10]1[CH:16]=[CH:15][C:13](N)=[CH:12][CH:11]=1>C(O)(=O)C>[CH3:8][O:9][C:10]1[CH:16]=[CH:15][C:13]([NH:1][C:2]2[CH2:6][C:5](=[O:7])[NH:4][N:3]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(N)cc1
Reactant: NC1=NNC(=O)C1
Solvent: CC(=O)O
Product: COc1ccc(NC2=NNC(=O)C2)cc1

Procedure:
A mixture of 3-amino-2-pyrazolin-5-one (20 mmol), 4-methoxyaniline (25 mol) in 50 ml of acetic acid was refluxed for 4 hours. The solvent was evaporated, the residue was suspended in water. The solid was filtered and crystallized from methanol.
Reaction SMILES: [CH2:1]([Al](CC)CC)[CH3:2].[CH2:8]([OH:19])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18]>C1(C)C=CC=CC=1>[CH2:1]=[CH2:2].[CH2:8]([OH:19])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18]
Reactant: CC[Al](CC)CC
Agent: C=CCCCCCCCCCO
Solvent: Cc1ccccc1
Product: C=C
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
900 ml of toluene was introduced into a 1-L glass polymerizer purged with nitrogen, and while an ethylene gas (100 L/h) was circulated, 5.0 ml (5.0 mmol) of stock solution (1.0 M toluene solution) of triethyl aluminum and 0.80 ml (4.0 mmol) of 10-undecen-1-ol were added thereto, and the mixture was stirred at 50° C. for 5 minutes. 17.6 mg of metallocene compound represented by the above formula (XXI) was introduced into another 20-ml Schlenk flask purged with nitrogen, and 1.14 ml of toluene solution of methyl aluminoxane (MAO) (A1=1.37 M) was added thereto and stirred for about 10 seconds, and the resulting solution was added to the polymerization solution. While an ethylene gas was circulated at 100 L/h, the mixture was stirred at 50° C. for 3 minutes (600 rpm). The reaction was terminated with isobutyl alcohol (15 ml) and conc. hydrochloric acid (2 ml), and the reaction solution was poured into 2 L of methanol to precipitate a polymer. The reaction solution was stirred overnight, and the polymer was filtered with a glass filter and then dried at 80° C. under reduced conditions at 10 Torr for 10 hours to give 10.09 g ethylene/10-undecen-1-ol copolymer. As a result of analysis by gel permeation chromatography (GPC), the molecular weight of the polymer was 109300 in terms of polyethylene-equivalent weight-average molecular weight (Mw), and the molecular weight distribution (Mw/Mn) was 3.04. From 1H-NMR measurement results, the content of the comonomer (10-undecen-1-ol) introduced was 0.78 mol-%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[S:16][C:15]2[C:10](=[N:11][CH:12]=[CH:13][C:14]=2[O:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]3[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][C:29]=3[F:35])=[O:26])=[C:20]([F:36])[CH:19]=2)[CH:9]=1)=[O:7].C(N(CC)C(C)C)(C)C.Br[CH2:47][C:48]([O:50][CH3:51])=[O:49].O>CN(C=O)C>[F:36][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[NH:24][C:25]([NH:27][C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][C:29]=1[F:35])=[O:26])[O:17][C:14]1[CH:13]=[CH:12][N:11]=[C:10]2[CH:9]=[C:8]([C:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][CH2:47][C:48]([O:50][CH3:51])=[O:49])=[O:7])[S:16][C:15]=12
Reactant: COC(=O)CBr
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCCN)sc34)cc2F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CNCCCNC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)c2s1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a stirred solution of N-(3-aminopropyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide (125 mg, 0.24 mmol) and N,N-diisopropylethylamine (46 mg, 0.36 mmol) in 10 ml of anhydrous DMF was added methyl bromoacetate (36 mg, 0.24 mmol). The mixture was stirred at room temperature for 50 minutes and poured into 100 ml of water with vigorous stirring. The precipitates were filtered and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 5˜8% of MeOH in CHCl3 to afford methyl ({3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}amino)acetate as light beige solid. Yield: 54 mg, 38%.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[NH2:29])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.IC1C=CC=CC=1N>>[NH2:29][C:28]1[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=1[C:24]1[O:23][C:22]([C:9](=[O:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:26][CH:25]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(-c2ccccc2N)o1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: Nc1ccccc1I
Product: Nc1ccccc1-c1cnc(C(=O)CCCCCCc2ccccc2)o1
Yield: 90 %

Procedure:
2-(2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)aniline. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (188 mg, 0.284 mmol) and 2-iodoaniline following General Procedure A. Flash chromatography (5-20% EtOAc/hexanes) yielded the title compound as a clear oil (122 mg, 90%): 1H NMR (CDCl3, 400 MHz) δ 7.48 (dd, 1H, J=6.4, 9.3 Hz), 7.29-7.25 (m, 2H), 7.21 (s, 1H), 7.18-7.13 (m, 4H), 6.84-6.80 (m, 1H), 6.77-6.75 (m, 1H), 4.85 (t, 1H, J=6.0 Hz), 3.81 (br s, 2H), 2.60 (t, 2H, J=7.5 Hz), 1.97-1.89 (m, 2H), 1.68-1.59 (m, 2H), 1.40-1.29 (m, 6H), 0.91 (s, 9H), 0.11 (s, 3H), 0.00 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 169.1, 155.2, 148.5, 147.9, 134.8, 133.5, 133.4, 132.5, 130.7, 127.8, 123.8, 121.9, 118.4, 73.8, 41.6, 41.1, 36.5, 34.3, 34.3, 30.9, 30.3, 23.3, 0.2, 0.0.
Reaction SMILES: [C:1]([C:3]1[S:12][C:6]2[S:7][CH2:8][C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1)#[N:2].CC(C)([O-])C.[K+].I[CH2:20][CH2:21][CH2:22][CH3:23].C(OCC)(=O)C>CN(C)C=O.O>[CH2:20]([N:10]1[C:9](=[O:11])[CH2:8][S:7][C:6]2[S:12][C:3]([C:1]#[N:2])=[CH:4][C:5]1=2)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCI
Reactant: N#Cc1cc2c(s1)SCC(=O)N2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCN1C(=O)CSc2sc(C#N)cc21
Reaction time: 0.17 h

Procedure:
To a solution of 6-cyano-2,3-dihydro-2-oxo-1H-thieno[2,3-b][1,4]thiazine (13.6 g) in N,N-dimethylformamide (270 ml) was added potassium tert-butoxide (9.3 g) under ice cooling. After stirring for 10 minutes under ice cooling, to the reaction mixture was added 1-iodobutane (9.5 ml). After stirring for 8 hours at room temperature, the reaction mixture was poured into a mixture of ethyl acetate and water. The organic layer was successively washed with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with chloroform. The fractions containing the object compounds were collected and evaporated in vacuo to give 1-n-butyl-6-cyano-2,3-dihydro-2-oxo-1H-thieno[2,3-b][1,4]thiazine (13.78 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:41]([NH2:44])(=[S:43])[CH3:42].C(N(C(C)C)CC)(C)C>ClCCl>[C:41]([NH:44][C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)=[O:16])(=[S:43])[CH3:42]
Reactant: CC(N)=S
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=S)NC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(tert-Butoxycarbonyl)piperidine-4-carboxylic acid (2.213 g, 9.65 mmol), HATU (4.050 g, 10.65 mmol) and thioacetamide (1.597 g, 21.26 mmol) were mixed in anhydrous dichloromethane (25 mL). The reaction mixture was stirred at room temperature for 30 min. N,N-diisopropyl-N-ethylamine (5.3 mL, 30.3 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The solution was concentrated and the crude residue was purified on SiO2 (10 to 60% ethyl acetate, hexanes) to afford the title compound, which was used without further purification. HPLC/MS: 112.1 (M−174), Rt=3.00 (LC4).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH:12]([CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[O:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.O>C1COCC1>[CH2:1]([N:8]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH:12]([CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:26])[CH3:27])[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCC1OCC(=O)N(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC1OCCN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of (6RS,7RS)-4-benzyl-7-({[tert-butyl(dimethyl)silyl]oxy}methyl)-6-(3,4-dichlorophenyl)-1,4-oxazepan-3-one (40.5 g) in THF (150 mL) was added dropwise 1.2 M borane.THF complex/THF solution (150 mL) at room temperature, and the mixture was stirred under nitrogen purging at 60° C. for 2 hr. After cooling to room temperature, water was added carefully, and the mixture was stirred at room temperature for 1 hr, and extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate (0%-50%)) to give the title compound (30.7 g) as a pale-yellow oil.