Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[C:6](Br)[CH:5]=1.[C:14]([O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B1OC(C)(C)C(C)(C)O1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+].[OH-].[Na+].[NH4+].[Cl-]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O.C1COCC1.CO.C1(C)C=CC=CC=1>[C:14]([O:18][C:19]([C:21]1[C:22]([C:6]2[C:7]([F:11])=[C:8]([F:10])[CH:9]=[C:4]([C:3]([OH:2])=[O:13])[CH:5]=2)=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)c1cc(F)c(F)c(Br)c1
Reactant: CC(C)(C)OC(=O)c1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccccc1-c1cc(C(=O)O)cc(F)c1F

Procedure:
3-Bromo-4,5-difluoro-benzoic acid methyl ester (194 mg, 772 μmol, 1.0 eq.) was mixed with 2-t-butoxycarbonylphenylboronic acid pinacol ester (282 mg, 927 μmol, 1.2 eq.). Toluene (1.1 mL) was added followed by MeOH (409 μL), then K2CO3 (214 mg, 1.5 mmol, 2.0 eq.) predissolved in water (202 μL). The mixture was stirred, and the reaction vessel was capped, placed under vacuum and purged with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (89.2 mg, 77.2 μmol) was added. The vessel was recapped and microwaved at 110° C. for 50 minutes. The organic layer was removed and the product was evaporated under vacuum. THF (3 mL) and 1 M aqueous NaOH (1.5 mL, 2.0 eq.) was added and the mixture was stirred for 2 hours. EtOAc was added and mixture was acidified with saturated NH4Cl. The organic layers were extracted, dried and evaporated to yield 5′,6′-difluoro-biphenyl-2,3′-dicarboxylic acid 2-t-butyl ester.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([N:6]=[C:7](SC)[NH:8][CH:9]([CH3:18])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)#[N:5].C[O-].[Na+]>CO>[C:4]([NH:6][C:7]1[NH:2][N:3]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]([CH3:18])[N:8]=1)#[N:5]
Reactant: NN
Reactant: CSC(=NC#N)NC(C)C(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1N=C(NC#N)NN=C1c1ccccc1
Reaction time: 1 h
Yield: 50.6 %

Procedure:
Hydrazine hydrate (4.55 g) was added to a solution of 2-(3-cyano-2-methyl-1-isothioureido)propiophenone (5.43 g) in methanol (20 ml), and the mixture was allowed to stand at room temperature for 1 hour. After addition of catalytic amount of sodium methoxide to the solution, the mixture was allowed to stand at room temperature for 2 hours with occasional shaking. The resultant preapitates were collected, washed successively with methanol, water and methanol and dried. Thus obtained product was dissolved with dimethylformamide (25 ml), the solution was filtered by suction and then water (25 ml) was added thereto little by little. After cooling, the resultant precipitates were collected by filtration, washed successively with ethanol, water and ethanol, and dried to give 3-cyanoamino-5-methyl-6-phenyl-2,5-dihydro-1,2,4-triazine (2.37 g), m.p. 244.5°~245° C. (decomp.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:22])[CH2:13][CH2:12][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:14]#[N:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:23]N(C=O)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([O:22][CH3:23])[CH2:13][CH2:12][C:11]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)([C:14]#[N:15])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: N#CC1(c2ccccc2)CCC(O)(c2ccc(F)cc2)CC1
Product: COC1(c2ccc(F)cc2)CCC(C#N)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
300 mg of 4-(4-fluorophenyl)-4-hydroxy-1-phenylcyclohexanecarbonitrile were dissolved in 2.5 ml of dry DMF in a flask which had been dried and flushed with argon, treated under argon with 73 mg of sodium hydride (80% strength in mineral oil) and stirred for 30 min at room temperature. Subsequently, 0.14 ml of iodomethane was slowly added dropwise under argon. The reaction mixture was stirred for 3 h, then treated with water and extracted with EA. The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo. The crude product, a brown oil, was purified by chromatography on silica gel using HEP/EA (2:1). 290 mg of the title compound were obtained as a white amorphous solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][CH2:14][O:15][CH2:16][C:17]1[CH:18]=[C:19](/[CH:23]=[CH:24]/[CH2:25][CH2:26][C:27]#[N:28])[CH:20]=[CH:21][CH:22]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C>[CH3:12][O:13][CH2:14][O:15][CH2:16][C:17]1[CH:18]=[C:19]([CH:23]2[O:9][CH:24]2[CH2:25][CH2:26][C:27]#[N:28])[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCOCc1cccc(/C=C/CCC#N)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COCOCc1cccc(C2OC2CCC#N)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 48.1 %

Procedure:
m-Chloroperbenzoic acid (3.77 g) was added to a solution of (E)-5-(3-((methoxymethoxy)methyl)phenyl)pent-4-enenitrile (2.08 g) in ethyl acetate (20 mL) at room temperature, and the mixture was stirred at 80° C. for 1 hr. Saturated aqueous sodium thiosulfate solution was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (1.07 g) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9]Br)[C:5]([Cl:8])=[N:6][CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[C:14]([CH:22]=[CH2:23])[CH:13]=1.ClC1C(CN(C2C=CC=CC=2C=C)C(=O)C)=CC(F)=C(Cl)N=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][N:18]([C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][C:14]=2[CH:22]=[CH2:23])[C:19](=[O:21])[CH3:20])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cc1CBr
Reactant: C=Cc1cc(Cl)ccc1NC(C)=O
Agent: C=Cc1ccccc1N(Cc1cc(F)c(Cl)nc1Cl)C(C)=O
Product: C=Cc1cc(Cl)ccc1N(Cc1cc(Br)cnc1Cl)C(C)=O
Yield: 93.1 %

Procedure:
Compound 76C (0.19 g, 94%) was prepared from 76B (0.145 g, 0.51 mmol) and 9B (0.1 mg, 0.51 mmol) using a procedure similar to the synthesis of 1C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1.[Br:16]Br>C(Cl)(Cl)Cl.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>[Br:16][C:5]1[S:1][C:2]([C:6]2([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]2)=[N:3][CH:4]=1
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)C1(c2nccs2)CC1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)C1(c2ncc(Br)s2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 46.9 %

Procedure:
The product from Step 2 (860 mg, 3.82 mmol) was taken up in CHCl3 (19 mL) and placed in a cool water bath. NaHCO3 (353 mg, 4.20 mmol) was added, followed by bromine (1.22 g, 7.63 mmol). After stirring for 90 min at room temperature, the reaction was diluted with 10% Na2S2O3 and saturated NaHCO3 and extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. Flash chromatography (0-10% ether in hexanes) afforded tert-butyl 1-(5-bromo-1,3-thiazol-2-yl)cyclopropanecarboxylate (545 mg, 47%) as a colorless oil. MS ESI: [M-t-Bu]+ m/z 247.9/249.9.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24]([O:28][C:29]([NH:31][C@@H:32]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:33](=[O:34])[C@@H:32]([NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CC(C)(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)[C@H](CC(C)(C)C)NC(=O)OC(C)(C)C

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and (S)-2-tert-butoxycarbonylamino-4,4-dimethyl-pentanoic acid to yield (3aR,4S,7aR)-4-((S)-2-tert-butoxycarbonylamino-4,4-dimethyl-pentanoyloxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. This NBoc-protected product was then stirred in hydrochloric acid dioxane solution (4M, 10 equiv.) at room temperature for 6 hrs. Subsequently the solvent was removed the residue dissolved in dichloromethane and washed with saturated sodium hydrogencarbonate solution. The organic layer was tried with sodium sulfate, filtrated and evaporated. The crude product was subjected to silica gel flash chromatography (ISCO CombiFlash; dichloromethane/methanol; 100/0 to 95/5) to yield (3aR,4S,7aR)-4-((S)-2-amino-4,4-dimethyl-pentanoyloxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 296 (ester elimination ion); RT=5.787 min; HPLC Method I
Reaction SMILES: Br[C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:17]1(B2OC(C)(C)C(C)(C)O2)[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1>>[C:17]1([C:2]2[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Reactant: O=[N+]([O-])c1cnc(OCC(F)(F)F)c(Br)c1
Product: O=[N+]([O-])c1cnc(OCC(F)(F)F)c(C2=CCCCC2)c1
Yield: 54.1 %

Procedure:
This compound was prepared following the same procedure as described for Example 1b using 3-bromo-5-nitro-2-(2,2,2-trifluoro-ethoxy)-pyridine (Example 1a, 1 g, 3.18 mmol) and 2-(1-cyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAN 141091-37-4, 0.73 g, 3.5 mmol) as starting materials. The title compound (520 mg, 54.0%) was isolated as off white solid; NMR complies.
Reaction SMILES: [F:1][C:2]1[C:10]2[C:9]([CH3:12])([CH3:11])[O:8][B:7]([OH:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:14]=O.[NH2:16][OH:17].Cl.CC([O-])=O.[Na+]>C1COCC1.O>[F:1][C:2]1[C:10]2[C:9]([CH3:12])([CH3:11])[O:8][B:7]([OH:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:14]=[N:16][OH:17]
Reactant: NO
Reactant: CC1(C)OB(O)c2ccc(C=O)c(F)c21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OB(O)c2ccc(C=NO)c(F)c21
Reaction time: 2 h

Procedure:
To a solution of 4-fluoro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde (136 mg, 0.7 mmol) and NH2OH.HCl (58.5 mg, 0.84 mmol) in THF (4 mL) and H2O (1 mL) at rt was added NaOAc (80.5 mg, 0.98 mmol). The reaction mixture was stirred for 2 h and diluted with H2O. The mixture was extracted three times with ethyl acetate and the organic layer was separated. The organic solution was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give crude compound 4-fluoro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde oxime as a light yellow solid. It was used in next step without further purification.
Reaction SMILES: C(CN)O.[Cl:5][C:6]1[O:10][C:9]([CH:11]2[C:16]3=[C:17]4[N:29]([CH3:30])[C:28](=[O:31])[N:27]([CH3:32])[C:26](=[O:33])[C:18]4=[C:19]([C:20]4[S:21][CH:22]=[C:23]([CH3:25])[N:24]=4)[N:15]3[CH2:14][CH:13]([CH2:34][N:35]3C(=O)C4C(=CC=CC=4)C3=O)[S:12]2)=[CH:8][CH:7]=1>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[NH2:35][CH2:34][CH:13]1[S:12][CH:11]([C:9]2[O:10][C:6]([Cl:5])=[CH:7][CH:8]=2)[C:16]2=[C:17]3[N:29]([CH3:30])[C:28](=[O:31])[N:27]([CH3:32])[C:26](=[O:33])[C:18]3=[C:19]([C:20]3[S:21][CH:22]=[C:23]([CH3:25])[N:24]=3)[N:15]2[CH2:14]1
Reactant: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CC(CN2C(=O)c4ccccc4C2=O)SC3c2ccc(Cl)o2)n1
Solvent: CCOC(C)=O
Solvent: NCCO
Solvent: Cc1ccccc1
Product: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CC(CN)SC3c2ccc(Cl)o2)n1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Ethanolamine (0.320 mL, 5.30 mmol) was added to a solution of 10-(5-chlorofuran-2-yl)-8-((1,3-dioxoisoindolin-2-yl)methyl)-1,3-dimethyl-5-(4-methylthiazol-2-yl)-7,8-dihydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]thiazine-2,4(3H,10H)-dione (537 mg, 0.883 mmol) in toluene (10 mL). The mixture was stirred at 70° C. for 3 hours and then cooled to room temperature for 16, then heated at 70° C. for a further 2.5 hours and again cooled to room temperature. The mixture was diluted with water (100 ml) and ethyl acetate (100 ml). The organic phase was separated, washed with 1M NaOH(aq) (50 ml) passed through a hydrophobic frit and evaporated under vacuum to afford the title compound as a mixture of diastereomers.
Reaction SMILES: O[N:2]=[C:3]([C:11](=O)[C:12]1[CH:17]=[N:16][CH:15]=[CH:14][N:13]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[C:20]1([C:19]2[NH:26][C:11]([C:12]3[CH:17]=[N:16][CH:15]=[CH:14][N:13]=3)=[C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[N:2]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)C(=NO)C(=O)c1cnccn1
Reactant: NCc1ccccc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1nc(-c2ccccc2)[nH]c1-c1cnccn1
Yield: 19 %

Procedure:
tert-Butyl 2-hydroxyimino-3-oxo-3-(2-pyrazinyl)propionate (4.1 g) and benzylamine (4.0 g) were dissolved in acetonitrile (100 ml), and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 5 to give tert-butyl 2-phenyl-5-(2-pyrazinyl)imidazole-4-carboxylate (1.0 g), melting point 196-197° C.
Reaction SMILES: [C:1]1([O:7][C:8]([N:10]2[CH:23]([C:24]#[C:25]/[CH:26]=[CH:27]\[C:28]#[C:29][Si](C)(C)C)[C:22]3[CH2:21][CH2:20][CH2:19][C:18](=[O:34])[C:17]=3[C:16]3[CH:15]=[CH:14][C:13]([O:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:12][C:11]2=3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K]>C1COCC1.C(O)C.O.C(Cl)Cl.[N+]([O-])([O-])=O.[Ag+]>[C:1]1([O:7][C:8]([N:10]2[CH:23]([C:24]#[C:25]/[CH:26]=[CH:27]\[C:28]#[CH:29])[C:22]3[CH2:21][CH2:20][CH2:19][C:18](=[O:34])[C:17]=3[C:16]3[CH:15]=[CH:14][C:13]([O:35][C:36](=[O:41])[C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:12][C:11]2=3)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)C(=O)Oc1ccc2c(c1)N(C(=O)Oc1ccccc1)C(C#C/C=C\C#C[Si](C)(C)C)C1=C2C(=O)CCC1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [K]
Solvent: C1CCOC1
Solvent: CCO
Solvent: ClCCl
Product: C#C/C=C\C#CC1C2=C(C(=O)CCC2)c2ccc(OC(=O)C(C)(C)C)cc2N1C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a solution of Compound 211 (2.80 g, 4.95 mmol) in THF-EtOH-H2O (1:1:1, 300 mL) was added silver nitrate (3.36 g, 19.8 mmol) followed by stirring at 25° C. for one hour. Potassium cynide (2.26 g, 34.65 mmol) was added to the reaction mixture following by stirring at 25° C. for another 10 minutes. The reaction mixture was diluted with CH2Cl2 (300 mL), washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 50 percent ethyl ether in petroleum ether) to furnish Compound 212 (2.20 g, 90 percent): Rf =0.43 (silica, 50 percent ethyl ether in petroleum ether); IR (CHCl3) δmax 3302, 2959, 1740 (shoulder), 1725 (shoulder), 1719, 1680, 1606, 1494, 1381, 1307, 1177, 1123 cm-1 ; 1H NMR (300 MHz, CDCl3 ) δ8.25 (d, J=8.8 Hz, 1 H, H1), 7.50-7.17 (m, 6 H, H4 and aromatic), 6.95 (dd, J=8.8, 1.1 Hz, 1 H, H2), 6.06 (s, 1 H, H6), 5.79 (s, 2 H, (olefinic), 3.32 (d, J=1.0 Hz, 1 H, acetylenic), 2.86 (dt, J=18.9, 4.5 Hz, 1 H, H9), 2.76-2.51 (m, 3 H, H7 and H9), 2.23-2.16 (m, 2 H, H8), 1.33 (s, 9 H, COC(CH3)3), MS (FAB+) m/e (rel intensity) 626 (M+Cs, 16), 418 (13); HRMS for C31H27NO5Cs (M+Cs), calcd 626.0944, found 626.0975.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:11]1[CH2:16][NH:15][CH2:14][CH2:13][CH:12]=1)(=[O:10])[NH2:9].Cl[C:18]1[C:19]2[C:27]([CH3:28])=[C:26]([CH3:29])[N:25]([C:30]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:32][C:31]=3[S:39][CH3:40])[C:20]=2[N:21]=[C:22]([CH3:24])[N:23]=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>C(O)C>[C:8]([C:11]1[CH2:16][N:15]([C:18]2[C:19]3[C:27]([CH3:28])=[C:26]([CH3:29])[N:25]([C:30]4[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[CH:32][C:31]=4[S:39][CH3:40])[C:20]=3[N:21]=[C:22]([CH3:24])[N:23]=2)[CH2:14][CH2:13][CH:12]=1)(=[O:10])[NH2:9]
Reactant: NC(=O)C1=CCCNC1
Reactant: CSc1cc(C(C)C)ccc1-n1c(C)c(C)c2c(Cl)nc(C)nc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CSc1cc(C(C)C)ccc1-n1c(C)c(C)c2c(N3CCC=C(C(N)=O)C3)nc(C)nc21
Yield: 26.7 %

Procedure:
In 4 ml of ethanol, 0.27 g of 5-carbamoyl-1,2,3,6-tetrahydropyridine trifluoroacetate and 0.36 g of 4-chloro-7-(4-isopropyl-2-methylthiophenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine were dissolved, and subsequently, 0.39 g of diisopropylethylamine was added thereto. The reaction mixture was heated under reflux for 8.5 hours, and subsequently, a saturated aqueous solution of sodium hydrogencarbonate was poured thereinto. The reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and was then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol=60:1), followed by crystallization from a mixed solvent of ethyl acetate-diethyl ether to yield 0.12 g of 4-(5-carbamoyl-1,2,3,6-tetrahydropyridin-1-yl)-7-(4-isopropyl-2-methylthiophenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.CN(C)[CH:22]=[O:23].[BH4-].[Na+]>O1CCCC1.O.C1(C)C=CC=CC=1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:22][OH:23])=[N:3][CH:4]=1
Reactant: Clc1ccc(Br)nc1
Reactant: CN(C)C=O
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: OCc1ccc(Cl)cn1
Reaction time: 1 h
Yield: 47.3 %

Procedure:
To a mixture of 2-bromo-5-chloropyridine (2.0 g, 10.4 mmol) and toluene (50 ml) was added a 1.6 M n-butyl lithium hexane solution (7.8 mL, 12.5 mmol) at −78° C., which was stirred for 1 hour. N,N-dimethylformamide (4.0 mL, 52.0 mmol) was then added dropwise into the mixture at the same temperature, which was then stirred for a further 15 minutes at room temperature. Water and tetrahydrofuran were added to this reaction solution, followed by vigorous stirring. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. Sodium borohydride (1.18 g, 31.2 mmol) was added at 0° C. to the filtrate, and stirred for 1 hour at room temperature. This reaction solution was partitioned into water and tetrahydrofuran. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (hexane:diethyl ether=1:2) to obtain the title compound (706 mg, 47%).
Reaction SMILES: Cl.C([N:9]([C@@H:13]1[C@@:20]2([CH3:24])[C:21]([CH3:23])([CH3:22])[C@H:17]([CH2:18][CH2:19]2)[CH2:16][N:15]2[C:25](=[O:41])[C:26]([OH:40])=[C:27]([C:29](=[O:39])[NH:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[N:28]=[C:14]12)C(=O)O)C1C=CC=CC=1.[CH3:42][N:43]([CH3:49])[C:44](=[O:48])[C:45]([OH:47])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:38][C:35]1[CH:34]=[CH:33][C:32]([CH2:31][NH:30][C:29]([C:27]2[N:28]=[C:14]3[C@H:13]([NH:9][C:45](=[O:47])[C:44]([N:43]([CH3:49])[CH3:42])=[O:48])[C@@:20]4([CH3:24])[C:21]([CH3:23])([CH3:22])[C@H:17]([CH2:18][CH2:19]4)[CH2:16][N:15]3[C:25](=[O:41])[C:26]=2[OH:40])=[O:39])=[CH:37][CH:36]=1
Reactant: CN(C)C(=O)C(=O)O
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)[C@@H](N(Cc1ccccc1)C(=O)O)c1nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n1C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)C(=O)N[C@H]1c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C[C@H]2CC[C@]1(C)C2(C)C
Yield: 72.8 %

Procedure:
A solution of benzyl((7S,10R,11R)-2-((4-fluorobenzyl)carbamoyl)-3-hydroxy-10,12,12-trimethyl-4-oxo-6,7,8,9,10,11-hexahydro-4H-7,10-methanopyrimido[1,2-a]azocin-11-yl)carbamate hydrochloride salt (0.0367 g, 0.081 mmol), 2-(dimethylamino)-2-oxoacetic acid (9.53 mg, 0.081 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (0.031 g, 0.081 mmol) and diisopropyl-ethylamine (0.014 mL, 0.081 mmol) in DMF (3 mL) was stirred at room temperature for 24 h. After this the crude reaction mixture was purified by preparative-HPLC using methanol/water (0.1% trifluoroacetic acid) to afford the title compound (0.0301 g, 0.059 mmol, 72% yield) as a purple solid. 1H NMR (500 MHz, CDCl3) δ: 12.01 (1H, s), 8.76 (1 H, t, J=6.0 Hz), 8.21 (1 H, d, J=9.8 Hz), 7.36-7.41 (2 H, m), 6.99-7.05 (2 H, m), 5.27 (1 H, d, J=9.8 Hz), 5.18 (1 H, dd, J=15.6, 8.9 Hz), 4.50-4.63 (2 H, m), 3.65 (1 H, d, J=15.6 Hz), 3.34 (3 H, s), 2.95 (3 H, s), 2.14 (1 H, t, J=8.2 Hz), 1.83-1.94 (1 H, m), 1.47-1.52 (1 H, m), 1.41 (1 H, dd, J=9.5, 5.2 Hz), 1.36 (3 H, s), 1.06 (1 H, dd, 9.8, 4.6 Hz), 1.03 (3 H, s), 0.97 (3 H, s). LCMS (M+H) calcd for C26H33FN5O5: 514.25; found: 514.29.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[N:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][O:29][CH2:30][CH2:31]Br.O>CC(N(C)C)=O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([CH:30]([O:29][CH3:28])[CH3:31])[CH2:18][CH2:17]2)=[N:13][CH:14]=1
Reactant: Brc1ccc(OC2CCNCC2)nc1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(C)N1CCC(Oc2ccc(Br)cn2)CC1
Temperature: 80 °C

Procedure:
5-Bromo-2-(piperidin-4-yloxy)pyridine trifluoroacetate (0.86 g) was stirred with potassium carbonate (0.838 g) in dimethylacetamide (5 ml). Bromoethyl methyl ether (0.342 ml) was added and the mixture was heated at 80° C. for 20 minutes. After cooling the mixture was poured into water (30 ml) and extracted three times with ether. The combined extracts were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography eluting with 0 to 2% 2M methanolic ammonia in dichloromethane to give the product as a colourless oil (0.71 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].C1C=C[NH+]=CC=1.[Br:17][Br-]Br>C1COCC1>[Br:17][C:3]1[C:2]([F:1])=[CH:8][C:6]([NH2:7])=[C:5]([O:9][CH3:10])[CH:4]=1
Reactant: COc1ccc(F)cc1N
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: COc1cc(Br)c(F)cc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
To a THF (20 mL) solution of 5-fluoro-2-methoxyaniline (1.76 g), a THF (30 mL) solution of pyridinium bromide perbromide (4.36 g) was added dropwise under ice-cooling, and the reaction solution was agitated for 30 minutes at room temperature. The solid which deposited from the reaction mixture was separated by filtering and the solid was washed by THF. After the obtained solid was dissolved with water and ethyl acetate, the aqueous layer was neutralized with a saturated sodium bicarbonate water, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent:hexane-ethyl acetate system), and 1.83 mg of the title compound was obtained.