Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][CH:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1>C(O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]2[CH2:10][CH2:11][CH:12]([OH:15])[CH2:13][CH2:14]2)=[CH:16][CH:17]=1
Reactant: O=C1CCC(Oc2ccc(Br)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1CCC(Oc2ccc(Br)cc2)CC1
Temperature: 0 °C
Yield: 71.4 %

Procedure:
Sodium borohydride (77.3 mg, 2.04 mmol) was added to a solution of 4-(4-bromophenoxy)cyclohexanone (500 mg, 1.86 mmol) in ethanol (10 mL) at room temperature. After 20 minutes the reaction was cooled to 0° C. and quenched by the addition of 1 N HCl (aq). The reaction was concentrated and the resulting residue was partitioned between ether and 1 N HCl (aq). The layers were separated, the organic layer was washed with water then dried (Na2SO4), filtered and concentrated. Purification on an Analogix SF15-12 g column (hexanes/ethyl acetate=8:2) afforded the title compound as a white solid (360 mg, 72%).
Reaction SMILES: CC(N(C)C)=O.Cl[C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[H-].[Na+].[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([F:24])[CH:18]=1>O>[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[C:19]([F:24])[CH:18]=1
Reactant: Clc1ncccn1
Reactant: Nc1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Fc1cc(Br)ccc1Nc1ncccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
Dimethylacetamide (10 ml) was added slowly to a mixture of 2-chloropyrimidine (1g, 8.7 mmol), sodium hydride (0.8 g, 34.9 mmol), and 4-bromo-2-fluoro-aniline (1.6 g, 8.7 mmol) and the resulting mixture was stirred overnight at room temperature. Water was added slowly and the resulting mixture extracted three times with ethyl acetate. The organic phase bas washed with brine, dried over sodium sulfate and concentrated to dryness. Flash chromatography on silica gel chromatography using a gradient of ethyl acetate and hexane afforded (4-bromo-2-fluoro-phenyl)-pyrimidin-2-yl-amine (1.3 g, 56% yield). 1H NMR (500 MHz, DMSO-d6) δ 6.85 (m, 1H), 7.37 (d, 1H), 7.55 (d, 1H), 7.74 (m, 1H), 8.44 (s, 2H), 9.21 (s, 1H). MS: m/z 269.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=2[N+:15]([O-:17])=[O:16])=O.[NH2:18][NH2:19]>CO>[CH3:14][C:10]1[CH:11]=[C:12]2[C:7](=[C:8]([N+:15]([O-:17])=[O:16])[CH:9]=1)[NH:6][C:5]([C:3]1[O:2][CH:1]=[N:18][N:19]=1)=[CH:13]2
Reactant: COC(=O)c1cc2cc(C)cc([N+](=O)[O-])c2[nH]1
Reactant: NN
Solvent: CO
Product: Cc1cc([N+](=O)[O-])c2[nH]c(-c3nnco3)cc2c1
Yield: 20 %

Procedure:
5-Methyl-7-nitro-1H-indole-2-carboxylic acid methyl ester (234 mg, 1 mmol) prepared in Preparation 15 was dissolved in methanol (10 mL), to which was added hydrazine (3 mL). The reaction solution was refluxed for 3 h, and concentrated under reduced pressure. To the concentrate was added trimethylorthoformate (10 mL), and the mixture was refluxed for 8 h. The reaction mixture was distilled under reduced pressure, and the resulting solid was washed with ethyl acetate to give the title compound (49 mg, Yield 20%).
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:13]3[O:14][CH2:15][CH2:16][CH2:17][C:12]3=[N:11][C:4]=1[CH:5]=[N:6]2.ClC1C=C(C=CC=1)C(OO)=[O:23]>ClCCl>[CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:13]3[O:14][CH2:15][CH2:16][CH2:17][C:12]3=[N:11][C:4]=1[CH:5]=[N+:6]2[O-:23]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc2c(c1)ncc1nc3n(c12)OCCC3
Solvent: ClCCl
Product: [O-][n+]1cc2nc3n(c2c2ccccc21)OCCC3
Reaction time: 1 h
Yield: 101.8 %

Procedure:
9,10-Dihydro-8H-[1,2]oxazino[2′,3′:1,2]imidazo[4,5-c]quinoline (0.3339 g, 1.482 mmol) was dissolved in 5 mL of dichloromethane and treated with 3-chloroperoxybenzoic acid (0.95 g, 57-86% purity). After stirring for 1 hour, the reaction mixture was diluted with 15 mL of dichloromethane, washed successively with dilute aqueous K2CO3, H2O, and brine, dried over Na2SO4, and concentrated under reduced pressure to give 0.364 g of 9,10-dihydro-8H-[1,2]oxazino[2′,3′:1,2]imidazo[4,5-c]quinoline 5-oxide as a tan solid.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[NH:8][N+:9]([O-:11])=[O:10].Cl.[NH:17]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:18]([C:26](O)=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CS(C1N=CC=CN=1)C>CN(C=O)C.CCOC(C)=O>[NH:17]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:18]([C:26]([NH:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[NH:8][N+:9]([O-:11])=[O:10])=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: N=C(NCCC[C@H](N)C(=O)O)N[N+](=O)[O-]
Agent: C[SH](C)c1ncccn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O

Procedure:
Next, 31.3 g (0.08 mole) of H-Arg(NO2)-CHA.HCl was dissolved in 160 ml of 1.5N-NEM/DMF, to this solution was added 31.0 g (0.08 mole) of BOC-Phe-SDP (dimethylmercaptopyrimidine) at 0° to 5° C. and reacted for 18 hours. After the reaction was completed, the reaction mixture was diluted with 1600 ml of AcOEt, and washed twice with 400 ml of cold 5% hydrochloric acid, and washed twice with 400 ml of an aqueous solution saturated with sodium chloride, then there was precipitated crystals. The crystals thus precipitated were collected by filtration and dried to obtain crude BOC-Phe-Arg(NO2)-CHA, then recrystallized from AcOEt/n-hexane to obtain 35.1 g (72.9%) of BOC-Phe-Arg(NO2)-CHA.
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][CH2:9][C@H:10]([N:15]2[CH2:20][CH2:19][N:18]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][CH2:16]2)[C:11]([O:13][CH3:14])=[O:12])=[O:7])=[CH:4][CH:3]=1.Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1>>[CH3:24][S:21]([N:18]1[CH2:17][CH2:16][N:15]([C@@H:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:25]=[CH:26][C:2]([O:1][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)=[CH:3][CH:4]=2)[C:11]([O:13][CH3:14])=[O:12])[CH2:20][CH2:19]1)(=[O:23])=[O:22]
Reactant: COC(=O)[C@H](CNC(=O)c1ccc(O)cc1)N1CCN(S(C)(=O)=O)CC1
Reactant: COc1ccc(CBr)cc1
Product: COC(=O)[C@H](CNC(=O)c1ccc(OCc2ccc(OC)cc2)cc1)N1CCN(S(C)(=O)=O)CC1
Yield: 96.4 %

Procedure:
In a manner similar to example 4-5, starting from 300 mg (0.8 mmol) of methyl (S)-3-(4-hydroxybenzoylamino)-2-(4-methanesulphonylpiperazin-1-yl)propanoate (prepared as described in example 4-4) and from 0.14 ml (0.9 mmol) of 1-bromomethyl-4-methoxybenzene; 390 mg (100%) of methyl (S)-2-(4-methanesulphonylpiperazin-1-yl)-3-[4-(4-methoxybenzyloxy)benzoylamino]propanoate are obtained in the form of a colourless oil.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)([OH:3])=[O:2].[Br:16]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>CO>[Br:16][CH:13]1[CH2:12][C:11](=[O:15])[C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:14]1
Reactant: O=C(O)CCCCCCC1=CCCC1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CO
Product: O=C(O)CCCCCCC1=CC(Br)CC1=O
Temperature: 5 °C

Procedure:
A stirred mixture of 35.9 g. (0.171 moles) of 2-(6-carboxyhexyl)cyclopent-2-en-1-one [Bagli et al., Tetrahedron Letters, No. 5, 465 (1966)], 35.0 g. (0.197 moles) of N-bromosuccinimide, and 600 ml. of carbon tetrachloride is refluxed for 35 minutes. The mixture is cooled to 5° C. and filtered. The filtrate is washed with cold water, dried over magnesium sulfate, and taken to dryness to give an oil, λmax.MeOH =225mμ(8850); νmax.=1705 (carbonyl groups) and 1625 cm-1 (olefin group).
Reaction SMILES: C1N=CN([C:6]([N:8]2C=N[CH:10]=[CH:9]2)=[S:7])C=1.[C:13]([O:17][C:18](=[O:31])[NH:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=CC(N)=[CH:26][CH:25]=1)([CH3:16])([CH3:15])[CH3:14]>CN(C)C=O>[C:13]([O:17][C:18](=[O:31])[NH:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:10][C:9]([N:8]=[C:6]=[S:7])=[CH:26][CH:25]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc(N)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCOc1ccc(N=C=S)cc1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 90.4 %

Procedure:
To a cooled (−15° C.) solution of 1,1-thiocarbonyidiimidazole (756 mg, 4.115 mmol) (Aldrich) in N,N-dimethylformamide (11 mL) was added dropwise a solution of [3-(4-aminophenoxy)propyl]carbamic acid tert-butyl ester (1.02 g, 3.84 mmol) (from Step B above) in N,N-dimethylformamide (11 mL) over 25 minute. After the addition was complete, the mixture was stirred at −15° C. for 20 minute and then at room temperature for 1 h. Ice-water was added and the mixture was extracted with ether. The ether layer was dried (MgSO4), filtered, and evaporated. The residue was purified on silica gel with 85:15 hexane/ethyl acetate to give [3-(4-isothiocyanatophenoxy)propyl]-carbamic acid tert-butyl ester (1.07 g, 91% yield). HRMS, observed: 308.1197; Calcd for M+:308.1195.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([NH:11][C@H:12]([C:24]([OH:26])=[O:25])[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=1)(=[O:16])=[O:15])(=[O:10])[CH3:9].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:8]([NH:11][C@H:12]([C:24]([OH:26])=[O:25])[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:19][CH:18]=1)(=[O:16])=[O:15])(=[O:10])[CH3:9]
Reactant: Sc1ccccc1
Reactant: CC(=O)N[C@@H](CS(=O)(=O)c1ccc(F)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](CS(=O)(=O)c1ccc(Sc2ccccc2)cc1)C(=O)O
Temperature: 9 °C
Reaction time: 2 h

Procedure:
Thiophenol (7.27 g, 71.0 mmol) was added to a solution of the title compound of Example 11b (17.0g, 59.0 mmol) and K2CO3 (24.4 g, 177 mmol) in DMF (200 mL). After heating at 9 degrees C. for 2 hours, the mixture was concentrated under a stream of N2. The solution was acidified to pH=1 with 1M KHSO4, extracted into EtOAc (2×) and the organic phases were washed with brine and dried over MgSO4. The solution was concentrated in vacuo to yield the title compound as a white solid and was carried on without additional purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([F:24])[CH:18]=1.NC1C=CC(N2C=CC=CC2=O)=CC=1F>>[NH2:21][C:20]1[CH:22]=[CH:23][C:17]([N:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]2=[O:15])=[CH:18][C:19]=1[F:24]
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: Nc1ccc(Br)cc1F
Agent: Nc1ccc(-n2ccccc2=O)cc1F
Product: Nc1ccc(-n2ccc(OCc3ccccc3)cc2=O)cc1F

Procedure:
1-(4-Amino-3-fluoro-phenyl)-4-benzyloxy-1H-pyridin-2-one was prepared from 4-benzyloxy-1H-pyridin-2-one and 4-bromo-2-fluoroaniline in analogy to the procedure described for the preparation of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one described in C. F. Bigge et al., patent application WO 2003045912. MS: 311 (M+H)+.
Reaction SMILES: Cl.Cl.[N:3]1([C@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[NH2:14])[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH:15]1([C:18]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:19]=2[C:20](O)=[O:21])[CH2:17][CH2:16]1>>[CH:15]1([C:18]2[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:19]=2[C:20]([NH:14][C@@H:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C@@H:8]2[N:3]2[CH2:4][CH2:5][CH2:6][CH2:7]2)=[O:21])[CH2:17][CH2:16]1
Reactant: N[C@@H]1CCCC[C@@H]1N1CCCC1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C1CC1
Agent: Cl
Product: O=C(N[C@@H]1CCCC[C@@H]1N1CCCC1)c1ccc(C(F)(F)F)cc1C1CC1

Procedure:
The title compound, white solid, MS: m/e=381.3 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclohexylamine dihydrochloride (intermediate F) and 2-cyclopropyl-4-trifluoromethyl-benzoic acid (intermediate K).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([C:15]([O:17]CC)=[O:16])[S:8][CH2:7][CH2:6]2.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([C:15]([OH:17])=[O:16])[S:8][CH2:7][CH2:6]2
Reactant: CCOC(=O)C1SCCc2cc(OC)c(OC)cc21
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2c(cc1OC)C(C(=O)O)SCC2
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Part B. A solution of the ester prepared in Part A above (1.68 g, 6.31 mmol) in ethanolic sodium hydroxide (60.0 mL, 0.25M in 95% ethanol, 15.0 mmol) was stirred at ambient temperature for 14 hours. The solution was evaporated, and the residue neutralized to pH 5 with 1N aqueous hydrochloric acid. This was diluted to 100 mL with water, and extracted with ethyl acetate (2×100 mL). The extracts were washed with brine, combined, dried over anhydrous magnesium sulfate, filtered and evaporated to afford the product, 6,7-dimethoxy-1,2,3,4-tetrahydro-2-thianaphthalene-1-carboxylic acid, as an oil (1.42 g, 5.96 mmol, 94%). 1H NMR (CDCl3): δ 7.06 (1H, s); 6.62 (1H, s); 5.30 (1H, s); 4.34-4.24 (1H, m); 4.02-3.92 (1H, m);3.87 (6H, s); 2.94-2.72 (2H, m). Mass spectrum (NH3 -CI/DDIP): m/z 241(2%); 240 (11%); 239 (87%); 221 (8%); 193 (100%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:9][O:10][C:5]2=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[C:29]([F:31])[CH:30]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O>[F:24][C:25]1[CH:26]=[C:27]([C:2]2[N:7]=[C:6]3[C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:9][O:10][C:5]3=[CH:4][CH:3]=2)[CH:28]=[C:29]([F:31])[CH:30]=1
Reactant: COC(=O)Cc1coc2ccc(Cl)nc12
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCOC(C)=O
Product: COC(=O)Cc1coc2ccc(-c3cc(F)cc(F)c3)nc12
Temperature: 100 °C
Yield: 83.9 %

Procedure:
A sealable microwave vial was charged with methyl 2-(5-chlorofuro[3,2-b]pyridin-3-yl)acetate (1.30 g, 5.74 mmol), palladium(II) acetate (0.129 g, 0.574 mmol), potassium phosphate (3.66 g, 17.2 mmol), 3,5-difluorophenylboronic acid (1.81 g, 11.5 mmol), and X-Phos (0.548 g, 1.15 mmol). The vial was sealed, flushed with N2, then dioxane (20 mL) and H2O (2 mL) were added. The solution was sparged with N2 for 10 min, then heated at 100° C. for 24 h. The mixture was then cooled to rt and concentrated for purification by MPLC (Teledine Isco combiFlash Companion). The crude residue was taken up in minimal CH2Cl2 and absorbed onto a 25 g loading cartridge and passed through a Redi-Sep® pre-packed silica gel column (120 g) using 98:2 Hexanes:EtOAc to 70:30 Hexanes:EtOAc gradient to afford methyl 2-(5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)acetate (1.46 g, 83.8% yield) as a colorless amorphous solid. LRMS (ESI) m/z calcd for C16H12F2NO3 (M+H) 304.1. found 304.2.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:23])[C@@:11]([CH3:22])([CH2:14][O:15]CC[Si](C)(C)C)[CH:12]=[CH2:13])([CH3:3])[CH3:2].F[B-](F)(F)F.[Li+]>C(#N)C.O.O.C(OCC)C>[OH:15][CH2:14][C@@:11]([CH3:22])([CH:12]=[CH2:13])[C:10]([N:5]1[C@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][O:7][C:6]1=[O:9])=[O:23]
Reactant: C=C[C@](C)(COCC[Si](C)(C)C)C(=O)N1C(=O)OC[C@H]1C(C)C
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: CC#N
Product: C=C[C@](C)(CO)C(=O)N1C(=O)OC[C@H]1C(C)C
Temperature: 25 °C
Yield: 91.3 %

Procedure:
To a stirred solution of (R)-4-isopropyl-3-[(R)-2-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-but-3-enoyl]-oxazolidin-2-one (2.93 g, 8.58 mmol) in a mixture of acetonitrile (86 mL) and water (1.72 mL) was added lithium tetrafluoroborate (1 M in acetonitrile, 42.9 mL, 42.9 mmol). The mixture was heated at reflux under nitrogen for 5 h and allowed to cool to ambient temperature. More lithium tetrafluoroborate (1 M in acetonitrile, 8.6 mL, 8.6 mmol) was added and the mixture heated at reflux for a further 75 minutes and allowed to cool to ambient temperature. The mixture was diluted with water/diethyl ether (2:3, 100 mL) and the organic layer was separated and washed with water. The combined aqueous washes were back-extracted with diethyl ether and the combined organic extracts dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound (1.89 g, 91%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 0.89 (d, J=6.9 Hz, 3H), 0.95 (d, J=6.9 Hz, 3H), 1.35 (s, 3H), 2.36-2.47 (m, 1H), 2.56-2.70 (br s, 1H), 3.47-3.54 (m, 1H), 3.91 (d, J=11.6 Hz, 1H), 4.22-4.31 (m, 2H), 4.47-4.53 (m, 1H), 4.97 (d, J=17.8 Hz, 1H), 5.17 (d, J=10.7 Hz, 1H), 6.09 (dd, J=17.8, 10.7 Hz, 1H). LCMS (m/z) 242.2 [M+H], Tr=1.82 min.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.CC(N(C)C)=O.C1(C)C=CC=CC=1.[CH:24]12[CH2:30][CH:27]([CH:28]=[CH:29]1)[CH:26]1[C:31]([O:33][C:34](=O)[CH:25]21)=[O:32]>O>[O:32]=[C:31]1[CH:26]2[CH:25]([CH:24]3[CH2:30][CH:27]2[CH:28]=[CH:29]3)[C:34](=[O:33])[N:1]1[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C1OC(=O)C2C3C=CC(C3)C12
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(O)c1ccc(N2C(=O)C3C4C=CC(C4)C3C2=O)cc1
Temperature: 165 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To 4-aminobenzoic acid (800 g, 5.83 mol) is added dimethylacetamide (2.5 l), toluene (1 l), and slowly with stirring bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride (956 g, 5.83 mol). After the addition the mixture is stirred for 1 hour, raised to 140° C. with removal of water (100 ml) azeotropically and then raised to 165° C. to remove the toluene. The mixture is cooled and the product precipitated into water (3 l). Filtration, washing with water, drying in an oven at 80° C. and recrystallisation from ethanol yields a white crystalline solid (1.56 kg, 94%). M.p.: 224°-228° C.
Reaction SMILES: [Mg].C(Br)C.II.Cl[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.[CH:19](=[O:21])[CH3:20].[Cl-].[NH4+]>O1CCCC1.II>[CH2:14]([C:11]1[CH:12]=[CH:13][C:8]([CH:19]([OH:21])[CH3:20])=[CH:9][CH:10]=1)[CH:15]=[C:16]([CH3:18])[CH3:17]
Reactant: CC=O
Reactant: CC(C)=CCc1ccc(Cl)cc1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CCBr
Solvent: C1CCOC1
Product: CC(C)=CCc1ccc(C(C)O)cc1
Temperature: 25 °C
Yield: 74.9 %

Procedure:
Under a nitrogen atmosphere, 9.6 g of magnesium turnings, 30 ml of tetrahydrofuran and about 50 mg of iodine were put in a flask. With stirring, 2 ml of ethyl bromide was added, whereupon coloration by iodine disappeared. With stirring, the mixture was heated and maintained at 110° C. to 120° C., and 60 g of p-chloroprenylbenzene was added. During the reaction, 20 ml of tetrahydrofuran was further added. After continuing the reaction for 4.5 hours, the reaction mixture was cooled to room temperature, and 200 ml of tetrahydrofuran was added. A solution of 22.0 g of acetaldehyde in 30 ml of tetrahydrofuran was added at 5° C. to 10° C. over the course of about 2 hours. After the addition, the mixture was stirred for 1 hour, and then 400 ml of a 10% by weight aqueous solution of ammonium chloride was added. The mixture was separated into an organic layer and an aqueous layer. The aqueous layer was extracted with 30 ml of diethyl ether. The diethyl ether layer was combined with the organic layer previously separated and washed with water, dried, concentrated and distilled to give 47.3 g (yield 74.9%) of 1-(p-prenylphenyl)ethanol having a boiling point of 108° C. to 110° C./0.5 mmHg. The nuclear magnetic resonance spectrum of the product was as follows. (The chemical shifts are expressed in δ (ppm) when hexamethylsiloxane is used as a standard.)
Reaction SMILES: [F:1][C@:2]1([CH3:19])[C@H:6]([OH:7])[C@@:5]([F:10])([CH2:8][OH:9])[O:4][C@H:3]1[N:11]1[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]1=[O:18].C([Mg]Cl)(C)(C)C.Cl[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[O:37][P:38](=[N:40][C@@H:41]([CH3:48])[C:42]([O:44][CH:45]([CH3:47])[CH3:46])=[O:43])=[O:39].CO>C1COCC1>[CH:45]([O:44][C:42](=[O:43])[C@@H:41]([N:40]=[P:38]([O:37][C:28]1[CH:29]=[CH:30][C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]=1[O:9][CH2:8][C@:5]1([F:10])[C@@H:6]([OH:7])[C@:2]([F:1])([CH3:19])[C@H:3]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]2=[O:18])[O:4]1)=[O:39])[CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)OC(=O)[C@H](C)N=[P+]([O-])Oc1ccc2ccccc2c1Cl
Reactant: C[C@]1(F)[C@H](n2ccc(=O)[nH]c2=O)O[C@](F)(CO)[C@H]1O
Agent: CC(C)(C)[Mg]Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)OC(=O)[C@H](C)N=[P+]([O-])Oc1ccc2ccccc2c1OC[C@@]1(F)O[C@@H](n2ccc(=O)[nH]c2=O)[C@](C)(F)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
To a solution of chiral 1-((2R,3R,4S,5S)-3,5-difluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (60 mg, 216 μmol) prepared in Preparation 6 in THF (8 ml) was added a THF solution (Aldrich, 1 M) of tert-butylmagnesium chloride (539 μl, 539 μmol) dropwise. The mixture was stirred at room temperature for 15 min. followed by the addition of THF solution (0.5 M) of (2S)-isopropyl 2-(chloro(naphthalen-2-yloxy)phosphorylamino)propanoate (1.08 mL, 539 μmol). The reaction mixture was stirred at room temperature for 1 h, then additional THF solution (Aldrich, 1 M) of tert-butylmagnesium chloride (270 μl, 270 μmol) and THF solution (0.5 M) of (2S)-isopropyl 2-(chloro(naphthalen-2-yloxy)phosphorylamino)propanoate (0.54 mL, 270 μmol) were added. The reaction mixture was then stirred at room temperature for 18 h. Methanol (2 mL) was added to quench the reaction. The mixture was purified by flash chromatography (silica gel, 1-18% MeOH in DCM) and dried in vacuo to give the title compound as a white solid (75 mg, 58%).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30].[N:40]1[CH:45]=[CH:44][CH:43]=[N:42][C:41]=1[N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([N:49]3[CH2:50][CH2:51][N:46]([C:41]4[N:40]=[CH:45][CH:44]=[CH:43][N:42]=4)[CH2:47][CH2:48]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30]
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Product: Cc1ccccc1-c1nc(N2CCN(c3ncccn3)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Yield: 48.8 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 19; 85.9 mg) was reacted with 1-(pyrimidine-2-yl)piperazine (30.0 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxo-2-[4-(pyrimidine-2-yl)piperazine-1-yl]pyrimido[4,5-b][1,5]diazocine (48.1 mg, 49%).