Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[Li]CCCC.CN(CCN(C)C)C.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH:35]=[O:36])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH:35]([C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=2)[OH:36])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: Clc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(Cl)cc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 29.4 %

Procedure:
To a solution of 4-bromochlorobenzene (1.35 g, 7.03 mmol) in THF (30 mL) cooled to −78° C. was added n-BuLi (2.5M in THF, 3.00 mL, 7.5 mmol) and the mixture was stirred at −78° C. for 30 minutes. TMEDA (1.06 mL, 7.02 mmol) and 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 4.69 mmol) in THF (10 mL) were added and the mixture stirred at −78° C. for 3 hours. The reaction was quenched with saturated aqueous NH4Cl (30 mL) and after work-up and purification afforded 4-[(4-chloro-phenyl)-hydroxy-methyl]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (450 mg, 30%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4]OO1.[C:7]([O:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])(=[O:11])C(C)C.Cl(O)(=O)(=O)=O.[C:23](=O)(O)[O-].[Na+]>>[C:13]([O:12][CH2:7][O:11][C:6](=[O:1])[CH:5]([CH3:23])[CH3:4])(=[O:17])[CH:14]([CH3:15])[CH3:16]
Reactant: O=C([O-])O
Reactant: C1COOOC1
Reactant: CC(C)C(=O)OC(=O)C(C)C
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(C)C(=O)OCOC(=O)C(C)C

Procedure:
A 30-g (0.33 mol) sample of trioxane was added to a solution of 158 g (1 mol) isobutyric anhydride and 0.5 ml 70 percent perchloric acid over a 30-minute period at 65°-70°C. The reaction mixture was then stirred until the temperature decreased to 27°C. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ether. The ether extracts were dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was distilled on a 30-cm column to give 112 g of methylene bisisobutyrate, b.p. 43°-48°C. at 0.2-0.3 mm of Hg and 30 g of oxybismethylene isobutyrate, b.p. 57°-63°C. at 0.2-0.3 mm of Hg.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=O)=[CH:4][CH:3]=1.[CH2:13]([Mg]Br)[CH3:14].[CH3:17][CH2:18]OCC>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])([CH2:13][CH3:14])[CH2:17][CH3:18])=[CH:11][CH:12]=1
Reactant: CC[Mg]Br
Reactant: CCOCC
Reactant: CCOC(=O)c1ccc(Br)cc1
Solvent: C1CCOC1
Product: CCC(O)(CC)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of ethyl 4-bromobenzoate (1.6 mL, 10 mmol) in anhyd THF (50 mL) was chilled to 0° C. and then charged dropwise with a 3.0 M solution of ethylmagnesium bromide in Et2O (7.0 mL, 21 mmol). After 15 min, the reaction mixture was removed from the ice-bath and stirred at ambient temperature. After 18 h the opaque mixture was quenched with satd ammonium chloride (50 mL) and extracted with Et2O (2×50 mL). The combined extracts were washed with brine, dried (anhyd Na2SO4) and concentrated under reduced pressure to give 3-(4-bromophenyl)-pentan-3-ol (2.45 g, quant) as a colorless liquid, which was used without purification in the next step: 1H-NMR (CDCl3) δ 7.46 (2H, d, J=8.3), 7.26 (2.3H, d, J=8.3), 1.78-1.86 (4H, overlapping quartets, J=7), 0.76 (6H, t, J=7.3).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:13][C:14]([CH:22]([CH3:24])[CH3:23])=[CH:15][C:16]=1[C:17](OCC)=[O:18]>CO>[CH3:24][CH:22]([C:14]1[S:13][C:12]2[N:11]=[C:2]3[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[CH:6][N:7]3[C:17](=[O:18])[C:16]=2[CH:15]=1)[CH3:23]
Reactant: CCOC(=O)c1cc(C(C)C)sc1N
Reactant: NC(=O)c1ccc(Cl)nc1
Solvent: CO
Product: CC(C)c1cc2c(=O)n3cc(C(N)=O)ccc3nc2s1
Yield: 20.1 %

Procedure:
A mixture of 24.0 g (0.1538 mol) of 6-chloro-3-pyridine-carboxamide (Aldrich Chemical Company) and 32.8 g (0.1538 mol) of 2-amino-5-(1-methylethyl)-3-thiophenecarboxylic acid, ethyl ester (Tetrahedron, Vol. 33, pages 2089-2092, 1977) is heated in a wax bath at 178°-182° C. for two hundred five minutes and then at 180°-196° C. for sixty-five minutes under nitrogen. The mixture is cooled, suspended in hot methanol and filtered to give 8.9 g of 2-(1-methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine 7-carboxamide; mp 280°-282° C. after recrystallization from dimetylformamide.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][NH:5][C:6]([C:8]1[C:17]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:20]=2[Cl:26])=[C:16]([F:27])[C:11]2[N:12]=[CH:13][N:14]([CH3:15])[C:10]=2[CH:9]=1)=[O:7].[C:28]([NH:35][C@H:36]([C:40](O)=[O:41])[CH:37]([CH3:39])[CH3:38])([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>O.CC(N(C)C)=O>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:17]2[C:8]([C:6]([NH:5][O:4][CH2:3][CH2:2][O:1][C:40](=[O:41])[CH:36]([NH:35][C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH:37]([CH3:39])[CH3:38])=[O:7])=[CH:9][C:10]3[N:14]([CH3:15])[CH:13]=[N:12][C:11]=3[C:16]=2[F:27])=[C:20]([Cl:26])[CH:21]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)NOCCO)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OCCONC(=O)c1cc2c(ncn2C)c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46.4 %

Procedure:
Dimethylacetamide (30 mL) was added to a mixture of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethoxy)-amide (3 g, 6.555 mmol), BOC-L-valine (1.710 g, 7.866 mmol), HOBT·H2O (1.004 g, 6.555 mmol) and, TEA (0.929 g, 9.177 mmol) in a 500 mL RBF with a magnetic stirrer and nitrogen line. After 5 minutes, EDCl (1.759 g, 9.177 mmol) was added to the brown solution in the 500 mL RBF. The mixture was stirred overnight at room temperature. The reaction mixture was added slowly to 210 mL of deionozied water with mechanical stirring. The white slurry was stirred for 1 hour, filtered through a medium fritted funnel. The cake was washed with about 100 mL of water and pulled air through the cake for 10-15 minutes. Tert-butyl methyl ether (70 mL) was added to the cake and stirred with a spatula. The vacuum filtration was continued. The solids were dried under vacuum at 50° C. to give 2 g of the product containing about 80% of the undesired isomer. The t-butyl methyl ether layer was concentrated to a foam (2.18 g) enriched in the desired product comprising a mixture of isomers.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][C:5]([O:10][CH2:11][CH2:12][O:13][CH:14]([CH3:16])[CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:18][C:19]1[C:24]2[B:25]([OH:28])[O:26][CH2:27][C:23]=2[CH:22]=[C:21]([OH:29])[CH:20]=1>>[Cl:1][C:2]1[C:3]([O:29][C:21]2[CH:20]=[C:19]([CH3:18])[C:24]3[B:25]([OH:28])[O:26][CH2:27][C:23]=3[CH:22]=2)=[N:4][C:5]([O:10][CH2:11][CH2:12][O:13][CH:14]([CH3:16])[CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: Cc1cc(O)cc2c1B(O)OC2
Reactant: CC(C)OCCOc1nc(Cl)c(Cl)cc1C#N
Product: Cc1cc(Oc2nc(OCCOC(C)C)c(C#N)cc2Cl)cc2c1B(O)OC2

Procedure:
This compound was prepared from 5,6-dichloro-2-(2-isopropoxyethoxy)nicotinonitrile and 7-methylbenzo[c][1,2]oxaborole-1,5(3H)-diol in a similar manner to that of D230. 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 1.02 (d, J=4.8 Hz, 6H), 2.44 (s, 3H), 3.45-3.56 (m, 3H), 4.21-4.23 (m, 2H), 5.02 (s, 2H), 7.03 (s, 1H), 7.11 (s, 1H), 8.58 (s, 1H), 10.0 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[CH:17]=[CH2:18]>>[CH2:18]([O:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[Br:1])[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: Oc1cc(F)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCOc1cc(F)ccc1Br
Yield: 100.7 %

Procedure:
Treatment of 2-bromo-5-fluorophenol (10.00 g, 0.052 mol) with potassium carbonate (29.30 g, 0.209 mol) and allyl bromide (7.60 g, 0.063 mol) generally according to the reaction procedure described for Intermediate 8 provided 12.1 g (99%) of 2-(allyloxy)-1-bromo-4-fluorobenzene as a colorless oil. Rf=0.37 (silica, ethyl acetate:hexanes 1:9); 1H NMR (DMSO-d6) δH 7.58 (dd, 1H); 7.05 (dd, 1H); 6.75 (dt, 1H); 6.02 (m, 1H); 5.43 (d, 1H); 5.27 (d, 1H); 4.65 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@H:4]([C@@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=[O:14])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(N(CC)CC)C.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[C:27]([NH:1][CH2:2][CH2:3][C@@H:4]([C@@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=[O:14])[C:5]([O:7][C:8]([CH3:10])([CH3:11])[CH3:9])=[O:6])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)C[C@@H](C(=O)O)[C@H](CCN)C(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](C(=O)O)[C@H](CCNC(=O)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
A solution of 1.0 g of 2(R)-[3-amino-1(S)-(tert-butoxycarbonyl)propyl]-4-methylvaleric acid in 20 ml of dichloromethane was cooled to 5° C. under nitrogen and treated with 1.3 ml of triethylamine and a solution of 0.54 g of benzoyl chloride in 10 ml of dichloromethane. The mixture was stirred overnight at room temperature and then the solvent was evaporated. The residue was dissolved in ethyl acetate and washed with 2M aqueous hydrogen chloride and water. Drying over anhydrous magnesium sulfate, filtration and evaporation of the solvent gave a pale yellow oil which was purified by flash column chromatography on silica gel, using ethyl acetate/hexane (3:1), to give 0.78 g of 2(R)-[3-benzamido-1(S)-(tert-butoxycarbonyl)propyl]-4-methylvaleric acid in the form of a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.C(Cl)(=O)C(C)(C)C.C([Li])CCC.[Li].[C:42]1([C@@H:48]2[CH2:52][O:51][C:50](=[O:53])[NH:49]2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1COCC1>[O:21]=[C:19]([N:49]1[C@H:48]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:52][O:51][C:50]1=[O:53])/[CH:18]=[CH:17]/[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH:9]=1
Reactant: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)O)c2ccccc21
Reactant: O=C1N[C@H](c2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)N2C(=O)OC[C@H]2c2ccccc2)c2ccccc21
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acrylic acid (7.14 g, 24.85 mmol) in THF (400 mL) at −78° C. were added Et3N (10.39 ml, 74.6 mmol) and pivaloyl chloride (6.12 ml, 49.7 mmol). The mixture was stirred for 15 min at −78° C. then warmed to 0° C. for 1.5 h. The mixture was cooled to −78° C., to which was added n-Butyllithium (1.6 M in Hexanes)(14 mL, 22.4 mmol), then added the lithium salt of (R)-4-phenyl-2-oxazolidinone [prepared by adding n-Butyllithium (1.6 M in Hexanes)(31 ml, 49.7 mmol), to a solution of (R)-4-phenyloxazolidin-2-one (8.11 g, 49.7 mmol)] in THF (200 mL) at −78° C.) via cannula. The reaction was stirred at −78° C. for 2 h then at rt for 16 h. The reaction was quenched with saturated NH4Cl aqueous solution. The organics were removed under vacuum and the aqueous was extracted with EtOAc. The organic layer was collected, washed with brine, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel chromatography using a gradient of 10-20% EtOAc/Hexanes. The product fractions were collected and the solvent removed under vacuum to give ((R,E)-tert-butyl 3-(3-oxo-3-(2-oxo-4-phenyloxazolidin-3-yl)prop-1-en-1-yl)-1H-indole-1-carboxylate, 7.12 g (66%). ESI-MS (+) m/z 433.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11]O)[CH:5]=[CH:6][C:7]=1[F:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCc1ccc(F)c(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc(CCCBr)cc1Cl
Yield: 92.9 %

Procedure:
Compound 61-2 (2.47 g) was dissolved in methylene chloride (20 ml), triphenylphosphine (3.78 g) and N-bromosuccinimide (2.56 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (3.06 g) as a colorless oil.
Reaction SMILES: [H-].[Na+].[BH4-].[Na+].O.[NH2:6][C:7]1[N:12]=[C:11]([SH:13])[N:10]=[C:9]([OH:14])[CH:8]=1.Cl[C@@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24])[CH3:17]>CN(C=O)C>[NH2:6][C:7]1[N:12]=[C:11]([S:13][C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[CH3:17])[N:10]=[C:9]([OH:14])[CH:8]=1
Reactant: Nc1cc(O)nc(S)n1
Reactant: C[C@@H](Cl)c1ccccc1F
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](Sc1nc(N)cc(O)n1)c1ccccc1F
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
NaH (60% in oil, 1.05 g, 26.3 mmol) was added in portions followed by NaBH4 (0.099 g, 2.7 mmol) to 6-amino-2-mercaptopyrimidin-4-ol monohydrate (4.23 g, 26.3 mmol) in DMF (40 mL). After 30 minutes, 1-[(1R)-1-chloroethyl]-2-fluorobenzene (5.0 g, 31.5 mmol) in DMF (10 mL) was added and the reaction mixture was stirred for 24 h. The reaction mixture was concentrated and partitioned between water and DCM, the organic phase was dried (MgSO4) and evaporated. The residue was purified by flash column chromatography (a stepwise gradient of 5-10% MeOH in CHCl3) to give the title compound (5.20 g, 75% yield).
Reaction SMILES: CC([O-])(C)C.[K+].Cl[CH:8]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28].Cl>CN(C=O)C.O>[CH:14]1([CH:8]([C:25]2[CH:24]=[CH:23][C:22]([N+:27]([O-:29])=[O:28])=[C:21]([F:20])[CH:26]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)C(Cl)C1CCCCC1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(c1ccc([N+](=O)[O-])c(F)c1)C1CCCCC1
Temperature: -45 °C
Reaction time: 0.33 h
Yield: 48.6 %

Procedure:
8.2 g of potassium tert-butylate were dissolved in 70 mL of DMF and cooled to −45° C. To this, a mixture of ethyl 2-chloro-2-cyclohexylacetate (36.6 mmol, 7.5 g) and 1-fluoro-2-nitrobenzene (36.6 mmol, 3.9 mL) was gently added dropwise and stirring was continued for a further 20 minutes. The reaction mixture was set to pH 4 with 16% strength aq. HCl, diluted with 25 mL of water, and extracted with EA (3×50 mL). After combining the organic phases, they were washed with water and sat. aq. NaCl solution, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel: mesh 100-200, eluent: 10% EA in cyclohexane) and yielded 5.5 g (49%) of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[N:10]([N:21]=[CH:22][C:23]=2[S:24]([OH:27])(=[O:26])=O)[C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[CH3:20])=[O:5])[CH3:2].[CH:28]1([NH2:31])[CH2:30][CH2:29]1>>[CH:28]1([NH:31][S:24]([C:23]2[CH:22]=[N:21][N:10]3[C:11]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=4[CH3:20])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[N:8][C:9]=23)(=[O:26])=[O:27])[CH2:30][CH2:29]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)O)cnn2c1Nc1ccc(F)cc1C
Product: CCOC(=O)c1cnc2c(S(=O)(=O)NC3CC3)cnn2c1Nc1ccc(F)cc1C
Yield: 99.9 %

Procedure:
Using 6-ethoxycarbonyl-7-(4-fluoro-2-methylphenylamino)pyrazolo[1,5-a]pyrimidine-3-sulfonic acid (0.400 g, 1.145 mmol) obtained in Example 1 step 2 and cyclopropylamine (0.261 g, 4.580 mmol) instead of tert-butylamine, and in the same manner as in Example 1 step 3, the title compound (0.496 g, 100%) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:37]1([CH3:49])[CH:42]=[C:41]([CH3:43])[CH:40]=[C:39]([CH3:44])[C:38]=1[S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH:18]=2)[S:45]([C:38]2[C:39]([CH3:44])=[CH:40][C:41]([CH3:43])=[CH:42][C:37]=2[CH3:49])(=[O:47])=[O:46])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc(NCc3cccc(OC4CCCCO4)c3)cc2)cc1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(OC3CCCCO3)c2)c2ccc(OCc3ccccc3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 47.3 %

Procedure:
To a solution of (4-benzyloxy-phenyl)-[3-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (12.7 g, 32.6 mmol) in 25 mL methylene chloride at 0° C. was added triethylamine (14.0 mL, 97.8 mmol), DMAP (0.400 g, 3.27 mmol) and 2-mesitylenesulfonyl chloride (14.3 g, 65.2 mmol). The reaction mixture was stirred at room temperature for 17 hr. The reaction mixture was diluted to a volume of 800 mL with methylene chloride and was washed with water (3×200 mL) and saturated aqueous sodium chloride (1×200 mL). The organic layer was dried (magnesium sulfate), filtered, and concentrated. Medium pressure silica gel chromatography (10% ethyl acetate/hexanes to 25% ethyl acetate/hexanes) afforded 8.82 g of the title compound of Step C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[O:4][C:5]2[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]([CH3:13])[C:6]=2[N:7]=1.[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Cl-:1].[CH3:13][C:8]1[C:6]2[N:7]=[C:3]([CH2:2][P+:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:4][C:5]=2[C:11]([CH3:12])=[CH:10][CH:9]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccc(C)c2oc(CCl)nc12
Solvent: Cc1ccccc1
Product: Cc1ccc(C)c2oc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Product: [Cl-]

Procedure:
The product of Step A above was heated with an equimolar amount of triphenylphosphine in refluxing toluene for 15-25 hours to obtain the title compound.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([OH:13])=[CH:6][CH:5]=1.N1C=CC=CC=1>ClCCl>[N+:10]([C:8]1[CH:9]=[C:4]([Cl:3])[CH:5]=[C:6]([Br:1])[C:7]=1[OH:13])([O-:12])=[O:11]
Reactant: BrBr
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Cl)cc(Br)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Bromine, Br2 (63.9 g) in 50 ml of dichloromethane was added dropwise to a solution of 4-chloro-6-nitrophenol (34.7 g) in 300 ml of dichloromethane. After the addition was completed, the mixture was stirred at room temperature for 30 min. Pyridine (19.0 g, 240 mmol) in 50 ml of dichloromethane was added. This mixture was stirred at room temperature for 2 hours and a white precipitate was formed. The reaction mixture was quenched with 200 ml of water and the white precipitate was dissolved. The organic layer was then washed with water (2×150 ml), 150 ml of brine and dried over MgSO4. The solvent was evaporated under vacuum to give the crude product which was recrystallized from ethyl acetate to afford 41.5 g (82%) yellow crystalline 2-nitro-4-chloro-6-bromophenol. 1H NMR (300 MHz, CDCl3) δ8.11 (d, J=2.5 Hz, 1 H), 7.87 (d, J=2.5 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:17]=[CH:16][C:11]3[B:12]([OH:15])[O:13][CH2:14][C:10]=3[CH:9]=2)=[CH:5][CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[C:48]([O:52][C:53]([NH:55][CH:56]([CH3:60])[C:57](O)=[O:58])=[O:54])([CH3:51])([CH3:50])[CH3:49]>C(Cl)Cl.O>[C:48]([O:52][C:53](=[O:54])[NH:55][CH:56]([C:57](=[O:58])[NH:1][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:17]=[CH:16][C:11]3[B:12]([OH:15])[O:13][CH2:14][C:10]=3[CH:9]=2)=[CH:5][CH:4]=1)[CH3:60])([CH3:49])([CH3:50])[CH3:51]
Reactant: NCc1ccc(Oc2ccc3c(c2)COB3O)cc1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(NC(=O)OC(C)(C)C)C(=O)NCc1ccc(Oc2ccc3c(c2)COB3O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 40 mL scintillation vial containing 5-(4-aminomethyl-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol (350 mg, 1.37 mmol, 1.0 eq.), EDCI (314.4 mg, 1.64 mmol, 1.2 eq.), HOBt (221.6 mg, 1.64 mmol, 1.2 eq.) and Et3N (0.46 mL mg, 3.29 mmol, 2.4 eq.) in DCM (15.0 mL) was added 2-tert-Butoxycarbonylamino-propionic acid (311.1 mg, 1.64 mmol, 1.2 eq.) drop wise. The mixture was stirred at room temperature overnight. The mixture was treated with H2O (10 mL) and the layers were separated. The aqueous was extracted with DCM (2×10 mL), combined organic phase was washed with brine (10 mL), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was applied to silica chromatography eluting with MeOH/DCM (0:100 to 10:90) to give {1-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester as a white solid. LCMS (m/z) 449 (M+23); 1H NMR (DMSO-d6) δ: 9.08 (s, 1H), 8.26 (t, J=5.7 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.22-7.31 (m, J=8.4 Hz, 2H), 6.96-7.01 (m, J=8.5 Hz, 2H), 6.88-6.95 (m, 3H), 4.89 (s, 2H), 4.21-4.30 (m, 2H), 3.88-4.02 (m, 1H), 1.35 (s, 9H), 1.18 (d, J=7.1 Hz, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]2)=[CH:10][CH:9]=1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23]Br>O>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]2)=[CH:10][CH:9]=1
Reactant: O=C1CCc2ccc(O)cc2N1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C1CCc2ccc(OCCCCBr)cc2N1
Yield: 68.4 %

Procedure:
To a solution of 4.06 g of potassium carbonate with 400 ml of water was added 40 g of 7-hydroxy-3,4-dihydrocarbostyril and 158 g of 1,4-dibromobutane, then the mixture was refluxed for 3 hours. The reaction mixture thus obtained was extracted with dichloromethane, dried with anhydrous magnesium sulfate, then the solvent was removed by evaporation. The residue thus obtained was purified by means of a silica gel column chromatography (eluent: dichloromethane), and recrystallized from n-hexane-ethanol to yield 50 g of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril.