Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.CCCCC.[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:13]=1[C:14]#[N:15].[I:24]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1.O>[F:11][C:12]1[C:19]([I:24])=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[C:13]=1[C:14]#[N:15]
Reactant: II
Reactant: N#Cc1c(F)cccc1C(F)(F)F
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCC
Product: N#Cc1c(C(F)(F)F)ccc(I)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 17.6 %

Procedure:
To a solution of 2 M n-BuLi in pentane (1.62 mL, 3.24 mmol) in 8 mL of dry THF under N2 at −78° C. was added 2-fluoro-6-(trifluoromethyl)benzonitrile (612 mg, 3.24 mmol) in 2 mL of dry THF. The mixture was stirred at −78° C. for 30 min, followed by the addition of iodine (1070 mg, 4.22 mmol) in 2 mL of dry THF. The reaction mixture was warmed up and stirred for 2 h at room temperature. Water was added followed by a solution of Na2S2O3. The mixture was extracted with EtOAc. The organic layer was separated and washed with water and brine. The organic layer was dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with 5% EtOAc/hexane. The product fractions were collected and concentrated to afford 180 mg (17.7%) of 2-fluoro-3-iodo-6-trifluoromethylbenzonitrile as a brown dark solid.
Reaction SMILES: [Na+].C(OC[C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:26])[CH:11]2[NH:15][C:16](=[O:25])[CH2:17][N:18]2[CH:22]=[CH:21][CH:20]=[C:19]2[CH:23]=[O:24])[C:8]=1[C:27]([O-:29])=[O:28])(=O)C.Cl[CH2:31][O:32][C:33](=[O:46])[C@H:34]([CH:43]([CH3:45])[CH3:44])[NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>CN(C)C=O.C(OCC)(=O)C>[C:39]([O:38][C:36]([NH:35][CH:34]([CH:43]([CH3:45])[CH3:44])[C:33]([O:32][CH2:31][O:29][C:27]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][CH:7]=1)[CH:11]([NH:15][C:16](=[O:25])[CH2:17][N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=[O:24])[C:10]2=[O:26])=[O:28])=[O:46])=[O:37])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)Cn3cccc3C=O)C2SC1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OCOC(=O)C1=CCSC2C(NC(=O)Cn3cccc3C=O)C(=O)N12
Reaction time: 72 h

Procedure:
A suspension of 5 grams of 3-[(acetyloxy)methyl]-7-[[(2-formyl-1-pyrryl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2ene-2-carboxylic acid sodium salt and 8.5 grams of N-tert-butoxycarbonyl-L-valine chloromethyl ester, prepared according to the general procedure described in W. German Offen. No. 2,236,620, are mixed in 100 ml of dimethylformamide (DMF) and stirred for 72 hours. The mixture is diluted with ethyl acetate, washed with water and aqueous sodium bicarbonate and again with water. The ethyl acetate portion is dried over magnesium sulfate, filtered and evaporated to dryness to give 3-](acetyloxy)methyl]-7-[[(2-formyl-1-pyrryl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid N-tert-butoxycarbonyl-2-amino-3-methylbutyryloxy-methyl ester from which the protecting group can be removed by standard procedures to give the title compound.
Reaction SMILES: CN(C)CCN=C=NCCC.[NH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[Br:22])[C:16]([OH:18])=O.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH2:36][NH2:37])[CH2:26][CH2:25]1.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[NH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[Br:22])[C:16]([NH:37][CH2:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[N:27]1[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]1)=[O:18]
Reactant: CN1CCN(c2ccccc2CN)CC1
Reactant: Nc1cc(C(=O)O)ccc1Br
Agent: CCCN=C=NCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN1CCN(c2ccccc2CNC(=O)c2ccc(Br)c(N)c2)CC1

Procedure:
N1,N1-dimethyl-N2-((propylimino)methylene)ethane-1,2-diamine (0.70 ml, 3.99 mmol) was added to a stirred solution/suspension of 3-amino-4-bromobenzoic acid (719 mg, 3.33 mmol), (2-(4-methylpiperazin-1-yl)phenyl)methanamine (820 mg, 3.99 mmol) and HOBt (140 mg, 1.0 mmol) in dry DCM (20 ml) under argon. After 24 hrs the reaction mixture was diluted with DCM and washed several times with water. The solvent was removed in vacuo and the resulting yellow oil was triturated with DCM/diethyl to give a yellow crystalline powder;
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2([CH2:12][NH:13][C:14]3[N:19]=[N:18][C:17](C#N)=[CH:16][CH:15]=3)[CH2:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C[Mg+].[Br-].Cl.CCO[C:29]([CH3:31])=[O:30]>C1COCC1.CCOCC>[F:1][C:2]1[C:3]([C:8]2([CH2:12][NH:13][C:14]3[N:19]=[N:18][C:17]([C:29](=[O:30])[CH3:31])=[CH:16][CH:15]=3)[CH2:9][CH2:10][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: N#Cc1ccc(NCC2(c3ncccc3F)CCC2)nn1
Agent: C[Mg+]
Agent: Cl
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc(NCC2(c3ncccc3F)CCC2)nn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 18 %

Procedure:
6-((1-(3-Fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazine-3-carbonitrile (500 mg, 1.8 mmol, 1.0 equiv) was dissolved in THF (4.5 mL) and transferred to a 20 dram vial. The mixture was cooled to 0° C. and MeMgBr (1.8 mL, 5.3 mmol of a 3M solution in Et2O, 2.9 equiv) was added. The reaction was stirred at this temperature for 15 min. The reaction mixture was poured into ice water, acidified to pH of 2 with 2N aqueous hydrochloric acid, and then extracted EtOAc (30 mL). The organic layer was then separated, dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography (50% EtOAc/hexanes) to give 104 mg (18%) of 1-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)ethanone as a white powder. m/z=301.1 [M+H]+.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].C([O-])(=O)C.[Pb+4:17].[CH3:18][C:19]1[C:24](B(O)O)=[C:23]([CH3:28])[CH:22]=[C:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:20]=1>C(Cl)(Cl)Cl>[C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].[CH3:18][C:19]1[C:24]([Pb+3:17])=[C:23]([CH3:28])[CH:22]=[C:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:20]=1
Reactant: [Pb+4]
Reactant: Cc1cc(-c2ccccc2)cc(C)c1B(O)O
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Product: Cc1cc(-c2ccccc2)cc(C)c1[Pb+3]
Temperature: 40 °C
Reaction time: 4 h
Yield: 67.7 %

Procedure:
To a solution of lead tetraacetate (4.3 g, 9.7 mmol) in dry chloroform (15 ml) at 40° C. is added 3,5-dimethylbiphen-4-ylboronic acid (2.0 g; 8.8 mmol) in one portion under an atmosphere of nitrogen. The mixture is stirred at 40° C. for 4 hours, and then is cooled to room temperature. The precipitate is removed by filtration, and the filtrate is then passed through a plug of potassium carbonate supported on diatomaceous earth to remove acetic acid. The filtrate is evaporated in vacuo to afford 3,5-dimethylbiphen-4-yllead triacetate (3.37 g).
Reaction SMILES: C([NH:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:9]=2[C:8]([C:16]([O:18]C)=[O:17])=[CH:7][C:6]=1[Cl:20])(=O)C.[OH-].[Na+]>CO>[NH2:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:9]=2[C:8]([C:16]([OH:18])=[O:17])=[CH:7][C:6]=1[Cl:20]
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)c2c1OCCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1c(Cl)cc(C(=O)O)c2c1CCCCO2

Procedure:
To a solution of 5 g (16.8 mmol) of methyl 6-acetylamino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylate in 10 ml of methanol is added 10 ml of a 10% aqueous sodium hydroxide solution in a single portion at room temperature. The solution is heated to reflux and maintained for 2 hours. After cooling, methanol is removed in vacuo and the residue is diluted with water. The pH of this solution is adjusted to 7 with 1N HCl. The neutral solution is extracted with CH2Cl2 and the combined organic extracts are dried over MgSO4, filtered and concentrated. Flash chromatography (30% EtOAc/hexanes) provides 6-amino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid.
Reaction SMILES: [CH3:1][N:2]([CH2:7][CH2:8][CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:3][CH2:4][CH2:5][NH2:6].[C:22]([NH:24][C:25](=[N:33][CH2:34][CH2:35][S:36][CH2:37][C:38]1[N:39]=[C:40]([NH:43][C:44]([NH2:46])=[NH:45])[S:41][CH:42]=1)OC1C=CC=CC=1)#[N:23]>>[C:22]([NH:24][C:25]([NH:33][CH2:34][CH2:35][S:36][CH2:37][C:38]1[N:39]=[C:40]([NH:43][C:44]([NH2:46])=[NH:45])[S:41][CH:42]=1)=[N:6][CH2:5][CH2:4][CH2:3][N:2]([CH2:7][CH2:8][CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH3:1])#[N:23]
Reactant: CN(CCCN)CCC(c1ccccc1)c1ccccn1
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Product: CN(CCCN=C(NC#N)NCCSCc1csc(NC(=N)N)n1)CCC(c1ccccc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.85 g (3 mmol) of N-methyl-N-[3-phenyl-3-(2-pyridyl)propyl]-1,3-propanediamine and 1.12 g (3 mmol) of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a dry foam; MS (+FAB method): m/z (rel. int.[%])=565 ([M+H]+, 2), 196 (100); IR (KBr): 2162 cm-1 (C≡N). For analytical purposes a sample is converted into the maleic acid salt and recrystallised from ether/isopropanol; m.p.: 110°-112° C. with decomposition.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[CH2:23][OH:24].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.O>C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH3:22])[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:26](=[O:28])[O:24][CH2:23][C:3]=2[CH:4]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(CO)c3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc2nccc(Oc3ccc4c(c3)COC(=O)N4)c2cc1OC
Temperature: 25 °C
Yield: 35.3 %

Procedure:
{2-Amino-5-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}methanol (63 mg) was dissolved in heated triethylamine/toluene (1.2 ml/6 ml) to prepare a solution. Triphosgene (98 mg) was added to the solution and was heated under reflux for 2 min. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography on silica gel using acetone-chloroform to give the title compound (24 mg, yield 39%).
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C@H:11]([C:16](O)=[O:17])[CH2:12][C:13](O)=[O:14])(=[O:9])=[O:8])=[CH:3][CH:2]=1.B>O1CCCC1.CO>[C:1]1([CH3:19])[CH:2]=[CH:3][C:4]([S:7]([NH:10][C@@H:11]([CH2:12][CH2:13][OH:14])[CH2:16][OH:17])(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](CC(=O)O)C(=O)O)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N[C@H](CO)CCO)cc1
Temperature: -5 °C
Reaction time: 8 h

Procedure:
N-(p-Toluenesulfonyl)-L-aspartic acid, 1, (110 g) was dissolved in tetrahydrofuran (300 mL) and the solution cooled to -5° C. under a nitrogen atmosphere. A 1.0M solution of borane in tetrahydrofuran was added dropwise over 1 hour at 0 to -5° C. and the resulting solution stirred at 20° to 25° C. overnight. The solution was recooled to 0° C. and methanol (250 mL) was added dropwise over 30 minutes (caution! gas evolution). The solution was concentrated under vacuum to an oil which was redissolved in methanol (1L) and the solution heated at reflux 1 hour. This solution was concentrated under vacuum to give a solid which was redissolved in methanol (1L) and this solution heated at reflux for 2 hours. Finally the solution was concentrated to a solid which was dried under vacuum at 50° C. to give (S)-2-(p-toluenesulfonylamino)-1,4-butanediol, 2, as an off white solid (97 g, 98%) which was used directly in the next step without further purification. A portion was recrystallized from isopropyl alcohol and hexanes: mp 90°-92° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH:9]([OH:11])[CH3:10])=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=1.[OH-].[Na+].O>C(#N)C>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH:9]([O:11][C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[CH3:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(OCC(C)O)cc1
Reactant: COc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COc1ccc(OCC(C)Oc2ccc(OC)cc2)cc1
Yield: 76.4 %

Procedure:
In 500 ml of acetonitrile were dissolved 168 g of 1-p-methoxyphenoxy-2-propanol and 62 g of p-methoxyphenol. To the solution was added 50 g of a 48% sodium hydroxide aqueous solution, and the mixture was allowed to react at 80° C for 3 hours while stirring. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration and recrystallized from methanol to obtain 110 g of 1,2-bis(4-methoxyphenoxy)propane having a melting point of 84 to 84.5° C.
Reaction SMILES: [C:1]1([CH:7]([SiH2:14][CH2:15][CH2:16][OH:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([O:20][P:21](Cl)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:19].N1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[P:21]([O:17][CH2:16][CH2:15][SiH2:14][CH:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([O:22][CH2:23][CH3:24])([O:20][CH2:18][CH3:19])=[O:25]
Reactant: OCC[SiH2]C(c1ccccc1)c1ccccc1
Reactant: CCOP(=O)(Cl)OCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCOP(=O)(OCC)OCC[SiH2]C(c1ccccc1)c1ccccc1

Procedure:
The reaction described in Example 10 was carried out using 2-(diphenylmethylsilyl)-ethanol (2.25 g), diethylphosphorochloridate (1.35 g), and pyridine (0.6 g) in carbon tetrachloride (10 ml). Diethyl 2-(diphenylmethylsilyl)ethyl phosphate was obtained as a colourless oil (1.35 g) (C17H23Si O4P requires: C, 60.5%; H, 7.1%; Found: C 63.4%; H, 7.8%).
Reaction SMILES: C(C1C=CC(CN2C(C)=C(C3C=CC=C(C(F)(F)F)C=3)C(=O)C(C(O)=O)=C2)=CC=1)#N.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[CH:35][N:34]=1.BrC1C(=O)C(C(O)=O)=CN(CC2C=CC(C#N)=CC=2)C=1C.Br[C:66]1[C:67](=[O:86])[C:68]([C:83]([OH:85])=[O:84])=[CH:69][N:70]([CH:73]([C:75]2[CH:80]=[CH:79][C:78]([C:81]#[N:82])=[CH:77][CH:76]=2)[CH3:74])[C:71]=1[CH3:72]>>[C:81]([C:78]1[CH:77]=[CH:76][C:75]([CH:73]([N:70]2[CH:69]=[C:68]([C:83]([OH:85])=[O:84])[C:67](=[O:86])[C:66]([C:37]3[CH:36]=[CH:35][N:34]=[C:33]([C:32]([F:43])([F:42])[F:31])[CH:38]=3)=[C:71]2[CH3:72])[CH3:74])=[CH:80][CH:79]=1)#[N:82]
Reactant: OB(O)c1ccnc(C(F)(F)F)c1
Reactant: Cc1c(Br)c(=O)c(C(=O)O)cn1C(C)c1ccc(C#N)cc1
Agent: Cc1c(-c2cccc(C(F)(F)F)c2)c(=O)c(C(=O)O)cn1Cc1ccc(C#N)cc1
Agent: Cc1c(Br)c(=O)c(C(=O)O)cn1Cc1ccc(C#N)cc1
Product: Cc1c(-c2ccnc(C(F)(F)F)c2)c(=O)c(C(=O)O)cn1C(C)c1ccc(C#N)cc1

Procedure:
Preparation 4 is prepared following the procedure described for preparation 1d, substituting 3-(trifluoromethyl)phenylboronic acid with 2-(trifluoromethyl)pyridine-4-boronic acid and substituting preparation 1c with preparation 2b as starting material. ESI mass spectrum: [M+H]+=428; Retention time HPLC: 0.99 min (Z018_S04).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.[Cl-].C[Zn+].[CH2:34](Cl)Cl>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:29][C@@H:24]1[C@@H:23]([N:13]2[C:12](=[O:30])[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]4=[C:9]([CH2:8][C:5]4[CH:6]=[N:7][C:2]([CH3:34])=[CH:3][CH:4]=4)[CH:10]=3)[N:15]=[CH:14]2)[CH2:28][CH2:27][O:26][CH2:25]1
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Reactant: ClCCl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C[Zn+]
Solvent: C1CCOC1
Product: Cc1ccc(Cc2cc3c(=O)n([C@H]4CCOC[C@@H]4O)cnc3c3ccccc23)cn1
Temperature: 50 °C

Procedure:
To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one (Example 1, 0.040 g, 0.095 mmol) in 1 mL of THF under an atmosphere of nitrogen was added methyl zinc chloride (0.095 mL, 2 M in THF, 1.90 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 1:1 complex with DCM (3 mol %). The reaction was heated at 50° C. for 18 h, cooled to rt, and quenched with water (2 mL). The mixture was filtered through celite and the aqueous layer was extracted 2× with dichloromethane. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 10-60% ethyl acetate in hexanes, to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 401.46 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 8.92 (d, J=7.5 Hz, 1H), 8.38 (s, 1H), 8.29 (s, 1H), 7.83 (d, J=7.3 Hz, 1H), 7.79 (s, 1H), 7.66-7.59 (m, 2H), 7.15 (d, J=8.1 Hz, 1H), 6.90 (d, J=7.9 Hz, 1H), 4.87-4.78 (m, 1H), 4.26-4.19 (m, 4H), 4.12-4.08 (m, 1H), 3.81 (br s, 1H), 3.61-3.54 (m, 1H), 3.44-3.37 (m, 1H), 2.43 (s, 3H), 2.33-2.23 (m, 1H), 2.03-1.99 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].[OH-].[K+].Cl[CH2:15][C:16]([NH2:18])=[O:17].O1CCOCCOCCOCCOCCOC=C1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([O:6][CH2:15][C:16]([NH2:18])=[O:17])=[O:5]
Reactant: O=C(O)c1c(F)cccc1F
Reactant: NC(=O)CCl
Agent: C1=COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: NC(=O)COC(=O)c1c(F)cccc1F

Procedure:
This compound was prepared in the manner of Example I, using 10.0 grams (0.063 mole) of 2,6-difluorobenzoic acid, 4.2 grams (0.063 mole) of potassium hydroxide, 5.9 grams (0.063 mole) of 2-chloroacetamide, and 1.7 grams of 1,4,7,10,13,16-hexaoxacyclooctadecene in 250 ml of dry toluene. The crude product was recrystallized once with ethyl acetate, then with ethyl acetate-hexane, using decolorizing carbon. The yield was 5.2 grams of (aminocarbonyl)methyl 2,6-difluorobenzoate; mp 108.5°-110°. The ir and the nmr spectra were consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(Cl)(=O)C([Cl:14])=O.CN(C)C=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([Cl:14])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-bromopyridine-2-carboxylic acid (2.5 g, 12 mmol) in methylene chloride (10.0 mL) was added oxalyl chloride (1.6 mL, 18 mmol), followed by N,N-dimethylformamide (0.020 mL, 0.26 mmol). After stirred at RT for 2 h, the mixture was evaporated under reduced pressure. The residue was the acid chloride which was used directly in next step reaction.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:2][CH:3]=[CH2:4].[Li]CCCC.Cl[CH2:19][C:20](=[O:41])[CH:21]=[P:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>C1COCC1>[CH2:1]([N:5]([CH2:19][C:20](=[O:41])[CH:21]=[P:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCNC(=O)OC(C)(C)C
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)CCl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C=CCCN(CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a mixture of tert-butyl N-but-3-enylcarbamate (3.16 g, 18.42 mmol, 1.30 Eq) in THF (20 mL), was added n-BuLi (2.5 M, 14.74 mL, 2.60 Eq) at −78° C. under N2. The mixture was stirred at −20° C. for 1 hr. Then 1-chloro-3-(triphenyl phosphoranylidene)propan-2-one (5.00 g, 14.17 mmol, 1.00 Eq) in THF (20 mL) was added to the mixture at −78° C. under N2. The mixture was stirred at −20° C. for 3 hr. The resulting mixture was poured into water (30 mL) and stirred for 20 min. The aqueous phase was extracted with EA (10 mL). The combined organic phase was washed with saturated brine (20 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (PE/EA=1/1) to afford tert-butyl but-3-en-1-yl(2-oxo-3-(triphenylphosphoranylidene)propyl)carbamate (5.80 g, 11.90 mmol, 83.98% yield) as yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.Cl.[NH:27]1[CH2:30][CH2:29][CH2:28]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)(=[O:25])=[O:24])=[C:6]([CH2:8][C:9]([N:27]2[CH2:30][CH2:29][CH2:28]2)=[O:11])[CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Reactant: C1CNC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)N2CCC2)c1
Reaction time: 3 h

Procedure:
To the mixture of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (500 mg, 1.4 mmol) and azetidine hydrochloride (470 mg, 5 mmol) in DMF (5 ml), added PyBOP (730 mg, 1.4 mmol) then triethyl amine (1.1 ml, 8 mmol). Stirring was kept for 3 hours. Diluted with EtOAc, washed with 1N HCl, water and brine. Dried over anhydrous sodium sulfate. Concentrated, the residue was dissolved in DMSO and purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column). The compound was obtained as white powder. MS calcd for (C18H20BN3O5S): 401.12. MS found (ESI negative): (M−H)−=400.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.69 (s, 1H), 7.36 (d, J=1.6 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.16 (d, J=8 Hz, 1H), 7.04 (dd, J=8.4 Hz, 1H), 6.34 (d, J=2.4 Hz, 1H), 6.30 (dd, J=8.8 Hz, 1H), 4.81 (s, 2H), 4.01 (t, J=7.2 Hz, 1H), 3.81 (t, J=7.6 Hz, 1H), 3.57 (s, 2H), 2.11 (m, 2H).