Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[N:8]2[N:18]=[N:19][N:20]=[C:7]2[NH:6][C:5]=1[CH3:21])(=[O:3])[CH3:2].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[C:1]([C:4]1[CH:9]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[N:8]2[N:18]=[N:19][N:20]=[C:7]2[N:6]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([C:23]([F:34])([F:33])[F:22])[CH:29]=2)[C:5]=1[CH3:21])(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)Nc2nnnn2C1c1ccc(C#N)cc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nnnn2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (rac)-4-(6-acetyl-5-methyl-4,7-dihydrotetrazolo[1,5-a]pyrimidin-7-yl)benzonitrile (50 mg, 178 μmol) was stirred in abs. dichloromethane (3 ml) with molecular sieve (0.5 g, 4 Å) for 1 h. 3-(Trifluoromethyl)phenylboronic acid (101.6 mg, 535 μmol, 3 eq.), anhydrous copper(II) acetate (97.2 mg, 535 μmol, 3 eq.), abs. pyridine (115 μl, 1.43 mmol, 8 eq.) and triethylamine (54.2 mg, 535 μmol, 3 eq.) were then added, and the mixture was stirred at RT for 12 h. More molecular sieve (0.5 g, 4 Å), 3-(trifluoromethyl)phenylboronic acid (33 mg, 178 μmol, 1 eq.), anhydrous copper(II) acetate (32 mg, 178 μmol, 1 eq.), triethylamine (18.1 mg, 178 μmol, 1 eq.) and abs. pyridine (57.5 μl, 715 μmol, 4 eq.) were then added, and the mixture was stirred at RT for a further 12 h. The reaction mixture was then filtered through kieselguhr, the filter residue was washed with dichloromethane and methanol and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC (Gromsil C18 column, 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The product was obtained as a colorless solid (14.6 mg, 19% of theory).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1.C([O-])(=O)C.[Na+].[Br:24]Br>CO>[Br:24][C:15]1[CH:16]=[CH:17][C:4]2[O:3][C:2]([CH3:18])([CH3:1])[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[C:5]=2[CH:14]=1
Reactant: BrBr
Reactant: CC1(C)N=C(c2ccccn2)c2ccccc2O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)N=C(c2ccccn2)c2cc(Br)ccc2O1
Temperature: -40 °C
Reaction time: 18 h
Yield: 25.9 %

Procedure:
Methanol (25 ml) was added to a mixture of Compound 2 (1.19 g) and sodium acetate (0.82 g). The mixture was cooled to -40° C. and bromine (0.96 g) was added to the mixture. After completion of the addition, the mixture was warmed and the mixture was stirred at 5° to 8° C. for 18 hours. The reaction was quenched by adding aqueous sodium sulfite solution, and the methanol was distilled off. The residue was extracted with ethyl acetate. The extract was successively washed with aqueous sodium bicarbonate solution and saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue was subjected to column chromatography on silica gel and eluted with ethyl acetate/hexane to obtain 6-bromo-2,2-dimethyl-4-(2-pyridyl)-2H-1,3-benzoxazine (0.41 g) (Compound 4).
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]([CH3:33])[CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][C:11](=[C:14]2[C:23]3[CH:24]=[C:25]([CH2:28][C:29]([O:31]C)=[O:30])[CH:26]=[CH:27][C:22]=3[O:21][CH2:20][C:19]3[CH:18]=[CH:17][S:16][C:15]2=3)[CH2:10][CH2:9]1>C(O)C>[O:3]=[C:4]([CH3:33])[CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][C:11](=[C:14]2[C:23]3[CH:24]=[C:25]([CH2:28][C:29]([OH:31])=[O:30])[CH:26]=[CH:27][C:22]=3[O:21][CH2:20][C:19]3[CH:18]=[CH:17][S:16][C:15]2=3)[CH2:10][CH2:9]1
Reactant: COC(=O)Cc1ccc2c(c1)C(=C1CCN(CCCC(C)=O)CC1)c1sccc1CO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)CCCN1CCC(=C2c3cc(CC(=O)O)ccc3OCc3ccsc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
A 2 mol/L aqueous sodium hydroxide solution (5 mL, equivalent to 10 mmol sodium hydroxide) was added to an ethanol (20 mL) solution of the compound obtained in Example 30 (2.40 g, 5.5 mmol), and the mixture was stirred at room temperature for 2 hours. The solvents were distilled off, water was then added to the residue, and the aqueous solution was adjusted to a pH of 7 with a diluted hydrochloric acid. The precipitated crystals were separated by filtration and dried, to give 1.30 g (56%) of the captioned compound.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[C:8](C1C3C(=CC=CC=3)C=CC=1)[CH:7]=[CH:6][CH:5]=2.C[Si]([N-][Si](C)(C)C)(C)C.[K+:30]>C1(C)C=CC=CC=1>[CH3:10][C:2]1[CH:1]=[C:10]([C:2]2[CH-:3][C:4]3[C:9]([CH:1]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[K+:30]
Reactant: CC1=Cc2c(cccc2-c2cccc3ccccc23)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(-c2cc3ccccc3[cH-]2)c2ccccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 228.5 %

Procedure:
2-Methyl-4-naphthylindene (1.00 g, 3.27 mmole) was dissolved in 20 ml of toluene, potassium bis(trimethylsilyl)amide (1.05 equivalent, 3.43 mmole, 0.684 g) was added and the reaction mixture was stirred at room temperature for 24 hours, during which a yellow solid precipitated. Hexane was added (20 ml) and the mixture was stirred for 2 h. The solid product was isolated by vacuum filtration through a medium porosity frit. The solid was pumped dry giving 1.10 g, 98 percent of the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[N:7][CH:8]=1)#[CH:2].I[C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:29][C:28]([NH:27][C:19]1[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:18]=1[C:2]#[C:1][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH:6]=[N:7][CH:8]=1)=[O:34])([CH3:33])([CH3:31])[CH3:32]
Reactant: C#Cc1cncc(NC(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc([N+](=O)[O-])cc1I
Product: CC(C)(C)OC(=O)Nc1cncc(C#Cc2cc([N+](=O)[O-])ccc2NC(=O)OC(C)(C)C)c1
Yield: 85 %

Procedure:
This compound was prepared according to the procedure of Example B19 step C, using tert-butyl (5-ethynylpyridin-3-yl)carbamate and tert-butyl (2-iodo-4-nitrophenyl)carbamate as the starting material in 85% yield. LCMS calculated for C23H27N4O6(M+H)+: m/z=455.1.
Reaction SMILES: C(O)(=O)C(C)(C)C.C=[S:9]1[C@H:15]2[N:12]([C:13](=[O:22])[C:14]2=[CH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[C@@H:11]([C:23]([OH:25])=[O:24])[C:10]1([CH3:27])[CH3:26].C(C(CCCC)C([O-])=O)C.[Na+:38]>CS(C)=O.P([O-])([O-])([O-])=O.CCOCC>[CH3:27][C:10]1([CH3:26])[S:9][C@H:15]2[N:12]([C:13](=[O:22])[C:14]2=[CH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[C@H:11]1[C:23]([O-:25])=[O:24].[Na+:38]
Reactant: C=S1[C@@H]2C(=CC(=O)C(C)C)C(=O)N2[C@@H](C(=O)O)C1(C)C
Agent: CC(C)(C)C(=O)O
Agent: CCCCC(CC)C(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC(C)C(=O)C=C1C(=O)N2[C@@H]1SC(C)(C)[C@@H]2C(=O)[O-]
Reaction time: 2 h

Procedure:
A suspension of 2.2 g of methylene-(2S,5R)-3,3-dimethyl-6-(3-methyl-2-oxobutylidene)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate in 300 ml of dimethyl sulphoxide and 500 ml of phosphate buffer (pH 7.1) is treated at 20° with 2 ml of a suspension of pig liver esterase (3 mg/ml). The reaction mixture is stirred at 20° for 2 hours and subsequently extracted with ether. The aqueous phase is acidified (pH 3.2) with 50% citric acid and extracted with ether. The organic extract is washed with distilled water, dried over magnesium sulphate, filtered and evaporated. There is obtained an oily residue which is dissolved in 200 ml of ether and treated with 2.4 ml of a 2M solution of sodium 2-ethylcaproate. The crystalline precipitate is filtered off under suction, washed with ether and dried over phosphorus pentoxide in vacuo. There is obtained sodium (2S,5R)-3,3-dimethyl-6-(3-methyl-2 -oxobutylidene)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate of melting point 145° (decomposition). [Rf : 0.41; chloroform/ethyl acetate/acetic acid (5:4:1); NMR (D2O) δ (ppm); 1.17 (6H); 1.53 (3H); 1.61 (3H); 2.95 (1H); 4.4 (1H); 6.05 (1H); 6.9 (1H)].
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C:9]2[C:4](=[C:5]([Cl:13])[C:6]([Cl:12])=[C:7]([OH:11])[CH:8]=2)[C:3]1=[O:14].C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].O>CN(C)C=O>[C:32]([O:31][C:29](=[O:30])[CH2:28][O:11][C:7]1[CH:8]=[C:9]2[C:4](=[C:5]([Cl:13])[C:6]=1[Cl:12])[C:3](=[O:14])[C:2]([CH3:1])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10]2)([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC1(c2ccccc2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccccc1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-methyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone (9.2 g., 0.03 mole), potassium carbonate (8.29 g., 0.06 mole) and tert-butyl bromoacetate (6.44 g., 0.033 mole) in dimethylformamide (30 ml.) is stirred at 25° C. for two hours. The reaction mixture is poured into cold water (150 ml.) and the tert-butyl(1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetate which separates is filtered, rinsed with water and dried.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[O:11]1[C:15]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[O:11]1[C:15]2([CH2:20][CH2:19][N:18]([C:2]3[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[CH:5]=[CH:4][N:3]=3)[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1
Reactant: NC(=O)c1ccnc(Cl)n1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: NC(=O)c1ccnc(N2CCC3(CC2)OCCO3)n1
Yield: 97.6 %

Procedure:
5 g (0.0318 mol) of 2-chloropyrimidine-4-carboxamide, 4.55 g (0.0318 mol) of 1,4-dioxa-8-azaspiro[4.5]decane and 6.6 g (0.0477 mol) of potassium carbonate are introduced into 100 ml of 2-butanone. The mixture is heated and stirred at reflux temperature for 6 hours. The mixture is filtered and the filtrate is concentrated under reduced pressure. 8.2 g of product are obtained which are recrystallised from 2-propanol. 4.1 g of product are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[C:5]([O:19][CH3:20])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:21][O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.[ClH:30]>C(O)(C)C.O1CCOCC1>[ClH:1].[ClH:30].[CH3:20][O:19][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([NH:27][C:26]1[CH:28]=[CH:29][C:23]([O:22][CH3:21])=[CH:24][CH:25]=1)[N:11]=[C:10]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(N)cc1
Reactant: COc1cccc2c(Nc3ccccc3)nc(Cl)nc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: COc1ccc(Nc2nc(Nc3ccccc3)c3cccc(OC)c3n2)cc1

Procedure:
A mixture of 2-chloro-8-methoxy-4-phenylamino-quinazoline (1.20 g) and 4-methoxy-aniline (0.66 g) is heated for 3 min to produce a melt which is dissolved in isopropanol (15 ml). 4N HCl in dioxane (0.2 ml) is added. Crystallization from isopropanol and diethylether yields 8-methoxy-2-(4-methoxy-phenylamino)-4-phenylamino-quinazoline dihydrochloride, m.p. 287-289° C., FAB-MS: (M+H)+=373. Analytical data: C22H20N4O2+HCl.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10](Cl)=[O:11])[CH:6]=[CH:7][CH:8]=1.[NH2:15][C:16]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[Br:26][C:23]1[CH:24]=[CH:25][C:16]([NH:15][C:10](=[O:11])[CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=2)=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19]
Reactant: O=C(Cl)Cc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1cc(Br)ccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(Br)ccc1NC(=O)Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3-(trifluoromethyl)phenyl)acetyl chloride (23.4 mmol assuming quantitative yield in previous step, Intermediate 5: step a) in DCM (50 mL) in an ice bath was added methyl 2-amino-5-bromobenzoate (4.90 g, 21.3 mmol) followed by triethylamine (6.51 mL, 46.8 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was washed with saturated aqueous NH4Cl then water. The organic phase was dried (Na2SO4), filtered, and concentrated and the residue was purified by flash column chromatography (50-70% DCM-heptanes). Some of the title compound was obtained in pure form from the column, along with mixed fractions containing the title compound and the starting aniline. The mixed fractions were left to stand in DCM:heptanes (1:1) overnight, forming crystalline needles of the title compound, which were collected by vacuum filtration and combined with clean fractions from the column.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.Cl.[NH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C1(N=C=NC2CCCCC2)CCCCC1.[2H]C(S(C([2H])([2H])[2H])=O)([2H])[2H].[2H]O[2H]>N1C=CC=CC=1>[C:1]([NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cccnc1
Reactant: NCCc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H]
Solvent: c1ccncc1
Product: O=C(NCCc1ccc(O)cc1)c1cccnc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To an ice cold suspension of 3.69 g (0.03 mol) nicotinic acid in a solution of 5.2 g (0.03 mol) tyramine hydrochloride in 100 ml of pyridine, 6.18 g (0.03 mol) of dicyclohexylcarbodiimide (DCC) were gradually added while stirring. Stirring was continued at room temperature for 24 hrs and the formed dicyclohexylurea was removed by filtration. The pyridine was removed by distillation in vacuo and the residue was triturated with cold water, filtered and crystallized from 50% aqueous methanol. Yield, 6.25 g (86%), m.p. 179°-181° C. PMR (DMSO-d6 /D2O) δ 9.0-8.66 (m, 2H, C2 and C6 pyridine protons), 8.33-8.10 (m, 1H, C4 pyridine proton), 7.66-7.46 (m, 1H, C5 pyridine proton), 7.23-6.70 (m, rH, C6H4), 3.56 (t, 2H, ##STR1535## 2.90 (t, 2H, CH2). Anal. (C14H14N2O2) C, H, N.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12](Cl)[C:11]=2[Cl:17])=[C:5]([C:18]([F:21])([F:20])[F:19])[N:4]=1.[Cl:22]C1C=C(Cl)C=CC=1CC#N>>[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:22])=[CH:12][C:11]=2[Cl:17])=[C:5]([C:18]([F:21])([F:20])[F:19])[N:4]=1
Reactant: Nc1nc(N)c(-c2cccc(Cl)c2Cl)c(C(F)(F)F)n1
Reactant: N#CCc1ccc(Cl)cc1Cl
Agent: Cl
Product: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(C(F)(F)F)n1

Procedure:
This compound was prepared in a manner analogous to the compound of Example 14 from 2,4-dichlorophenylacetonitrile (Aldrich): mp. 220.5°-221° C.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]1([CH:19]2[CH2:24][CH2:23][O:22][C:20]2=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:25][O:26][CH2:27]Cl>C1COCC1>[C:13]1([C:19]2([CH2:25][O:26][CH3:27])[CH2:24][CH2:23][O:22][C:20]2=[O:21])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COCCl
Reactant: O=C1OCCC1c1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COCC1(c2ccccc2)CCOC1=O
Temperature: -90 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
Butyl lithium (62.5 mL of 1.6M solution in hexanes) was treated dropwise with a solution of diisopropylamine (14.0 mL) in THF (200 mL) at −20° C. and the resulted mixture was stirred for additional 30 min at the same temperature. After that the mixture was cooled to −90° C., treated dropwise with a solution of 2-phenyl-γ-butyrolactone (11.0 g) in THF (50 mL) and then stirred for 45 min at the same temperature. Next the reaction mixture was treated dropwise with a solution of chloromethyl methyl ether (8.05 g) in THF (50 mL), stirred for additional 10 min, then allowed to slowly warm-up to room temperature and stirred at this temperature for 16 h. Subsequently the reaction mixture was quenched by pouring onto a mixture of ice and 10% aqueous phosphoric acid. The formed organic phase was separated and the aqueous phase was extracted with chloroform. The combined organic phases were washed with saturated aqueous solution of potassium bicarbonate, then water, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator and distilled in vacuum to give 11.5 g (82%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:19]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([O:27]C)[CH:21]=4)[CH2:18][C:17](=[O:29])[NH:16][C:15]=3[CH3:30])=[O:13])[CH:9]=2)[NH:4][N:3]=1.B(Cl)(Cl)Cl>C(Cl)Cl.CCOC(C)=O.O.[OH-].[Na+]>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:19]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([OH:27])[CH:21]=4)[CH2:18][C:17](=[O:29])[NH:16][C:15]=3[CH3:30])=[O:13])[CH:9]=2)[NH:4][N:3]=1
Reactant: COc1cc(C2CC(=O)NC(C)=C2C(=O)Nc2ccc3[nH]nc(Br)c3c2)ccc1Cl
Agent: ClB(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Br)c3c2)C(c2ccc(Cl)c(O)c2)CC(=O)N1
Temperature: 35 °C
Reaction time: 90 h
Yield: 27.7 %

Procedure:
The product from Example 94 (95 mg, 0.19 mmol, 1.0 equiv) was cooled to −78° C. in 2.0 mL CH2Cl2 and BCl3 (1.0 M in CH2Cl2, 2.90 mL, 2.91 mmol, 15.0 equiv) was added dropwise. The reaction was warmed to 35° C. and stirred for 90 hours. An additional portion of BCl3 (2.90 mL, 2.91 mmol, 15.0 equiv) was added dropwise and the reaction was stirred for another 96 hours. The reaction mixture was diluted with EtOAc and water and basified to pH 14 with 6N NaOH. The phases were separated, and the aqueous phase was acidified to pH 4 with 6N HCl. The precipitate was filtered and washed with Et2O. The residue was purified by reverse-phase HPLC (10-95% CH3CN/H2O, 0.1% TFA over 18 minutes, retention time 10.63 min) to provide 25 mg (27%) of the title compound as a white solid. MS (ES+) m/e 476 [M+H]+
Reaction SMILES: [Br:1][C:2]1[C:3]([N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH2:14][CH2:13][CH2:12][CH:11]=3)=[C:7]([C:15]([NH:17][CH3:18])=[O:16])[C:6]=2[CH:19]=1.[Zn](CC)[CH2:27]C.C(I)I.[NH4+].[Cl-]>C(Cl)Cl>[C:10]12([C:8]3[O:9][C:5]4[CH:4]=[C:3]([N:20]([CH3:25])[S:21]([CH3:24])(=[O:22])=[O:23])[C:2]([Br:1])=[CH:19][C:6]=4[C:7]=3[C:15]([NH:17][CH3:18])=[O:16])[CH2:27][CH:14]1[CH2:13][CH2:12][CH2:11]2
Reactant: CNC(=O)c1c(C2=CCCC2)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Reactant: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ICI
Solvent: ClCCl
Product: CNC(=O)c1c(C23CCCC2C3)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.6 %

Procedure:
To a solution of 5-bromo-2-(cyclopent-1-en-1-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (600 mg, 1.40 mmol) and ZnEt2 (15 mL, 14.04 mmol) in DCM (10 mL) was added dropwise CH2I2 (1.2 mL, 14.04 mmol) at 0° C., and then the mixture was stirred at 25° C. After 3 hours, 10 mL NH4Cl (a.q.) was added, and the mixture was extracted with DCM (30 mL*3), and dried over Na2SO4. After concentration, the residue was purified by column chromatography (DCM:EtOAc=3:1) to give the product of 2-(bicyclo[3.1.0]hexan-1-yl)-5-bromo-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (300 mg, yield: 48%). 1H-NMR (CDCl3, 400 MHz) δ 8.30 (s, 1H), 7.60 (s, 1H), 6.16 (d, J=2.0 Hz, 1H), 3.34 (s, 3H), 3.12 (d, J=4.8 Hz, 3H), 3.07 (s, 3H), 2.10˜2.21 (m, 2H), 2.01˜2.09 (m, 2H), 1.86˜1.99 (m, 2H), 1.38˜1.46 (m, 1H), 1.37 (d, J=4.0 Hz, 2H). MS (M+H)+: 441/443.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:10]=2)=[CH:6][CH:5]=[C:4]([N+:23]([O-])=O)[N:3]=1.[NH4+].[Cl-]>CO.C1COCC1.CCOC(C)=O.[Zn]>[NH2:23][C:4]1[N:3]=[C:2]([CH3:1])[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH:10]=2)=[CH:6][CH:5]=1
Reactant: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(NC(=O)OC(C)(C)C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(N)ccc1Oc1ccnc(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of tert-butyl (4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)carbamate (0.438 g, 1.265 mmol) and NH4Cl (2.029 g, 37.9 mmol) in MeOH (10 mL) and THF (10 mL) was treated with zinc dust (0.827 g, 12.65 mmol) and stirred at RT overnight. The mixture was diluted with EtOAc, the solids removed via filtration through diatomaceous earth, washed with EtOAc and the filtrate concentrated to dryness to afford crude tert-butyl (4-((6-amino-2-methylpyridin-3-yl)oxy)pyridin-2-yl)carbamate (100% yield assumed) which was used without further purification. MS (ESI) m/z: 317.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].Cl[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=1>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:23][C:24]3[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=3)[CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: Cn1cc(CCl)cn1
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1cc(CN2C[C@@H]3COCCN3c3nc(Cl)ncc32)cn1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x5 using (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 300 mg, 1.324 mmol) in DMSO (6 mL), sodium tert-butoxide (153 mg, 1.588 mmol) and 4-(chloromethyl)-1-methyl-1H-pyrazole (190 mg, 1.456 mmol) (113 mg, 26%). ESI-MS m/z [M+H]+ calc'd for C41H17ClN6O, 321.12; found 321.2.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4](OC)=[O:5].[K].[NH2:18][NH2:19]>CO>[OH:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4]([NH:18][NH2:19])=[O:5]
Reactant: NN
Reactant: COC(=O)c1cc(S(=O)(=O)O)cc(O)c1O
Agent: [K]
Solvent: CO
Product: NNC(=O)c1cc(S(=O)(=O)O)cc(O)c1O

Procedure:
2,3-Dihydroxy-5-sulfobenzoic acid, methyl ester, monopotassium salt (2.7 g, 9.4 mmole) and neat hydrazine (0.88 ml, 28 mmoles) in 100 ml of methanol were refluxed for 48 hours. The resulting white precipitate was filtered, dried, and dissolved in water (10 ml). Acidification to pH=2.5 with 2N hydrochloric acid, filtering and drying gave 940 mg of the title compound as a solid.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=1)[S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>CCOCC>[Br:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:12]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)(=[O:15])=[O:14])[C:5]2[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=2[C:3]([OH:32])=[O:2])=[CH:30][CH:29]=1
Reactant: COC(=O)c1cc(C)cc(C)c1N(Cc1ccc(Br)cc1)S(=O)(=O)c1ccc(OC)cc1
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)N(Cc2ccc(Br)cc2)c2c(C)cc(C)cc2C(=O)O)cc1
Yield: 71.9 %

Procedure:
In the same manner as described in Example 109, 0.836 g (1.61 mmol) of the product of Example 108 provided 0.584 g (72%) of the desired carboxylic acid as a white solid after trturation with ether. Electrospray Mass Spec 504 (M+H).