Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:10]=1[CH2:11][N:12]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)[C:13]1[N:18]=[CH:17][C:16](Br)=[CH:15][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=[O:45])C.[K+].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C(OCC)(=O)C>CS(C)=O.[Cl-].[Na+].O>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:10]=1[CH2:11][N:12]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)[C:13]1[N:18]=[CH:17][C:16]([OH:45])=[CH:15][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cc(CN(Cc2cc(C(F)(F)F)ccc2OCc2ccccc2)c2ncc(Br)cn2)cc(C(F)(F)F)c1
Reactant: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: Oc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2OCc2ccccc2)nc1
Temperature: 80 °C
Yield: 65.8 %

Procedure:
(2-Benzyloxy-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amine (12.9 g) is dissolved in dimethylsulfoxide (150 ml), and thereto are added [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (3.17 g), potassium acetate (5.71 g) and bis(pinacolato)diboron (9.85 g), and the mixture is heated to 80° C. under nitrogen atmosphere for 1 hour and 30 minutes. The reaction solution is cooled to room temperature, and thereto are added a saturated brine and ethyl acetate, and the mixture is separated, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (150 ml), and thereto is added dropwise a 30% aqueous hydrogen peroxide solution (40 ml) under ice-cooling. Two hours thereafter, thereto is added a saturated aqueous sodium thiosulfate solution to consume the excess hydrogen peroxide, and thereto is added ethyl acetate, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 7:3) to give 2-[(2-benzyloxy-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl)-amino]-pyrimidin-5-ol (7.68 g). MS (m/z): 602 [M+H]+
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])[N:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[C:10]=1[CH3:11])=[O:5])C.[OH-].[K+].Cl>CO.O>[CH2:19]([O:18][C:15]1[CH:14]=[CH:13][C:12]([N:9]2[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[C:8]2[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])=[CH:17][CH:16]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccc(OCc3ccccc3)cc2)c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
To a suspension of 1-(4-benzyloxyphenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxylic acid ethyl ester, from Ex. 1, Step 2 (3.62 g, 7.5 mmol) in 60 ml methanol was added potassium hydroxide (4.05 g, 72 mmol) in water (20 ml), and the reaction mixture was refluxed for 2 hours. The mixture was cooled to room temperature, acidified to pH˜2 with 1 M HCl and extracted with ethyl acetate (2×200 ml). The combined organic phases were dried (Na2SO4), filtered and concentrated to give 3.38 g (99%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][F:12])[NH:7][C:6]=2[CH:5]=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[CH3:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][F:12])[N:7]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[CH3:25])[C:6]=2[CH:5]=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)c2nc(CF)[nH]c2c1
Reactant: Cc1c(Cl)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Cl)cccc1Cn1c(CF)nc2c(Br)cc([N+](=O)[O-])cc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 27.2 %

Procedure:
Into a 250 ml flask with 4-bromo-2-(fluoromethyl)-6-nitro-1H-benzo[d]imidazole (3 g, 10.95 mmol) in N,N-Dimethylformamide (DMF) (100 mL) was added 1-(bromomethyl)-3-chloro-2-methylbenzene (3.60 g, 16.42 mmol) and potassium carbonate (4.54 g, 32.8 mmol). The resulting reaction mixture was stirred 1 h at 80° C., cooled to room temperature and poured into water, extracted with ethyl acetate, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified on a silica gel cartridge and eluted with a gradient of 0% ethyl acetate/hexanes to 80% over 10 column volumes. The expected compound was collected and evaporated to yield 4-bromo-1-(3-chloro-2-methylbenzyl)-2-(fluoromethyl)-6-nitro-1H-benzo[d]imidazole (1.23 g, 2.98 mmol, 27.2% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.48 (s, 3H) 5.71 (s, 1H) 5.83 (s, 1H) 5.85 (s, 2H) 6.10 (d, J=7.58 Hz, 1H) 7.05 (t, J=7.83 Hz, 1H) 7.38 (d, J=7.83 Hz, 1H) 8.39 (d, J=2.02 Hz, 1H) 8.67 (d, 1H); LC/MS: MS (ES+) m/e 413 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[NH:6][CH:7]=[CH:8][N:9]=1.Cl[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>CN(C)C=O>[CH3:3][S:4][C:5]1[N:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][N:9]=1
Reactant: CCOC(=O)CCl
Reactant: CSc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccnc1SC
Temperature: 20 °C
Yield: 82.7 %

Procedure:
Sodium hydride (4.22 g.) (50% suspension in mineral oil) is added, under a nitrogen atmosphere, to a solution of 2-methylthio-imidazole (10 g.) in dimethylformamide (100 cc.). Ethyl chloroacetate (10.8 g.) is then added and reacted for 20 hours, with stirring, at a temperature of about 20° C. The mixture is concentrated to dryness under reduced pressure (20 mm.Hg), the residue is taken up in water (1.8 liters) and the aqueous solution is extracted with methylene chloride (560 cc.). The methylene chloride extracts are washed with water, dried over sodium sulphate, treated with decolorising charcoal and concentrated to dryness under reduced pressure (20 mm.Hg) to give ethyl (2-methylthio-imidazol-1-yl)-acetate (14.5 g.) in the form of an oil.
Reaction SMILES: C(OC1C=C(OCC2C=CC=CC=2)C(Cl)=CC=1C1C(C2C=CC(CN)=CC=2)=CN(COCC[Si](C)(C)C)N=1)C1C=CC=CC=1.C(N(CC)CC)C.O=C1CCC(=O)N1[O:59][C:60](=[O:86])[C:61]1[CH:69]=[CH:68][C:67]([C:70]2[C:71]3[C:76]([O:77][C:78]4[C:83]=2[CH:82]=[CH:81][C:80](=[O:84])[CH:79]=4)=[CH:75][C:74]([OH:85])=[CH:73][CH:72]=3)=[C:63]([C:64]([OH:66])=[O:65])[CH:62]=1>C(Cl)Cl>[OH:85][C:74]1[CH:75]=[C:76]2[C:71](=[CH:72][CH:73]=1)[C:70]([C:67]1[C:63]([C:64]([OH:66])=[O:65])=[CH:62][C:61]([C:60]([OH:86])=[O:59])=[CH:69][CH:68]=1)=[C:83]1[C:78](=[CH:79][C:80](=[O:84])[CH:81]=[CH:82]1)[O:77]2
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(-c2c3ccc(=O)cc-3oc3cc(O)ccc23)c(C(=O)O)c1
Agent: C[Si](C)(C)CCOCn1cc(-c2ccc(CN)cc2)c(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)c1ccc(-c2c3ccc(=O)cc-3oc3cc(O)ccc23)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 111.6 %

Procedure:
To a mixture of 4-[3-(2,4-bis-benzyloxy-5-chloro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-yl]-benzylamine (0.02 g, 0.03 mmol) and triethylamine (0.02 ml, 0.15 mmol) in DCM (1 ml) was added 4-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-isophthalic acid 2,5-dioxo-pyrrolidin-1-yl ester (0.016 g, 0.03 mmol). The mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. The mixture was purified by column chromatography using ethyl acetate and hexanes as eluent to give N-4-[3-(2,4-bis-benzyloxy-5-chloro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-yl]-benzyl)-6-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-isophthalic acid as a yellow solid (0.0126 g, 40%).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH:13]=[CH2:14])=[CH:7][C:5]=1[NH2:6])([O-])=O.O>C1C=CC=CC=1.[Fe]>[CH2:12]([S:11][C:8]1[CH:9]=[CH:10][C:4]([NH2:1])=[C:5]([NH2:6])[CH:7]=1)[CH:13]=[CH2:14]
Reactant: C=CCSc1ccc([N+](=O)[O-])c(N)c1
Agent: [Fe]
Solvent: O
Solvent: c1ccccc1
Product: C=CCSc1ccc(N)c(N)c1

Procedure:
To a solution of 4 g of 2-nitro-5-(2-propenylthio)aniline in 200 ml of benzene there is added 4.0 g of activated iron (Sandler and Karo, Organic Functional Group Preparations, Vol. 1, 1968, pp. 339-340), and the mixture is refluxed for three hours. During the reflux period, water is added in small portions every 15 minutes until a total of 20 ml is reached. The solvent is decanted. The iron sludge is extracted with hot benzene and the combined dried benzene fractions are evaporated in vacuo. The resulting residue is stored under nitrogen at 0°.
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1C(=O)C2=CC=CC=C2C1=O>>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26]
Reactant: Sc1nc2ccccc2o1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NCCCCCCCCSc1nc2ccccc2o1
Temperature: 60 °C

Procedure:
To a round bottom flask with 2-mercaptobenzoxazole (2.14 g, 14.2 mmol) andDMF (100 mL) at room temperature was added K2CO3 (2.61 g, 18.9 mmol) followed by N-(8-bromooctyl)phthalimide (4.00 g, 11.8 mmol). The resulting solution was heated to 60° C. for 0.5 h and then cooled back to room temperature. At this point, the reaction mixture was quenched with H2O (100 mL) and then diluted with EtOAc (600 mL). The organic layer was washed with 1 N HCl (60 mL), sat. aq. NaHCO3 (60 mL), and brine (60 mL) and then dried (MgSO4). After concentration, the residue was purified by the Biotage Flash 40 apparatus (10 to 20% EtOAc/petroleum ether gradient) to afford the thioether intermediate.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[N:11]=[C:12]([CH3:14])[S:13][C:7]2=[N:6][C:5]=1[CH3:15].[CH2:16]1[C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[NH:21][C:20]=2[CH2:19][CH2:18][NH:17]1.C(=O)(O)[O-].[Na+].[I-].[K+]>C(O)CCC>[CH2:16]1[C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[NH:21][C:20]=2[CH2:19][CH2:18][N:17]1[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[N:11]=[C:12]([CH3:14])[S:13][C:7]2=[N:6][C:5]=1[CH3:15]
Reactant: c1ccc2c3c([nH]c2c1)CCNC3
Reactant: Cc1nn2c(=O)c(CCCl)c(C)nc2s1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: Cc1nn2c(=O)c(CCN3CCc4[nH]c5ccccc5c4C3)c(C)nc2s1
Yield: 27.4 %

Procedure:
A mixture of 6-(2-chloroethyl)-2,7-dimethyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one (4.2 g), 1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole (2.65 g), sodium bicarbonate (2 g), potassium iodide (0.1 g) in 1-butanol (122 ml) was refluxed for 20 hours. The reaction mixture was filtered while hot and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CHCl3/CH3OH 95/5). The solvent of the desired fraction was evaporated and the residue was crystallized from acetonitrile, yielding 1.6 g (28.1%) of 6-[2-(1,3,4,5-tetrahydro-2H-pyrido[4,3-b]-indol-2-yl)ethyl]-2,7-dimethyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one (compound 42).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[C:4]([CH2:7][C:8]([OH:10])=[O:9])[CH:3]=1.[CH:11](OCC)(OCC)[O:12]CC.O>C(O)(C(F)(F)F)=O>[CH:11]([C:5]1[NH:6][C:2]([CH3:1])=[CH:3][C:4]=1[CH2:7][C:8]([OH:10])=[O:9])=[O:12]
Reactant: Cc1cc(CC(=O)O)c[nH]1
Reactant: CCOC(OCC)OCC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(CC(=O)O)c(C=O)[nH]1
Reaction time: 0.17 h
Yield: 84 %

Procedure:
To a solution of (5-methyl-1H-pyrrol-3-yl)-acetic acid (8.2 mmol) in TFA (6 mL) at 0° C. was added triethyl orthoformate (6 mL), it was then at 0° C. for 10 mins and at rt for 0.5 hours. The reaction was poured into water, extracted with ethyl acetate, dried and concentrated. The residue was purified on a silica gel column to give 1.15 g (84%) of (2-formyl-5-methyl-1H-pyrrol-3-yl) acetic acid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)[OH:4].Cl[O-].[Na+].O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[F:13][C:2]([F:1])([F:12])[C:3]([C:5]1[CH:6]=[CH:7][C:8]([Br:11])=[CH:9][CH:10]=1)=[O:4]
Reactant: OC(c1ccc(Br)cc1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccc(Br)cc1)C(F)(F)F

Procedure:
6.88 g (0.027 mol) of 2,2,2-trifluoro-1-(4-bromophenyl)ethanol and 0.46 g (0.00135 mol) of tetrabutylammonium hydrogen sulfate are dissolved in 100 ml of methylene chloride at room temperature. 16.6 ml (0.032 mol) of an approximately 12% strength sodium hypochlorite solution are metered in within 15 minutes with vigorous stirring and the mixture is stirred for a further 6 hours during which the reaction temperature rises to 28° C. The reaction mixture is added to 100 ml of water, the phases are separated, the aqueous phase is extracted several times with methylene chloride and the combined organic phases are washed with saturated aqueous sodium chloride solution. After drying the organic phase with sodium sulfate, the volatiles are distilled off. Following distillation of the crude product in a kugelrohr (0.5 mbar, 90°-110° C. bath temperature), 4.13 g (60.4% of theory) of 4-trifluoroacetylbromobenzene are obtained. nD20 : 1.5112.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]([F:13])([F:12])[CH2:8][CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1>C(OCC)C>[F:12][C:9]1([F:13])[CH2:10][CH2:11][CH:6]([CH2:4][OH:3])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C1CCC(F)(F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCC1CCC(F)(F)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4,4-difluorocyclohexanecarboxylic acid ethyl ester (150 mg, 0.78 mmol) in diethylether (5 mL) at 0° C. was added a 2 M solution of lithium aluminum hydride in THF (0.39 mL, 0.78 mmol) dropwise. The reaction mixture was stirred at 0° C. for one h. The reaction was quenched with water (1 mL) and 1N NaOH (2 mL) was added, forming a white slurry. The aqueous layer with extracted with EtOAc (2×10 mL) and the organic layers combined, washed with brine, dried with Na2SO4, filtered, and concentrated to yield a clear oil. 1H NMR (CD3OD, 400 MHz) δ (ppm): 3.38 (d, J=6.4 Hz, 2H), 2.05-1.97 (m, 2H), 1.83-1.64 (m, 4H), 1.58-1.50 (m, 1H), 1.29-1.19 (m, 2H).
Reaction SMILES: C[O:2][C:3]1[C:4]([C:9]2[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.[BrH:18]>>[BrH:18].[OH:2][C:3]1[C:4]([C:9]2[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccnc1-c1cccc([N+](=O)[O-])c1
Agent: Br
Product: O=[N+]([O-])c1cccc(-c2ncccc2O)c1

Procedure:
A solution of 3-(3-methoxypyridin-2-yl)nitrobenzene (0.5 g) in 47% hydrobromic acid (10 ml) was stirred at 130° C. for 24 hours. After cooling, the precipitate was collected by filtration, washed with water and acetone and dried to give 3-(3-hydroxypyridin-2-yl)-nitrobenzene hydrobromide (0.54 g).
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([N:16]=[CH:17][C:18]=2C(OC)=O)[CH:12]=[C:13]([Cl:15])[CH:14]=1)C1C=CC=CC=1.CC(O)=O.Br.[OH-].[Na+]>Br>[Cl:15][C:13]1[CH:14]=[C:9]([OH:8])[C:10]2[N:11]([N:16]=[CH:17][CH:18]=2)[CH:12]=1
Reactant: COC(=O)c1cnn2cc(Cl)cc(OCc3ccccc3)c12
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Oc1cc(Cl)cn2nccc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Methyl 4-(benzyloxy)-6-chloropyrazolo[1,5-a]pyridine-3-carboxylate (152 mg, 0.480 mmol) was dissolved in HBr (48%, 2.0 mL) and the reaction was heated to 100° C. for 1.5 h. AcOH/HBr (1.0 mL) was added and the reaction was stirred overnight. The mixture was cooled to 0° C. and neutralized with 1M NaOH. The aqueous layer was extracted with dichloromethane (3×) and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated to afford 6-chloropyrazolo[1,5-a]pyridin-4-ol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[C:38]([CH2:42]Cl)=[C:37]([O:44][CH3:45])[CH:36]=[CH:35]2.[Na+].[I-]>C1COCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:42][C:38]2[C:39]3[C:34](=[CH:33][C:32]([Br:31])=[CH:41][CH:40]=3)[CH:35]=[CH:36][C:37]=2[O:44][CH3:45])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2cc(Br)ccc2c1CCl
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a solution of ((S)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester (Intermediate 2) (6.5 g, 23.48 mmol) in THF (100 mL) at −78° C. was added 1 M LiHMDS (4.7 g, 28 mL, 28 mmol). The cooling bath was removed and the mixture stirred at RT for 1 h. The mixture was cooled to −78° C. and a mixture of 6-bromo-1-chloromethyl-2-methoxy-naphthalene (8.0 g, 28.12 mmol) and NaI (4.2 g, 28.12 mmol) in dry THF (30 mL) was added dropwise. The cooling bath was removed and the mixture stirred at RT for 18 h. The mixture was diluted with saturated NH4Cl, extracted with ethyl acetate and the organic layer washed with water, brine, dried (Na2SO4) and concentrated to give a material which was purified by silica gel chromatography to afford the title compound (9 g, 72%) as a yellow solid. LC-MS: 528.0 (M+H).
Reaction SMILES: [CH:1]1([C@H:5]([O:7][C:8](=[O:23])[NH:9][C:10]2[C:11]([CH3:22])=[N:12][O:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH3:6])[CH2:4][CH2:3][CH2:2]1.[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][C:35]([C:18]3[CH:19]=[CH:20][C:15]([C:14]4[O:13][N:12]=[C:11]([CH3:22])[C:10]=4[NH:9][C:8]([O:7][C@@H:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)[CH3:6])=[O:23])=[CH:16][CH:17]=3)=[CH:34][CH:33]=2)[CH2:30][CH2:31]1)=[O:28])[CH3:25]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)C1CCC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)O[C@H](C)C4CCC4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-cyclobutyl-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:6]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[C:13]2[CH:14]=[C:15]([CH:19]([OH:24])[C:20]([F:23])([F:22])[F:21])[CH:16]=[N:17][CH:18]=2)[CH:7]=1>ClCCl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[C:6]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[C:13]2[CH:14]=[C:15]([C:19](=[O:24])[C:20]([F:22])([F:23])[F:21])[CH:16]=[N:17][CH:18]=2)[CH:7]=1
Reactant: OC(c1cncc(-c2sccc2-c2cc(Cl)ccc2OCc2ccccc2)c1)C(F)(F)F
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=C(c1cncc(-c2sccc2-c2cc(Cl)ccc2OCc2ccccc2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.4 %

Procedure:
To a solution of the alcohol of example 4 (0.7 g, 1.5 mmol) in dichloromethane was added manganese dioxide (1.26 g, 14.5 mmol) and the slurry was stirred overnight at room temperature. The reaction mixture was then filtered through a pad of celite and the volatils were evaporated under reduced pressure to give a residue which was purified by flash chromatography (70% CH2Cl2/30% AcOEt) to provide the title compound (0.33 g). 1H nmr (400 MHz, acetone-d6) δ ppm 8.78 (1H, d, J=2.1 Hz), 8.48 (1H, d, J =2.2 Hz), 7.96 (1H, t, J=2.1 Hz), 7.60 (1H, d, J=5.1 Hz), 7.35-7.05 (9H, m), 4.94 (2H, s).
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:33]([N:38]([CH3:46])[C:39](=[O:45])[C@H:40]([CH:42]([CH3:44])[CH3:43])[NH2:41])[C@@H:34]([CH3:37])[CH2:35][CH3:36])[CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6].[CH:47]1[C:59]2[CH:58]([CH2:60][O:61][C:62]([NH:64][CH2:65][C:66]([CH3:71])([CH3:70])[C:67](O)=[O:68])=[O:63])[C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:51]=2[CH:50]=[CH:49][CH:48]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C)C=O>[CH:56]1[C:57]2[CH:58]([CH2:60][O:61][C:62]([NH:64][CH2:65][C:66]([CH3:71])([CH3:70])[C:67]([NH:41][C@H:40]([C:39]([N:38]([C@@H:33]([C@@H:34]([CH3:37])[CH2:35][CH3:36])[C@H:3]([O:2][CH3:1])[CH2:4][C:5]([N:7]3[CH2:11][CH2:10][CH2:9][C@H:8]3[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)[CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:6])[CH3:46])=[O:45])[CH:42]([CH3:44])[CH3:43])=[O:68])=[O:63])[C:59]3[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:52]=2[CH:53]=[CH:54][CH:55]=1
Reactant: CC(C)(CNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)CNC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reaction time: 18 h
Yield: 60.5 %

Procedure:
To #86 (100 mg, 0.152 mmol, 1 eq.) in dichloromethane (4 mL, 0.038 M) and N,N-dimethylformamide (0.5 mL) was added #93 (51.6 mg, 0.152 mmol, 1 eq.) followed by diisopropylethylamine (80.0 μL, 0.457 mmol, 3 eq.) and HATU (89.8 mg, 0.229 mmol, 1.5 eq.). The reaction was stirred for 18 hours and then concentrated in vacuo. The residue was taken up in ethyl acetate (6 mL) and was washed with 1 M aqueous hydrochloric acid solution (2×2 mL) and with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was taken up in dichloromethane (250 mL) and filtered; the filtrate was concentrated in vacuo onto silica and purified by silica gel chromatography (Gradient: 0% to 50% acetone in heptane) to provide #94 (90 mg, 60%) as a white solid. LC-MS: m/z 979.8 [M+H+], 1002.7 [M+Na+], retention time=1.15 minutes; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic product signals: δ [8.64 (br d, J=8.6 Hz) and 8.86 (br d, J=8.6 Hz), total 1H], 7.86-7.91 (m, 2H), [7.77 (d, J=3.3 Hz) and 7.79 (d, J=3.3 Hz), total 1H], 7.67-7.73 (m, 2H), [7.63 (d, J=3.3 Hz) and 7.65 (d, J=3.3 Hz), total 1H], 6.87-6.95 (m, 1H), [5.39 (ddd, J=11, 8, 4 Hz) and 5.52 (ddd, J=11.5, 9, 4 Hz), total 1H], [4.44 (dd, J=8.4, 8.4 Hz) and 4.55 (dd, J=8.4, 8.4 Hz), total 1H], 3.16, 3.20, 3.21 and 3.25 (4 s, total 6H), 2.96 and 3.06 (2 br s, total 3H), 0.69-0.77 (m, 3H).