Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=2)[C:10]([OH:12])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][N:25]1[CH:29]=[CH:28][C:27]([NH2:30])=[N:26]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:15]=2)[C:10]([NH:30][C:27]2[CH:28]=[CH:29][N:25]([CH3:24])[N:26]=2)=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cc(OCc2ccccc2)cc(OC2CCCC2)c1
Reactant: Cn1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OC3CCCC3)c2)n1
Yield: 47.8 %

Procedure:
3-(Cyclopentyloxy)-5-[(phenylmethyl)oxy]benzoic acid (3.14 g, 10.0 mmol), 1-methyl-1H-pyrazol-3-amine (1.95 g, 20 mmol) and HATU (4.95 g, 13 mmol) were dissolved in DMF (12.5 mL) then DIPEA (3.49 mL, 20 mmol) was added. The resultant mixture was stirred at RT for 20 hours. The mixture was quenched with water (150 mL) and extracted with ethyl acetate (2×75 mL), washed with brine, dried (MgSO4), filtered and concentrated in vacuo to leave a yellow oil. The residue was chromatographed on silica, eluting with 0-30% ethyl acetate in isohexane, to give the desired product as a clear gum (1.87 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:21])=[CH:4][C:5]([Cl:20])=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[N:10]([CH2:16][C:17]#[CH:18])[C:9]2=[O:19])[CH:7]=1.[C:22]1(=O)[O:27][C:25](=[O:26])[C:24]2[CH2:28][CH2:29][CH2:30][CH2:31][C:23]1=2.C(OCC)(=O)C>C(O)(=O)C>[Cl:20][C:5]1[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[N:10]([CH2:16][C:17]#[CH:18])[C:9]2=[O:19])=[CH:7][C:2]([N:1]2[C:22](=[O:27])[C:23]3[CH2:31][CH2:30][CH2:29][CH2:28][C:24]=3[C:25]2=[O:26])=[C:3]([F:21])[CH:4]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: C#CCn1c(=O)[nH]c(=O)n(-c2cc(N)c(F)cc2Cl)c1=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C#CCn1c(=O)[nH]c(=O)n(-c2cc(N3C(=O)C4=C(CCCC4)C3=O)c(F)cc2Cl)c1=O
Yield: 55.9 %

Procedure:
A solution of 1-(5-amino-2-chloro-4-fluorophenyl)-3-(2-propynyl)-s-triazine-2,4,6-(1H, 3H,5H)-trione (1.50 g, 4.83 mmol), and 3,4,5,6-tetrahydrophthalic anhydride (0.73 g, 4.83 mmol) in acetic acid (3 mL) is heated at 100° C. for 5 hours, cooled, and poured into ethyl acetate. The organic mixture is washed sequentially with water, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a yellow semi-solid. Flash column chromatography of the semi-solid using silica gel and an ethyl acetate/hexanes (1:2) solution gives the title product as a white solid (1.20 g, mp 127°-135° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH:15]=[C:14]([CH:16]=[O:17])[C:13]([CH3:18])=[N:12]2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH:19]1([Mg]Br)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCCC1>[CH:19]1([CH:16]([C:14]2[C:13]([CH3:18])=[N:12][N:11]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)[CH:15]=2)[OH:17])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COc1cc(OC)cc(-n2cc(C=O)c(C)n2)c1
Reactant: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: COc1cc(OC)cc(-n2cc(C(O)C3CCCCC3)c(C)n2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
To a solution (10 mL) of 1-(3,5-dimethoxyphenyl)-3-methyl-1H-pyrazole-4-carbaldehyde (2.0 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added dropwise cyclohexylmagnesium bromide (15.0 mL, 1M tetrahydrofuran solution) under ice-cooling. After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (2.6 g, 40%) as a pale-yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:50])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[C:39]([CH2:41][O:42]C3CCCCO3)[N:38]=[C:37]([CH3:49])[CH:36]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:42][CH2:41][C:39]1[CH:40]=[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:50])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:22])([F:21])[F:23])[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)[CH:36]=[C:37]([CH3:49])[N:38]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cc(COC2CCCCO2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)cc(CO)n1

Procedure:
The title compound was prepared from (RS)-[2-(3-{3-[2-methyl-6-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-3-oxo-propionylamino)-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M300) (0.49 g, 0.67 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (230 mg, 65%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[CH2:14]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[CH2:14][N:20]=[N+:21]=[N-:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1COS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1CN=[N+]=[N-]
Temperature: 75 °C
Reaction time: 8 h

Procedure:
A mixture of (2S,4R)-4-fluoro-2-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (3.3 g, 11.1 mmol) and NaN3 (721 mg, 11.1 mmol) in DMF (50 mL) was stirred at 75° C. under nitrogen overnight. The mixture was diluted with water and extracted with EtOAc (×3). The combined organic extracts were washed with water (×3), dried over Na2SO4, and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 100/0 to 0/100) to give the desired material. 1H-NMR (400 MHz, DMSO): δ (ppm) 5.25 (d, 1H), 4.03 (m, 1H), 3.92-3.70 (m, 2H), 3.5-3.25 (m, 2H), 2.27 (m, 1H), 2.2-1.8 (m, 1H), 1.43 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13](=[O:19])[CH2:14][C:15]([CH2:17]Cl)=O)[CH3:11]>C(O)C>[NH2:8][C:7]1[C:2]2[N:3]([C:14]([C:13]([O:12][CH2:10][CH3:11])=[O:19])=[C:15]([CH3:17])[N:1]=2)[CH:4]=[C:5]([CH3:9])[CH:6]=1
Reactant: Cc1cnc(N)c(N)c1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(N)cc(C)cn12
Yield: 26.4 %

Procedure:
A stirred mixture of 2,3-diamino-5-methyl-pyridine (4.0 g, 32.5 mmol) and (5.9 g, 36.0 mmol) of ethyl—chloroacetoacetate in 75 ml abs. ethanol was refluxed over night. The ethanol was evaporated under reduced pressure. The residue was dissolved in 2 M HCl and washed 3 times with diethyl ether, pH was adjusted to 9 and extracted 3 times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel with dichloromethane: methanol 95:5 as eluent to give the title product 2.0 g (28%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[CH:11]([CH2:17]Br)[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:14][C:12]([CH:11]1[CH2:17][NH:1][C:2]2[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=2[O:9]1)=[O:13])[CH3:16]
Reactant: Nc1cc(Br)ccc1O
Reactant: CCOC(=O)C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1CNc2cc(Br)ccc2O1
Yield: 78.2 %

Procedure:
A mixture of 2-amino-4-bromophenol (5.00 g, 26.6 mmol), ethyl 2,3-dibromo-propionate (7.84 g, 29.2 mmol), and potassium carbonate (10.3 g, 81.8 mmol) in acetone (55 mL) was heated at reflux for 16 h. After evaporation of volatile material, the residue was partitioned between dichloromethane and water. The organic layer was washed with 1 M aq. sodium carbonate solution and brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient produced 6-bromo-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid ethyl ester (5.95 g, 78%). Orange solid, MS (ISP)=286.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.CCN(CC)CC.[CH2:17]([NH2:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>C(O)CCC>[Cl:9][C:3]1[N:4]=[CH:5][N:6]=[C:7]([NH:22][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:2]=1[NH2:1]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: CC(C)(C)CN
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CC(C)(C)CNc1ncnc(Cl)c1N
Reaction time: 12 h

Procedure:
A solution of 5-amino-4,6-dichloropyrimidine (1 mmol) in nBuOH was treated with Et3N (1.2 mmol) and neopentylamine (1.05 mmol) at 80° C. After 12 h, the cooled reaction mixture was evaporated under vacuum and the residue was chromatographed to give 6-chloro-5-amino-4-(neopentylamino)-pyrimidine as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9](Br)[CH:10]=2)[S:5][CH2:4][CH2:3]1.C([Li])CCC.CN([CH:22]=[O:23])C.[Cl-].[NH4+]>C1COCC1>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:22]=[O:23])[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCSc2ccc(Br)cc21
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)CCSc2ccc(C=O)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
9.4 g (36.6 mmol) of 4,4-dimethyl-6-bromothiochroman and 100 ml of THF were introduced into a three-necked flask under a stream of nitrogen. 16.1 ml of an n-butyllithium solution (2.5M in hexane) were added dropwise at -78° C. and stirring was carried out for 30 min. 2.7 ml (38.4 mmol) of DMF were then added dropwise and the mixture was permitted to heat to room temperature. The reaction mixture was poured into an aqueous ammonium chloride solution and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with a mixture of dichloromethane and hexane (50/50). After evaporating the solvents, 6.1 g (81%) of the expected aldehyde were recovered in the form of a yellow oil.
Reaction SMILES: [H-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[N:16]=[C:15]2[N:10]([C:11]([NH2:20])=[N:12][C:13]3[NH:19][CH:18]=[CH:17][C:14]=32)[N:9]=1.Cl[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH3:37])[CH2:26][CH2:25]1.O>CN(C=O)C>[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[N:16]=[C:15]2[N:10]([C:11]([NH2:20])=[N:12][C:13]3[N:19]([CH2:22][CH2:23][N:24]4[CH2:25][CH2:26][N:27]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[O:36][CH3:37])[CH2:28][CH2:29]4)[CH:18]=[CH:17][C:14]=32)[N:9]=1
Reactant: Nc1nc2[nH]ccc2c2nc(-c3ccco3)nn12
Reactant: COc1ccccc1N1CCN(CCCl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1N1CCN(CCn2ccc3c2nc(N)n2nc(-c4ccco4)nc32)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (13 mg, 0.32 mmol) in anhydrous DMF (2 mL) at 0° C. is added slowly a solution of the title B compound, 2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine (60 mg, 0.25 mmol) in 2 mL of anhydrous DMF. After stirring at 0° C. under N2 for 15 min, 1-(2-chloroethyl)-4-(2-methoxyphenyl)piperazine (0.275 mmol) is added at 0° C. The mixture is warmed to RT and stirred overnight. The reaction mixture is then poured into water and extracted with DCM (3×). The organic layer is dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product is purified by flash chromatography using DCM/MeOH/NH4OH (98/2/0 2) as eluent to give 2-(furan-2-yl)-7-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=459.2). 1H NMR (DMSO-d6, 400 MHz) δ 2.56 (m, 4H), 2.67 (t, 2H, J=6.0 Hz), 2.94 (m, 4H), 3.76 (s, 3H), 4.28 (t, 2H, J=6.0 Hz), 6.60 (d, 1H, J=3.2 Hz), 6.71 (m, 1H), 6.85 (m, 2H), 6.92 (m, 2H), 7.18 (m, 2H), 7.49 (brs, NH2), 7.91 (d, 1H, J=1.6 Hz).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2]1.CCN(C(C)C)C(C)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>ClCCl>[C:26]([N:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2]1)(=[O:28])[CH3:27]
Reactant: O=C(OCc1ccccc1)C1CNCCO1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCOC(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.5 %

Procedure:
Phenylmethyl 2-morpholinecarboxylate (450 mg, 2.034 mmol) was dissolved in dichloromethane (30 ml). DIPEA (0.71 ml, 4.07 mmol) and acetic anhydride (0.23 ml, 2.441 mmol) were added and the mixture was stirred under nitrogen at room temperature for 18 hr. The solvent was removed in vacuo, the residue was portioned between dichloromethane (20 ml) and water (20 ml) and separated by hydrophobic frit. The aqueous layer was washed with dichloromethane (2×10 ml) and to the combined organic phases was added saturated sodium bicarbonate solution (20 ml). The phases were separated by hydrophobic frit and the aqueous layer was washed with dichloromethane (2×10 ml). The solvent was removed in vacuo, the residue was dissolved in dichloromethane (˜5 ml) and the residue was purified by flash chromatography (20 g silica, gradient elution, 0-100% EtOAc-Cyclohexane then 0-20% MeOH). The solvent was removed in vacuo to give the title compound (313 mg, 1.19 mmol) as a colourless oil.
Reaction SMILES: [CH2:1]([Li])CCC.[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[Cl:16])[C:10]([OH:12])=[O:11].CI>O1CCCC1>[Cl:6][C:7]1[C:8]([CH3:1])=[C:9]([CH:13]=[CH:14][C:15]=1[Cl:16])[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(C(=O)O)ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
n-Butyl lithium (2.5M in hexanes, 180 ml) was added during 1 hour to a stirred solution of 3,4-dichlorobenzoic acid (40.0 g) at -78° C. and stirring maintained at that temperature overnight. A solution of methyl iodide (72 ml) in tetrahydrofuran was then added during 1.5 hours and the mixture kept at -78° C. for 3 hours and allowed to warm to room temperature overnight. The solvent was evaporated and the mixture added to water, acidified (concentrated hydrochloric acid) and extracted (ethyl acetate). The extract was dried (magnesium sulphate), evaporated and triturated (ether) to give 3,4-dichloro-2-methylbenzoic acid (33.3 g) as a white solid, m.p. 177°-178° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([SH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.Br[CH2:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:13]([C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:9])[C:6]=2[CH:7]=1
Reactant: CC(=O)c1cc(F)ccc1S
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)C(C)(C)C)sc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5.20 g 1-(5-fluoro-2-mercaptophenyl)ethanone in 100 mL anhydrous DMF was added 5.47 g 1-bromopinacolone and 10.95 g cesium carbonate. The resulting mixture was stirred at room temperature overnight and then heated at 70° C. for 3 days. After diluting the reaction mixture with ice and water, it was extracted with ether several times. The combined ether extract was washed with 0.05 N NaOH (2×), water (3×), and saturated brine, dried over anhydrous Na2SO4, and evaporated to give the crude product. The latter was purified by SGC using 10˜15% EtOAc in hexanes to give the title compound as an oil. 1H NMR (CDCl3, 500 MHz) 7.77 (dd, JH-H=8.7 Hz, JH-F=4.8 Hz, 1H), 7.49 (dd, JH-H=2.5 Hz, JH-F=9.6 Hz, 1H), 7.24 (ddd, JH-H=2.5 & 8.7 Hz, JH-F=8.7 Hz, 1H), 2.53 (s, 3H), 1.40 (s, 9H). LC-MS: 4.11 min. (m/Z=209.1, 251.1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([OH:10])=[C:4]([O:11][CH3:12])[C:3]=1[O:13][CH3:14].[C:15]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:14][O:13][C:3]1[C:4]([O:11][CH3:12])=[C:5]([O:10][CH3:15])[C:6]([O:8][CH3:9])=[CH:7][C:2]=1[CH3:1]
Reactant: COc1cc(C)c(OC)c(OC)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(C)c(OC)c(OC)c1OC
Yield: 97.6 %

Procedure:
According to a modification of the procedure by Brimble et al.,36 11 (0.660 g, 3.33 mmol) and K2CO3 (4.08 g, 29.5 mmol) were added to a flame-dried 250 mL round bottom flask followed by dry acetone (120.0 mL) and MeI (2.0 mL, 32 mmol) at room temperature. A water-jacketed reflux condenser was attached and the reaction was heated under reflux for 12 hours. The reaction was then cooled, filtered, and the solvent was removed under reduced pressure. The brown residue was then resuspended in CH2Cl2, dried over MgSO4, filtered, and condensed. The resulting colorless oil was then purified by flash chromatography (1:9 EtOAc:hexanes) to provide 6 (0.690 g, 3.25 mmol, 99%) as a colorless oil.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:28]=[CH:27][C:10]2[C:11]3[C:12](=[CH:23][NH:24][C:25]=3[CH3:26])[CH2:13][N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:9]=2[CH:8]=1.[C:29](=O)([O-])[O-:30].[Na+].[Na+]>CN(C)C=O>[Cl:6][C:7]1[CH:28]=[CH:27][C:10]2[C:11]3[C:12](=[C:23]([CH:29]=[O:30])[NH:24][C:25]=3[CH3:26])[CH2:13][N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:9]=2[CH:8]=1
Reactant: Cc1[nH]cc2c1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1[nH]c(C=O)c2c1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reaction time: 1 h

Procedure:
By means of a syringe 0.6 ml (6.5 mmol) of phosphorous oxychloride was added to a solution of 0.7 g (2.0 mmol) of 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine in 8 ml of dimethylformamide which was cooled to 0°. The mixture was stirred at 0° for 1 hr, poured into 50 ml of saturated aqueous sodium carbonate and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a red amorphous solid. Purification by column chromatography (silica gel, 20 g; 4% ether in methylene chloride, eluent) gave an off-white solid. Recrystallization from a mixture of methylene chloride and ethyl acetate gave off-white crystals, mp 274°-276°.
Reaction SMILES: [OH:1][CH:2]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24](=[O:26])[NH2:25])[CH:17]=1)[CH:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:4]1[S:9][CH2:8][CH2:7][CH2:6][S:5]1.C(N(CC)CC)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C1COCC1.CN(C1C=CN=CC=1)C>[C:34]([O:1][CH:2]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24](=[O:26])[NH2:25])[CH:17]=1)[CH:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:4]1[S:9][CH2:8][CH2:7][CH2:6][S:5]1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)COc1cccc(C(O)C(c2ccccc2)C2SCCCS2)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OC(c1cccc(OCC(N)=O)c1)C(c1ccccc1)C1SCCCS1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5 (192 mg, 0.5 mmol) in 10 mL THF was added DMAP (2 mg), triethylamine (70 mL, 0.5 mmol), and acetic anhydride (94 mL, 1.0 mmol). The solution was stirred at room temperature for 4 h, and then partitioned between ethyl acetate (50 mL) and 5% sodium bicarbonate (50 mL). The organic phase was washed with water (3 X 5 50 mL), dried with Mg2SO4, and evaporated to yield a colorless oil. Yield 205 mg (98%). IR: 3479, 3331 (br), 1747, 1694, 1589, 1 443, 1224, 1033, 910, 718 cm-1. 1H NMR (CDCl3, TMS) d 7.740 (dd, J=8.15, 1.55 Hz, 2 H), 7.348-7.281 (m, 3 H), 7.111 (t, J=7.96 Hz, 1 H), 6.801 (dd, J=8.18, 2.53 Hz, 1 H), 6.686 (d,J=7.59 Hz, 1 H), 6.521 (s, 2 H), 6.312 (s, 1 H), 6.136 (s, 1 H), 4.238 (s, 2 H), 2.751-2.597 (m, 4 H), 2.104 (s, 3 H), 1.933-1.857 (s, 1 H). 13C NMR (CDCl3, TMS) d 171.080, 169.318, 156.012, 136.974, 130.771, 128.402, 128.045, 127.738, 122.586, 115.072, 114.635, 79.890, 66.982, 63.133, 27.270, 27.109, 24.568, 20.848. Anal. Calcd. for C21H23NO4S2 : C, 60.41; 11, 5.55; N, 3.5. Found: C, 5 9.92; H, 5.76; N, 3.14.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)=[O:18].C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1>[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH:11][C:12]([CH:14]4[CH2:16][CH2:15]4)=[O:13])[CH:10]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:21][CH:20]=1)=[O:18]
Reactant: O=C(Nc1cc2c(Br)cccn2n1)C1CC1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2cccn3nc(NC(=O)C4CC4)cc23)cc1
Temperature: 25 °C

Procedure:
N-(4-Bromopyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (4.66 g, 17 mmol), 4-formylphenyl boronic acid (3.06 g, 20.4 mmol), PdCl2dppf (0.37 g, 0.45 mmol) and Na2CO3 (3.6 g, 34 mmol) were stirred in 1,4-dioxane (140 mL) and water (28 mL) at 100° C. for 3 h. The reaction mixture was cooled to room temperature, filtered through celite, washed through with DCM and concentrated in vacuo. The residue was triturated with EtOAc and dried in vacuo to afford N-(4-(4-formylphenyl)pyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([N:10]1[C:13]2([CH2:16][CH2:15][CH2:14]2)[CH2:12][C:11]1=[O:17])=[O:9])([CH3:6])([CH3:5])[CH3:4].C([O:20]CC)C.O>O1CCCC1>[C:3]([O:7][C:8]([NH:10][C:13]1([CH2:12][C:11]([OH:17])=[O:20])[CH2:16][CH2:15][CH2:14]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC12CCC2
Reactant: CCOCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(CC(=O)O)CCC1
Reaction time: 2 h

Procedure:
An 1 N aqueous solution of lithium hydroxide (227 ml, 227 mmol) was added to a solution of 2-oxo-1-azaspiro[3.3]heptane-1-carboxylic acid tert-butylester (48 g, 0.227 mmol) in tetrahydrofuran (200 ml). The reaction mixture was stirred for 2 h. Diethyl ether (200 ml) and water (200 ml) were added. The mixture was stirred for 16 h. The organic layer was isolated. The aqueous phase was extracted with diethyl ether (200 ml). The aqueous phase was acidified with a 10% aqueous solution of sodium hydrogen sulfate until pH 3. The formed precipitation was filtered off, washed with water, and dried in vacuo, to give 38.84 g of (1-(tert-butoxycarbonylamino)cyclobutyl)acetic acid.
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:15])=[N:6][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8][C:9]=1O)([O-:3])=[O:2].[Cl:16]CCl>C1(P(Cl)(Cl)=O)C=CC=CC=1>[Cl:16][C:9]1[CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[N:6]=[C:5]([OH:15])[C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: ClCCl
Reactant: O=[N+]([O-])c1c(O)cc(C(F)(F)F)nc1O
Agent: O=P(Cl)(Cl)c1ccccc1
Product: O=[N+]([O-])c1c(Cl)cc(C(F)(F)F)nc1O
Temperature: 0 °C

Procedure:
3-Nitro-6-trifluoromethyl-pyridine-2,4-diol (5.8 gm, 26 mmol) was heated in phenylphosphonic dichloride (30 mL) at 100° C. for 19 hours. The resulting mixure was then cooled and poured on to ice (60 gm), and then extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with aqueous sodium hydrogen carbonate solution (10% w/v) until the washings remained basic (pH ˜8). The deep yellow organic layer was then washed with saturated brine, dried over sodium sulphate, filtered and evaporated to give a yellow gum. Trituration of the gum with dichloromethane gave a yellow solid which was filtered off and dried (4.65 gm). The solid was dissolved in water (25 mL) and acidified with 2N hydrochloric acid (7.5 mL) to give a thick white precipitate which was filtered off and washed with water. The precipitate was dissolved in ethyl acetate, dried over sodium sulphate, filtered and evaporated to give the title compound as a white solid (3.75 gm).