Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[CH3:14][N:15]1[C:24]2[CH2:23][CH2:22][CH2:21][C:20](=O)[C:19]=2[CH:18]=[CH:17][C:16]1=[O:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][NH:11][CH:20]2[CH2:21][CH2:22][CH2:23][C:24]3[N:15]([CH3:14])[C:16](=[O:26])[CH:17]=[CH:18][C:19]2=3)=[CH:7][CH:8]=1
Reactant: Cn1c2c(ccc1=O)C(=O)CCC2
Reactant: NCCc1ccc(C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cn1c2c(ccc1=O)C(NCCc1ccc(C(F)(F)F)cc1)CCC2
Temperature: 25 °C
Reaction time: 40 h
Yield: 64.1 %

Procedure:
A mixture of 2-(4-trifluoromethylphenyl)ethylamine (4.1 g), 5,6,7,8-tetrahydro-1-methyl-5-oxo-2(1H)-quinolinone (3.0 g), and para-toluenesulfonic acid (256 mg) was heated in refluxing toluene (50 ml), was azeotroptic removal or water, for 40 hrs. An additional 2.0 g of the amine was added and the mixture was refluxed for 36 hr. The solution was cooled, and the mixture was concentrated in vacuo. Sodium borohydride (0.6 g) was added to a solution of the residue in ethyl alcohol (50 ml), and the resulting mixture was stirred at room temperature for 1 hr. The mixture was concentrated in vacuo, the residue was quenched with water, and the mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was recrystallized from ethyl acetate/hexanes to provide, in two crops, 3.8 g (65%) of product, mp 104°-106° C.
Reaction SMILES: C(OC([N:8]1[C:12]2=[CH:13][N:14]=[C:15]([N:17]3[CH:21]=[N:20][N:19]=[CH:18]3)[CH:16]=[C:11]2[C:10]([CH:22]=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N:19]1[N:20]=[CH:21][N:17]([C:15]2[CH:16]=[C:11]3[C:10]([CH:22]=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:9][NH:8][C:12]3=[CH:13][N:14]=2)[CH:18]=1
Reactant: CCOC(=O)C=Cc1cn(C(=O)OC(C)(C)C)c2cnc(-n3cnnc3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C=Cc1c[nH]c2cnc(-n3cnnc3)cc12
Yield: 58.8 %

Procedure:
A solution of ethyl 3-[1-tert-butyloxycarbonyl-5-(1,2,4-triazol-4-yl)pyrrolo[2,3-c]pyridin-3-yl]prop-2-enoate (0.92 g) and trifluoroacetic acid (5 mL) in dry DCM (20 mL) was stirred at ambient temperature under nitrogen for 16 hours. The solvent was evaporated in vacuo and the residue azeotroped with toluene. The residue was chromatographed on silica eluting with 5 to 20% MeOH in DCM to give a cream solid. This was triturated with MeOH and the solid was collected by filtration to afford the title compound (0.4 g, 62%) as a a cream solid. mp 235° C. (dec.). 1H NMR (360 MHz, d6 -DMSO) δ 1.29 (3H, t, J=7.1Hz), 4.21 (2H, q, J=7.1Hz), 6.68 (1H, d, J=16.2Hz), 7.91 (1H, d, J=16.1Hz), 8.33 (1H, s), 8.36 (1H, s), 8.74 (1H, s), 9.35 (2H, s) and 12.44 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>ClCCl>[C:17]([O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[Cl:1])(=[O:19])[CH3:18]
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C=O)cc1Cl
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 94.9 %

Procedure:
To 3-chloro-4-hydroxybenzaldehyde (5.00 g, 31.9 mmol) and pyridine (5.0 mL, 61.8 mmol) in dichloromethane (40 mL) at 0° C. was added acetic anhydride (4.0 mL, 42.3 mmol) over a 20-minute period. The mixture was stirred for 1.5 hours more, warmed to 20° C., then worked-up (10% hydrochloric acid wash) to afford 4-acetoxy-3-chlorobenzaldehyde as a pale-yellow solid (6.01 g, 92% yield): m.p. 33–35° C.; Rf0.30 (20% ethyl acetate/hexane); 1H NMR spectrum (400 MHz, CDCl3) δ 2.39 (s, 3, CH3), 7.34 (d, J=8.0 Hz, 1, ArH), 7.82 (dd, J=7.6,2 Hz, 1, ArH), 7.98 (d, J=1.6 Hz, 1, ArH), 9.96 ppm (s, 1, CHO).
Reaction SMILES: Cl[C:2]1[C:3](=[O:8])[NH:4][CH2:5][CH2:6][CH:7]=1.Cl/[C:10](=[N:15]\[NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)/[S:11]([CH3:14])(=[O:13])=[O:12].CCN(CC)CC.O>C1(C)C=CC=CC=1.CCOC(C)=O.C(Cl)Cl>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([N:16]2[C:2]3[C:3](=[O:8])[NH:4][CH2:5][CH2:6][C:7]=3[C:10]([S:11]([CH3:14])(=[O:13])=[O:12])=[N:15]2)=[CH:22][CH:21]=1
Reactant: O=C1NCCC=C1Cl
Reactant: COc1ccc(N/N=C(\Cl)S(C)(=O)=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(-n2nc(S(C)(=O)=O)c3c2C(=O)NCC3)cc1
Temperature: 85 °C
Yield: 31.4 %

Procedure:
Part A. 3-Chloro-5,6-dihydro-2(1H)-pyridinone (10.0 g, 38.17 mmol) and (1Z)-1-[chloro(methylsulfonyl)methylene]-2-(4-methoxyphenyl)hydrazine (5.0 g, 38.17 mmol) were stirred in toluene (200 mL) at RT under N2. Et3N (30 mL, 215.24 mmol) in toluene (150 mL) was added dropwise to the solution. After addition, the mixture was heated at 85° C. overnight. After cooling, H2O was added. It was extracted with EtOAc (2×). The organic layers were washed with H2O (2×) and brine, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (silica gel, CH2Cl2, then CH2Cl2:EtOAc=1:1, then EtOAc) to give 1-(4-methoxyphenyl)-3-(methylsulfonyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one (3.85 g, yield: 31%). LC/MS (ESI+) 322.4 (M+H)+, tR=1.79 min (10–90% CH3CN/H2O in a 4-min run).
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][N:6]1[C:10](=[O:11])[N:9]([CH2:12][CH:13]=[CH2:14])[C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[N:7]1)C.[OH-].[K+]>CO>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:8]2[N:9]([CH2:12][CH:13]=[CH2:14])[C:10](=[O:11])[N:6]([CH2:5][C:4]([OH:22])=[O:3])[N:7]=2)=[CH:16][CH:17]=1
Reactant: C=CCn1c(-c2ccc(Cl)cc2)nn(CC(=O)OCC)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=CCn1c(-c2ccc(Cl)cc2)nn(CC(=O)O)c1=O

Procedure:
4.88 g (15.9 mmol) of ethyl[3-(4-chlorophenyl)-4-allyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetate from Example 214A are placed in 48 ml methanol and stirred with 5 ml 20% aqueous potassium hydroxide for 2 hrs at room temperature. The solution is concentrated to ca. one half, then diluted with water and extracted with ethyl acetate. The aqueous phase is acidified with ca. 2 ml of conc. hydrochloric acid and extracted twice with 100 ml ethyl acetate each time. The last organic extracts are combined, dried over sodium sulphate, filtered and concentrated in vacuo. After drying in high vacuum, 4.20 g (90% of theory) of the target compound are thus obtained.
Reaction SMILES: [Br-].[CH2:2]([Zn+])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[C:12]1[C:17]([Br:18])=[CH:16][CH:15]=[CH:14][N:13]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[Br:18][C:17]1[C:12]([CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Brc1cccnc1Br
Reactant: [Zn+]CCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Brc1cccnc1CCc1ccccc1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (2.0 g) is added to a flask charged with a stir bar, phenethylzinc bromide (0.5 mol/L in tetrahydrofuran, 100 mL), 2,3-dibromopyridine (10.50 g), and tetrahydrofuran (100 ml) and kept under argon atmosphere at room temperature. The resulting mixture is stirred at room temperature for 3 h and at 40° C. for another 16 h. After cooling the mixture to room temperature, the solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→75:25) to afford the title compound as an oil that solidified upon treatment with ether. Yield: 9.32 g (81% of theory); LC (method 1): tR=4.28 min; Mass spectrum (ESI+): m/z=262/264 (Br) [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=O)[CH2:4][CH2:3]1.Cl.[NH2:14][OH:15].C(=O)(O)[O-].[Na+]>CO>[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[N:14][OH:15])[CH2:4][CH2:3]1
Reactant: CC1CCC(=O)c2ccccc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC1CCC(=NO)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 801 mg (5.0 mmol) of 4-methyl-1-tetralone in 20 mL of dry methanol was treated with 417 mg of hydroxylamine hydrochloride (6.0 mmol, 1.2 eq) and 504 mg (6.0 mmol, 1.2 eq) of sodium bicarbonate and the resulting mixture was stirred at room temperature for 16 hours. The solid was filtered off and the solvent was removed under vacuum. The white residue was redissolved in 10 mL of methylene chloride and filtered. The filtrate was evaporated to dryness under vacuum to give the product in quantitative yield. 1H NMR (400 MHz, CDCl3): 1.30 (d, 8 Hz, 3H), 1.69 (m, 1H), 2.45 (m, 1H), 2.88 (m, 3H), 7.15-7.35 (m, 3H), 7.86 (d, 8 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:28])[C@@H:15]([N+:25]([O-])=O)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([Cl:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.[Ni](Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:28])[C@@H:15]([NH2:25])[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([Cl:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(Cl)c2)[N+](=O)[O-])CO1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(Cl)c2)CO1
Temperature: 25 °C
Yield: 100 %

Procedure:
Dissolve (2R,5R)-5-[(1R,2S)-3-(3-chloro-5-fluorophenyl)-1-hydroxy-2-nitropropyl]-2-(2,2-dimethylpropoxy)-morpholine-4-carboxylic acid tert-butyl ester (0.455 g, 0.901 mmol) in methanol (8 mL) and stir at room temperature in an oil bath. Add anhydrous nickel (II) chloride (0.175 g, 1.35 mmol) followed by sodium borohydride (0.170 mg, 4.50 mmol) in 3 portions over 5 minutes and stir for 15 minutes. Add water (2 mL), 0.1 N sodium hydroxide (2 mL) and extract with ethyl acetate (2×30 mL). Combine organic extracts, wash with saturated aqueous sodium chloride (30 mL), dry (sodium sulfate), filter through a pad of Celite® and concentrate to give the desired compound as a colorless oil (0.428 g).
Reaction SMILES: C(OC([N:8]([CH2:16][C:17]1[CH:18]=[C:19](Br)[CH:20]=[CH:21][CH:22]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=O)(C)(C)C.CC(C)([O-])C.[K+].[NH2:30][C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][N:32]=1.C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2].O.C(OCC)(=O)C>[C:12]([O:11][C:9]([NH:8][CH2:16][C:17]1[CH:18]=[C:19]([NH:30][C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][N:32]=2)[CH:20]=[CH:21][CH:22]=1)=[O:10])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(Br)c1)C(=O)OC(C)(C)C
Reactant: Cc1ccnc(N)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccnc(Nc2cccc(CNC(=O)OC(C)(C)C)c2)c1
Temperature: 80 °C
Yield: 13.8 %

Procedure:
A mixture of 3-(di-(t-butoxycarbonyl)aminomethyl)bromobenzene (260 mg), tris(dibenzylideneacetone)dipalladium (42 mg), diphenylphosphinoferrocene (50 mg), potassium t-butoxide (102 mg), 2-amino-4-methylpyridine (108 mg) and toluene (10 ml) was heated under a nitrogen atmosphere at 80° C. for 22 h. Ethyl acetate and water were added to the reaction mixture. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:n-hexane=1:1) to give 29.2 mg of the titled compound (yield, 10%).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13]2[N:15]([CH2:27][C:28]([OH:30])=O)[C:16](=[O:26])[N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[CH2:18][C:12]2=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)[N:49]2[CH2:53]CC[CH2:50]2)C2C=CC=CC=2N=N1.CNC>CN(C)C=O>[CH2:1]([S:8][C:9]1[N:14]=[C:13]2[N:15]([CH2:27][C:28]([N:49]([CH3:53])[CH3:50])=[O:30])[C:16](=[O:26])[N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[CH2:18][C:12]2=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: O=C(O)CN1C(=O)N(c2ccccc2Cl)Cc2cnc(SCc3ccccc3)nc21
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CN(C)C(=O)CN1C(=O)N(c2ccccc2Cl)Cc2cnc(SCc3ccccc3)nc21
Reaction time: 2 h

Procedure:
To a solution of 7-benzylthio-3-(2-chlorophenyl)-1-(hydroxycarbonylmethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (500 mg, 1.13 mmol) and benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate) (885 mg, 1.70 mmol) in N,N-dimethylformamide (15 mL) was bubbled dimethylamine gas into the solution for two minutes, then stirred in a sealed tube for 2 hours. The reaction mixture was quenched with water and extracted into ethyl acetate. The combined organic extracts were washed with water, dried, filtered, concentrated in vacuo, and the residue was purified by column chromatography on silica gel using 36:1 dicloromethane/methanol as eluant. The column fractions containing product were combined and concentrated in vacuo to give 490 mg of 7-benzylthio-3-(2-chlorophenyl)-1-(dimethylaminocarbonyl-methyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH2:19][CH:20]=[CH2:21])[CH2:4][C@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[H-].[Na+].[CH2:24](Br)[CH:25]=[CH2:26]>C1COCC1>[CH2:26]([O:1][CH2:2][C@H:3]([CH2:19][CH:20]=[CH2:21])[CH2:4][C@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:25]=[CH2:24]
Reactant: C=CC[C@@H](CO)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOC[C@H](CC=C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
To a solution of (S)-tert-butyl 4-((R)-2-(hydroxymethyl)pent-4-enyl)-2,2-dimethyloxazolidine-3-carboxylate (30 g, 100 mmol, 1 eq) in anhydrous THF (600 mL) was added NaH (60%, 16 g, 400 mmol, 4 eq) in portions at 0° C. The mixture was stirred for 10 min at 0° C., followed by the dropwise addition of allyl bromide (48 g, 400 mmol, 4 eq) over 15 min. After stirring for 30 min at 0° C., the mixture was allowed to warm to rt and stirred for 16 h. The reaction was quenched with aq. NH4Cl and the mixture was extracted with EA (3×). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under reduced pressure to afford the crude product. It was purified by column chromatography on silica gel (PE:EA=100:1→60:1) to give (S)-tert-butyl 4-((R)-2-(allyloxymethyl)pent-4-enyl)-2,2-dimethyloxazolidine-3-carboxylate (26.15 g, 77.0%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]2[N:8]=[C:9]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[C:10]([C:11]#[N:12])=[C:4]2[NH:3]1.[H-].[Na+].[CH3:21]I.O>CN(C=O)C>[CH3:21][N:3]1[C:2](=[O:1])[CH2:7][CH2:6][N:5]2[N:8]=[C:9]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[C:10]([C:11]#[N:12])=[C:4]12
Reactant: CI
Reactant: N#Cc1c(-c2cccnc2)nn2c1NC(=O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)CCn2nc(-c3cccnc3)c(C#N)c21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-oxo-2-(pyridin-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (50 mg, 0.21 mmol) in DMF (2 mL) was added NaH (17 mg, 0.42 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 30 mins, then methyl iodide (30 mg, 0.21 mmol) was added. The mixture was stirred at 0° C. for an additional 30 mins. 1 mL of water was added to quench the reaction which was extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated in vacuo. The residue was purified by HPLC to afford 4-methyl-5-oxo-2-(pyridine-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile: MS (m/z): 254.1 [M+H]+, 1H NMR (CD3OD, 400 MHz): δ8.06 (s, 1 H), 8.60 (d, 1 H, J=1.6 Hz), 8.36 (d, 1H, J=8.0 Hz), 7.59 (dd, 1 H, J=8.0 Hz, J=56 Hz), 4.44 (t, 2 H, J=7.6 Hz), 3.04 (t, 2H, J=7.6 Hz).
Reaction SMILES: [OH:1][CH:2]([C:7]1[C:8]([I:21])=[C:9]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:10]2=[N:11][C:12]=1[CH3:13])[C:3]([O:5][CH3:6])=[O:4].Cl(O)(=O)(=O)=O.C(=O)([O-])O.[Na+]>C(OC(C)(C)C)(=O)C>[C:7]([O:1][CH:2]([C:7]1[C:8]([I:21])=[C:9]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:10]2=[N:11][C:12]=1[CH3:13])[C:3]([O:5][CH3:6])=[O:4])([CH3:8])([CH3:12])[CH3:2]
Reactant: COC(=O)C(O)c1c(C)nc2sc3c(c2c1I)CCCC3
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1I)CCCC3
Reaction time: 0.08 h
Yield: 38 %

Procedure:
A suspension of methyl hydroxy(4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)acetate (Preparation 9, 10.0 g, 23.97 mmol) in tert-butyl acetate (250 mL) was stirred vigorously for 5 minutes prior to the dropwise addition of perchloric acid (70%, 6.15 mL, 71.90 mmol). The resulting mixture was stirred at room temperature for 20 minutes. The mixture was neutralised by addition of a saturated aqueous sodium hydrogen carbonate solution (60 mL) and extracted with ethyl acetate (250 mL). The layers were separated and the aqueous layer was further extracted with ethyl acetate (250 mL). The combined organic layers were washed with brine (250 mL), dried over MgSO4 and concentrated in vacuo to yield the crude product. The residue was purified by flash column chromatography eluting with ethyl acetate/heptane (10-40%) to give the title compound, 4.26 g, in a 38% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.23 (s, 9H), 1.81-1.92 (m, 4H), 2.66 (s, 3H), 2.79-2.89 (m, 2H), 3.21-3.27 (m, 2H), 3.68 (s, 3H), 5.95 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:16][C:15]2[CH:14]=[N:13][CH:12]=[N:11][C:10]=2[CH:9]=1.[I:17]N1C(=O)CCC1=O>CC(C)=O.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:16][C:15]2[CH:14]=[N:13][CH:12]=[N:11][C:10]=2[C:9]=1[I:17]
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1ccccc1-c1cc2ncncc2[nH]1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Fc1ccccc1-c1[nH]c2cncnc2c1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a slurry of 6-(2-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidine (1.0 g) in acetone (25 mL) was added N-iodosuccinimide (1.4 g). The reaction was stirred at rt for 3 h, until complete conversion was observed by LC-MS. The reaction mixture was diluted with EtOAc (150 mL) and the solid was collected via filtration and washed with EtOAc yielding 1.23 g of desired (77% yield). LC-MS calculated for C12H7FIN3: 339.1, found 339.96 [M+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1([B-](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1[PH+](C(C)(C)C)C(C)(C)C.C1(C)C(C)=CC=CC=1>[C:2]1([N:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: Brc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1C
Product: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Yield: 87 %

Procedure:
A 100-ml four-necked flask was equipped with a stirrer, a thermometer and a reflux condenser. 7.536 g (48 mmol) of bromobenzene, 6.769 g (40 mmol) of diphenylamine, 4.613 g (48 mmol) of sodium-tert-butoxide, 0.009 g (0.04 mmol) of palladium (II) acetate and 5 ml of xylene were weighed in the flask, followed by stirring. Further, 0.074 g (0.12 mmol) of 2-biphenylyl-di-tert-butylphosphonium tetraphenylborate obtained in Example B-10 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 125° C. for 4 hours. After the completion of the reaction, 45 ml of xylene and 50 ml of saturated sodium chloride solution were added, followed by separation. The organic phase was purified by column chromatography to afford 8.537 g of triphenylamine (yield: 87 mol % based on diphenylamine). The melting point was 125-126° C.
Reaction SMILES: [CH3:1][CH:2]([OH:7])[CH2:3][CH:4]([OH:6])[CH3:5].[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].N1C=CN=C1>CN(C)C=O.CCOCC>[Si:8]([O:6][CH:4]([CH3:5])[CH2:3][CH:2]([OH:7])[CH3:1])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(O)CC(C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(O)CC(C)O[Si](C)(C)C(C)(C)C
Reaction time: 12 h
Yield: 56.9 %

Procedure:
To a solution of 1.00 g (9.60 mmol) 2,4-pentanediol in 9 mL dimethylformamide was added 1.52 g (10.1 mmol) t-butyldimethylsilyl chloride and 915 mg (13.4 mmol) imidazole. The solution was stirred for 12 hrs, diluted in 100 mL of ether, and washed 5 ×, each with 2 mL water. The organic phase was dried over MgSO4, filtered, and concentrated. Chromatography on a 2×18 cm column, packed with hexane and eluted with 100 mL each of 5%, 10%, and 25% ethyl acetate/hexane provided 1.192 g of a clear colorless oil in 10 mL fractions 6-14.
Reaction SMILES: [C:1]([NH:7][C:8](=[O:31])[NH:9][C:10]1[N:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23]C(=O)OC(C)(C)C)[CH:18]=2)=[CH:12][CH:11]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]>C(O)(C(F)(F)F)=O>[NH2:23][C:19]1[CH:18]=[C:17]([O:16][C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:8]([NH:7][C:1](=[O:6])[C:2]([CH3:4])([CH3:3])[CH3:5])=[O:31])=[N:15][CH:14]=2)[CH:22]=[CH:21][N:20]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C(C)(C)C)nc2)ccn1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(N)c2)cn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
tert-Butyl (4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)carbamate (1.6 g, 3.73 mmol) was suspended in TFA (20 mL), stirred at RT for 45 min, then concentrated to dryness. The residue was suspended in THF, treated with satd. NaHCO3 and the layers separated. The aqueous layer was diluted with brine, extracted with THF (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford crude N-((5-((2-aminopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide (100% yield assumed) which was used without further purification. MS (ESI) m/z: 330.2 (M+H+).
Reaction SMILES: O[C:2]1([C:6]2[C:16]3[O:15][CH2:14][CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1>[Pd].CO>[CH:2]1([C:6]2[C:16]3[O:15][CH2:14][CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2C2(O)CCC2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2C2CCC2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 39 %

Procedure:
A mixture of tert-butyl 9-(1-hydroxycyclobutyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (108 mg, 0.338 mmol) and 10% palladium on carbon (100 mg) in methanol (10 ml) was stirred at room temperature for 24 hr under a hydrogen atmosphere, and the insoluble material was filtered off. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (40.0 mg, 39.0%) as an oil.