Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][NH:8][C:7](=[O:11])[CH:6]=1.[C:12]1(=O)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[O:13]1.CCN(C(C)C)C(C)C>C1(C)C(C)=CC=CC=1>[O:11]=[C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][N:2]2[C:12](=[O:13])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:21])[CH:10]=[CH:9][NH:8]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCc1cc[nH]c(=O)c1
Agent: Br
Solvent: Cc1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1CCc1cc[nH]c(=O)c1
Temperature: 140 °C
Reaction time: 6 h
Yield: 75.4 %

Procedure:
A mixture of 4-(2-aminoethyl)pyridin-2(1H)-one hydrobromide (400 mg, 1.83 mmol), isobenzofuran-1,3-dione (271 mg, 1.83 mmol) and DIEA (472 mg, 3.66 mmol) in 30 mL of xylene was stirred at 140° C. for 6 hours. The solvent was removed under reduce pressure. The residue was purified by silica gel chromatography, eluting with DCM/MeOH (30/1) to give 2-(2-(2-oxo-1,2-dihydropyridin-4-yl)ethyl)isoindoline-1,3-dione (370 mg, 76%) as a white sold. LC-MS: 269 [M+H]+, tR=1.23 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:13]=[C:12]([CH:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH:18]=[CH:17][C:16]4[CH:25]=[CH:26][CH:27]=[CH:28][C:15]3=4)[C:11](=[O:29])[NH:10][C:9]2=[O:30])[CH:5]=[CH:4][N:3]=1.Cl.[CH3:32][O:33][C:34](=[O:37])[CH2:35][NH2:36].C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[CH:25]1[C:16]2[CH:17]=[CH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH:14]([C:12]3[C:11](=[O:29])[NH:10][C:9](=[O:30])[N:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:36][CH2:35][C:34]([O:33][CH3:32])=[O:37])[N:7]=4)[CH:13]=3)[C:15]=2[CH:28]=[CH:27][CH:26]=1
Reactant: O=c1[nH]c(=O)n(-c2ccnc(Cl)n2)cc1C1c2ccccc2C=Cc2ccccc21
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC(=O)CNc1nccc(-n2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)n1
Temperature: 90 °C

Procedure:
A mixture of the product from example 6 step (i) (1 g), glycine methyl ester hydrochloride (0.339 g) and N,N-diisopropylethylamine (1.13 ml) in 1-methyl-2-pyrrolidinone (20 ml) was heated at 90° C. for 7 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4) and evaporated. The residue was dissolved in methanol/chloroform and the product precipitated by the addition of 50% ethyl acetate in isohexane. Yield 0.96 g.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH3:19][NH:20][CH3:21].C(N(CC)CC)C>C1COCC1>[C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16]([N:20]([CH3:21])[CH3:19])=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Reactant: CNC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)N(C)C)n2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above, (110 mg; 0.36 mmol; 1 eq.) is dissolved in anhydrous THF (10 ml). Under nitrogen, dimethylamine (0.27 ml; 0.55 mmol; 1.5 eq) and triethylamine (0.08 ml; 0.55 mmol; 1.5 eq) are added. The reaction mixture is stirred at RT for 1 hour. The solvents are evaporated and the crude product is directly purified by preparative HPLC, affording Compound (61) as a white-off solid (65.0 mg; 57%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([Br:15])[CH:5]=[CH:4][C:3]=1[OH:16].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25](Br)=[O:26]>C(#N)C.O>[Br:15][C:6]1[CH:5]=[CH:4][C:3]2[O:16][CH2:24][C:25](=[O:26])[NH:1][C:2]=2[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Br)CBr
Reactant: Nc1c(O)ccc(Br)c1Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C1COc2ccc(Br)c(Oc3ccccc3)c2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
A solution of 2-amino-4-bromo-3-phenoxyphenol (0.060 g, 0.214 mmol) in acetonitrile (3.88 mL) and water (1.21 mL) was treated with potassium carbonate (0.118 g, 0.857 mmol), followed by the addition of bromoacetyl bromide (0.0279 mL, 0.321 mmol), and the resultant reaction mixture was stirred at RT for 30 min, after which time additional bromoacetyl bromide (0.0186 mL, 0.214 mmol) was added dropwise and the reaction mixture was stirred at RT for 1 h, then warmed to 75° C. and stirred at that temperature for 30 min. The reaction mixture was concentrated and diluted with ethyl acetate and water. Layers were separated and the organic layer was washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo the yield a crude product. Purification by flash column chromatography (100% hexanes to 50% EtOAc/hexanes) gave the desired product (59.5 mg, 87%) as a white solid. LCMS calculated for C14H11BrNO3 (M+H)+: m/z=320.0, 322.0. found: 319.9, 321.9.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[C:11]([O:15][C:16]([C:18]1[CH:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C=O)C>[C:11]([O:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)=[CH:20][N:19]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccc(N)cc2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
A mixture of 4-aminophenol (2.6 g, 24 mmol) and NaH (1.1 g, 28 mmol) in dry DMF (50 ml) was stirred at RT for 30 min. 4-Chloro-pyridine-2-carboxylic acid t-butyl ester (5.0 g, 24 mmol) was added and the resulting mixture was stirred in a sealed tube at 80° C. for 12 h. The reaction mixture was concentrated in vacuo and was purified on silica gel to give 5-(4-amino-phenoxy)-pyridine-2-carboxylic acid t-butyl ester as a yellow solid (2.4 g, 35% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.48 (d, J=5.7 Hz, 1H), 7.33 (d, J=1.8 Hz, 1H), 7.03 (m, 1H), 6.84 (d, J=8.4 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 5.18 (s, 2H), 1.50 (s, 9H); MS (ESI) m/z: 287.2 (M+H+).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.COC(=O)C1C=CC(OC[C:36]2[C:37]([C:42]3C=CC=CC=3F)=[N:38]OC=2C)=NC=1.C(N)(C)C>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:38][CH:37]([CH3:42])[CH3:36])=[O:24])=[CH:5][N:6]=3)=[CH:16][O:15][N:14]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3F)noc2C)nc1
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Solvent: CC(C)N
Product: CC(C)NC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Yield: 98 %

Procedure:
As described for example 84f, 6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (150 mg, 0.46 mmol) was converted, instead of [6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester, using isopropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (160 mg, 98%) which was obtained as a white solid. MS: m/e=356.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:11]=[CH:10][NH:9][C:4]=2[N:5]=[C:6](N)[N:7]=1.[Sb](Cl)(Cl)[Cl:13].C(ON=O)(C)(C)C>ClCCCl.C(Cl)(Cl)Cl>[Cl:13][C:6]1[N:7]=[C:2]([Cl:1])[C:3]2[CH:11]=[CH:10][NH:9][C:4]=2[N:5]=1
Reactant: Nc1nc(Cl)c2cc[nH]c2n1
Reactant: Cl[Sb](Cl)Cl
Agent: CC(C)(C)ON=O
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: Clc1nc(Cl)c2cc[nH]c2n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 42.8 %

Procedure:
To a suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (500 mg, 2.97 mmol) in 1,2-dichloroethane (40 mL) at −10° C. under argon was added antimony chloride (750 mg, 3.29 mmol). After stirring for 5 min, tert-butylnitrite (2.50 mL, 20.8 mmol) was added to the solution. The reaction was stirred at −10° C. for 3 h. The reaction was diluted with CHCl3 (100 mL) and poured into ice water (50 mL). The CHCl3 layer was separated, washed with brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=50:50) yielded 239 mg (43%) of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine as a tan solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C@H:15]2[C@:10]([CH3:22])([CH2:11][CH2:12][C:13]3[C:20](Br)=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23](/B(O)O)=[CH:24]/[CH3:25]>C([O-])([O-])=O.[Na+].[Na+].COCCOC.CCO>[CH2:1]([N:8]1[CH2:16][C@H:15]2[C@:10]([CH3:22])([CH2:11][CH2:12][C:13]3[C:20](/[CH:23]=[CH:24]\[CH3:25])=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C/C=C\B(O)O
Reactant: C[C@]12CCc3c(Br)cccc3[C@H]1CN(Cc1ccccc1)C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: C/C=C\c1cccc2c1CC[C@]1(C)CN(Cc3ccccc3)C[C@H]21
Temperature: 160 °C

Procedure:
Tetrakis(triphenylphosphine)Pd(0) (0.021 mmol, 24.32 mg) was added in one portion to a mixture of cis-2-benzyl-6-bromo-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (0.421 mmol, 150 mg) and (Z)-prop-1-enylboronic acid (0.631 mmol, 54.2 mg) in 2 N aq Na2CO3 (1 ml), DME (1 ml) and EtOH (0.5 ml) The reaction mixture was heated under microwave irradiation at 160° C. for 900 seconds and then the mixture was filtered through celite. The resulting filtrate was diluted with water and extracted with DCM (3×). The combined organic extracts were dried over Na2SO4 and conc in vauco to afford a brown oil that was purified by silica column chromatography (eluting with 10% EtOAc in heptane) to afford cis-2-benzyl-3a-methyl-6-((Z)-prop-1-enyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole) (127 mg), m/z: 318.3 [M+H]+.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([NH:17]C(=O)C)[N:16]=1)[C:8](N(OC)C)=[O:9])(=O)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][CH:23]=1.Cl>C1COCC1>[NH2:17][C:15]1[CH:14]=[C:7]([C:8]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)=[O:9])[CH:6]=[C:5]([NH2:4])[N:16]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)c1cc(NC(C)=O)nc(NC(C)=O)c1
Agent: Cl
Solvent: C1CCOC1
Product: Nc1cc(C(=O)c2ccc(F)cc2)cc(N)n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
To a solution of 0.5 g (1.78 mmol) 2,6-bis-acetylamino-N-methoxy-N-methyl-isonicotinamide in 8 ml THF was added at room temperature 7.14 ml (7.14 mmol) of a 1M solution of 4-fluorophenylmagnesium bromide in THF and stirred for 80 min at room temperature and subsequently for 2 h at 40° C. After cooling to room temperature 0.8 ml 37% HCl was added and the mixture was evaporated to dryness. The residue was taken up in ethyl acetate and 2M Na2CO3. The aqueous phase was extracted with ethyl acetate and the combined organic fraction were dried with MgSO4 and evaporated to dryness. The residue was taken up in 3 ml MeOH and 1 ml 37% HCl and heated to reflux for 4 h. After evaporation to dryness the residue was taken up in ethyl acetate and 2M Na2CO3. The aqueous phase was extracted with ethyl acetate and the combined organic fraction were dried with MgSO4 and evaporated to dryness. The title compound was further purified by reversed phase HPLC eluting with an acetonitrile/water gradient and yielded 131 mg (32%) yellow crystals.
Reaction SMILES: CN(C=O)C.[N:6]1([CH2:10][C@@H:11]2[CH2:14][C@H:13]([N:15]3[C:19]4[N:20]=[CH:21][N:22]=[C:23]([NH2:24])[C:18]=4[C:17](I)=[CH:16]3)[CH2:12]2)[CH2:9][CH2:8][CH2:7]1.[C:26]1([C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][C:36](B4OC(C)(C)C(C)(C)C4)=[CH:37][CH:38]=3)[N:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>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.O>[N:6]1([CH2:10][C@@H:11]2[CH2:14][C@H:13]([N:15]3[C:19]4[N:20]=[CH:21][N:22]=[C:23]([NH2:24])[C:18]=4[C:17]([C:36]4[CH:35]=[C:34]5[C:39]([CH:40]=[CH:41][C:32]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)=[N:33]5)=[CH:38][CH:37]=4)=[CH:16]3)[CH2:12]2)[CH2:9][CH2:8][CH2:7]1
Reactant: Nc1ncnc2c1c(I)cn2[C@H]1C[C@@H](CN2CCC2)C1
Reactant: CC1(C)CB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2[C@H]1C[C@@H](CN2CCC2)C1
Temperature: 80 °C

Procedure:
To the DMF solution from the preparation of cis-7-(3-azetidin-1-ylmethylcyclobutyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine were added 2-phenyl-7-(4,4,5,5-tetramethyl-[2,3,2]dioxaborolan-2-yl)-quinoline (40 mg, 0.12 mmol), Na2CO3 (27 mg, 0.25 mmol), Pd(PPh3)4 (7 mg, 0.006 mmol), and water (0.6 mL). The solution was purged with nitrogen for 10 min and heated to 80° C. for 16 h. To the cooled reaction solution was added sat. Na2CO3 solution (10 mL), the mixture was extracted with EtOAc (3×20 mL), the combined organic layers were washed with water (3×15 mL) and brine, dried over MgSO4, filtered, and concentrated to give a brown oil. Purification by HPLC gave the title compound as brown oil. 1H NMR (CDCl3, 400 MHz): δ=2.06-2.26 (m, 5H), 2.56-2.57 (d, 2H, J=6.2), 2.71-2.77 (m, 2H), 3.21-3.24 (m, 4H), 5.17 (brs, 2H), 5.19-5.26 (m, 1H), 7.31 (s, 1H), 7.46-7.56 (m, 3H), 7.69-7.71 (dd, 1H, J=1.6 & 8.4 Hz), 7.90-7.94 (m, 2H), 8.18-8.20 (m, 2H), 8.26-8.29 (m, 2H), 8.35 (s, 1H). MS (ES+): 461.2 [MH+]. HPLC: tR=2.0 min (polar—5 min).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[N:15]=[C:14]2[C:10]([C:11]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[NH:13]2)=[CH:9][CH:8]=1.CN(C1C=CC=CN=1)C.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][S:2]([NH:6][C:7]1[N:15]=[C:14]2[C:10]([C:11]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[C:12]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[NH:13]2)=[CH:9][CH:8]=1)(=[O:4])=[O:3]
Reactant: Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Reaction time: 24 h

Procedure:
Methanesulfonyl chloride (5 ml, 0.07 mmol) was added dropwise to 6-amino-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (17) (20 mg, 0.066 mmol), dimethylamino pyridine (1 mg, 0.007 mmol), and chloroform (3 mL). After 24 h at 23° C., an additional 4 equivalents of methanesulfonyl chloride was added. After 4 h at 23° C., NaOH (10N, 3 mL) was added. After 3 h, the mixture was extracted with ethyl acetate (50 mL), washed with water (3×15 mL), and dried (Na2SO4). After concentration in vacuo, the residue was purified by application of preparative plate chromatography (two 2 mm silica gel plates, ethyl acetate) to afford 6-(methylsulfonyl amino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (56): Mass Spectrum (CI) 383 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([S:13]([OH:16])(=[O:15])=[O:14])[C:11]=1[OH:12])[C:5](OC)=[O:6].O.[NH2:18][NH2:19]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([S:13]([OH:16])(=[O:15])=[O:14])[C:11]=1[OH:12])[C:5]([NH:18][NH2:19])=[O:6]
Reactant: COC(=O)c1cc(O)c(O)c(S(=O)(=O)O)c1
Reactant: NN
Solvent: O
Product: NNC(=O)c1cc(O)c(O)c(S(=O)(=O)O)c1
Temperature: 0 °C

Procedure:
3,4-Dihydroxy-5-sulfobenzoic acid, methyl ester (15.0 g, 52.9 mmoles) was dissolved in 100 ml of hydrazine hydrate and refluxed for 15 hours. The mixture was then evaporated in vacuo, the residue dissolved in water and the pH adjusted to 1.0 with 2N hydrochloric acid. The mixture was chilled at 0° C. for 15 hours and the white precipitate which formed was filtered and dried to give 12.83 g of the title compound as a white solid, m.p >300° C.
Reaction SMILES: [N:1]([C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:11]([O:23][CH3:24])[C:10]([CH3:25])=[C:9]2[C:5]=1[C:6](=[O:26])[O:7][CH2:8]2)=[C:2]=[O:3].[CH3:27][NH:28][CH3:29]>O1CCCC1.O>[CH3:27][N:28]([CH3:29])[C:2](=[O:3])[NH:1][C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:11]([O:23][CH3:24])[C:10]([CH3:25])=[C:9]2[C:5]=1[C:6](=[O:26])[O:7][CH2:8]2
Reactant: CNC
Reactant: COC(=O)CC/C(C)=C/Cc1c(N=C=O)c2c(c(C)c1OC)COC2=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CC/C(C)=C/Cc1c(NC(=O)N(C)C)c2c(c(C)c1OC)COC2=O

Procedure:
A solution of 0.65 g (1.8 mmol) of methyl (E)-6-(1,3-dihydro-4-isocyanato-6-methoxy-7-methyl -3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate in 10 ml of tetrahydrofuran was treated with 5 ml of a solution of 40% dimethylamine in water. After 1 hour the reaction was partitioned between water and ethyl acetate. The organic phase was washed with water three times, dried over magnesium sulfate, and concentrated under reduced pressure to give 0.4 g of methyl (E)-6-[1,3-dihydro-4-(3,3-dimethylureido)-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoate, mp 116°-118° C.
Reaction SMILES: [CH2:1]([N:3]([C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[CH2:10][CH2:11][C:12]#[N:13])[CH2:4][CH2:5][OH:6])[CH3:2].[C:17](OC(=O)C)(=[O:19])[CH3:18].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[CH2:1]([N:3]([C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[CH2:10][CH2:11][C:12]#[N:13])[CH2:4][CH2:5][O:6][C:17](=[O:19])[CH3:18])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCN(CCO)c1cccc(CCC#N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCN(CCOC(C)=O)c1cccc(CCC#N)c1

Procedure:
A mixture of 218 parts of 3-(N-ethyl-N-β-hydroxyethylamino)-hydrocinnamonitrile, 100 parts by volume of glacial acetic acid and 115 parts by volume of acetic anhydride was heated under reflux for 4 hours. At the end of the reaction, easily followed by chromatography on thin layers of silica, the product was neutralized with sodium carbonate and 200 parts were decanted of 3-(N-ethyl-N-β-acetoxyethyl-amino)-hydrocinnamonitrile of the formula: ##STR13## in the form of an oil which boiled at 192° C. under 20 mm of mercury.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1>[CH2:10]([N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C1CCCN1
Reactant: CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCN1CCCC1=O
Yield: 31 %

Procedure:
Following example 1, on refluxing 13 g of 50% oil dispersion of sodium hydride (6.5 g NaH, 0.271 M), 20.35 g (0.239 M) of azacyclopentan-2-one and 47.28 g (0.264 M) of 1-bromoheptane in dry toluene for 21 hours was obtained 13.6 g (31%) of colorless oil; boiling point 115°-120°/0.6 mm.
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.[C:10]([C:13]1[CH:38]=[CH:37][C:16]([CH2:17][NH:18][C:19]2[C:29]3[CH2:28][CH2:27][N:26]([C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[CH2:25][CH2:24][C:23]=3[CH:22]=[CH:21][C:20]=2[Cl:36])=[CH:15][CH:14]=1)(=O)[CH3:11]>C(O)C>[Cl:36][C:20]1[CH:21]=[CH:22][C:23]2[CH2:24][CH2:25][N:26]([C:30](=[O:35])[C:31]([F:34])([F:32])[F:33])[CH2:27][CH2:28][C:29]=2[C:19]=1[NH:18][CH2:17][C:16]1[CH:15]=[CH:14][C:13]([C:10](=[N:2][OH:3])[CH3:11])=[CH:38][CH:37]=1
Reactant: NO
Reactant: CC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=NO)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 94.3 %

Procedure:
Add hydroxylamine hydrochloride (19 mg, 0.27 mmol) and pyridine (0.04 mL, 0.54 mmol) to a solution of 6-(4-acetylbenzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (115 mg, 0.27 mmol) in ethanol (10 mL). Heat the mixture to reflux for 2 h. Remove the solvent in vacuo and partition the residue between DCM and 0.1N aqueous HCl. Dry the organic phase over Na2SO4, filter and concentrate. Dissolve the oil into the minimum amount of ether and add hexane to precipitate the solid. Filter to obtain 7-chloro-6-[4-(1-hydroxyiminoethyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a solid (112 mg, 94%) that was used without further purification. MS (ES+) m/z: 440 (M+H)+.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:46]=[CH:45][N:13]([C@@H:14]2[O:44][C@H:18]([CH2:19][O:20]C(C3C=CC=CC=3)(C3C=CC(OC)=CC=3)C3C=CC(OC)=CC=3)[C@@H:16]([OH:17])[CH2:15]2)[C:12](=[O:47])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:48](O[C@@H]1[C@@H](CO)O[C@@H](N2C3N=C(NC(=O)C(C)C)NC(=O)C=3N=C2)C1)([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49]>>[Si:48]([O:17][C@@H:16]1[C@@H:18]([CH2:19][OH:20])[O:44][C@@H:14]([N:13]2[CH:45]=[CH:46][C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:11][C:12]2=[O:47])[CH2:15]1)([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49]
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)O2)c(=O)[nH]1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(NC(=O)c4ccccc4)nc3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc(NC(=O)c3ccccc3)nc2=O)O[C@@H]1CO

Procedure:
This compound was prepared from N4 -benzoyl-5'-O-(4,4'-dimethoxytrityl)-2'-deoxycytidine by the same procedure used for the preparation of 3'-O-t-butyldimethylsilyl-N2 -isobutyryl-2'-deoxyguanosine.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(O)(C(F)(F)F)=O.[CH3:19][C:20]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:21]=1[NH2:22]>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:21]2[C:23]([CH3:28])=[CH:24][C:25]([CH3:27])=[CH:26][C:20]=2[CH3:19])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: Clc1nc(Cl)c2sccc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(Nc2nc(Cl)nc3ccsc23)c(C)c1
Temperature: 90 °C
Reaction time: 15 h
Yield: 23.2 %

Procedure:
To a solution of 2,4-dichlorothieno[3,2-d]pyrimidine (148 mg, 0.73 mmol), TFA (0.17 mL, 2.19 mmol) in TFE (2 mL) was added 2,4,6-trimethylaniline (0.15 mg, 1.1 mmol) in a sealed tube. The reaction was stirred at 90° C. for 15 h. The reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 solution (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography eluting with Hexanes:ethyl acetate (4:1) to afford the product as a white solid (51.4 mg, 23%):
Reaction SMILES: C1C2C(OC(=O)[N:16](C)[C@@H:17]3[CH2:36][C:35]4=[CH:37][CH:38]=[C:32]([CH:33]=[CH:34]4)[O:31][CH2:30][CH:29]=[CH:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][O:22][CH2:21][C@H:20]([CH:39]([CH3:41])[CH3:40])[NH:19][C:18]3=[O:42])C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CO.[Pd]>[NH2:16][C@@H:17]1[CH2:36][C:35]2=[CH:34][CH:33]=[C:32]([CH:38]=[CH:37]2)[O:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][O:22][CH2:21][C@H:20]([CH:39]([CH3:40])[CH3:41])[NH:19][C:18]1=[O:42]
Reactant: CC(C)[C@H]1COCCCCCC=CCOc2ccc(cc2)C[C@@H](N(C)C(=O)OC2c3ccccc3-c3ccccc32)C(=O)N1
Agent: [Pd]
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)[C@H]1COCCCCCCCCOc2ccc(cc2)C[C@@H](N)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.87 (1.46 mmol) of 9H-fluoren-9-yl-methyl((13S,16R)-13-isopropyl-15-oxo-2,11-dioxa-14-azabicyclo[16.2.2]docosa-1(21),4,18(22),19-tetraen-16-yl)-carbamate and 0.16 g of 10% Pd/C in 100 ml of methanol was stirred under a hydrogen atmosphere at RT. After stirring overnight and addition of 0.5 ml of piperidine, stirring was continued for 2 h, and the mixture was filtered and freed of solvent. The residue was separated by preparative HPLC. The required fractions were combined and freeze dried. 0.18 g of the title compound was obtained as trifluoroacetate.