Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[CH:2]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9](C=O)[C:4]=2[CH:3]=1.S(=O)(O)[O-:13].[Na+]>C(#N)C>[OH:13][C:5]12[CH:6]=[CH:7][CH:8]=[CH:9][CH:4]1[CH2:3][CH2:2]2
Reactant: O=Cc1cccc2c1C=C2
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: OC12C=CC=CC1CC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A solution of the thus prepared permonophosphoric acid (18 mL, 1.2M) in acetonitrile was added to a flask equipped with ice bath, stirrer and water-cooled condenser. To the stirred solution was added 3-benzocyclobutene aldehyde (5 g, 0.037 moles) dropwise over a period of 30 minutes. The reaction mixture was stirred for an additional 2 hours and cooled to 0° C. Water (20 mL) was added to the cooled reaction mixture, followed by the addition of sodium bisulfite solution until the reaction mixture was free from permonophosphoric acid, as tested with starch iodide paper. The organic solvent was removed by rotary evaporation, and sodium hydroxide was added until the reaction mixture became alkaline. The reaction mixture was cooled to 0° C., acidified and extracted with ethyl acetate. The organic layer was washed with water, sodium bicarbonate and brine. Drying and removal of the solvent was followed by flash chromatography using 10 percent ethyl acetate in hexanes to afford 3.19 g 3-hydroxybenzocyclobutene as a solid. This represents a yield of approximately 70 percent. The 3-benzocyclobutene phenol was recrystallized from pentane. The 3-benzocyclobutene phenol product has a melting point of 47° C. Product analysis indicated substantially complete conversion of 3-benzocyclobutene aldehyde with the product, other than the desired 3-hydroxybenzocyclobutene, comprising unidentified polymer-like substance with substantially no formation of 3-benzocyclobutene carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH2:15][CH2:16][OH:17])=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=2)[CH:5]=[CH:6][N:7]=1.[F:18][C:19]([F:29])([F:28])[O:20][C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH2:15][CH2:16][O:17][C:24]3[CH:23]=[CH:22][C:21]([O:20][C:19]([F:18])([F:28])[F:29])=[CH:26][CH:25]=3)=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: COC(=O)c1nc2c(Cl)nccn2c1CCO
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1nc2c(Cl)nccn2c1CCOc1ccc(OC(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
To a suspension of methyl 8-chloro-3-(2-hydroxyethyl)imidazo[1,2-a]pyrazine-2-carboxylate (18 mg, 0.070 mmol) in toluene (1 mL) was added 4-trifluoromethoxyphenol (0.014 mL, 0.106 mmol), Ph3P (27.7 mg, 0.106 mmol), and DIAD (0.021 mL, 0.106 mmol). After 30 min, the reaction was concentrated in vacuo and then purified on silica (gradient elution, 0-100% EtOAc/hexanes) to yield the title product (10 mg). HRMS (ESI) calc (M+H)+=416.0619. found 416.0616.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][C:21]=2[C:27]([O:29][CH3:30])=[O:28].C([O-])(O)=O.[Na+]>N1C=CC=CC=1.C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][C:21]=2[C:27]([O:29][CH3:30])=[O:28])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1cccc2cc(O)cnc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cccc2cc(OS(=O)(=O)C(F)(F)F)cnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.5 %

Procedure:
Trifluoromethanesulfonic anhydride (0.55 mL, 3.4 mmol) was added to a solution of methyl 3-hydroxyquinoline-8-carboxylate (650 mg, 3.2 mmol) in pyridine (2.3 mL) and CH2Cl2 (13 mL) at 0° C. The reaction mixture was allowed to warm to room temperature. After 3 h, additional trifluoromethanesulfonic anhydride (0.55 mL, 3.4 mmol) was added and the reaction was stirred for an additional 18 h. Saturated aqueous NaHCO3 (20 mL) was added and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3×). The combined organic phase was dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified on silica gel eluting with CH2Cl2 to afford 971 mg (91%) of methyl 3-(((trifluoromethyl)sulfonyl)oxy)quinoline-8-carboxylate.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH2:8][CH2:7]2)=[C:2]=[O:3].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:24][C:23]([C:25]([NH:27][CH:28]([CH:33]([CH3:35])[CH3:34])[C:29]([O:31][CH3:32])=[O:30])=[O:26])=[N:22][CH:21]=2)=[CH:16][CH:15]=1>>[CH2:9]1[C:10]2[C:6](=[CH:5][C:4]([NH:1][C:2](=[O:3])[NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[O:24][C:23]([C:25]([NH:27][C@@H:28]([CH:33]([CH3:35])[CH3:34])[C:29]([O:31][CH3:32])=[O:30])=[O:26])=[N:22][CH:21]=4)=[CH:16][CH:15]=3)=[CH:12][CH:11]=2)[CH2:7][CH2:8]1
Reactant: O=C=Nc1ccc2c(c1)CCC2
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc(N)cc2)o1)C(C)C
Product: COC(=O)[C@@H](NC(=O)c1ncc(-c2ccc(NC(=O)Nc3ccc4c(c3)CCC4)cc2)o1)C(C)C
Yield: 92 %

Procedure:
The title compound was synthesized analogous to Example 1, using 5-isocyanato-2,3-dihydro-1H-indene (84.87 mg, 0.533 mmol) and intermediate 1. Yield: 92%; 1H NMR (DMSO-d6, 300 MHz): δ 9.005-8.978 (d, 1H), 8.912 (s, 1H), 8.624 (s, 1H), 7.804 (s, 1H), 7.781-7.752 (d, J=8.7 Hz, 2H), 7.617-7.587 (d, J=9 Hz, 2H), 7.395 (s, 1H), 7.172-7.106 (m, 2H), 4.328-4.277 (m, 1H), 3.681 (s, 3H), 2.860-2.772 (m, 4H), 2.286-2.217 (m, 1H), 2.052-2.154 (m, 2H), 0.980-0.928 (d, J=6.9 Hz, 6H); MS (ESI) m/z 475 [M−H], 477 [M+H]+.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[C:18]([NH:23][C:24]3[S:25][CH:26]=[C:27]([CH3:29])[N:28]=3)=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:10]=1)(C)(C)C.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>C(Cl)Cl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[CH3:29][C:27]1[N:28]=[C:24]([NH:23][C:18]2[C:17]([O:16][CH2:15][C:11]3[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=3)[O:8][CH2:7][C:6]([OH:30])=[O:5])=[CH:22][CH:21]=[CH:20][N:19]=2)[S:25][CH:26]=1
Reactant: Cc1csc(Nc2ncccc2OCc2cccc(OCC(=O)OC(C)(C)C)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1csc(Nc2ncccc2OCc2cccc(OCC(=O)O)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
tert-Butyl-2-(3-((2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)methyl)phenoxy)acetate (680 mg, 1.59 mmol) and CH2Cl2 (5 mL) were combined in a 50 mL round-bottomed flask. Trifluoroacetic acid (5 mL) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the resultant solid was triturated with 40% methanol in CH2Cl2 to provide 2-(3-((2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)methyl)phenoxy)acetic acid trifluoroacetate salt (621 mg, 80.4% yield) as a white solid. 1H NMR (d6-DMSO) δ 7.92 (dd, 1H), 7.49 (dd, 1 h), 7.32 (t, 1H), 7.16 (m, 2H), 7.00 (dd, 1 h), 6.88 (dd, 1H), 6.72 (q, 1H), 5.26 (s, 2H), 4.69 (s, 2h), 2.29 (d, 3H). Mass spectrum (apci) m/z=372 (M+H-TFA).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][NH:7][CH2:8][CH3:9])=[O:5])[CH3:2].C(=O)(O)[O-].[Na+].C(Cl)Cl.[N:18]#[C:19]Cl>O>[CH2:1]([O:3][C:4]([NH:6][N:7]([CH2:8][CH3:9])[C:19]#[N:18])=[O:5])[CH3:2]
Reactant: N#CCl
Reactant: CCNNC(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)NN(C#N)CC
Reaction time: 1 h
Yield: 87.9 %

Procedure:
66.0 g of 2-ethylhydrazinecarboxylic acid ethyl ester and 42.0 g of sodium bicarbonate are stirred into 200 ml of methylene chloride and 400 ml of water. There is then introduced at room temperature in the course of 20 minutes, with continuous stirring, 30.8 g of gaseous cyanogen chloride. After one hour's subsequent stirring, the methylene chloride phase is separated and dried over sodium sulphate, and the solvent is distilled off in vacuo. There is obtained as residue 69.0 g (88% of theory) of 2-ethyl-2-cyano-hydrazinecarboxylic acid ethyl ester as colourless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][S:21][CH2:22][C@H:23]([OH:26])[CH2:24][OH:25])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([N:37]=[C:38]=[O:39])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][S:21][CH2:22][C@H:23]([O:26][C:38](=[O:39])[NH:37][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:24][O:25][C:38](=[O:39])[NH:37][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCN=C=O
Reactant: CC(C)(C)OC(=O)[C@H](CSC[C@H](O)CO)NC(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccccc1
Product: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C)OC(=O)NCCCCCCCCCC
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A solution of (R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((R)-2,3-dihydroxypropylthio)propanoate (13) was stirred in anhydrous benzene (0.1 M) under nitrogen at room temperature. Decyl isocyanate (2.02 eq) and DMAP (dimethylaminopyridine, 2.02 eq) were added and the resulting mixture heated to 40° C. and stirred overnight. The reaction mixture was concentrated to remove benzene then reconstituted in DCM and purified on a COMBIFLASH® system (ISCO) using a gradient of 0-50% EtOAc/Hex to give the title product as a colorless oil.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([C:23]5[CH:28]=[CH:27][NH:26][C:25](=[O:29])[CH:24]=5)=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].I[CH:31]([CH3:33])[CH3:32]>>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([C:23]5[CH:28]=[CH:27][N:26]=[C:25]([O:29][CH:31]([CH3:33])[CH3:32])[CH:24]=5)=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3cc[nH]c(=O)c3)cc1-2
Reactant: CC(C)I
Product: CC(C)Oc1cc(-c2ccc3c(c2)-c2nc(-c4ncnn4C(C)C)sc2CCO3)ccn1

Procedure:
Following the procedure for Example 478, 4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-1H-pyridin-2-one 505 and 2-iodopropane were reacted to give 540. 1H NMR (400 MHz, DMSO) δ 8.81 (s, 1H), 8.24 (d, J=5.4 Hz, 1H), 8.13 (s, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.25 (d, J=5.3 Hz, 1H), 7.19 (d, J=8.7 Hz, 1H), 5.85 (dt, J=13.3, 6.7 Hz, 1H), 5.38-5.22 (m, 1H), 4.44 (s, 2H), 3.48 (s, 2H), 1.59 (d, J=6.5 Hz, 6H), 1.32 (d, J=6.0 Hz, 6H). MS (ESI(+)): m/z 448.1 (M+H)
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>CN(C=O)C>[O:23]=[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:21][N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A one liter three necked round bottom flask was charged with Boc-piperazine (20 g), dry potassium carbonate (44.5 g) and dry DMF (150 ml) under nitrogen atmosphere. The reaction mixture was cooled to 0° C. and bromoacetophenone (23.5 g) was added into the reaction mixture very slowly. The reaction mixture was stirred at room temperature for overnight. The progress of reaction was monitored by TLC. After consumption of starting material, ice-cold water (200 ml) was added to reaction mixture. The precipitated white solid was filtered, washed with water (4×50 ml) and dried to afford tert-butyl 4-(2-oxo-2-phenylethyl)piperazine-1-carboxylate as pure product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH2:24][C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[N:11](COCC[Si](C)(C)C)[N:10]=1.C(O)(C(F)(F)F)=O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH2:24][C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[NH:11][N:10]=1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(CC(=O)N(C)C)c3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(CC(=O)N(C)C)c3)cc12

Procedure:
To the crude 2-{3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-N,N-dimethyl-acetamide obtained in last step was added TFA (2 mL) and the resulting mixture was sonicated till the residue was completely dissolved. The TFA was evaporated. The residue was treated with ethylene diamine (0.2 mL) to scavenge the formaldehyde which generated from the de-protection of the trimethylsilanylethoxymethyl group. The resulting mixture was sonicated till the residue was completely dissolved to give a greenish blue solution. DMSO was added to make a 2 mL solution which was used in preparative LCMS purification on a reverse phase column to yield 2-{3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-N,N-dimethyl-acetamide as a white solid (21 mg, 29% over two steps) MS: m/z 387 (M+H+). 1H NMR (500 MHz, DMSO-d6) δ 2.84 (s, 3H), 3.04 (s, 3H), 3.78 (s, 2H), 3.86 (s, 6H), 7.10 (t, 1H), 7.23 (d, 1H), 7.25 (d, 1H), 7.43 (t, 1H), 7.47 (t, 1H), 7.61 (s, 1H), 7.62 (d, 1H), 7.66 (d, 1H), 8.30 (s, 1H), 8.82 (d, sH), 13.82 (s, 1H).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([O:25][CH3:26])=[C:9]([O:23][CH3:24])[CH:10]=2)[N:5]=1>C(O)(C)C.C(OCC)(=O)C>[CH:9]([O:23][C:4]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([O:25][CH3:26])=[C:9]([O:23][CH3:24])[CH:10]=2)[N:5]=1)([CH3:10])[CH3:8]
Reactant: COc1cc2nc(Cl)nc(-c3ccc(C(C)C)cc3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: COc1cc2nc(OC(C)C)nc(-c3ccc(C(C)C)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11 mg (0.44 mmol) NaH is dissolved in 2 ml isopropanol and stirred for 2 h at rt. After that time 30 mg (0.088 mmol) 2-chloro-4-(4-isopropyl-phenyl)-6,7-dimethoxy-quinazoline is added and the solution is stirred at 55° C. overnight. The reaction mixture is diluted with ethyl acetate and extracted with brine. The organic layer is dried and evaporated. After chromatography (hexane/ethyl acetate) the product is obtained as yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[S:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1>>[CH3:20][C:2]1([CH3:1])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:23]3[CH:24]=[CH:25][S:21][CH:22]=3)[CH:9]=2)[C:4](=[O:19])[CH2:3]1
Reactant: OB(O)c1ccsc1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: CC1(C)CC(=O)c2ccc(-c3ccsc3)cc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and thien-3-yl boronic acid according to the procedure described in example 21. MS m/z 243; HRMS: calcd for C15H14OS+H+, 243.08381; found (ESI, [M+H]+), 243.084.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:13]1[O:15][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([NH2:28])[CH2:24][CH:25]([CH3:27])[CH3:26]>C(O)(C)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:13]([OH:15])[CH2:14][NH:28][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H]1CO1)OCc1ccccc1
Reactant: CC(C)CCN
Solvent: CC(C)O
Product: CC(C)CCNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 81 %

Procedure:
Part C. A solution of N-benzyloxycarbonyl 3(S)-amino-1,2-(S)-epoxy-4-phenylbutane (30.1 g, 0.10 mol) and 165mL of isoamylamine in 150 mL of isopropyl alcohol was heated to reflux for 2.5 hours. The solution was cooled to room temperature, concentrated/n vacuo and then recrystallized. The product was isolated by filtration and from ethylacetate/hexane to afford 1.7 g (81%) of N[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl]N-isoamylamine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[CH:12]1[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([OH:19])[CH:13]=1>C(O)C>[OH:19][C:14]1[CH:15]=[CH:16][C:17]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[N:4][N:3]=2)=[CH:12][CH:13]=1
Reactant: Clc1nncc2ccccc12
Reactant: Nc1ccc(O)cc1
Solvent: CCO
Product: Oc1ccc(Nc2nncc3ccccc23)cc1

Procedure:
This example describes the synthesis of a compound having the formula ##STR62## A mixture of 2.00 g (12.1 mmol) of 1-chlorophthalazine and 2.64 g (24.2 mmol) of p-aminophenol in 40 ml of absolute ethanol was heated to reflux for 2 h. The precipitate was collected and successively washed with a saturated solution of NaHCO3 and water. The product was crystallized from methanol: mp 245°-247° C. The HCl salt had a mp>300° C.; the IR and NMR spectra were consistent with the assigned structure and the elemental analysis was consistent with the empirical formula (C14H11N3O.HCl).
Reaction SMILES: [O:1]=[C:2]1[NH:10]/[C:9](=[N:11]\[N:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)/[N:8]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:7]2[N:6]=[CH:5][NH:4][C:3]1=2>C(O)(=O)C>[CH2:20]([N:8]1[C:7]2[N:6]=[CH:5][NH:4][C:3]=2[C:2](=[O:1])[N:10]2[C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[N:12][N:11]=[C:9]12)[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCn1/c(=N/N=Cc2ccccc2)[nH]c(=O)c2[nH]cnc21
Solvent: CC(=O)O
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(-c3ccccc3)nnc12
Yield: 21.5 %

Procedure:
A solution of benzaldehyde[(2E)-6-oxo-3-pentyl-1,3,6,7-tetrahydro-2h-purin-2-ylidene]hydrazone (140 mg, 0.432 mmol) in acetic acid (5 ml) was stirred at 130° C. for 5 hours. The reaction mixture was concentrated in vacuo and purified by prep LCMS to yield the desired product (30 mg, 22% yield). LCMS calculated for C17H19N6O (M+H): 323.2. Found: 323.2.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.FC(F)(F)C(O)=O.[F:16][C:17]1[C:32]([F:33])=[CH:31][C:20]2[NH:21][C:22]([NH:24][C:25]3[C:29]([CH3:30])=[CH:28][S:27][CH:26]=3)=[N:23][C:19]=2[CH:18]=1>C(O)(=O)C>[Br:1][C:26]1[S:27][CH:28]=[C:29]([CH3:30])[C:25]=1[NH:24][C:22]1[NH:21][C:20]2[CH:31]=[C:32]([F:33])[C:17]([F:16])=[CH:18][C:19]=2[N:23]=1
Reactant: Cc1cscc1Nc1nc2cc(F)c(F)cc2[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Cc1csc(Br)c1Nc1nc2cc(F)c(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At room temperature, a solution of N-bromosuccinimide (8 mg) in glacial acetic acid (0.5 ml) was added dropwise to a solution of (5,6-difluoro-1H-benzimidazol-2-yl)-(4-methylthiophen-3-yl)amine trifluoroacetic acid salt (15 mg, example 45) in glacial acetic acid (0.5 ml) in a ReactiVial, and the mixture was stirred at room temperature for 0.5 h. The acetic acid was then removed under reduced pressure and saturated potassium carbonate solution and ethyl acetate were added to the residue. The organic phase was removed and the aqueous phase was then extracted twice with ethyl acetate. The combined organic phases were dried using magnesium sulfate and the drying agent was then filtered off. The residue that remained after removal of the solvent under reduced pressure was purified by preparative chromatography. The product-containing fractions were combined and freed from acetonitrile, saturated sodium bicarbonate solution was added to the residue and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried (MgSO4) and filtered. After removal of the ethyl acetate under reduced pressure, the residue was coevaporated with toluene and then dried under high vacuum. This gave 8.1 mg of the desired compound.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:47])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=5)=[C:36]([Cl:48])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:47])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:58])=[C:36]([Cl:48])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccccn4)c(Cl)c2)CCN3C(=O)C(F)(F)F)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(Cl)c2)CCN3C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[3-chloro-4-[hydroxy(pyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.37 g) was dissolved in dichloromethane (25 ml), and to the solution was added 3-chloroperbenzoic acid (0.2 g) under ice-cooling and the mixture was stirred overnight at room temperature. An aqueous solution of sodium thiosulfate was added to the mixture, the mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[3-chloro-4-[hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.24 g) as pale red oil.
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[C:11]([S:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:12]3[C:13](Br)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].CC1(C)C(C)(C)OB([C:36]2[C:40]([CH3:41])=[CH:39][S:38][CH:37]=2)O1>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([S:20][C:11]2[C:12]3[C:13]([C:36]4[C:40]([CH3:41])=[CH:39][S:38][CH:37]=4)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]3[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=23)=[CH:26][CH:25]=1
Reactant: CC(C(=O)[O-])C1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Reactant: Cc1cscc1B1OC(C)(C)C(C)(C)O1
Product: Cc1cscc1-c1cc(F)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1CC(=O)O

Procedure:
Starting from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate (Example 7, Step 9) and 4,4,5,5-tetramethyl-2-(4-methylthien-3-yl)-1,3,2-dioxaborolane, the title compound was synthesized following the procedures described Example 108.