Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:6]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[CH:5][CH:4]=1.[F:23][C:24]1[C:29]([OH:30])=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:7]1[N:8]=[C:3]([CH2:2][O:30][C:29]2[C:24]([F:23])=[C:25]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:26]=[CH:27][CH:28]=2)[CH:4]=[CH:5][C:6]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22]
Reactant: CCOC(=O)CCc1cccc(O)c1F
Reactant: COc1ccc(F)c(-c2ccc(CCl)nc2CC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1F
Yield: 70.5 %

Procedure:
To a solution of 6-(chloromethyl)-2-(2,2-dimethylpropyl)-3-(2-fluoro-5-methoxyphenyl)pyridine (321 mg) in acetonitrile (10 mL) were added ethyl 3-(2-fluoro-3-hydroxyphenyl)propanoate (430 mg) and cesium carbonate (980 mg), and the mixture was heated under reflux for 15 hr. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered off. The solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (350 mg) as a white solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[CH:42]1([CH2:45][N:46]2[CH2:51][CH2:50][N:49]([CH:52]3[CH2:57][CH2:56][CH:55]([NH2:58])[CH2:54][CH2:53]3)[CH2:48][CH2:47]2)[CH2:44][CH2:43]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:58][C@H:55]5[CH2:54][CH2:53][C@@H:52]([N:49]6[CH2:48][CH2:47][N:46]([CH2:45][CH:42]7[CH2:43][CH2:44]7)[CH2:51][CH2:50]6)[CH2:57][CH2:56]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:58][C@H:55]5[CH2:56][CH2:57][C@H:52]([N:49]6[CH2:50][CH2:51][N:46]([CH2:45][CH:42]7[CH2:43][CH2:44]7)[CH2:47][CH2:48]6)[CH2:53][CH2:54]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: NC1CCC(N2CCN(CC3CC3)CC2)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N[C@H]2CC[C@@H](N3CCN(CC4CC4)CC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Product: COc1cc(C(=O)N[C@H]2CC[C@H](N3CCN(CC4CC4)CC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.08 g (0.18 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.19 mL (1.1 mmole) of ethyldiisopropyl amine and 0.068 mg (0.20 mmole) of the cis/trans mixture of 4-(4-cyclopropylmethyl-piperazin-1-yl)-cyclohexylamine with trihydrochloride in 2.0 mL of dimethylformamide was added 0.085 g (0.20 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-70:30) gave 0.026 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-[cis-4-(4-cyclopropylmethyl-piperazin-1-yl)-cyclohexyl]-3-methoxy-benzamide (I-299) (Rf: 0.56 in dichloromethane:methanol 7:3) as a white solid, and 0.063 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-[trans-4-(4-cyclopropylmethyl-piperazin-1-yl)-cyclohexyl]-3-methoxy-benzamide (I-300) (Rf: 0.44 in dichloromethane:methanol 7:3) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][N:28]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[C:17]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=2[N:13]=1)=[O:7].Cl.[C:30](OC(=O)C)(=[O:32])[CH3:31].C(=O)(O)[O-].[Na+]>C1COCC1.O.C(N(CC)CC)C>[C:30]([N:21]1[CH2:20][CH2:19][CH:18]([C:17]2[C:11]3[S:10][C:9]([NH:8][C:6](=[O:7])[C:5]4[CH:26]=[CH:27][N:28]=[C:3]([O:2][CH3:1])[CH:4]=4)=[N:13][C:12]=3[C:14]([O:24][CH3:25])=[CH:15][CH:16]=2)[CH2:23][CH2:22]1)(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C(=O)Nc2nc3c(OC)ccc(C4CCNCC4)c3s2)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)Nc2nc3c(OC)ccc(C4CCN(C(C)=O)CC4)c3s2)ccn1
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a solution of 0.07 g (0.16 mMol) 2-methoxy-N-(4-methoxy-7-piperidin-4-yl-benzothiazol-2-yl)-isonicotinamide 1:2 hydrochloride in 4 ml THF were added 0.049 ml triethyl amine. At 0° C. 0.018 ml (0.11 mMol) acetic anhydride was added dropwise and stirred for 1 h. Then a mixture of 5 ml sat. aqueous sodium bicarbonate and 10 ml water were added. This was extracted three times with 15 ml ethyl acetate, the combined organic phases were dried over sodium sulfate and evaporated to dryness in vacuo. One obtained 0.036 g (51%) N-[7-(1-acetyl-piperidin-4-yl)-4-methoxy-benzothiazol-2-yl]-2-methoxy-isonicotinamide as a white solid. F.p.: 242-244° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:16]=3[N:12]2[CH2:11][CH2:10]1.[Cu][C:28]#[N:29]>CN1CCCC1=O.O.C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N:9]2[C:13]3=[N:14][C:15]4[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:16]=4[N:12]3[CH2:11][CH2:10]2)=[C:2]([CH:7]=1)[C:28]#[N:29]
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3c1ccc(Cl)cc1Br
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3c1ccc(Cl)cc1C#N
Temperature: 150 °C
Reaction time: 6 h

Procedure:
To a solution of 1-(2-bromo-4-chlorophenyl)-8-chloro-5-(1-ethylpropyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole (30.7 mg, 0.0677 mmol) in 1-methyl-2-pyrrolidone (0.5 mL) was added copper(I) cyanide (18.2 mg, 0.203 mmol). The reaction mixture was stirred at 150° C. for 6 hr. After cooling, the reaction mixture was diluted with water and ethyl acetate and the precipitate was removed by filtration. The filtrate was extracted with ethyl acetate (×3). The combined organic layer was washed with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-15% ethyl acetate/n-hexane gradient mixture to give the title compound as an amorphous (18.7 mg, 0.468 mmol, 69%).
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:18])=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH3:16])[C:6]=2[CH:17]=1.C(=O)([O-])[O-].[K+:23].[K+].Cl[CH:26](Cl)[C:27]([O:29]C)=[O:28].O>CN(C)C=O>[K+:23].[C:11]1([CH3:16])[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:7]1[C:6]2[CH:17]=[C:2]3[O:1][CH:26]([C:27]([O-:29])=[O:28])[O:18][C:3]3=[CH:4][C:5]=2[O:9][N:8]=1
Reactant: COC(=O)C(Cl)Cl
Reactant: Cc1ccccc1-c1noc2cc(O)c(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1-c1noc2cc3c(cc12)OC(C(=O)[O-])O3
Reaction time: 1.5 h
Yield: 47.4 %

Procedure:
A mixture of 5,6-dihydroxy-3-(o-tolyl)-1,2-benzisoxazole (4.7 g), potassium carbonate (12.1 g), methyl dichloroacetate (4.2 g) in N,N-dimethylformamide (40 ml) was stirred at 90°-95° C. for 1.5 hours. After cooling, water (10 ml) was added to the mixture followed by stirring at 80°-90° C. for 10 minutes. After cooling the mixture was extracted with ether, and then the ether layer was washed with water, dried and evaporated to remove the solvent. The residue was dissolved in a potassium bicarbonate aqueous solution, and then ethanol was added to the solution. The resulting precipitate was collected by filtration, washed with ethanol and dried in air to give 3.1 g of 3-(o-tolyl)-1,3-dioxolo [4,5-f]-1,2-benzisoxazole-6-carboxylic acid potassium salt. The resulting potassium salt was dissolved in a small amount of water, and after acidifying it with hydrochloric acid, was extracted with ether. The ether layer was washed with water, dried and evaporated to remove the solvent. The residue was recrystallized from acetonitrile to give 1.9 g of 3-(o-tolyl)-1,3-dioxolo[4,5-f]-1,2-benzisoxazole-6-carboxylic acid. m.p.: 166-170 (decomposition)
Reaction SMILES: S(O[CH2:6][C:7]1[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[C:9]([Cl:18])[CH:8]=1)(=O)(=O)C.[C-:19]#[N:20].[Na+]>CS(C)=O>[Cl:18][C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=1)[CH2:6][C:19]#[N:20]
Reactant: CS(=O)(=O)OCc1cc(Cl)cc(OC(F)(F)F)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1cc(Cl)cc(OC(F)(F)F)c1
Temperature: 50 °C
Yield: 99.8 %

Procedure:
To a solution of 3-chloro-5-trifluoromethoxybenzyl mesylate (8.2 g, 26.8 mmol; see step (i) above) in DMSO (50 mL) was added sodium cyanide (2.6 g, 53.6 mmol). The resulting heterogeneous solution was warmed to 50° C. and sonicated for 1 hour. The reaction was cooled and partitioned between Et2O and H2O. The organics were washed with H2O (2×) and brine (2×). The combined aqueous phases were extracted with Et2O (1×). The combined organics were dried (Na2SO4), filtered and concentrated under a low heat and partial vacuum to afford the sub-title compound (6.3 g, 100%) as a reddish volatile oil which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[Cl:11].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[Cl:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[O:18][CH2:17][C:16]1[CH:19]=[CH:20][C:13]([Cl:12])=[CH:14][CH:15]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(OCc2ccc(Cl)cc2)c(Cl)c1
Temperature: 120 °C
Yield: 46.9 %

Procedure:
N,N-Dimethylacetamide (42 mL), 16.2 g of 1,2-dichloro-4-nitrobenzene, 12 g of 4-chlorobenzyl alcohol, and 8.7 g of potassium carbonate were mixed together, and the mixture was stirred with heating at 100 to 140° C. for 30 hr. This reaction solution was concentrated under the reduced pressure. The residue was dissolved in 100 mL of ethyl acetate and 100 mL of toluene, and the solution was washed with water and brine. The organic layer was concentrated under the reduced pressure, and the residue was recrystallized from ethanol to give 11.77 g of 2-chloro-1-(4-chlorobenzyloxy)-4-nitrobenzene (yield 46.9%).
Reaction SMILES: [O-]CC.[Na+].[NH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=[CH:13]2.Cl[CH2:23][CH2:24][C:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])=[O:26]>C(O)C>[CH3:20][N:16]1[C:17]2[C:12](=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][NH:5][CH2:23][CH2:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[O:26])=[CH:19][CH:18]=2)[CH:13]=[CH:14][C:15]1=[O:21]
Reactant: Cc1ccccc1NC(=O)CCCl
Reactant: Cn1c(=O)ccc2cc(OCCCN)ccc21
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccccc1NC(=O)CCNCCCOc1ccc2c(ccc(=O)n2C)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 58.5 %

Procedure:
Sodium ethoxide(34 mg) was added to an ethanol solution (5 ml) of 6-(3-amino-propoxy)-1-methyl-1H-quinolin-2-one (116 mg) and 3-chloro-N-o-tolyl-propionamide(148 mg). The mixture was stirred at 60° C. for 5 hours. The reaction mixture was condensed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol=20:1→10:1). The purified product was condensed under reduced pressure to give the title compound(115 mg) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=O)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[O:10][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[F:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([N:39]3[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]3)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[O:10][C:4]=2[CH:3]=1
Reactant: O=C1Nc2ccc(F)cc2Oc2sc3ccccc3c21
Reactant: CN1CCNCC1
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(C2=Nc3ccc(F)cc3Oc3sc4ccccc4c32)CC1

Procedure:
In the same manner as in Example 80 and using 8-fluoro-[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 8-fluoro-12-(4-methylpiperazin-1-yl)-[1]benzothieno[2,3-b][1,5]benzoxazepine is obtained.
Reaction SMILES: [S-:1][C:2]#N.[NH4+].O.[CH3:6][C:7]1[CH:8]=[C:9]([OH:14])[CH:10]=[C:11]([CH:13]=1)[OH:12].C([O:17]CC)C>O.S([O-])([O-])(=O)=O.[Cu+2]>[OH:12][C:11]1[CH:13]=[C:7]([CH3:6])[C:8]2[S:1][C:2](=[O:17])[O:14][C:9]=2[CH:10]=1
Reactant: N#C[S-]
Reactant: CCOCC
Reactant: Cc1cc(O)cc(O)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: O
Product: Cc1cc(O)cc2oc(=O)sc12
Reaction time: 18 h

Procedure:
Ammonium thiocyanate (10.71 g, 141 mmol) was added slowly to a solution of 5-methylresorcinol hydrate (5.0 g, 35 mmol) and copper(II) sulfate (17.56 g, 70 mmol) in water (100 mL), and the solution was stirred for 18 h. Diethyl ether (100 mL) was added and the mixture was filtered through Celite®, washing the cake with diethyl ether (100 mL). The diethyl ether layers were separated and the aqueous layer was re-extracted with diethyl ether (100 mL). The combined organic fractions were dried (MgSO4) and evaporated to a yellow-orange solid (5.30 g, 83%). 1H NMR showed the material to be 80–90% pure and this was taken on without further purification; δH (d6-DMSO, 400 MHz) 2.30 (3H, s), 6.57 (1H, s), 6.65 (1H, s), 9.90 (1H, brs).
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]([C:15]3[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([C:22]#[C:23][CH2:24][N:25]([CH2:33][CH3:34])C(=O)OC(C)(C)C)[CH:16]=3)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>[OH-].[Na+]>[ClH:21].[C:1]12([CH2:11][NH:12][C:13](=[O:14])[C:15]3[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([CH2:22][CH2:23][CH2:24][NH:25][CH2:33][CH3:34])[CH:16]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: CCN(CC#Cc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Product: CCNCCCc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1
Product: Cl
Yield: 19 %

Procedure:
The titled compound was prepared from tert-butyl 3-(4-{[(1-adamantylmethyl)amino]-carbonyl}-5-chloropyridin-2-yl)prop-2-ynyl(ethyl)carbamate (Example 7(ii)) (0.30 g) by the method of Example 6(ii). The crude hydrochloride salt was suspended in 2M aqueous sodium hydroxide solution (25 ml), extracted into ethyl acetate (3×25 ml). and the combined extracts were concentrated. The residue was purified by chromatography on silica gel eluting with dichloromethane:methanol:0.88 aqueous ammonia (89:10:1). The isolated material was dissolved in a solution of hydrogen chloride in 1,4-dioxane (10 ml of a 4M solution) and concentrated; the resultant solid was triturated with ethyl acetate and the solid collected by filtration. Final purification was by preparative reverse phase HPLC to afford the titled compound (0.025 g) as a colourless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH:9](O)[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:20]>C(Cl)(Cl)(Cl)Cl>[Cl:20][CH:9]([NH:8][C:6](=[O:7])[C:5]1[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)C(=O)C(O)NC(=O)c1ccc(Cl)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)C(Cl)NC(=O)c1ccc(Cl)cc1

Procedure:
12.1 g (0.05 mol) of 1-(p-chlorobenzamido)-3,3-dimethyl-1-hydroxy-butan-2-one were dissolved in 80 ml. of carbon tetrachloride. 10.4 g (0.05 mol) of phosphorus pentachloride were added at 50° C. and the mixture was then heated for 2 hours under reflux. It was then filtered hot and the filtrate was concentrated in a waterpump vacuum. The crude 1-chloro-1-(p-chlorobenzamido)-3,3-dimethyl-butan-2-one thus obtained could be directly reacted further. The melting point was 132°-135° C. ##STR45##
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:21])=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13].[N:32]1[CH:37]=[CH:36][CH:35]=[C:34](B(O)O)[CH:33]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)=[O:13]
Reactant: COc1c(C)c(Cc2ccc(O)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Reactant: OB(O)c1cccnc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COc1c(C)c(Cc2ccc(Oc3cccnc3)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Yield: 42.4 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzoyl]morpholine (0.100 g, 0.232 mmol) was dissolved in methylene chloride (2.5 ml) and after adding thereto in sequence copper acetate (0.042 g, 0.232 mmol), 3-pyridylboronic acid (0.076 g, 0.464 mmol), Molecular Sieves 4A (0.100 g), triethylamine (0.059 g, 0.580 mmol) and pyridine (0.046 g, 0.580 mmol), the solution was stirred at room temperature for 12 hours. The reaction solution was filtered and the filtrate was poured into water and then extracted with methylene chloride. The extract was washed with saturated brine, then dried and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to obtain the titled compound (0.050 g, 0.0984 mmol, 42%).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:22]=[C:21]4[C:15]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20]4)=[N:14]3)=[CH:9][CH:8]=2)[O:4][N:3]=1.[C:23]1(=O)[CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CO>[CH:23]1([N:18]2[CH2:19][CH2:20][C:21]3=[CH:22][N:13]([C:10]4[CH:11]=[CH:12][C:7]([C:5]5[O:4][N:3]=[C:2]([CH3:1])[N:6]=5)=[CH:8][CH:9]=4)[N:14]=[C:15]3[CH2:16][CH2:17]2)[CH2:26][CH2:25][CH2:24]1
Reactant: Cc1noc(-c2ccc(-n3cc4c(n3)CCNCC4)cc2)n1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1noc(-c2ccc(-n3cc4c(n3)CCN(C3CCC3)CC4)cc2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine (prepared as described in Description 35) (31 mg, 0.10 mmol) in dichloromethane (4 ml) was added cyclobutanone (30 mg, 0.42 mmol) and acetic acid (3 drops). The resulting mixture was stirred at room temperature, under argon, for 20 minutes. Sodium triacetoxyborohydride (89 mg, 0.42 mmol) was added and stirring continued overnight. The resulting crude mixture was diluted with methanol and then purified by SCX, eluting with methanol and then with 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo to afford the title compound (E25). MS (ES+) m/e 350 [M+H]+.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH2:2][CH:3]=[CH2:4].[CH2:7]1[CH2:12][CH2:11][CH:10]([N:13]=[C:14]=[N:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:9][CH2:8]1>C1COCC1>[C:1]([OH:6])(=[O:5])[CH2:2][CH:3]=[CH2:4].[C:14]([NH:13][CH:10]1[CH2:9][CH2:8][CH2:7][CH2:12][CH2:11]1)([NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:5]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C=CCC(=O)O
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
NHS ester of 3-butenoic acid was synthesized based following literature procedure.32 3-butenoic acid (1.0 g, 1.2 mmol) and NHS (1.47 g, 1.28 mmol) were dissolved in THF (30 ml). The solution was cooled in an ice bath and N,N′-dicyclohyxylcarbodiimide (DCC, 2.4 g, 1.2 mmol) was added under stirring. A white precipitate, dicyclohexylurea (DCU), formed after ˜5 min and the mixture was stirred for 1 hour at 0° C. The reaction proceeded at 4° C. overnight without any agitation. DCU was then removed by filtration. The filtrate was concentrated to give a viscous oil containing some residual DCU. The crude product was re-dissolved in a small volume of THF and then filtered. This procedure was repeated until a clear THF solution was obtained. The solvent was removed and the product was then washed with hexane. Residual solvents were removed under vacuum until a constant weight was obtained. 1H-NMR (500 MHz, CDCl3, δ ppm): 2.64, 2.90, 5.21, 5.24, 5.94.
Reaction SMILES: O.[NH2:2]N.C[N:5](C)/[CH:6]=[CH:7]/[C:8]([C:10]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[CH:17][C:16]2[CH2:26][NH:27][CH2:28][C:29](=[O:30])[N:14]3[C:15]=2[C:11]=1[CH:12]=[CH:13]3)=O>C1COCC1>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]2[C:10]([C:8]3[NH:2][N:5]=[CH:6][CH:7]=3)=[C:11]3[C:15]4=[C:16]([CH2:26][NH:27][CH2:28][C:29](=[O:30])[N:14]4[CH:13]=[CH:12]3)[CH:17]=2)=[CH:24][CH:23]=1
Reactant: CN(C)/C=C/C(=O)c1c(-c2ccc(F)cc2)cc2c3c1ccn3C(=O)CNC2
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: O=C1CNCc2cc(-c3ccc(F)cc3)c(-c3ccn[nH]3)c3ccn1c23
Reaction time: 42 h
Yield: 22.5 %

Procedure:
Hydrazine monohydrate (5.14 mmol, 0.26 mL) was added to a solution of 7-[(E)-3-Dimethylamino-allanoyl]-6-(4-fluoro-phenyl)-3,4-dihydro-2H-[1,4]diazepino[6,7,1-hi]indol-1-one (Example 159) (0.257 mmol, 0.097 g) in 10 mL THF at rt. The reaction mixture was stirred for 42 h. The reaction mixture was evaporated to dryness. The residue was taken up in 2N HCl and extracted with EtOAc several times. The combined organic layers was dried over anhydrous MgSO4 and concentrated to give a yellow oil which was purified by flash silica gel chromatography eluting with a gradient of 0-3% MeOH in CHCl3 to give 0.020 g (23%) of a yellow solid: mp=173-175° C.; 1H NMR (DMSO-d6) δ 3.45-3.52 (m, 2H), 4.03-4.08 (m, 2H), 5.64 (br s, 1H), 7.23 (t, 1H, J=6.0 Hz), 7.32 (t, 2H, J=9.0 Hz), 7.38-7.55 (m, 3), 7.88 (d, 1H, J=6.0 Hz), 8.36-8.43 (m, 2H), 12.67 (br s, 1H); HRMS calcd. for C20H15N4OF (M+) 346.1221, found (M+) 346.1225; Anal. for (C20H15N4OF.1.0MeOH) C, H, N.