Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]3([CH2:16][CH2:15][CH2:14]3)[CH2:8][N:7]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:48]=[CH:47][C:27]([C:28]([NH:30][C@H:31]2[CH2:36][CH2:35][C@H:34]([N:37]3[CH2:42][CH2:41][N:40]([CH2:43][CH:44]4[CH2:46][CH2:45]4)[CH2:39][CH2:38]3)[CH2:33][CH2:32]2)=[O:29])=[CH:26][C:25]=1[O:49][CH3:50].C(O)(C(F)(F)F)=O>>[CH:17]1([N:7]2[CH2:8][C:9]3([CH2:16][CH2:15][CH2:14]3)[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:48]=[CH:47][C:27]([C:28]([NH:30][C@H:31]5[CH2:32][CH2:33][C@H:34]([N:37]6[CH2:42][CH2:41][N:40]([CH2:43][CH:44]7[CH2:46][CH2:45]7)[CH2:39][CH2:38]6)[CH2:35][CH2:36]5)=[O:29])=[CH:26][C:25]=4[O:49][CH3:50])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1cc(C(=O)N[C@H]2CC[C@H](N3CCN(CC4CC4)CC3)CC2)ccc1N
Reactant: CN1C(=O)C2(CCC2)CN(C2CCCC2)c2nc(Cl)ncc21
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N[C@H]2CC[C@H](N3CCN(CC4CC4)CC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CCC1)C(=O)N2C

Procedure:
2′-Chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclobutane-1,7′-pyrimido[4,5-b][1,4]diazepin]-6′(5′H)-one (Intermediate 4) (0.065 g, 0.2 mmol, 1 eq), 4-amino-N-(trans-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-3-methoxybenzamide (Intermediate 11) (0.24 g, 0.6 mmol, 3 eq) and TFA (75 μL, 1 mmol, 5 eq) in TFE (6 mL) were heated to reflux together 40 hours. RM was concentrated in vacuo and the residue was partitioned between EtOAc and saturated sodium hydrogen carbonate. The organic layer was separated, washed with saturated brine and concentrated in vacuo to a residue that was purified by preparative RP-HPLC-MS (Preparative—1) to give 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclobutane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-N-((trans)-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-3-methoxybenzamide.
Reaction SMILES: [OH-].[Na+].S(O)(O)(=O)=O.[CH3:8][O:9][C:10](=[NH:12])[NH2:11].O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>ClCCl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:23])[NH:12][C:10](=[NH:11])[O:9][CH3:8])=[CH:17][CH:16]=1
Reactant: COC(=N)N
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COC(=N)NC(=O)Nc1ccc(Cl)cc1
Temperature: 5 °C
Reaction time: 6 h

Procedure:
320 Parts of a 50% sodium hydroxide solution was added dropwise to 345 parts of 2-methylpseudourea hydrogen sulfate in a mixture of 3500 parts of water and 4000 parts of dichloromethane which mixture was maintained at approximately 5°C. by a cooling bath. 307 Parts of p-chlorophenyl isocyanate was added to the resulting mixture and the cooling bath was removed. The reaction mas was stirred vigorously for 6 hours at room temperature. The dichloromethane layer was separated, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was triturated in hexane and the solid was collected by filtration affording 400 parts of methyl 4-(4-chlorophenyl)allophanimidate, m.p. 115°-117°C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([CH:9]2[CH2:16][C:12]3[S:13][CH:14]=[CH:15][C:11]=3[C:10]2=O)=O)=[CH:3][CH:2]=1.O.[NH2:19][NH2:20].C(O)(=O)C>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:9]3[CH2:16][C:12]4[S:13][CH:14]=[CH:15][C:11]=4[C:10]=3[NH:20][N:19]=2)=[CH:3][CH:2]=1
Reactant: O=C(c1ccncc1)C1Cc2sccc2C1=O
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: c1cc(-c2n[nH]c3c2Cc2sccc2-3)ccn1
Temperature: 25 °C
Yield: 52.5 %

Procedure:
5-(Pyridine-4-carbonyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (1.95 g, 8 mmol), hydrazine monohydrate (0.6 mL, 12 mmol), glacial acetic acid (1.4 mL) and ethanol (20 mL) were heated at 100° C. under nitrogen for 4 hr. The mixture was cooled to 25° C. and concentrated under reduced pressure to give a solid which was recrystallized from ethanol to provide the corresponding 6-Pyridin-4-yl-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (1.16 g, 4.2 mmol) as white solid in 53% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[CH:14]1([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(#N)C>[CH:14]1([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH2:24]2)=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: O=C(NC1CCCCC1)C1CCCNC1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1)C1CCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
To a solution of 2-nitrobenzene-1-sulfonyl chloride (12.3 mg) and N-cyclohexylpiperidine-3-carboxamide (TFA salt, 18 mg) from Step 2 in 0.2 mL acetonitrile was added triethylamine (19.3 μL). The reaction mixture was stirred at RT for 2 hours and directly purified by HPLC to give 13.2 mg of desired product. LCMS: m/z 396.1 (M+H)+; 813.3 (2M+Na)+.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][S:16]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:28]=2[N:27]=[CH:26][CH:25]=[CH:24]3)(=[O:18])=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[N:27]1[C:28]2[C:23](=[CH:22][CH:21]=[CH:20][C:19]=2[S:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7]2)(=[O:18])=[O:17])[CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)C1(NS(=O)(=O)c2cccc3cccnc23)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1(NS(=O)(=O)c2cccc3cccnc23)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
The mixture of 2-(quinoline-8-sulfonylamino)-indan-2-carboxylic acid ethyl ester (35) (210 mg, 0.53 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (8 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate came out of the water. The precipitate is filtered to give a pure product (36) as white solid (195 mg, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15](=[O:33])[N:16]([CH2:29][CH:30]([CH3:32])[CH3:31])[N:17]=[C:18]([C:21]3[CH:26]=[CH:25][C:24](C)=[C:23](F)[CH:22]=3)[C:19]=2[CH3:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C(=O)C(OS(C)(=O)=O)=CC(C2C=CC=CC=2)=N1)C(C)C.N1(C(OC(C)(C)C)=O)CCNCC1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15](=[O:33])[N:16]([CH2:29][CH:30]([CH3:31])[CH3:32])[N:17]=[C:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:19]=2[CH3:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(C)Cn1nc(-c2ccccc2)cc(OS(C)(=O)=O)c1=O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)nn(CC(C)C)c(=O)c1N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 83.5 %

Procedure:
Following the procedure of Example 1 (10), 2-isobutyl-4-methanesulfonyloxy-6-phenyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted in N,N-dimethylformamide as a solvent to yield the title compound as a yellow oil (yield: 83.5%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7]12(N)[CH2:13]C(CC1)C[CH2:8]2.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(OCC)C>[CH:7]12[CH2:13][CH:3]([CH:2]=[CH:8]1)[CH2:4][CH:5]2[CH2:6][NH:1][S:16]([CH3:15])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: NC12CCC(CC1)C2
Reactant: c1ccncc1
Solvent: CCOCC
Product: CS(=O)(=O)NCC1CC2C=CC1C2
Temperature: 0 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
Into a dry 500 ml round bottom flask equipped with a magnetic stirrer, condenser and an addition funnel was added 75 ml of dry distilled tetahydrofuran, 32 g (0.41 moles) of pyridine and 50 g (0.41 moles) of norbornyl amine. The reaction mixture was cooled to 0° C. To the mixture was added via the additional funnel 47 g (0.41 moles) of methanesulfonyl chloride and the reaction mixture was stirred overnight. The reaction mixture was filtered to remove the pyridinium hydrochloride salt and the filtrate was rotovaped to remove tetrahydrofuran, resulting in a solid. The solid was dissolved in diethylether, and the resulting solution was extracted several times with deionized water. After treating with decolorizing carbon and drying over anhydrous sodium sulfate, the solution was filtered and the solvent was removed by rotary evaporation. The solid product was recrystallized from toluene and dried under reduced pressure in 76% yield, mp 60-62° C. The product was identified by 1H and 13C NMR and IR spectroscopy.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:6][CH2:7][C:8](O)=[O:9])[C:3](O)=[O:4].[NH2:12]C(N)=O>O>[CH3:1][C:2]1([CH3:11])[CH2:6][CH2:7][C:8](=[O:9])[NH:12][C:3]1=[O:4]
Reactant: NC(N)=O
Reactant: CC(C)(CCC(=O)O)C(=O)O
Solvent: O
Product: CC1(C)CCC(=O)NC1=O
Temperature: 160 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
The mixture of 10 g of 2,2-dimethylglutaric acid and 37.5 g of urea was stirred for 8 hours at 160° C. Into the reaction mixture was added water at 100° C., and the mixture was cooled to near room temperature. The mixture was extracted with ethyl acetate three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 7.6 g of 3,3-dimethylpiperidin-2,6-dione.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:14][C:15]([CH3:17])=[O:16]>>[S:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[CH:14]/[C:15](=[O:16])[CH3:17])=[CH:2]1
Reactant: CC(C)=O
Reactant: O=Cc1ccsc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)/C=C/c1ccsc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.6 g of 3-thiophenecarboxaldehyde was dissolved in 30 ml of acetone, and 20 g of potassium carbonate was added. The mixture was stirred overnight at room temperature. The solvent was evaporated, and the residue was worked up in a customary manner. The resulting alcohol compound was dissolved in 10 ml of methylene chloride, and 1.1 ml of methanesulfonyl chloride and 2.3 ml of triethylamine were added. The mixture was stirred overnight at room temperature, and then the solvent was evaporated. The residue was worked up in a customary manner, and purified by silica gel column chromatography [hexane/ethyl acetate=40/1] to give 650 mg of the captioned compound as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([N:15]=[C:16]=[O:17])=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11]C(=O)C)=[CH:7][CH:6]=1.C[O-].[Na+]>CO>[CH3:1][O:2][C:3]([N:15]=[C:16]=[O:17])=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1
Reactant: COC(=Cc1ccc(OC(C)=O)cc1)N=C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=Cc1ccc(O)cc1)N=C=O
Temperature: 50 °C

Procedure:
A suspension of 23.5 g (0.1 mol) of p-(2-methoxy-carbonylaminovinyl)-acetoxybenzene in 300 ml of absolute methanol, which is mixed with a solution of 5.4 g of sodium methoxide in 30 ml of methanol, is warmed to 50° C for 15 minutes. Thereafter the mixture is evaporated to dryness under reduced pressure. The resulting crude sodium salt of [2-methoxy-carbonylaminovinyl]-phenol is dissolved in 100 ml of water, 50 ml of 2 N hydrochloric acid are added to the solution and the phenol which has separated out is extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulphate and evaporated in vacuo. Crude p-(2-methoxy-carbonylaminovinyl)-phenol is obtained as an oil. This can be used, as shown below, without further purification. A sample crystallised from ether showed a melting point of 169°-170° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10](=O)[CH3:11])[CH:5]=[CH:6][CH:7]=1.Br[CH2:14][CH2:15][CH:16]([NH:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C:17]([O:19]CC)=[O:18].Br.[NH:34]1[CH2:38][CH2:37][N:36]=[C:35]1[NH:39][NH2:40]>CO>[NH:36]1[CH2:37][CH2:38][N:34]=[C:35]1[NH:39][N:40]=[C:10]([CH3:11])[CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([O:1][CH2:14][CH2:15][C@@H:16]([C:17]([OH:19])=[O:18])[NH:22][C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[CH:7]=[CH:6][CH:5]=1
Reactant: NNC1=NCCN1
Reactant: CCOC(=O)C(CCBr)NC(=O)OCc1ccccc1
Reactant: CC(=O)CCc1cccc(O)c1
Agent: Br
Solvent: CO
Product: CC(CCc1cccc(OCC[C@H](NC(=O)OCc2ccccc2)C(=O)O)c1)=NNC1=NCCN1
Yield: 10.9 %

Procedure:
The operation is carried out as in Example 1 Stages A, B and C but using 390 mg of 4-(3-hydroxyphenyl)-2-butanone and 818 g of ethyl 4-bromo-2-[[(phenylmethoxy)carbonyl]amino]butanoate (Stage A) then, during Stage B, 380 mg of 4,5-dihydro-1H-imidazol-2-yl-hydrazine hydrobromide. The saponification stage is carried out in the presence of soda in methanol. 110 mg of expected product is obtained in the form of an E/Z mixture 45/55.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:30]=[CH:29][C:7]([O:8][CH:9]([N:24]2[CH:28]=[N:27][CH:26]=[N:25]2)[C:10](=[O:23])[C:11]([CH3:22])([CH3:21])[CH2:12][S:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:6][CH:5]=1>O.CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([N:24]2[CH:28]=[N:27][CH:26]=[N:25]2)[CH:10]([OH:23])[C:11]([CH3:22])([CH3:21])[CH2:12][S:13][C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[CH:29][CH:30]=1
Reactant: CC(C)(CSc1ccc(Cl)cc1)C(=O)C(Oc1ccc(Cl)cc1)n1cncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(CSc1ccc(Cl)cc1)C(O)C(Oc1ccc(Cl)cc1)n1cncn1
Temperature: 20 °C
Reaction time: 4 h
Yield: 54.5 %

Procedure:
0.35 g (0.0092 mol) of sodium borohydride in 8 ml of water was added in portions to 10 g (0.023 mol) of 1-(4-chlorophenoxy)-4-(4-chlorophenylmercapto)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one (Example 4e) in 200 ml of methanol. The reaction mixture was subsequently stirred at 20° C. for 4 hours, poured onto water and extracted with ether. The ether phase was dried over sodium sulphate and concentrated. 5.5 g (54.6% of theory) of 1-(4-chlorophenoxy)-4-(4-chlorophenylmercapto)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-ol of melting point 132° C. were obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]2.C([Li])CCC.CCCCCC.[CH3:30][S:31]SC>O1CCCC1.O>[CH2:13]([N:12]([CH2:16][CH2:17][CH3:18])[CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([S:31][CH3:30])[CH:3]=[CH:4][CH:5]=2)[CH2:10]1)[CH2:14][CH3:15]
Reactant: CSSC
Reactant: CCCN(CCC)C1CCc2cccc(Br)c2C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCN(CCC)C1CCc2cccc(SC)c2C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a solution of 8-bromo-2-di-n-propylamino-1,2,3,4-tetrahydronaphthalene (600 mg, 1.93 mMol) in tetrahydrofuran (20 mL) at -78° C. was added a solution of n-butyllithium in hexane (1.6M, 1.9 mL, 3.04 mMol). The solution was stirred at -78° C. for one hour, forming a light orange solution. Dimethyl disulfide (0.24 mL, 3.00 mMol) was added, and the reaction mixture was allowed to warm gradually to room temperature. The colorless solution was diluted with water and extracted with dichloromethane. The dichloromethane extracts were combined, dried (Na2SO4), and concentrated in vacuo to give the crude product as a light yellow oil. Purification by flash chromatography (3% methanol in dichloromethane+tr. NH4OH) gave the product as a colorless, viscous oil (430 mg, 80%). The hydrochloride salt was formed. Recrystallization (ethanol/diethyl ether) gave a colorless, crystalline solid (m.p.=185° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:27](O)=[O:28])[CH:25]=[CH:26][C:17]=4[C:16]=3[N:30]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH:36]C(=O)OC(C)(C)C.C(OC(=O)NCCNC(C1C=CC2C3N=C(NC4C=CC(OC)=C(OC)C=4)N=CC=3CC(=O)NC=2C=1)=O)(C)(C)C>>[NH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:27]([C:24]1[CH:25]=[CH:26][C:17]2[C:16]3[N:30]=[C:12]([NH:11][C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:13]=[CH:14][C:15]=3[CH2:21][C:20](=[O:22])[NH:19][C:18]=2[CH:23]=1)=[O:28]
Reactant: COc1ccc(Nc2ncc3c(n2)-c2ccc(C(=O)O)cc2NC(=O)C3)cc1OC
Reactant: CC(C)(C)OC(=O)NCCCCN
Agent: COc1ccc(Nc2ncc3c(n2)-c2ccc(C(=O)NCCNC(=O)OC(C)(C)C)cc2NC(=O)C3)cc1OC
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(C(=O)NCCCCN)cc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to that described Method N, 2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carboxylic acid (I-53) and tert-butyl 4-aminobutylcarbamate were converted to (2-{[2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carbonyl]-amino}-ethyl)-carbamic acid tert-butyl ester, which was subsequently deprotected (Method K) to give I-73 (25%): HRMS Calcd. for C25H28N6O4: 477.2250, Found 477.2250.
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[N:11][CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([CH2:8][CH2:7][C:6]([OH:19])=[O:5])=[CH:10][N:11]=1
Reactant: CC(C)(C)OC(=O)CCc1cncc2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCc1cncc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 251 %

Procedure:
To a solution of 800 mg of 3-isoquinolin-4-yl-propionic acid tert.-butyl ester in 6.2 mL of DCM was added 6.2 mL of TFA. The reaction mixture was stirred for 2 h at rt and evaporated to dryness to yield 1.57 g of 3-isoquinolin-4-yl-propionic acid as the trifluoroacetic acid salt as a brown solid.
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:23]1[CH:27]=[C:26]([C:28]2[C:29]3[CH:36]=[CH:35][N:34](COCC[Si](C)(C)C)[C:30]=3[N:31]=[CH:32][N:33]=2)[CH:25]=[N:24]1)[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=2)[C:16]#[N:17])[CH:8]([F:22])[CH2:7]1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH2:3][CH:4]([N:23]1[CH:27]=[C:26]([C:28]2[C:29]3[CH:36]=[CH:35][NH:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH:25]=[N:24]1)[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=2)[C:16]#[N:17])[CH:8]([F:22])[CH2:7]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCC(Oc5cc(F)cc(C#N)c5)C(F)C4)c3)ncnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCC(CN1CCC(Oc2cc(F)cc(C#N)c2)C(F)C1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 1 h
Yield: 61.4 %

Procedure:
To a solution of 3-[(1-{3-cyano-2-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-3-fluoropiperidin-4-yl)oxy]-5-fluorobenzonitrile (11 mg, 0.018 mmol) in DCM (0.5 mL) was added 0.5 ml TFA. The mixture was stirred for 1 hour and solvent was removed. The residue was dissolved in methanol (1 mL), and 0.2 ml EDA was added. After stirring for 2 hours, The reaction solution was diluted with methanol and purified by preparative-LCMS (C18 column eluting with a gradient of ACN/H2O containing 0.15% NH4OH) afforded product (5.4 mg, 62%). The product was synthesized from diastereomer 1 using same procedure in 61% yield LCMS (M+H)+: 489.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH:22]([OH:24])[CH2:21][CH2:20][CH:19]2[C:25]([OH:27])=[O:26])(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:31].Cl>C1COCC1.CN1CCCC1=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([S:15]([N:18]2[CH2:23][CH:22]([O:24][CH3:31])[CH2:21][CH2:20][CH:19]2[C:25]([OH:27])=[O:26])(=[O:16])=[O:17])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: O=C(O)C1CCC(O)CN1S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: COC1CCC(C(=O)O)N(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
A mixture of 1-(4-benzyloxy-benzenesulfonyl)-5-hydroxy-piperidine-2-carboxylic acid (0.10 g, 0.26 mmol) and 1:1 THF-N-methylpyrrolidin-2-one (1 mL) was treated with NaH (0.031 g, 0.78 mmol, 60% dispersion in mineral oil). After stirring for 10 min, the mixture was warmed to room temperature, stirred for 20 min and treated with iodomethane (0.016 mL, 0.26 mmol). After stirring fro 3 h, the mixture was treated with an additional 0.010 g of NaH and 0.015 mL of iodomethane. The resulting mixture was stirred for 24 h, acidified with 1M HCl, extracted 3× with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue by radial chromatography (1:1 to 2:1 ethyl acetate hexane containing 1% of acetic acid, 2 mm silica gel plate) afforded 0.077 g (75%) of 1-(4-benzyloxy-benzenesulfonyl)-5-methoxy-piperidine-2-carboxylic acid as a colorless syrup:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18](Cl)[N:17]=[C:16]([C:30]3C=CN=CC=3)[N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[OH:36][CH2:37][CH2:38][CH2:39][NH:40][S:41]([C:44]1[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=1)(=[O:43])=[O:42]>C1COCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:36][CH2:37][CH2:38][CH2:39][NH:40][S:41]([C:44]3[CH:45]=[CH:46][C:47]([CH3:50])=[CH:48][CH:49]=3)(=[O:43])=[O:42])[N:17]=[C:16]([CH3:30])[N:15]=2)(=[O:11])=[O:12])=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)NCCCO)cc1
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)c1ccc(C(C)C)cn1
Solvent: C1CCOC1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(C)nc1OCCCNS(=O)(=O)c1ccc(C)cc1

Procedure:
According to the procedure described in Example 1a) 256 mg 5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was reacted with N-(3-hydroxy-propyl)-4-methylbenzenesulfonamide in THF in the presence of potassium tert.-butylate to give 280 mg 5-isopropyl-N-[6-(3-(4-methylbenzenesulfonylamino)-propoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide. LC-MS: tR=4.83 min, [M+1]+=705.70, [M−1]−=703.79.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([CH3:22])[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:16][C@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1.Cl>C(O)C>[OH:3][CH:4]([CH3:22])[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:16][C@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1
Reactant: CC(=O)CCc1ccc2[nH]cc(C[C@H]3CCCN3)c2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)CCc1ccc2[nH]cc(C[C@H]3CCCN3)c2c1
Reaction time: 18 h

Procedure:
Sodium borohydride (423 mg, 11 mol) was added portion-wise over 20 minutes at room temperature, under nitrogen, to a stirred solution of the title compound of Example 37 (1.34 g, 5 mmol) in ethanol (50 ml), then stirring continued for 18 hours. The pH of the resulting reaction mixture was adjusted to 2 with 2N hydrochloric acid, then to 8 with solid sodium carbonate, and the volume reduced to about half by evaporation under reduced pressure, before partitioning between ethyl acetate and water was effected. The organic phase was separated, washed with water, dried (Na2SO4) and evaporated under reduced pressure to give a foam which was purified by column chromatography on silica gel, eluting with a solvent gradient of 0.880 aqueous ammonia:methanol:dichloromethane (0:0:100 to 0:10:90 to 1:10:90 to 1.5:15:85), to afford the title compound as a foam. Rf 0.10 (SS 7). [α]D25 -22° (c=0.1, CH3OH). Found: C,72.07; H,8.96; N,9.56. C17H24N2O; 0.10 CH2Cl2 ; 0.17 H2O requires C,72.34; H,8.71; N,9.87%.