Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:15][O:14][C:3]2([CH2:8][CH2:7][C:6]([CH3:13])([C:9](OC)=[O:10])[CH2:5][CH2:4]2)[O:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)(=O)C.O>CCOCC>[CH2:15]1[CH2:1][O:2][C:3]2([CH2:4][CH2:5][C:6]([CH3:13])([CH2:9][OH:10])[CH2:7][CH2:8]2)[O:14]1
Reactant: COC(=O)C1(C)CCC2(CC1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: CC1(CO)CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 89.8 %

Procedure:
The thus-obtained methyl 4,4-ethylenedioxy-1-methylcyclohexanecarboxylate (37.8 g) was dissolved in ether (100 ml), and the solution was added dropwise to a refluxing suspension of LiAlH4 (6.7 g) in ether (400 ml). After the addition, the mixture was stirred at room temperature for an hour and then cooled with ice. Ethyl acetate (20 ml) and then water (35 ml) were added dropwise cautiously thereto. The solid precipitate was filtered off, and the filtrate was distilled under reduced pressure to give 4,4-ethylenedioxy-1-methylcyclohexanemethanol (29.5 g, 89.9% yield, b.p. 120°-125° C./0.5 mmHg, m.p. 42°-43° C.).
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]([CH:25]=[CH:26][CH:27]=3)[C:21](=[NH:24])OC)[CH:16]=2)[NH:11][N:10]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(N(CC)CC)C>CO>[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]([C:21](=[NH:24])[N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH:25]=[CH:26][CH:27]=3)[CH:16]=2)[NH:11][N:10]=1
Reactant: COC(=N)c1cccc(-c2cnc3[nH]nc(-c4ccccc4OC)c3c2)c1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(C(=N)N4CCOCC4)c3)cc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 10 %

Procedure:
A solution of methyl 3-(3-(2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzimidate from Step in MeOH (1.0 mL) was added morpholine (15.3 mg, 0.176 mmol) and triethylamine (90 mg, 0.88 mmol), the mixture was stirred at room temperature for 3 days. The solvent was then removed and the crude product purified by reverse phase HPLC to afford C-{3-[3-(2-Methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-C-morpholin-4-yl-methyleneamine (3.7 mg, 10% yield two steps) as a white solid. 1H-NMR (500 MHz, CD3OD) δ 8.86 (d, 2 Hz, 1H), 8.45 (d, 2 Hz, 1H), 8.37 (br s, 1H), 8.02 (m, 1H), 7.96 (t, 1.8 Hz, 1H), 7.76 (t, 7.8 Hz, 1H), 7.66 (dd, 1.8 Hz, 7.8 Hz, 1H), 7.63 (m, 1H), 7.49 (m, 1H), 7.21 (d, 8 Hz, 1H), 7.12 (dt, 1 Hz, 7.8 Hz, 1H), 3.95 (m, 2H), 3.88 (s, 3H), 3.82 (m, 2H) 3.78 (m, 2H), 3.59 (m, 2H). MS: m/z 414.1 [MH+].
Reaction SMILES: [C:1]([O-])(=O)[CH3:2].[Na+].[Cl:6][CH2:7][CH2:8][NH:9][C:10]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:11][C:12]([O:14][CH3:15])=[O:13].CC(C)=O>O>[Cl:6][CH2:7][CH2:8][N:9]1[CH:2]=[CH:1][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]1[CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C=C(CC(=O)OC)NCCCl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)Cc1c(C(=O)OC)ccn1CCCl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.2 %

Procedure:
The hydrolysis solution was added to a mechanically-stirred slurry of sodium acetate (17.8 g, 212 mmol) in water (15 mL) at 0° C. over 1 hour, then stirred for a further 10 minutes. Dimethyl 3-(2-chloroethylamino)-2-pentenedioate (20.0 g, 85 mmol) was added, followed by acetone (50 mL), and the solution allowed to warm to room temperature and stirred for 20 hours. The resulting slurry was cooled to 0° C. and kept at that temperature for 4 hours, then filtered through a coarse frit. The precipitate was washed with water (300 mL) and dried, to give 19.9 g (90% yield) of methyl N-(2-chloroethyl)-3-methoxycarbonyl-2-pyrroleacetate as white crystals, m.p. 110°-111° C., NMR (CDCl3): δ:
Reaction SMILES: [C:1](CP(=O)(OCC)OCC)#[N:2].[Li+].[Cl-].[CH2:14]1CCN2C(=NCCC2)CC1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([N:37]2[C:45]3[C:40](=[C:41]([NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[CH:42]=[CH:43][CH:44]=3)[CH:39]=[CH:38]2)([CH2:35][CH3:36])[CH:33]=O)=[CH:28][CH:27]=1>C(#N)C>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]([N:37]2[C:45]3[C:40](=[C:41]([NH:46][C:47](=[O:53])[O:48][C:49]([CH3:51])([CH3:52])[CH3:50])[CH:42]=[CH:43][CH:44]=3)[CH:39]=[CH:38]2)([CH2:33][CH3:14])/[CH:35]=[CH:36]/[C:1]#[N:2])=[CH:30][CH:31]=1
Reactant: CCC(C=O)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Product: CCC(/C=C/C#N)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of diethyl cyanomethylphosphonate (145 mg, 0.76 mmol), LiCl (43 mg, 1.01 mmol) and DBU (255 mg, 1.01 mmol) in acetonitrile (15 mL) was added a solution of tert-butyl 1-(2-(4-chlorophenyl)-1-oxobutan-2-yl)-1H-indol-4-ylcarbamate (210 mg, 1.02 mmol), as described in Example 21 Step B, in acetonitrile (3 mL). The mixture was stirred at room temperature for 2 h and the volatile was evaporated. The residue was purified by silica gel chromatography eluting with PE/EA (10/1 to 3/1, v/v) to afford the title compound as a white solid. LC/MS m/z=458.1 [M+Na]+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:3])[CH3:2].[CH3:12][N:13]([S:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=1)[C:14](F)=[O:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:14](=[O:15])[N:13]([CH3:12])[S:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:26])([CH3:28])[CH3:27])=[CH:21][CH:20]=1)([CH3:3])[CH3:2]
Reactant: CN(SSc1ccc(C(C)(C)C)cc1)C(=O)F
Reactant: CC(C)Oc1ccccc1O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccccc1OC(=O)N(C)SSc1ccc(C(C)(C)C)cc1
Reaction time: 48 h
Yield: 23.7 %

Procedure:
To a solution of 4.0 g (0.026 m) of 2-isopropoxyphenol and 7.11 g (0.026 m) of N-methyl-N-(p-tert-butylphenylthiosulfenyl)carbamoyl fluoride in 75 ml of toluene was added 2.63 g (0.026 m) of triethylamine. After stirring for 48 hours the reaction mixture was washed with water and dried over anhydrous MgSO4. The product was purified by dry column chromatography to give 2.5g of a white solid. m.p. 84°-85° C.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 63 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-{3-[(dimethylamino)carbonyl]-1,2,4-oxadiazol-5-yl}hexanoate (Preparation 10) (2.35 g, 5.97 mmol) in dichloromethane (10 ml) was treated with trifluoroacetic acid (2 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 17 hours. The solvent was removed under reduced pressure and the residue azeotroped from dichloromethane. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol (98:2) to afford the title compound (1.27 g).
Reaction SMILES: [Si]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)(O)[CH:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][Si](C(C)(C)C)(C)C)=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.CC1C=CC(S(O)(=O)=O)=CC=1.C(O)C>CO>[OH:25][C:22]1[CH:21]=[CH:20][C:19]([C:14]2[CH2:15][O:16][C:17]3[C:12]([C:13]=2[C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=[CH:11][CH:10]=[C:9]([OH:8])[CH:18]=3)=[CH:24][CH:23]=1
Reactant: COc1ccc(C2(O)c3ccc(O[Si](C)(C)C(C)(C)C)cc3OCC2c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCO
Product: COc1ccc(C2=C(c3ccc(O)cc3)COc3cc(O)ccc32)cc1
Reaction time: 8 h

Procedure:
7(tert-Butyldimethylsilyloxy)-3-(4-(tert-butyldimethylsilyloxy)phenyl)-4-(4-methoxyphenyl)chroman-4-ol (42 g), pTsOH (435 g), boiling chips and 2.5 L of ethanol were combined in a 2-neck 5 L round bottom flask with condenser attached. The reaction was heated at reflux for 3 hours. The solvent was concentrated in vacuo to ˜100 ml before being poured into chilled, stirred water (700 ml). The mixture was then extracted with ethyl acetate, the combined organic layers washed with water (3×2 L), brine (1×500 ml), dried over anhydrous magnesium sulphate and filtered and solvent removed in vacuo to give red/brown oil. The oil was dissolved in methanol (˜100 ml) and put in freezer overnight.
Reaction SMILES: [CH3:1][OH:2].C[O-].[Na+].C(S([C:11]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[C:14]2=[N:15][CH:16]=[CH:17][C:18]([CH3:19])=[C:13]2[N:12]=1)(=O)=O)C>ClCCl>[CH3:1][O:2][C:11]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[C:14]2=[N:15][CH:16]=[CH:17][C:18]([CH3:19])=[C:13]2[N:12]=1
Reactant: CCS(=O)(=O)c1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
420 mg (2.2 mmol) of 28% methanol solution of sodium methoxide was added to 10 ml of a methanol solution of 0.44 g (0.96 mmol) of 2-ethylsulfonyl-7-methyl-3[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl] 3H-imidazo[4.5-b]-pyridine was dispersed in 150 ml of dichloromethane. The mixture was refluxed for 40 minutes. The solvent was distilled out at a reduced pressure. The residue was mixed with water and neutralized with 2N HCl. An extract with dichloromethane was washed with a saturated saline and dried with anhydrous magnesium sulfate. The solvent was distilled out at a reduced pressure. The residue was treated with ethanol and ether for recrystallization to obtain 300 mg of the above named compound.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][Si:10]([CH3:19])([CH3:18])[C:11]1[O:15][CH:14]=[C:13]([CH:16]=[O:17])[CH:12]=1.S(=O)(=O)(O)O>O1CCCC1>[OH:17][CH:16]([C:13]1[CH:12]=[C:11]([Si:10]([CH3:19])([CH3:18])[CH3:9])[O:15][CH:14]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: Br[Mg]c1ccccc1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc(C(O)c2ccccc2)co1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of phenylmagnesium bromide (0.41 ml, 1.27 mmol, 3.1M solution in ethyl ether) under argon at 0°, was added dropwise 5-trimethylsilyl-3-furaldehyde (0.194 g., 1.15 mmol) in 2 ml tetrahydrofuran. This solution was allowed to warm to room temperature, stirred for 30 minutes, and poured over crushed ice containing several drops of concentrated sulfuric acid. The resulting mixture was partitioned between ethyl ether and 5% sodium bicarbonate. The organic portion was washed with water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a colorless oil. This material was purified by flash chromatography (silica, 10% ethyl acetate/hexane) to give the desired alcohol.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([OH:18])=O)[CH:14]=2)[C:9](=[O:19])[N:8]([CH2:20][CH:21]2[CH2:23][CH2:22]2)[C:7]=1[CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:2][CH2:3][CH3:4].Cl.C([N:36]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([NH2:36])=[O:18])[CH:14]=2)[C:9](=[O:19])[N:8]([CH2:20][CH:21]2[CH2:23][CH2:22]2)[C:7]=1[CH2:24][NH:25][C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC2CC2)c(=O)c2ccc(C(=O)O)cc12
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC2CC2)c(=O)c2ccc(C(N)=O)cc12
Yield: 92.4 %

Procedure:
A solution 4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-cyclopropylmethyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylic acid (0.89 g, 2 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.77 g, 4 mmol) and 1-hydroxybenzotriazole ammonium salt (0.61 g, 4 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-cyclopropylmethyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide (0.82 g, 93.2%) as crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[CH:15][CH:14]=[C:13]2[CH2:17][OH:18])=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:26]([Si:30](Cl)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH3:29])([CH3:28])[CH3:27]>ClCCl.CN(C)C1C=CN=CC=1>[Si:30]([O:18][CH2:17][C:13]1[N:12]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[CH:16]=[CH:15][CH:14]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(=O)c1ccc(-n2cccc2CO)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(-n2cccc2CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Temperature: 5 °C

Procedure:
To a solution of 1-(4-ethoxycarbonylphenyl)-2-hydroxymethylpyrrole (8.97 g) in dichloromethane (90 ml) was added triethylamine (12.1 ml), 4-dimethylaminopyridine (100 mg) and tert-butylchlorodiphenylsilane (10.6 ml) in that order at 5° C. under nitrogen atmosphere. After stirring for half an hour at 5° C., the mixture was allowed to warm to ambient temperature and stirred for 13.5 hours. The mixture was washed with water and brine, dried, concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution by ethyl acetate/n-hexane=1/7) to yield 2-tert-butyldiphenylsilyloxymethyl-1-(4-ethoxycarbonylphenyl)pyrrole (18.67 g) as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]3[C:15](=[CH:16][CH:17]=1)[C:14]([CH2:18][CH3:19])=[C:13]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:22][CH:21]=1)[C:12]3=[C:34]([CH2:36][O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]Cl)[CH:35]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[NH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1.C(O)C>CN(C)C=O.O>[CH2:1]([O:8][C:9]1[C:10]2[N:11]3[C:15](=[CH:16][CH:17]=1)[C:14]([CH2:18][CH3:19])=[C:13]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:22][CH:21]=1)[C:12]3=[C:34]([CH2:36][O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][N:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1)[CH:35]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2c(COCCCCCCl)cc3c(OCc4ccccc4)ccc1n32
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2c(COCCCCCN3CCCCC3)cc3c(OCc4ccccc4)ccc1n32
Reaction time: 120 h
Yield: 36.4 %

Procedure:
5-Benzyloxy-2-(4-benzyloxyphenyl)-3-((5-chloropentyloxy)methyl)-1-ethylpyrrolo[2,1,5-cd ]indolizine (0.41 g, 0.69 mmol) was dissolved in 50 ml of dry dimethylformamide under a nitrogen atmosphere. Sodium hydride (60% in oil) (0.40 g, 10 mmol) and piperidine (0.93 g, 11mmol) was added, and the mixture was stirred at 60° for 5 days. Ethanol (10 ml) was added dropwise, and the reaction mixture was diluted with 200 ml of water. The organic material was extracted into ethyl acetate (3×100 ml), and the combined organic layers were washed with brine and dried over sodium sulfate. The solvent was evaporated and the crude produce was purified by column chromatography over silica gel 60, using 10% of methanol in dichloromethane as the eluent. Fractions containing the product were collected and crystallised from diethyl ether and dichloromethane to afford 161 mg (36%) of 5-benzyloxy-2-(4-benzyloxyphenyl)-1-ethyl-3-((5-piperidinopentyloxy)methyl)pyrrolo[2,1,5-cd ]indolizine as yellow crystals. M.p. 106-107° C. MS(SP): m/z 627 (M+1). 1H-NMR (DMSO-d6, 300 MHz) δ: 1.16-1.75 (m, 15H); 2.61-2.95 (m, 4H); 3.07 (q, 2H); 3.21-3.24 (m, 4H); 4.71 (s, 2H); 5.20 (s, 2H); 5.56 (s, 2,H); 7.30-7.64 (m, 14H); 7.99 (d, 1H).
Reaction SMILES: [CH3:1][N:2]([C:4]1[N:14]=[CH:13][C:7]2[N:8]=[CH:9][NH:10][C:11](=O)[C:6]=2[CH:5]=1)[CH3:3].P(Cl)(Cl)([Cl:17])=O>C(N(CC)CC)C>[Cl:17][C:11]1[C:6]2[CH:5]=[C:4]([N:2]([CH3:3])[CH3:1])[N:14]=[CH:13][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)c1cc2c(=O)[nH]cnc2cn1
Solvent: CCN(CC)CC
Product: CN(C)c1cc2c(Cl)ncnc2cn1
Yield: 33 %

Procedure:
6-(N,N-Dimethylamino)-3H-pyrido[3,4-d]pyrimidin-4-one (1.0 g, 5.25 mmol) was heated at reflux with phosphorous oxychloride (8.5 ml) and triethylamine (5.3 ml) for 3 hours. The mixture was concentrated in vacuo, azeotroping with toluene twice. The residue was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate (8%), the layers separated, and the aqueous extracted once more with ethyl acetate. The combined organics were washed with water and brine, dried (sodium sulphate), and concentrated in vacuo. The residue was triturated with hexane to give the product as a solid (0.36 g, 33%).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][CH2:20][CH2:21][O:22][CH3:23]>C(#N)C>[CH3:23][O:22][CH2:21][CH2:20][CH2:19][N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1
Reactant: COCCCBr
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C1CCN(CCCOC)CC1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
To a stirred solution of ethyl isonipecotate (22.0 grams, 140 mmol) in acetonitrile (250 mL) at room temperature was added cesium carbonate (97 grams, 298 mmol) followed by 1-bromo-3-methoxypropane (20 mL, 154 mmol) and the reaction mixture was heated to reflux for 4 hours. The reaction mixture was cooled to room temperature and filtered through a small pad of celite. The volatiles were removed under reduced pressure to obtain ethyl 1-(3-methoxy propyl)piperidin-4-carboxylate (31.0 grams).
Reaction SMILES: [CH:1]1([CH2:6][C:7]([NH:9][C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][CH2:16][C:17]3=[O:20])=[CH:12][CH:11]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:21]Br.C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>Cl.C(Cl)Cl>[Br:21][CH:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][C:10]([NH:9][C:7](=[O:8])[CH2:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:11][CH:12]=2)[C:17]1=[O:20]
Reactant: O=C(CC1CCCC1)Nc1ccc2c(c1)C(=O)CCC2
Reactant: BrBr
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(CC1CCCC1)Nc1ccc2c(c1)C(=O)C(Br)CC2
Reaction time: 3 h
Yield: 95 %

Procedure:
To a mixture of 7-cyclopentylacetamido-1-tetralone (1.02 g) in ethereal HCl (0.2 ml) and methylene chloride (20 ml) was added a solution of bromine (0.19 ml) in a mixture of ethereal HCl (10 drops) and carbon tetrachloride (1 ml). The reaction was stirred for 3 h and ethyl acetate (60 ml) was added. The mixture was washed (saturated sodium bicarbonate, water, brine), dried (MgSO4), and evaporated. The residue was recrystallized from methylene chloride and petroleum ether to give 2-bromo-7-cyclopentylacetamido-1-tetralone (1.23 g, 95%) as a colorless solid; mp 162.5°-164.0° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][N:14]([CH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1)[C@H:15]1[CH2:20][CH2:19][C@H:18]([N:21]2[C:26](=[O:27])[C:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=4)=[CH:31][CH:30]=3)=[C:24]([CH2:43][CH2:44][CH3:45])[N:23]3[N:46]=[CH:47][N:48]=[C:22]23)[CH2:17][CH2:16]1>O.C(OCC)(=O)C>[CH3:13][N:14]([CH:49]1[CH2:50][CH2:51][O:52][CH2:53][CH2:54]1)[C@H:15]1[CH2:16][CH2:17][C@H:18]([N:21]2[C:26](=[O:27])[C:25]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[C:41]4[NH:3][C:4](=[O:7])[O:5][N:42]=4)=[CH:33][CH:34]=3)=[C:24]([CH2:43][CH2:44][CH3:45])[N:23]3[N:46]=[CH:47][N:48]=[C:22]23)[CH2:19][CH2:20]1
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](N(C)C3CCOCC3)CC2)c2ncnn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](N(C)C3CCOCC3)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.24 g), sodium hydrogen carbonate (0.40 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C. for 30 min, 4′-[(4-{trans-4-[methyl(tetrahydro-2H-pyran-4-yl)amino]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.13 g) was added, and the mixture was stirred at 90° C. for 16 hr. Hydroxylammonium chloride (0.24 g) and sodium hydrogen carbonate (0.40 g) were added, and the mixture was further stirred at 90° C. for 6 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.046 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.043 mL) were added, and the mixture was stirred at room temperature for 20 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 7 with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.044 g, 29%).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([CH:14]3[CH2:17][N:16]([C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[CH2:15]3)=[N:12][CH:11]=[CH:10][N:9]=2)[CH2:4]1.N1C=CC=CC=1.N1(C2C=CN=CC=2)CCCC1.[C:45](Cl)(=[O:48])[O:46][CH3:47]>C(Cl)Cl>[CH3:1][N:2]([CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([CH:14]3[CH2:17][N:16]([C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[CH2:15]3)=[N:12][CH:11]=[CH:10][N:9]=2)[CH2:4]1)[C:45](=[O:48])[O:46][CH3:47]
Reactant: COC(=O)Cl
Reactant: CNC1CCN(c2nccnc2C2CN(c3ccc4ccccc4n3)C2)C1
Agent: c1cc(N2CCCC2)ccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)N(C)C1CCN(c2nccnc2C2CN(c3ccc4ccccc4n3)C2)C1
Reaction time: 2 h
Yield: 26.4 %

Procedure:
14 Mar. 2011 To a round bottomed flask was added N-methyl-1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-amine (0.0999 g, 0.277 mmol), pyridine (0.045 ml, 0.554 mmol), and 4-(pyrrolidin-1-yl)pyridine (0.041 g, 0.277 mmol) to stir at RT in DCM (0.924 ml). Methyl carbonochloridate (0.027 ml, 0.416 mmol) was added and allowed to stir for 2 h. Solvent was evaporated and the crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage 50 g SNAP HP-silica column, eluting with a gradient of 1% to 4% MeOH in CH2Cl2, to provide methyl methyl(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate (0.0307 g, 0.073 mmol, 26.5% yield).