Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH3:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[CH:21]=O)[CH3:2].[NH2:23][C:24]1[C:25]([C:38]([NH2:40])=[O:39])=[N:26][N:27]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[C:28]=1[CH2:29][CH3:30]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[N:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH3:20])[CH2:15][CH2:14]2)(=[O:11])=[O:12])=[CH:6][C:5]=1[CH:21]1[NH:23][C:24]2=[C:28]([CH2:29][CH3:30])[N:27]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[N:26]=[C:25]2[C:38](=[O:39])[NH:40]1)[CH3:2]
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C=O
Reactant: CCc1c(N)c(C(N)=O)nn1Cc1ccccn1
Solvent: Cc1ccccc1
Product: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C1NC(=O)c2nn(Cc3ccccn3)c(CC)c2N1
Yield: 51.5 %

Procedure:
A solution of 1-(6-ethoxy-5-formyl-3-pyridylsulfonyl)-4-ethylpiperazine(1.1 g, 4.9 mmol, from step (a) above) and 4-amino-5-ethyl-1-(2-pyridylmethyl)-1H-pyrazole-3-carboxamide (1.2 g, 4.9 mmol) in toluene (10 mL) was heated to reflux for 4 hours and the solution was concentrated under vacuum. The resulting product was recrystallised from ethyl acetate to give a pale brown solid (1.4 g, 52%).
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].I[C:8]1[CH:21]=[CH:20][C:11]([O:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=1>N1CCCCC1.[Cu]I>[CH3:4][Si:3]([C:1]#[C:2][C:8]1[CH:21]=[CH:20][C:11]([O:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=1)([CH3:6])[CH3:5]
Reactant: Ic1ccc(OCCN2CCCC2)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: C1CCNCC1
Product: C[Si](C)(C)C#Cc1ccc(OCCN2CCCC2)cc1
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere 7.0 mL (49.5 mmol) ethynyl-trimethyl-silane is slowly added to a mixture of 14.3 g (45 mmol) 1-[2-(4-iodo-phenoxy)-ethyl]-pyrrolidine, 1.04 g (0.9 mmol) tetrakis-triphenylphosphane-palladium and 171 mg (0.4 mmol) CuI in 140 mL piperidine (exothermic reaction) and stirred for 30 minutes. The solvent is distilled off i.vac., the residue is taken up in water, exhaustively extracted with EtOAc and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified on silica gel (EtOAc/MeOH/NH3 95:5:0.5).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:23])[CH2:4][CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:18])=[C:14]([CH3:17])[CH:15]=2)[N:10]=[C:9]([C:19]([OH:21])=O)[C:8]1=[O:22].[NH2:24][C:25]1[NH:29][N:28]=[N:27][N:26]=1>CN(C)C=O>[ClH:1].[CH3:23][N:3]([CH3:2])[CH2:4][CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:18])=[C:14]([CH3:17])[CH:15]=2)[N:10]=[C:9]([C:19]([NH:24][C:25]2[NH:29][N:28]=[N:27][N:26]=2)=[O:21])[C:8]1=[O:22]
Reactant: Cc1cc2nc(C(=O)O)c(=O)n(CCCN(C)C)c2cc1C
Reactant: Nc1nnn[nH]1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc2nc(C(=O)Nc3nnn[nH]3)c(=O)n(CCCN(C)C)c2cc1C
Reaction time: 1 h

Procedure:
4-(3-Dimethylaminopropyl)-3,4-dihydro-6,7-dimethyl-3-oxo-2-quinoxalinecarboxylic acid, hydrochloride (Example 18b) (0.26 g) and N,N'-carbonyldiimidazole (0.14 g) in dimethylformamide (5 ml) were heated at 100° for 5.5 hours. 5-Amino-1H-tetrazole (0.78 g) was added and heating at 100° was continued for 1 hour. The solid was collected and dissolved in hot aqueous dimethylaminoethanol (8 ml) (5%) and the solution was acidified with 2N hydrochloric acid. The solid that crystallised as the solution cooled was collected and dried. It had m.p. 280°-283° (d) (14%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:15]([NH:16][C:17](=[O:28])[C:18]([C:22]3[N:23]=[C:24]([NH2:27])[S:25][CH:26]=3)=[N:19][O:20][CH3:21])[C:14](=[O:29])[N:9]2[C:10]=1[C:11]([OH:13])=[O:12])=[N+:2]=[N-:3].C([O-])(=O)C.[Na+:34].C(O)C>CO>[N:1]([CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:15]([NH:16][C:17](=[O:28])[C:18]([C:22]3[N:23]=[C:24]([NH2:27])[S:25][CH:26]=3)=[N:19][O:20][CH3:21])[C:14](=[O:29])[N:9]2[C:10]=1[C:11]([O-:13])=[O:12])=[N+:2]=[N-:3].[Na+:34]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CN=[N+]=[N-])CS[C@H]12)c1csc(N)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(CN=[N+]=[N-])CS[C@H]12)c1csc(N)n1

Procedure:
A mixture of the product of Example 3 and 5 ml of a molar solution of sodium acetate in methanol was stirred and was vacuum filtered to recover a brown solid. The fltrate was added to 1 ml of ethanol and was vacuum filtered to remove a second insoluble. The solid phases were added to 5 ml of ethanol and the mixture was vacuum filtered. The filtrate was evaporated to dryness and the residue was taken up in a little ethanol to obtain a second crop which was added to 2 ml of methanol. 5 ml of ethanol were added thereto and the mixture was vacuum filtered. The filtrate was evaporated to dryness and the residue was triturated with a little absolute ethanol to obtain 0.4 g of the syn isomer of sodium 3-azidomethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylate.
Reaction SMILES: CN(N=O)C(N[C@H:6]1[CH:11]([OH:12])[O:10][C@H:9]([CH2:13][OH:14])[C@@H:8]([OH:15])[C@@H:7]1[OH:16])=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:22]>>[O:14]=[CH:13][C@@H:9]([C@H:8]([C@@H:7]([C@@H:6]([CH2:11][OH:12])[OH:22])[OH:16])[OH:15])[OH:10]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CN(N=O)C(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 16 h

Procedure:
SD/IGS rats at 7 weeks of age (male, Charles River Laboratories Japan Inc.) were fasted for about 16 hours and then injected with 50 mg/kg streptozotocin (STZ) via the tail vein under ether anesthesia to prepare diabetic model rats. Similarly, another group of SD/IGS rats was injected with 1.25 mmol/L citric acid in physiological saline (1 mL/kg) via the tail vein under ether anesthesia to prepare normal control rats. At one week (8 weeks of age) after injection of STZ or 1.25 mmol/L citric acid in physiological saline, the rats were provided for an oral glucose tolerance test.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([CH3:30])[CH:24]=[CH:23][CH:22]=[C:21](/[CH:25]=[CH:26]/[C:27](O)=[O:28])[CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:27](=[O:28])/[CH:26]=[CH:25]/[C:21]3[CH:20]=[C:19]([CH3:30])[CH:24]=[CH:23][CH:22]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1cccc(/C=C/C(=O)O)c1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)/C=C/c3cccc(C)c3)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and (E)-3-m-tolyl-acrylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(Cl)Cl>CCCCCC.[O-2].[O-2].[Mn+4]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][CH:15]=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=CCO)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(=CC=O)CC1
Reaction time: 10 h
Yield: 88.8 %

Procedure:
To a solution of 4-(2-hydroxyethylidene)piperidine-1-carboxylic acid t-butyl ester (10.4 g, 46 mmol) in a mixture of hexane (300 mL)-chloroform (100 mL) was added manganese dioxide (100 g), and stirred for 10 hours. After the reaction was completed, insoluble materials were filtered off through Celite and the filtrate was concentrated under a reduced pressure to obtain 9.2 g (yield 89%) of 4-(2-oxoethylidene)piperidine-1-carboxylic acid t-butyl ester (VII-18, 20, 21, 24, 30, 41, 42, 43, 44, 45).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=1>O>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)=[N:24][CH:25]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(-c2ccc(Cl)cn2)cc(OC)c1OC
Temperature: 100 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
Under argon, 3,4,5-trimethoxyphenylboronic acid (5.05 g, 24.0 mmol), dichloro[1,2-bis(diphenylphosphino)ethane]palladium (574.0 mg, 1.00 mmol) and a 2.0 M aqueous sodium carbonate (20 mL, 40 mmol) were added to a solution of 2,5-dichioropyridine (2.95 g, 20.0 mmol) in ethanol-toluene (1:5, 54.0 mL). After stirring at 100° C. for 3 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford the title compound as a colorless crystalline powder (melting point: 61.0-63.0° C.)(4.13 g, yield 73%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[NH2:45]>>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:45][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=3)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccn1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Cl)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccccn4)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1

Procedure:
A solution of the product from Example 43D and Pyridin-2-ylamine was reacted to provide 4-(4-Benzyloxy-phenoxy)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-N-pyridin-2-yl-benzamide using the procedure from Example 43E. The material was then deprotected using the procedure from Example 43F to provide the crude title compound which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (5 mg, 10%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J=6.99 Hz, 6 H) 3.28 (m, 1 H) 6.78 (m, 2 H) 6.87 (d, J=8.82 Hz, 1 H) 6.94 (m, 2 H)7.18 (dd, J=7.35, 4.78 Hz, 1 H) 7.88 (m, 2 H) 8.09 (dd, J=8.46, 2.21 Hz, 1 H) 8.17 (d, J=8.46 Hz, 1 H) 8.22 (d, J=2.21 Hz, 1 H) 8.38 (d, J=2.94 Hz, 1 H) 8.94 (s, 1 H) 9.03 (d, J=8.82 Hz, 1 H) 9.48 (s, 1 H) 10.80 (s, 1 H) 11.61 (s, 1 H); MS (ESI+) m/z 493 (M+H)+.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[S:6]1[C:10]([CH2:11][C:12]2[O:16][C:15]([CH3:17])=[C:14]([CH3:18])[CH:13]=2)=[CH:9][C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]1=2.[C:23](Cl)(=O)[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1>C(=S)=S>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]2[C:9]3[C:8]4[C:7](=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:6][C:10]=3[CH:11]=[C:12]3[O:16][C:15]([CH3:17])=[C:14]([CH3:18])[C:13]=23)=[CH:25][CH:26]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Cc1cc(Cc2cc3ccccc3s2)oc1C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: S=C=S
Product: COc1ccc(-c2c3c(C)c(C)oc3cc3sc4ccccc4c23)cc1
Temperature: 0 °C
Yield: 18.8 %

Procedure:
Tin tetrachloride (7.6 mL, 65.2 mmol) was added dropwise to a -78° C., stirred solution of benzo[b]thiophen-2-yl-(2,3-dimethyl-furan-5-yl)-methane (3.96 g, 16.3 mmol) and anisoyl chloride (3.07 g, 17.93 mL) in carbon disulfide (100 mL) under a try N2 atmosphere over a period of 30 min. After the addition completed, the solution was allowed to warm to 0° C. After 9 h. the reaction mixture was carefully quenched with and further diluted with water (350 mL). Aqueous mixture was extracted with ethyl ether. The ethyl ether extracts were washed with water, 10% aqueous sodium bicarbonate and water and dried with brine. Silica gel (90 mL) was added. Solvents were removed and the silica adsorbate was flash chromatographed (eluent 99:1 petroleum ether:ethyl acetate) to provide the title compound as a light yellow solid (1.1 g, 25%): NMR (CDCl3); δ7.81 (s, 1H), 7.76 (d, J=8, Hz, 1H), 7.36-7.24 (m, 3H), 7.11-7.00 (m, 3H), 6.85 (d, J=8 Hz, 1H), 3.96 (s, 3H), 2.37 (s, 3H), 1.55 (s, 3H); MS (EI): [M+], 358.
Reaction SMILES: [CH2:1]([N:5]1[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([N+:18]([O-])=O)[CH:10]=2)[CH:2]([CH3:4])[CH3:3].CO.[H][H]>[Pd].C(OCC)(=O)C>[CH2:1]([N:5]1[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([NH2:18])[CH:10]=2)[CH:2]([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)Cn1c2c(c3cc([N+](=O)[O-])ccc31)CCCC2
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)Cn1c2c(c3cc(N)ccc31)CCCC2
Yield: 92.2 %

Procedure:
A solution of the compound obtained in Step 1 (290 mg, 1.06 mmol) and 10% palladium on carbon (50% wet, 10 mg, 0.09 mmol) in a mixed solvent of methanol (4 mL) and ethyl acetate (4 mL) was stirred at room temperature for 14 hr under 1 atm of hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give 9-isobutyl-2,3,4,9-tetrahydro-1H-carbazol-6-amine (237 mg, 0.977 mmol, 92%) as a brown oil.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[N:12]=[CH:11][N:10]=[C:9]2[N:13]([C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:19]#[N:20])[N:14]=[CH:15][C:8]=12>>[Cl:3][C:7]1[N:12]=[CH:11][N:10]=[C:9]2[N:13]([C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:19]#[N:20])[N:14]=[CH:15][C:8]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(C#N)cc1-n1ncc2c(O)ncnc21
Product: Cc1ccc(C#N)cc1-n1ncc2c(Cl)ncnc21
Temperature: 100 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
Phosphorus oxychloride (8.90 mL, 95.52 mmol) was added to 3-(4-hydroxy-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-4-methylbenzonitrile (Intermediate AM3) (1.2 g, 4.78 mmol). The resulting solution was stirred at 100° C. for 4 hours. The reaction mixture was evaporated and then azetroped with toluene to remove any residual POCl3. Ice/water was added and the formed precipitate was filtered washing well with water and dried overnight in vacuo over P2O5 to afford 3-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-4-methylbenzonitrile (1.16 g, 90%). 1H NMR (400 MHz, DMSO) 2.21 (3H, s), 7.73 (1H, d), 7.97-8.00 (1H, m), 8.06 (1H, d), 8.81 (1H, s), 8.91 (1H, s); HPLC tR=2.05 min.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1/[CH:15]=[CH:16]/[CH:17]=[CH:18]/[CH:19]([OH:28])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])C.[OH-].[Na+].S(=O)(=O)(O)O.C(OCC)(=O)C>CO>[OH:28][CH:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])/[CH:18]=[CH:17]/[CH:16]=[CH:15]/[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:29])=[O:3]
Reactant: CCCCCCCCC(O)/C=C/C=C/c1ccccc1OCCCC(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCCCC(O)/C=C/C=C/c1ccccc1OCCCC(=O)O
Yield: 64.5 %

Procedure:
A solution of 130 mg of 4-[2-[(1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl]-phenoxy]butyric acid ethyl ester in 10 ml of methanol and 2.5 ml of 0.5 n sodium hydroxide solution is stirred under argon atmosphere for 3 hours at room temperature. The reaction mixture is poured on ice water, acidified to pH 5 with 0.5 n sulfuric acid and shaken out with ethyl acetate. The organic phase is dried, concentrated by evaporation and the residue is chromatographed on silica gel with n-hexane/diethyl ether=7/3. 78 mg of the title compound is obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.[OH-].[NH4+:17]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([NH2:17])=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C(Cl)N1CC(Oc2ccc(Cl)cc2)C1
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)N1CC(Oc2ccc(Cl)cc2)C1
Reaction time: 18 h
Yield: 52.9 %

Procedure:
A solution of 5 g (0.02 mole) of 3-(4-chlorophenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was stirred while 4 ml (0.06 mole) of 57% ammonium hydroxide was added all at once. After stirring for 18 hr, the reaction mixture was diluted with 200 ml of water and the solid which separated was collected by filtration, 10.5 g. Recrystallization from isopropanol yielded 2.4 g (52.9%) of gray crystalline powder, m.p. 187°-188° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].CS(O[CH2:40][CH:41]=[C:42]1[CH2:51][CH2:50][C:45]2([O:49][CH2:48][CH2:47][O:46]2)[CH2:44][CH2:43]1)(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:40][CH:41]=[C:42]3[CH2:51][CH2:50][C:45]4([O:46][CH2:47][CH2:48][O:49]4)[CH2:44][CH2:43]3)[N:9]=2)[CH:7]=1
Reactant: CS(=O)(=O)OCC=C1CCC2(CC1)OCCO2
Reactant: O=C(Nc1c[nH]nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Nc1cn(CC=C2CCC3(CC2)OCCO3)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.1 %

Procedure:
To a solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (1.50 g, 3.71 mmol) in N,N-dimethylformamide (120 mL) was added Cs2CO3 (3.62 g, 11.11 mmol) and 2-[1,4-dioxaspiro[4.5]decan-8-ylidene]ethyl methanesulfonate (1.94 g, 7.39 mmol) at room temperature. The resulting solution was stirred for 4 h at room temperature and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/petroleum ether (3/2) to give 1.59 g (75%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[1,4-dioxaspiro[4.5]decan-8-ylidene]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow solid. LCMS (Method 31) [M+H]+=571.4, RT=1.21 min.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)(=[O:8])[CH3:7].O>ClCCl>[C:6]([N:9]1[CH2:10][CH2:11][CH:12]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:20][CH:21]=2)[CH2:13][CH2:14]1)(=[O:8])[CH3:7]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)N1CCC(Cc2ccccc2)CC1
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCC(Cc2ccc(S(=O)(=O)Cl)cc2)CC1

Procedure:
To chlorosulfonic acid (92 mL), a solution of 1-acetyl-4-benzylpiperidine (60.00 g) in dichloromethane (100 mL) was dropwise added for an hour at 0° C. under stirring, and the mixture was stirred at 0° C. for 30 minutes and at room temperature for 1.5 hours. The reaction mixture was poured into ice-cooled water (1 L) and extracted with dichloromethane (500 mL, 250 mL). The organic phase was washed with an aqueous solution of 5% sodium carbonate (500 mL×2) and saturated brine (250 mL). The organic phase was dried over magnesium sulfate (anhydrous), and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel 250 g, ethyl acetate). The objective fraction was concentrated under reduced pressure to give the title compound as a white solid (54.22 g).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([N:19]([CH3:21])[CH3:20])=[CH:16][CH:17]=3)[C:11](=[O:12])[O:10]2)=[CH:5][CH:4]=1.[CH3:23][N:24]([CH3:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:28]2[CH:29]=[CH:30][C:25]([N:24]([CH3:31])[CH3:23])=[CH:26][CH:27]=2)[C:18]2[CH:17]=[CH:16][C:15]([N:19]([CH3:21])[CH3:20])=[CH:14][C:13]=2[C:11]([OH:10])=[O:12])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccccc1
Reactant: CN(C)c1ccc(C2OC(=O)c3cc(N(C)C)ccc32)cc1
Product: CN(C)c1ccc(C(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2C(=O)O)cc1

Procedure:
In a second synthetic route to CVL, which is also a multi-step synthesis, 4-dimethylaminobenzaldehyde is reacted with 3-dimethylaminobenzoic acid to obtain 3-(4-dimethylaminophenyl)-6-dimethylaminophthalide in the first step. In a second step, the 3-(4-dimethylaminophenyl)-6-dimethylaminophthalide from step one is interacted with N,N-dimethylaniline in the presence of a Friedel-Crafts type catalyst to obtain 2-[bis(4-dimethylaminophenyl)methyl]-5-dimethylaminobenzoic acid. In a third step, the benzoic acid from step two is oxidized to obtain 3,3-bis(4-dimethylaminophenyl)-6-dimethylaminophthalide.
Reaction SMILES: [OH:1][P:2]([CH2:5][N:6]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10][N:9]([CH2:15][P:16]([OH:19])([OH:18])=[O:17])[CH2:8][CH2:7]1)([OH:4])=[O:3].Cl[CH2:21][C:22]([OH:24])=[O:23].[OH-].[Na+].Cl>O>[C:22]([CH2:21][N:12]1[CH2:13][CH2:14][N:6]([CH2:5][P:2]([OH:4])([OH:1])=[O:3])[CH2:7][CH2:8][N:9]([CH2:15][P:16]([OH:18])([OH:19])=[O:17])[CH2:10][CH2:11]1)([OH:24])=[O:23]
Reactant: O=C(O)CCl
Reactant: O=P(O)(O)CN1CCNCCN(CP(=O)(O)O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CN1CCN(CP(=O)(O)O)CCN(CP(=O)(O)O)CC1
Temperature: 80 °C

Procedure:
To a solution of 0.25 millimoles of N,N'-bis(dihydroxyphosphorylmethyl)-1,4,7-triazacyclononane in water were added 0.3 millimoles of chloroacetic acid, and the pH was adjusted to 9.0 by dropwise, addition of NaOH. The mixture was then heated to 80° C. and held at that temperature overnight. Hydrochloric acid was then added to a pH of 1.5, and the water was evaporated. The solids were then triturated with ether followed by ethanol to remove contaminants, and the remaining solid product was identified by proton NMR as N-carboxymethyl-N',N"-bis(dihydroxyphosphorylmethyl)-1,4,7-triazacyclononane.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:18])[CH2:7][CH:8]([C:12]2[CH2:13][O:14][CH2:15][CH2:16][CH:17]=2)[CH2:9][C:10]=1[OH:11])(=[O:4])[CH2:2][CH3:3].ClC1C=CC=C(C(OO)=[O:27])C=1>ClCCl>[C:1]([C:5]1[C:10](=[O:11])[CH2:9][CH:8]([C:12]23[O:27][CH:17]2[CH2:16][CH2:15][O:14][CH2:13]3)[CH2:7][C:6]=1[OH:18])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)C1=C(O)CC(C2=CCCOC2)CC1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCC(=O)C1=C(O)CC(C23COCCC2O3)CC1=O

Procedure:
14.8 parts by weight of 2-propionyl-5-(5,6-dihydro-2H-pyran-3-yl)-3-hydroxy-2-cyclohexen-1-one are dissolved in 100 parts by volume of dichloromethane, and m-chloroperbenzoic acid is added at room temperature, and the reaction is monitored by means of thin layer chromatography. After the reaction has ended, the precipitated m-chlorobenzoic acid is filtered off, the filtrate is washed twice with semiconcentrated sodium bicarbonate solution and water and dried over sodium sulfate, and the solvent is distilled off under reduced pressure to leave 2-propionyl-5-(3,4-epoxy-tetrahydropyran-3-yl)-3-hydroxy-2-cyclohexen-1-one (compound No. 30).