Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([Si](C)(C)C)[CH3:3].[F:8][C:9]([P:15]([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])(=[O:17])[O-:16])([F:14])[C:10]([F:13])([F:12])[F:11].[CH3:25][N:26]([C+:28]([N:30]([CH3:32])[CH3:31])Cl)[CH3:27]>C(Cl)(Cl)Cl>[F:14][C:9]([P:15]([C:18]([F:23])([F:24])[C:19]([F:22])([F:21])[F:20])(=[O:16])[O-:17])([F:8])[C:10]([F:13])([F:12])[F:11].[CH3:1][N:2]([CH3:3])[C:28](=[N+:26]([CH3:27])[CH3:25])[N:30]([CH3:32])[CH3:31]
Reactant: CN(C)[Si](C)(C)C
Reactant: CN(C)[C+](Cl)N(C)C
Agent: O=P([O-])(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CN(C)C(N(C)C)=[N+](C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20 ml of dry chloroform and 1.85 g (15.78 mmol) of N,N-dimethyltrimethylsilylamine are added to 6.23 g (14.27 mmol) of bis(dimethylamino)chlorocarbenium bis(pentafluoroethyl)phosphinate. The reaction mixture is stirred for 1 hour at room temperature, and all volatile products are removed under reduced pressure. The residue is subsequently dried at 7.0 Pa and an oil-bath temperature of 50° C. for 1 hour, giving 6.29 g of hexamethylguanidinium bis(pentafluoroethyl)phosphinate, corresponding to a yield of 99%.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([O:14]C)[C:8]=2[N:7]=[C:6]1[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[F:23].Br>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.C(O)(=O)C>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([OH:14])[C:8]=2[N:7]=[C:6]1[C:16]1[C:17]([F:23])=[CH:18][CH:19]=[CH:20][C:21]=1[F:22]
Reactant: COc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Agent: Br
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Solvent: CC(=O)O
Product: Oc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Yield: 85.9 %

Procedure:
To 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-methoxylbenzimidazole (Example 46) (0.30 g, 0.78 mmol) and hexadecyltrimethylammonium bromide (0.30 g) dissolved in acetic acid (9.0 mL) was added HBr (1.0 mL). After refluxing for 7 h, the reaction was concentrated. The residue was then diluted with EtOAc, and washed with NaHCO3 (sat. aq) and NaCl (sat. aq). The combined washing were dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash chromatography eluting with 2% methanol/CH2Cl2 and recrystallization from diethylether, yielding 1-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)-4-hydroxyl-benzimidazole (0.25 g, 0.67 mmol, 86% yield). M.p. 257-259° C. 1H NMR (200 MHz, CD2Cl2): δ 7.57 (m, 1H, H4′), 7.25 (m, 1H, H4″), 7.17 (dd, J=7.9, 8.3 Hz, 1H, H6), 7.12 (m, 2H, H3′,5′), 6.99 (d, J=8.3 Hz, 1H, H7), 6.82 (m, 2H, H3″,5″), 6.73 (dd, J=7.9, 1.0 Hz, H5), 5.35 (s, 2H, CH2PhF2).
Reaction SMILES: [C:1]([Si:5]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[O:6][CH2:7][C:8]([NH:12][C:13]([C:15]1[N:19]2[CH:20]=[CH:21][CH:22]=[C:23]([O:24][CH2:25][C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[C:18]2=[N:17][C:16]=1[CH3:34])=[O:14])([C:10]#[N:11])[CH3:9])([CH3:4])([CH3:3])[CH3:2].C[Sn]([N:51]=[N+:52]=[N-:53])(C)C.Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.CO>[C:1]([Si:5]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[O:6][CH2:7][C:8]([NH:12][C:13]([C:15]1[N:19]2[CH:20]=[CH:21][CH:22]=[C:23]([O:24][CH2:25][C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[C:18]2=[N:17][C:16]=1[CH3:34])=[O:14])([C:10]1[N:51]=[N:52][NH:53][N:11]=1)[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(C)(C#N)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1nn[nH]n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.2 %

Procedure:
To a solution of 300 mg of N-(1-{[tert-butyl (diphenyl)silyl]oxy}-2-cyanopropan-2-yl)-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide in 6 ml of toluene was added 240 mg of trimethyltin azide, followed by stirring for 4 hours under heating to reflux. The reaction mixture was left to be cooled to room temperature, and 10 ml of methanol and 10 ml of 1 M hydrochloric acid were then added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was neutralized by the addition of 1 M sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 292 mg of N-[1-{[tert-butyl (diphenyl)silyl]oxy}-2-(2H-tetrazol-5-yl)propan-2-yl]-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=O)=[CH:4][CH:3]=1.[O-]CC.[Na+].O[NH:18][C:19](=[NH:22])[CH2:20][CH3:21]>C(O)C>[CH2:20]([C:19]1[N:22]=[C:6]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:12][CH:11]=2)[O:8][N:18]=1)[CH3:21]
Reactant: CCC(=N)NO
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCc1noc(-c2ccc(O)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
To a mixture of 29.9 parts of ethyl 4-hydroxybenzoate and 316 parts of ethanol there were added portionwise 35.6 parts of sodiumethoxide. After stirring for 1/2 hour at room temperature, there was added dropwise a solution of 31.7 parts of N-hydroxypropanimidamide in 79 parts of ethanol. Stirring was continued for 1/2 hour at room temperature and overnight at reflux temperature. The reaction mixture was evaporated and the residue was taken up in water. After neutralizing with acetic acid, the precipitate was filtered off and dried. It was purified by column chromatography (HPLC; silica gel; CH2Cl2 /CH3OH 99:1). The eluent of the desired fraction was evaporated and the residue was stirred in petroleumether. The precipitate was filtered off and dried, yielding 7.56 parts (22.1%) of 4-(3-ethyl-1,2,4-oxadiazol-5-yl)phenol; mp. 137.7° C. (interm. 6).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=2)[CH3:12])=[O:9])[CH:5]=[C:4]([CH3:25])[N:3]=1.[F:26][C:27]([F:31])([F:30])[CH2:28][NH2:29]>>[CH3:25][C:4]1[N:3]=[C:2]([NH:29][CH2:28][C:27]([F:31])([F:30])[F:26])[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=2)[CH3:12])=[O:9])[CH:5]=1
Reactant: NCC(F)(F)F
Reactant: Cc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)nc(Cl)n1
Product: Cc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)nc(NCC(F)(F)F)n1
Temperature: 100 °C
Yield: 12 %

Procedure:
A mixture of 2-chloro-6-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carb oxamide (50 mg, 0.13 mmol, Step-1 of Example 536, single enantiomer) and 2,2,2-trifluoroethanamine (3.5 mL) is heated at 100° C. for 4 days in a sealed tube. After cooled to room temperature, the mixture is concentrated and then purified by preparative LC-MS to give 7 mg (12% yield) of the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8](OCC)=[O:9])[C:3]1=[O:13].[OH-].[NH4+:15]>C(#N)C>[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([NH2:15])=[O:9])[C:3]1=[O:13]
Reactant: [NH4+]
Reactant: CCOC(=O)CN1CCC(O)C1=O
Agent: [OH-]
Solvent: CC#N
Product: NC(=O)CN1CCC(O)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.50 g of ethyl (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetate are treated with 11.5 ml of approximately 25% ammonium hydroxide solution, whereupon the mixture is stirred at room temperature for 1 hour. The mixture is treated with acetonitrile and evaporated. The residue is treated five times with acetonitrile and in each case again evaporated. There is obtained (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide which melts at 163°-164° after recrystallization from methanol/diethyl ether (1:2).
Reaction SMILES: [CH:1]1([C@H:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:5]([OH:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH3:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45](OC)OC)=[CH:41][CH:40]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[C:16]([O:15][C:13]([N:12]1[C@@H:4]([CH:1]2[CH2:3][CH2:2]2)[C@H:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[O:11][CH:45]1[C:42]1[CH:43]=[CH:44][C:39]([O:38][CH3:37])=[CH:40][CH:41]=1)=[O:14])([CH3:18])([CH3:17])[CH3:19]
Reactant: COc1ccc(C(OC)OC)cc1
Reactant: CCOC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C1CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1OC(c2ccc(OC)cc2)N(C(=O)OC(C)(C)C)[C@H]1C1CC1
Yield: 53 %

Procedure:
A solution of 2.07 g of ethyl (2R,3S)-3-cyclopropyl-3-tert-butoxycarbonylamino-2-hydroxypropionate and 213 mg of pyridinium p-toluenesulfonate in 125 ml of toluene is refluxed under heating. To the mixture is added dropwise a solution of 2.76 g of p-anisaldehydedimethylacetal in 25 ml of toluene for 20 minutes. The reaction mixture is evaporated to remove the generated methanol. The mixture is stirred under heating for 1.5 hours and cooled. After the reaction mixture is condensed under reduced pressure, ethyl acetate and water are added to the residue. The ethyl acetate layer is obtained by separation. The aqueous layer is extracted with ethyl acetate. The extract is washed with water and brine, dried and condensed under reduced pressure. The residue is purified by silica gel column chromatography (solvent; toluene:ethyl acetate=40:l) to give 1.572 g of ethyl (4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-cyclopropyl-5-oxazolidinecarboxylate (diastereomeric mixture).
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=[C:16]([F:22])[C:17](OCC)=[O:18])[C:7]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:8]=3[O:9][CH2:10][C:4]=2[CH:3]=1.CO.[NH3:27]>C1COCC1>[Br:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=[C:16]([F:22])[C:17]([NH2:27])=[O:18])[C:7]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:8]=3[O:9][CH2:10][C:4]=2[CH:3]=1
Reactant: N
Reactant: CCOC(=O)C(F)=C1c2ccc(Br)cc2COc2cc(F)ccc21
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)C(F)=C1c2ccc(Br)cc2COc2cc(F)ccc21
Temperature: 55 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
[step 2] Ethyl 2-(8-bromo-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)-2-fluoroacetate (1.6 g, 4.05 mmol) obtained in step 1 was dissolved in THF (14 mL), 2 mol/L ammonia methanol solution (20 mL, 40.5 mmol) was added, and the mixture was stirred at 55° C. overnight. The mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1 v/v) to give 2-(8-bromo-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)-2-fluoroacetamide (910 mg, 61%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:16][CH2:15][N:14]([C:17](=[O:22])[CH2:18][N:19]([CH3:21])[CH3:20])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:38]3[O:39][C:40]4[C:46]([CH3:47])=[CH:45][C:44]([CH3:48])=[CH:43][C:41]=4[N:42]=3)=[CH:33][CH:32]=2)O1.NC1N=CN=C2N([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)N=C(C3C=CC(NC4OC5C=CC=CC=5N=4)=C(F)C=3)C=12>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:16][CH2:15][N:14]([C:17](=[O:22])[CH2:18][N:19]([CH3:21])[CH3:20])[CH2:13]3)[N:9]=[C:10]([C:31]3[CH:32]=[CH:33][C:34]([NH:37][C:38]4[O:39][C:40]5[C:46]([CH3:47])=[CH:45][C:44]([CH3:48])=[CH:43][C:41]=5[N:42]=4)=[CH:35][CH:36]=3)[C:3]=12
Reactant: CN(C)CC(=O)N1CCC(n2nc(I)c3c(N)ncnc32)C1
Reactant: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
Agent: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6ccccc6o5)c(F)c4)c4c(N)ncnc43)CC2)CC1
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CCN(C(=O)CN(C)C)C5)c5ncnc(N)c45)cc3)nc2c1

Procedure:
rac-1-[3-(4-Amino-3-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydro-1H-1-pyrrolyl]-2-(dimethylamino)-1-ethanone was prepared from rac-1-[3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydro-1H-1-pyrrolyl]-2-(dimethylamino)-1-ethanone (0.278 g, 0.669 mmol) and N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5,7-dimethyl-1,3-benzoxazol-2-amine (0.305 g, 0.837 mmol) in a manner similar to that used for the preparation of cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-1,3-benzoxazol-2-amine. The compound was formed as a white powder (0.219 g, 62%). 1H NMR (DMSO-d6, 400 MHz) 2.17 (s, 3H), 2.23 (s, 3H), 2.3-2.50 (m, 4H), 2.34 (s, 3H), 2.40 (s, 3H), 2.99-4.26 (m, 4H), 5.44-5.49 (m, 1H), 6.80 (s, 1H), 7.11 (s, 1H), 7.65 (d, 2H), 7.92 (d, 2H), 8.26 (s, 1H), 10.86 (s, 1H); RP-HPLC Rt 10.765 min, 96% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 526 (MH+).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)=[CH:6][CH:5]=1.[C:25](#[N:27])[CH3:26].[H-].[Na+]>CN(C)C=O.O1CCCC1>[O:2]=[C:3]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)=[CH:6][CH:5]=1)[CH2:26][C:25]#[N:27]
Reactant: COC(=O)c1ccc(CCc2cc(OC)c(OC)c(OC)c2)cc1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(CCc2ccc(C(=O)CC#N)cc2)cc(OC)c1OC
Temperature: 65 °C

Procedure:
To a solution of 10 g (30 mmol) of methyl-4-[2-(3,4,5-trimethoxyphenyl)ethyl]benzoate and 1.74 ml (33 mmol) of acetonitrile in a mixture of 30 ml of dry N,N-dimethylformamide and 20 ml of dry tetrahydrofuran was added, portionwise under a nitrogen atmosphere at 0° C., 3 g (76 mmol) of a 60% suspension of sodium hydride in mineral oil. The resulting suspension was heated under a flow of nitrogen to 65° C. and maintained at this temperature for 2 hours. After cooling to 25° C., the resultant mixture was quenched with 3 ml of methanol and the solvent was removed in vacuo. The resultant residue was dissolved in 60 ml of water, acidified with 2N hydrochloric acid to a pH between 4 and 5 and then extracted with ethyl acetate. The combined organic phase was then washed successively with water and saturated sodium chloride solution and dried over magnesium sulfate, after which time the solvent was removed under reduced pressure. The crude product was then purified on silica gel employing a mixture of ethyl acetate and hexane in a 1:1 ratio as the eluent to yield a white crystalline solid.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[N:7]=1.C(N(CC)CC)C.[CH:22]([N:25]([CH:29]([CH3:31])[CH3:30])[C:26](Cl)=[O:27])([CH3:24])[CH3:23]>C1C=CC=CC=1>[CH:22]([N:25]([CH:29]([CH3:31])[CH3:30])[C:26]([N:5]([CH2:4][CH2:3][N:2]([CH3:14])[CH3:1])[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:27])([CH3:24])[CH3:23]
Reactant: CC(C)N(C(=O)Cl)C(C)C
Reactant: Cc1cc(C)nc(NCCN(C)C)c1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(C)nc(N(CCN(C)C)C(=O)N(C(C)C)C(C)C)c1
Yield: 24.1 %

Procedure:
A solution of 5.80 g (30.0 mmoles) of 2-(2-dimethylaminoethylamino)-4,6-dimethylpyridine (from Example 1, B) and 2.20 ml (30.0 mmoles) of triethylamine in 50 ml of benzene is dried by azeotropic distillation. After adding 4.91 g (30.0 mmoles) of diisopropylcarbamoyl chloride, the reaction mixture is heated at reflux for 24 hours. The crude product, after removal of solvent, is chromatographed on silica gel using 5% methanol in chloroform as eluant. Appropriate fractions are combined, the solvent removed and product distilled through a short path still to give 2.32 g (24.1% yield) of N,N-diisopropyl-N'-(2-dimethylaminoethyl)-N'-(4,6-dimethyl-2-pyridyl)urea as a colorless oil boiling at 148°/0.35 mm.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([OH:14])[CH3:13].[OH2:15]>S(=O)(=O)(O)O>[O:14]=[C:12]([CH3:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]#[C:4][CH2:3][C:2]([OH:15])=[O:1]
Reactant: O
Reactant: CC(O)CCCCCCC#CCCO
Agent: O=S(=O)(O)O
Product: CC(=O)CCCCCCC#CCC(=O)O
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a vigorously stirred, ice-cold solution of chromic trioxide (5.4 g, 54 mmol) in 50 mL of 6N sulfuric acid was added dropwise over 3 hr, 1.76 g (8.9 mmol) of 20 in 50 mL of acetone5. The reaction was kept in an ice-bath for 30 min and then warmed to 23° C. before workup. Water (200 mL) was added and the reaction extracted with ether (4×75 mL). The ether extract was washed with brine (3×50 mL). Product isolation yielded crude 11-keto-3-dodecynoic acid (23) which was purified by crystallization from 10% ether in hexane (mp 49°-51° C.) to yield 1.28 g (68% yield).
Reaction SMILES: [CH:1]1[C:10]([OH:11])=[C:6]([CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][C:2]=1C.[C:12](OCC)(=O)C1C(=CC=CC=1)C(OCC)=O>>[CH3:12][C@:6]12[C:10](=[O:11])[CH2:1][C@@H:2]([C:7]1([CH3:8])[CH3:9])[CH2:4][CH2:5]2
Reactant: Cc1ccc(C(C)C)c(O)c1
Reactant: CCOC(=O)c1ccccc1C(=O)OCC
Product: CC1(C)[C@H]2CC[C@@]1(C)C(=O)C2

Procedure:
Thymol--10% in Diethyl Phthalate: 2%
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][N:15]2[C:19](=[O:20])[C:18]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]3[C:16]2=[O:25])[CH2:9]1)C1C=CC=CC=1.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C1(C)C=CC=CC=1>[CH2:30]([O:29][C:27]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][N:15]2[C:16](=[O:25])[C:17]3=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]3[C:19]2=[O:20])[CH2:9]1)=[O:28])[CH3:31]
Reactant: O=C1c2ccccc2C(=O)N1CC1CN(Cc2ccccc2)CCO1
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCOC(CN2C(=O)c3ccccc3C2=O)C1
Reaction time: 1 h
Yield: 97.9 %

Procedure:
To a stirred solution of N-[(4-benzyl-2-morpholinyl)methyl]phthalimide (30.0 g) in toluene (200 ml), ethyl chloroformate (19.4 g) is added dropwise at 60° C., and the mixture is refluxed with stirring for 1 hour. The reaction mixture is washed successively with water and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is recrystallized from isopropyl alcohol-diethyl ether to give N-[(4-ethoxycarbonyl-2-morpholinyl)methyl]phthalimide (27.8 g), mp 113°-115° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C([O-])(O)=O.[Na+].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:26]>CC#N.C1COCC1>[N+:34]([C:31]1[CH:32]=[CH:33][C:28]([O:27][C:25]([NH:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:4][CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:26])=[CH:29][CH:30]=1)([O-:36])=[O:35]
Reactant: CC(C)(C)OC(=O)N[C@H](CN)CC1CCCCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CNC(=O)Oc1ccc([N+](=O)[O-])cc1)CC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
To a stirred solution of (S)-tert-butyl 1-amino-3-cyclohexylpropan-2-ylcarbamate (0.65 g, 2.54 mmol) in MeCN (20 mL) and THF (5 mL) was added powdered NaHCO3 (0.43 g, 5.08 mmol) followed by a solution of p-nitrophenyl chloroformate (0.51 g, 5.08 mmol) in MeCN (20 mL) dropwise over 10 min. The mixture was stirred at rt for 2 h, filtered through a pad of Celite and concentrated to leave a white solid. This material was purified by chromatography on a 40-g silica cartridge eluted with a gradient from 0-100% EtOAc in hexanes to afford (S)-tert-butyl 1-(p-nitrophenoxycarbonylamino)-3-cyclohexylpropan-2-ylcarbamate (0.67 g, 67%) as an off-white solid.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][OH:14])=[O:6])#[N:2].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.N1C=CC=CC=1>C(#N)C>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:14][CH2:13][C@@H:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]2[C:5]([NH:4][CH2:3][C:1]#[N:2])=[O:6])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@H]1CO
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCC[C@H]2C(=O)NCC#N)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To (1R,2R)-N-(cyanomethyl)-2-(hydroxymethyl)cyclohexanecarboxamide (62 mg, 0.31 mmol) in a 4 mL sample vial was added 4-toluenesulfonyl chloride (73 mg, 0.38 mmol), 0.63 mL acetonitrile and pyridine (33 SL, 0.41 mmol). The reaction mixture was stirred at ambient temperature for 5 h after which the solvent was removed on a rotary evaporator. Chromatography of the residue on silica gel with 4:96 methanol:chloroform as eluent provided ((1R,2R)-2-{[(cyanomethyl)amino]carbonyl}cyclohexyl)methyl 4-methylbenzenesulfonate as a colorless, waxy solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][Li])[CH3:3].[O:8]1[CH:18]2[CH:9]1[CH2:10][C:11]1[C:16]([CH2:17]2)=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CCOCC>[CH3:1][N:2]([CH3:3])[CH2:4][CH2:5][CH2:6][C@@H:18]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]1[OH:8]
Reactant: c1ccc2c(c1)CC1OC1C2
Reactant: [Li]CCCN(C)C
Solvent: CCOCC
Solvent: O
Product: CN(C)CCC[C@@H]1Cc2ccccc2C[C@H]1O

Procedure:
to a solution of 0.1 mol of dimethylamino propyllithium in 500 ml of ether cooled to 0°-5° C. is added dropwise a solution of 7.3 g (0.05 mol) of 2,3-epoxy-1,2,3,4-tetrahydronaphthalene in 100 ml of ether. The reaction mixture is then heated under reflux for 2 hours and decomposed with water. The organic layer is separated and dried and the desired 1,2,3,4-tetrahydro-3-(3-dimethylaminopropyl)-2-naphthalenol separated from byproducts by column chromatography on neutral alumina.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[N:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.[S:51]1[CH:55]=[CH:54][N:53]=[C:52]1[NH2:56]>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([N:11]2[N:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[C:8]([NH:56][C:52]2[S:51][CH:55]=[CH:54][N:53]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCC1)n1ncc2ccccc2c1=O
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nccs1)C(CC1CCCC1)n1ncc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
A solution of 3-cyclopentyl-2-(1-oxo-1H-phthalazin-2-yl)-propionic acid (0.31 g, 1.09 mmol) in methylene chloride (6.10 mL, 0.18M) at 25° C. was treated with N,N-diisopropylethylamine (0.57 mL, 3.29 mmol) and N,N,N′,N′-tetramethyl-O—(N-succinimidyl)uronium tetrafluoroborate (0.39 g, 1.31 mmol). The resulting solution was stirred at 25° C. for 2 h. After this time, the reaction was treated with thiazol-2-ylamine (143 mg, 1.42 mmol). The resulting solution was stirred at 25° C. overnight. After this time, the reaction was partitioned between water (100 mL) and methylene chloride (3×75 mL). The combined organics were washed with water (1×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (ISCO, 40 g, 50% ethyl acetate/hexanes) afforded 3-cyclopentyl-2-(1-oxo-1H-phthalazin-2-yl)-N-thiazol-2-yl-propionamide as a white solid (247.7 mg, 61%); ES+-HRMS m/e calcd for C19H20N4O2S [M+H+] 369.1380 found 369.1378. 1H-NMR (300 MHz, DMSO-d6) δ ppm 0.99-1.17 (m, 1H), 1.20-1.80 (m, 8H), 2.04-2.18 (m, 1H), 2.23-2.36 (m, 1H), 5.73 (dd, J=10.4, 4.4 Hz, 1H), 7.22 (d, J=3.4 Hz, 1H), 7.47 (d, J=3.4 Hz, 1H), 7.83-7.93 (m, 1H), 7.94-8.02 (m, 2H), 8.26 (d, J=7.8 Hz, 1H), 8.52 (s, 1H), 12.46 (s, 1H).