Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])=[CH:22][N:21](S(C4C=CC(C)=CC=4)(=O)=O)[C:18]3=[N:19][CH:20]=2)=[CH:11][C:5]=1[C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[C:2]=[O:3].C(N(CC)C(C)C)(C)C.[CH:51]([NH:54][CH2:55][CH:56]1[CH2:60][CH2:59][CH2:58][O:57]1)([CH3:53])[CH3:52]>C(Cl)Cl>[CH:51]([N:54]([CH2:55][CH:56]1[CH2:60][CH2:59][CH2:58][O:57]1)[C:2](=[O:3])[NH:1][C:4]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])=[CH:22][NH:21][C:18]3=[N:19][CH:20]=2)=[CH:11][C:5]=1[C:6]([N:8]([CH3:10])[CH3:9])=[O:7])([CH3:53])[CH3:52]
Reactant: CC(C)NCC1CCCO1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(N=C=O)c(C(=O)N(C)C)c3)cc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1c[nH]c2ncc(-c3ccc(NC(=O)N(CC4CCCO4)C(C)C)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 12.3 %

Procedure:
2-Isocyanato-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide (125 mg, 0.22 mmol), N,N-diisopropylethylamine (0.06 mL, 0.34 mmol), isopropyl-(tetrahydro-furan-2-ylmethyl)-amine (315 mg, 2.2 mmol), and methylene chloride (3 ml) were combined and stirred at room temperature for 18 hours. The reaction was concentrated to dryness in vacuo. The crude material was dissolved in a solution of tetrahydrofuran (4 mL) and methanol (1 mL). To the mixture was added 0.2 mL 50% w/v aqueous potassium hydroxide and the combined mixture stirred for 30 minutes. The reaction was quenched with saturated sodium bicarbonate, and the mixture was extracted with methylene chloride. The organic layer was dried over sodium sulfate and concentrated to dryness in vacuo. The crude material was purified by preparative HPLC to give 15 mg (27 μmol, 12%) of 2-[3-isopropyl-3-(tetrahydro-furan-2-ylmethyl)-ureido]-5-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide. 1H-NMR (250 MHz, CDCl3) δ 11.90 (s, 1H), 8.52 (d, J=2.1 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.72-7.52 (m, 4H), 7.30 (t, J=7.1 Hz, 1H), 7.13 (d, J=7.9 Hz, 1H), 7.05 (t, J=7.4 Hz, 1H); MS: m/z 556.4 (M+H+).
Reaction SMILES: [C:1]([C:3]1[N:7]([CH3:8])[N:6]=[C:5]([CH3:9])[C:4]=1[NH:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])#[N:2].[OH-].[Na+].OO.C(O)(=[O:22])C>O>[CH3:8][N:7]1[C:3]2[C:1]([OH:22])=[N:2][C:11]([CH:12]([CH3:14])[CH3:13])=[N:10][C:4]=2[C:5]([CH3:9])=[N:6]1
Reactant: Cc1nn(C)c(C#N)c1NC(=O)C(C)C
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nn(C)c2c(O)nc(C(C)C)nc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A solution of 24 g (0.176 mol) of 4-amino-5-cyano-1,3-dimethylpyrazole and 28 ml of triethylamine in 200 ml of chloroform is treated dropwise with 19.3 g (0.18 mol) of isobutyryl chloride and stirred overnight. The mixture is stirred with 100 ml of saturated sodium bicarbonate solution, the organic layer is separated and evaporated in vacuo. The residue is crystallized from ethyl acetate to give 30 g (83%) of N-(5-cyano-1,3-dimethylpyrazol-4-yl)isobutyramide. This amide (30 g, 0.0146, mol) is added in portions to a solution of 7.1 g (0.017 mol) sodium hydroxide in 250 ml of water containing 36 ml of 30% hydrogen peroxide at 80° C. After stirring at 80° C. overnight, the solution is cooled and acidified with glacial acetic acid to give 23 g (74%) of 1,3-dimethyl-5-isopropyl-1H-pyrazolo[4,3-d]pyrimidin-7-ol, mp 264°-266° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N:15]1[C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][C:17]([O:25][CH2:26][C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[N:16]1.[OH-].[K+].Cl>C(O)C.O>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:13])([F:12])[F:14])=[CH:4][C:3]=1[N:15]1[C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]([O:25][CH2:26][C:27]([F:32])([F:33])[C:28]([F:29])([F:30])[F:31])=[N:16]1
Reactant: CCOC(=O)c1cc(OCC(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)cc2C(=O)O)cc1SCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
0.95 g of ethyl 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole-5-carboxylate was dissolved in 20 mL of ethanol. To this solution, a solution having 0.42 g of potassium hydroxide dissolved in 10 mL of water was added, followed by stirring at room temperature for 30 minutes. Concentrated hydrochloric acid was added to adjust the pH to 2, the solvent was distilled off under reduced pressure, extraction with ethyl acetate was carried out, and the organic layer was dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to obtain 0.90 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole-5-carboxylic acid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][N:4]=1)#[N:2].[N-:10]=[N+:11]=[N-:12].[Na+].[Cl-].[NH4+].O>CN(C)C=O>[NH:10]1[C:1]([C:3]2[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][N:4]=2)=[N:2][N:12]=[N:11]1
Reactant: N#Cc1ccc(Br)cn1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(-c2nnn[nH]2)nc1
Temperature: 110 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
10 g of 2-cyano-5-bromopyridine prepared in the Preparation example 5 was dissolved in 100 ml of dimethylformamide, 5.33 g of sodiumazide, and 4.4 g of ammonium chloride were added to the solution at room temperature, and the solution was stirred at the temperature of 110° C. for 3 hours for reaction. The reaction mixture was added with water and then was extracted with ethyl acetate. The organic layer, thus separated, was washed with brine, dehydrated, filtrated and concentrated in vacuo thereby to obtain 10.5 g of the title compound. Yield 85%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH:14]([F:16])[F:15])[CH:11]=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[F:15][CH:14]([F:16])[C:12]1[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([NH2:27])=[N:29][CH:30]=3)[CH:7]=[CH:6][CH:5]=2)[N:13]=1
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-difluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.8) (0.22 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as an off-white solid (0.035 g, 16%). MS (ISP) 443.3 [(M+H)+]; mp 191° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.[CH3:19][N:20]1[C:27](=[O:28])[CH:26]([C:29](OCC)=[O:30])[C:24](=[O:25])[N:23]([CH3:34])[C:21]1=[O:22]>C1(C)C=CC=CC=1>[CH3:34][N:23]1[C:24](=[O:25])[CH:26]([C:29](=[O:30])[NH:16][C:15]2[CH:14]=[CH:13][C:12]([O:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[CH:18][CH:17]=2)[C:27](=[O:28])[N:20]([CH3:19])[C:21]1=[O:22]
Reactant: Nc1ccc(Oc2ccc3ccccc3n2)cc1
Reactant: CCOC(=O)C1C(=O)N(C)C(=O)N(C)C1=O
Solvent: Cc1ccccc1
Product: CN1C(=O)C(C(=O)Nc2ccc(Oc3ccc4ccccc4n3)cc2)C(=O)N(C)C1=O
Reaction time: 3 h

Procedure:
6.1 g of 4-(quinolin-2-yloxy)aniline and 5.8 g of 1,3-dimethyl-5-ethoxycarbonylbarbituric acid are heated under reflux in 50 ml of toluene. When the temperature is at 80° C., a thick crystalline slurry is formed which at 120° C. is again of a stirrable consistency. After stirring for 3 hours, the mixture is cooled and the crystals are isolated by suction filtration.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.N1CC[CH2:15][C@H:11]1[C:12](O)=O>CC(C)=O>[CH3:15][C:11]1[CH:12]=[CH:8][C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[N:1]=1
Reactant: Nc1ncccc1C=O
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CC(C)=O
Product: Cc1ccc2cccnc2n1
Temperature: 25 °C
Yield: 641.6 %

Procedure:
To a solution of 2-amino-3-pyridinecarboxaldehyde (from step c, 24.57 g) in acetone (750 mL) was added proline (2.3 g, 20 mmole), then the mixture was heated to reflux. After 48 hr the mixture was cooled to RT, filtered, and concentrated. Flash column chromatography on silica gel (35% acetone/hexanes) gave the title compound (18.5 g, 64% over 3 steps) as an orangish-yellow solid: 1H NMR (300 MHz, CDCl3) δ 9.07 (m, 1 H), 8.10 (m, 2H), 7.40 (m, 2H), 2.80 (s, 3H); MS (ES) m/e 145 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10](Cl)=[O:11])=[CH:6][CH:5]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C>ClCCl>[N:14]1([C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:13])=[CH:5][CH:6]=2)=[O:11])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNC1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)N2CCCC2)cc1

Procedure:
29.0 g (0.146 mol) of 4-chlorocarbonyl benzoic acid monomethyl ester, 14.2 g (200 mmol) of pyrrolidine and 21.0 g (208 mmol) of triethylamine were reacted in 350 ml of dichloromethane. After the treatment in an ordinary manner, methyl 4-(1-pyrrolidylcarbonyl)benzoate was obtained. 29.0 g of this ester compound was hydrolyzed with 12.0 g of sodium hydroxide in a mixed solvent comprising 70 ml of water, 70 ml of methanol and 70 ml of tetrahydrofuran. After the completion of the reaction, the solvent was distilled off. After the addition of 1 N hydrochloric acid followed by the treatment with dichloromethane as the extractant in an ordinary manner, the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][Cl:28].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[ClH:28].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])[C:12]3[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc([C@@H]2Sc3cc(F)ccc3NC(=O)[C@@H]2O)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2Sc3cc(F)ccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Yield: 74.8 %

Procedure:
A mixture of 4 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-fluoro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 1.99 g of 2-(dimethylamino)ethyl chloride hydrochloride, 4.3 g of potassium carbonate and 50 ml of acetone is refluxed for 18 hours. After the reaction is completed, insoluble materials are removed by filtration and washed with hot acetone. The filtrate and the washings are combined and then evaporated to remove solvent. The residue is converted to its hydrochloride and recrystallized from a mixture of isopropanol, ethanol and ether. 4 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-8-fluoro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:5])[CH2:4][NH:3]1.C(N(CC)CC)C.[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[C:21]([N:3]1[CH2:4][C:2]1([CH3:5])[CH3:1])([O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:22]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1(C)CN1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,2-Dimethyl aziridine is dissolved in CH2Cl2 and triethylamine under argon at 0° C. Benzylchloroformate is added and the contents of the flask are stirred at room temperature overnight. The mixture is poured into 10% citric acid and extracted with CHCl3. The organic layer is washed with dilute aqueous NaHCO3 and dried over MgSO4. The solution is evaporated to yield N-Cbz-2,2-dimethylaziridine.
Reaction SMILES: I[C:2]1[C:10]2[N:9]([CH3:11])[C@H:8]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C@H:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=C[C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[CH:25][CH:24]=1.[H-].[Na+]>[Cu](I)I.CN1CCCN(C)C1=O>[CH3:16][N:14]1[CH2:13][CH2:12][C@@H:8]2[N:9]([CH3:11])[C:10]3[C:2]([S:29][C:26]4[CH:27]=[CH:28][C:23]([CH3:18])=[CH:24][CH:25]=4)=[CH:3][CH:4]=[CH:5][C:6]=3[C@@H:7]2[CH2:15]1
Reactant: Cc1ccccc1-c1ccc(S)cc1
Reactant: CN1CC[C@H]2[C@@H](C1)c1cccc(I)c1N2C
Agent: I[Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Product: Cc1ccc(Sc2cccc3c2N(C)[C@H]2CCN(C)C[C@@H]32)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
(4aS,9bR)-6-Iodo-2,5-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (910 mg, 2.7 mmol) was combined with p-tolylthiophenol (426 mg, 3.3 mmol), sodium hydride (132 mg, 3.3 mmol, 60% in oil dispersion), copper iodide (515 mg, 2.7 mmol) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (5 mL) and stirred at 100° C. for 16 hours. The reaction mixture was partitioned between water and CHCl3. The aqueous layer was extracted with CHCl3 (3×20 mL). The combined organics were washed with sat. NaCl (10 mL), water (10 mL), dried (MgSO4) and evaporated. The residue was loaded onto a SCX resin. The resin was washed with 150 mL of MeOH followed by washing with 2.0 M methanolic ammonia. The collected residue was dissolved in CH3CN and 1N HCl/Ether was added until no further precipitation was observed. The solid was filtered and washed with CH3CN affording the title compound (315 mg, 36%) as a white solid. 1H NMR (CD3OD, 300 MHz) δ 7.20 (d, 1H, J=7.7 Hz), 7.14 (d, 1H, J=7.3 Hz), 7.06 (d, 2H, J=8.1 Hz), 6.97 (d, 2H, J=8.4 Hz), 6.82-6.87 (m, 1H), 3.99-4.05 (m, 1H), 3.71-3.80 (m, 1H), 3.15-3.25 (m, 4H), 3.08 (s, 3H), 2.99 (s, 3H), 2.38-2.43 (m, 1H), 2.26 (s, 3H), 1.90-2.03 (m, 1H) ppm.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Si:11]([N:18]1[C@H:21]([CH2:22][C:23](OC)=[O:24])[C@@H:20]([C@H:27]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH3:28])[C:19]1=[O:37])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>C1(C)C=CC=CC=1>[Si:11]([N:18]1[C@H:21]([CH2:22][CH:23]=[O:24])[C@@H:20]([C@H:27]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH3:28])[C:19]1=[O:37])([C:14]([CH3:17])([CH3:15])[CH3:16])([CH3:13])[CH3:12]
Reactant: COC(=O)C[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1[Si](C)(C)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1CC=O
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Diisobutylaluminum hydride (3.72 ml of 0.91 M in hexane, 3.38 mmol) is added slowly by syringe to a solution of (3S, 4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-carbomethoxymethyl azetidin-2-one (936 mg, 2.26 mmol) in 25 ml of freshly distilled toluene at -78° C. The resulting solution is stirred at -78° C. for 3 hrs., then quenched by addition of 2.5 N hydrochloric acid (5 ml). The resulting mixture is stirred for 2 min., then poured into a separatory funnel containing 100 ml of ether and 50 ml of 1.25 N hydrochlorid acid saturated with tartaric acid. The organic phase is separated and the aqueous phase is extracted with ether (2×50 ml). The combined organic phases are washed with brine and dried over magnesium sulfate. Removal of solvents in vacuo gives a white solid which is recrystallized from ether-petroleum ether to give (3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)- 1-(t-butyldimethylsilyloxy)ethyl]-4-(2-oxoethyl)-azetidin-2-one. m.p. 115°-116° C.; n.m.r. (CDCl3) δ4.1(m,l), δ4.03(m,l), δ2.7-3.2(m,3), δ1.23(d,3,J=6.4), δ1.08(s,9), δ0.9(s,9), δ0.25(s,6), δ0.1(s,6), δ9.83(t,l,J=1.4).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][N:22]1[C:26]([CH3:27])=[C:25]([CH:28]=O)[C:24]([CH3:30])=[N:23]1.C([O-])(=O)C.[NH4+]>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:28]([C:25]3[C:24]([CH3:30])=[N:23][N:22]([CH3:21])[C:26]=3[CH3:27])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Cc1nn(C)c(C)c1C=O
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: Cc1nn(C)c(C)c1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 34.7 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (75.00 mg, 0.2553 mmol), 1,3,5-Trimethyl-1H-pyrazole-4-carbaldehyde (38.8 mg, 0.281 mmol), and Ammonium acetate (39.4 mg, 0.511 mmol) were reacted to produce 36.49 mg (37%) of the title compound. (300 MHz, DMSO-d6) 12.47 (s, 1H), 7.91 (s, 1H), 7.72 (s, 1H), 7.21 (s, 1H), 7.00 (d, J=9 Hz, 1H), 6.32 (m, 1H), 6.26 (m, 1H), 5.17 (t, J=17 Hz, 9 Hz, 1H), 3.73 (s, 3H), 2.85 (s, 1H), 2.77 (s, 1H), 2.57 (d, J=8 Hz, 1H), 2.47 (s, 3H), 2.35 (s, 3H), 2.24 (d, J=8 Hz, 1H), 1.38 (d, J=8 Hz, 1H). MS=412 (M+H), HPLC: 1.97 min. (G Method)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.[CH3:13][O-:14].[Na+].C=O>CS(C)=O.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:12])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)[CH2:13][OH:14]
Reactant: C[O-]
Reactant: COC(=O)Cc1ccc(Cl)cc1
Agent: C=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)C(CO)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
To a stirred solution of (4-Chloro-phenyl)-acetic acid methyl ester (2 g, 10.8 mmol) in DMSO (22 mL) was added sodium methoxide (29.2 mg, 0.54 mmol) at 0° C. Paraformaldehyde (342 mg, 11.4 mmol) was then added and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with EtOAc (100 mL), washed with water (3×20 mL), brine (20 mL), dried (Na2SO4) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of hexane:EtOAc 100:0 to 84:16) to afford the title compound as a colourless gum in 52% yield, 1.2 g.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][O:11][C:12]1[C:13]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[N:16][CH:17]=1>O1CCOCC1>[CH3:10][O:11][C:12]1[C:13]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:8](=[O:9])[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:20][CH:19]=2)=[N:16][CH:17]=1
Reactant: COc1cnc(-c2ccc(O)cc2)nc1N1CCOCC1
Reactant: O=C=Nc1ccccc1
Solvent: C1COCCO1
Product: COc1cnc(-c2ccc(OC(=O)Nc3ccccc3)cc2)nc1N1CCOCC1
Temperature: 80 °C
Yield: 24.03 %

Procedure:
Phenyl isocyanate (0.03 ml, 2.0 eq) was added to a solution of 4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenol (0.05 g, 1.0 eq) in dioxane (6 ml) and heated at 80° C. for 20 hrs. The solvent was removed in vacuo, and the residue was extracted with EA and water. The combined organic layers were washed with brine, dried and evaporated in vacuo. The crude was purified by chromatography to give a white solid (0.07 g, 24.03%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=2)[C:5]([N+:18]([O-])=O)=[CH:4][CH:3]=1>CO.[Pd]>[NH2:18][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=2)=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc([N+](=O)[O-])c(Nc2ccc(CCO)cc2)n1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(N)c(Nc2ccc(CCO)cc2)n1
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a solution of 2-{4-[(6-methyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol (step 1, 4.6 g, 16.9 mmol) in methanol (100 mL) was added 10% Pd—C (300 mg). The resulting mixture was stirred for 2 h under hydrogen atmosphere. The mixture was filtered through a pad of Celite and the filtrate was concentrated. The residue was purified by flash column chromatography eluting with hexane/ethyl acetate (gradient elution from 1:2 to 1:5) to afford 3.8 g (92%) of the title compound as yellow solids: 1H-NMR (CDCl3) δ: 7.10–7.16 (4H, m), 6.91 (1H, d, J=8.4 Hz), 6.70 (1H, d, J=8.4 Hz), 6.19 (1H, s), 3.83 (2H, t, J=6.4 Hz), 2.81 (2H, t, J=6.4 Hz), 2.35 (3H, s).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([C:6]([F:10])([F:9])[CH2:7][CH3:8])=[CH:4][F:5].[FH:13]>>[F:1][C:2]([F:11])([F:12])[CH:3]([C:6]([F:9])([F:10])[CH2:7][CH3:8])[CH:4]([F:13])[F:5]
Reactant: F
Reactant: CCC(F)(F)C(=CF)C(F)(F)F
Product: CCC(F)(F)C(C(F)F)C(F)(F)F

Procedure:
As another example, 4-difluoromethyl-3,5,5,5-tetrafluoro-1-pentene may be prepared by fluorinating 3-pentanone to form 3,3-difluoropentane which may then be dehydrogenated to form 3,3-difluoro-1-pentene. CF3 may then be reacted with the 3,3-difluoro-1-pentene to form 2-trifluoromethyl-1,3,3-trifluoropentane which may then be dehydrogenated to form 2-trifluoromethyl-1,3,3-trifluoro-1-pentene. The 2-trifluoromethyl-1,3,3-trifluoro-1-pentene may then be reacted with hydrogen fluoride to form 2-trifluoromethyl-1,1,3,3-tetrafluoropentane which may then be dehydrohalogenated to form 4-difluoromethyl-3,5,5,5-tetrafluoro-1-pentene.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][C@H:11]2[O:15][C:14]([NH2:16])=[N:13][CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O:21][C:22](=O)[CH:23]([CH:26]=O)[CH2:24][CH3:25])C>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][CH:11]2[O:15][C:14]3=[N:16][C:22](=[O:21])[C:23]([CH2:24][CH3:25])=[CH:26][N:13]3[CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CN=C(N)O2)cc1
Reactant: CCOC(=O)C(C=O)CC
Solvent: ClC(Cl)Cl
Product: CCc1cn2c(nc1=O)OC(COc1ccc(C(C)(C)C)cc1)C2

Procedure:
The title compound was prepared from (S)-5-(4-tert-butyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine and 2-formyl-butyric acid ethyl ester employing the procedure described in Step2 of Example 87. [α]D25 −31.20 (c 0.5, CHCl3).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:11])[CH3:10].C([O-])(O)=O.[Na+].[Cl:17][C:18]1[N:23]=[C:22](Cl)[C:21]([Cl:25])=[CH:20][N:19]=1>C1COCC1.CCO>[Cl:17][C:18]1[N:23]=[C:22]([NH:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9](=[O:11])[CH3:10])[C:21]([Cl:25])=[CH:20][N:19]=1
Reactant: CC(=O)c1ccccc1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reaction time: 96 h

Procedure:
1-(2-Amino-phenyl)-ethanone hydrochloride (1.72 g, 1.0 mmol) and NaHCO3 (3.4 g, 4 mmol) were slurried in a mixture of THF (4 mL) and EtOH (16 mL) prior to adding 2,4,5-trichloropyrimidine (1.84 g, 1.0 mmol). The reaction was stirred for 4 days, filtered and washed with water (10×10 mL) to afford -[2-(2,5-dichloro-pyrimidin-4-ylamino)-phenyl]-ethanone as a white solid that was used without further purification in the subsequent step.