Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:19])([C@@H:16]([SH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>ClCCl>[C:27]([S:18][C@@H:16]([CH3:17])[C@@:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([OH:19])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: C[C@H](S)[C@@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)S[C@@H](C)[C@@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To dichloromethane (1 ml) was added (2S,3S)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol (3 mg), followed by addition of a dichloromethane solution of triethylamine (10%, 16 μl) with ice-cooling. Then, a dichloromethane solution of acetyl chloride (10%, 8.2 μl) was added and the mixture was stirred at room temperature for 30 minutes. The solvent was then distilled off under reduced pressure and the residue was subjected to silica gel chromatography (1×1 cm) using ethyl acetate-hexane (2:1) as the eluent. The desired fraction was concentrated to give (2S,3S)-3-acetylthio-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (compound 44:1.2 mg) as a colorless solid.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.C([Li])CCC.[Br:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[C:24]([F:30])[CH:23]=1.[Cl-].[NH4+]>C1COCC1>[Br:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)[OH:27])=[C:24]([F:30])[CH:23]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: COc1cc2nccc(Br)c2cc1OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc2nccc(C(O)c3ccc(Br)cc3F)c2cc1OC
Reaction time: 0.25 h
Yield: 52 %

Procedure:
A solution of 4-bromo-6,7-dimethoxyquinoline (1.0 g, 3.73 mmol) in dry THF (20 mL) was cooled to −78° C. A solution of 2.5M n-butyllithium in hexanes (1.50 mL, 3.73 mmol) was added and stirred 15 min. A solution of 4-bromo-2-fluoro-benzaldehyde (0.757 g, 3.73 mmol) in THF (10 mL) was added dropwise over 5 min. After stirring 30 min. at −78° C., saturated ammonium chloride solution (1 mL) was added. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. After the solvent was removed under vacuum, the residue was purified by chromatography with 0-5% MeOH in dichloromethane to give (4-bromo-2-fluoro-phenyl)-(6,7-dimethoxy-quinolin-4-yl)-methanol in 52% yield. 1H NMR (CDCl3) δ: 8.63 (d, 1H, J=4.1 Hz), 7.57 (d, 1H, J=4.7 Hz), 7.34 (s, 1H), 7.25-7.17 (m, 2H), 7.08 (s, 1H), 6.67 (s, 1H), 4.02-3.96 (m, 1H), 3.94 (s, 3H), 3.88 (s, 3H).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1I)([O-])=O.C([O-])([O-])=O.[K+].[K+].[CH3:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(OCC)(=O)C>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:4]1([C:19]2[CH:18]=[CH:17][CH:22]=[CH:21][CH:20]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCCCC
Reactant: O=[N+]([O-])c1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: c1ccc(-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
4,4,5,5-Tetramethyl-2-(4-indanone-1-yl)[1,3,2]-dioxoborolane (2.17 g, 8.4 mmol) and o-nitroiodobenzene (2.70 g, 10.9 mmol) were dissolved in a mixture of dioxane (30 mL) and water (5 mL). K2CO3 (2.30 g, 16.7 mmol) and Pd(PPh3)4 (0.48 g, 0.4 mmol) were added. The reaction mixture was heated in a flow of argon to 80° C., kept at this temperature over a period of 24 h (TLC monitoring: hexane/ethyl acetate, 4:1), cooled, and filtered through Celite. The filtrate was evaporated. The residue was dissolved in CH2Cl2. An undissolved precipitate was filtered off. The filtrate was partially evaporated, and the product was purified in a short silica gel column (hexane/ethyl acetate) to give 2.5 g of a product containing PPh3O. The product was cyclized without additional purification.
Reaction SMILES: CO[C:3](OC)([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([F:15])[CH:8]=1)[CH3:4].[S-:18][C:19]#[N:20].[K+].Cl>C(O)C.O>[F:15][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[O:13][CH3:14])[CH2:6][N:5]1[CH:3]=[CH:4][N:20]=[C:19]1[SH:18]
Reactant: N#C[S-]
Reactant: COc1ccc(CNC(C)(OC)OC)cc1F
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc(Cn2ccnc2S)cc1F
Yield: 60.7 %

Procedure:
To a solution of 1-(3-fluoro-4-methoxybenzyl)aminoacetaldehyde dimethyl acetal (6.68 g, 0.0275 mole) in ethyl alcohol (40 ml) was added potassium thiocyanate (2.94 g, 0.0302 mole) in water (65 ml) followed by 12 N hydrochloric acid (6 ml) and the reaction mixture was heated under reflux for 3 hours. The solvent was partially removed under reduced pressure and the mixture was cooled in ice and the product filtered. The product was recrystallized from ethyl alcohol to give 1-(3-fluoro4-methoxybenzyl)-2-mercaptoimidazole as a solid melting at 156-157° (3.98 g, 61%).
Reaction SMILES: [C:1]1(=[O:16])[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.[H][H]>[Pd].C(O)C>[C:1]1(=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC=CCCCCCCC=CCC1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C1CC/C=C/CCCCCC/C=C/CC1
Solvent: CCO
Product: O=C1CCCCCCCCCCCCCC1
Yield: 89.1 %

Procedure:
A flask was charged with cyclopentadeca-4E,12E-dien-1-one (0.10 g, 0.45 mmole), ethanol (5 ml) and 5% palladium-on-carbon (0.01 g). The mixture was stirred at room temperature under 1 atm of hydrogen gas for 1 hour. The reaction mixture was filtered through celite and concentrated to provide cyclopentadecanone (exaltone) (0.09 g, 88% yield). C15H28O (224.39 g/mole). 1HNMR (500 MHz, CDCl3): 1.25 (m, 20H), 1.60 (m, 4H), 2.35 (t, 4H) ppm. 13CNMR (125 MHz, CDCl3): 23.40, 26.25, 26.39, 26.69, 26.74, 27.54, 42.05, 212.50, ppm. IR (νmax(cm−1)): 2924(s), 2854(s), 1708(s), 1458(m).
Reaction SMILES: [CH3:1][C:2]1[C:20]([F:21])=[C:19]([F:22])[CH:18]=[C:17]([F:23])[C:3]=1[C:4]([CH:6](C(OCC)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:1][C:2]1[C:20]([F:21])=[C:19]([F:22])[CH:18]=[C:17]([F:23])[C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1c(F)cc(F)c(F)c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)CC(=O)c1c(F)cc(F)c(F)c1C
Yield: 82.6 %

Procedure:
To diethyl 2-methyl-3,4,6-trifluorobenzoylmalonate (5.1 g) are added water (20 ml) and p-toluenesulfonic acid (30 mg) and the mixture is refluxed for 2.5 hours. After cooling, the resultant is extracted with diethyl ether, and the extract is dried over magnesium sulfate and concentrated to give ethyl 2-methyl-3,4,6-trifluorobenzoylacetate (3.3 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][C@@H:10]1[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24](OC(=O)C)(=[O:26])[CH3:25].Cl.C(OCC)(=O)C>N1C=CC=CC=1>[C:24]([O:15][CH:12]1[CH2:13][CH2:14][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@@H:10]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11]1)(=[O:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC(O)CC[C@H]1NC(=O)OC(C)(C)C
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OC1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
(1R*,2S*)-N1,N2-Bis(tert-butoxycarbonyl)-4-hydroxy-1,2-cyclohexanediamine (Stereoisomer B) (1.74 g) was dissolved in pyridine (15 ml), and acetic anhydride (5 ml) was added to stir the mixture at room temperature for 4 days. 1N Hydrochloric acid was added to the reaction mixture, extraction was conducted with ethyl acetate, and the resultant organic layer was successively washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:3) to obtain the title compound (1.96 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31][CH3:32])[C:20]([NH:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.[C:38](OC(=O)CN)(C)(C)C.Cl.C(OC(=O)[C@@H](C)N)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@H:19]([CH2:31][CH3:32])[C:20]([NH:22][C@H:23]([CH3:38])[C:24]([OH:26])=[O:25])=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CN
Agent: C[C@@H](N)C(=O)OC(C)(C)C
Agent: Cl
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)N[C@H](C)C(=O)O

Procedure:
Instead of the starting material compound of Example 220, that is, the glycine tert-butyl ester hydrochloride, D-alanine tert-butyl ester hydrochloride was used for the similar procedure as in Example 220 and Example 245 to obtain the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]([OH:26])[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24]C)=[O:23])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>Cl>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][CH:13]([OH:26])[CH2:12][CH2:11][C:8]2[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=2)=[CH:21][CH:20]=1)([OH:24])=[O:23]
Reactant: COC(=O)c1ccc(CCC(O)CCc2ccc(C(=O)OC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(CCC(O)CCc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture of 1,5-bis(4'-methoxycarbonylphenyl)-3-pentanol and 1 L of 3 M aqueous sodium hydroxide are heated at reflux for 7 hours, the resulting reaction mixture is allowed to cool to room temperature and added to a stirred mixture of 300 mL concentrated hydrochloric acid and 200 g of ice. The precipitate is collected by filtration and recrystallized from 3 L of acetic acid. The purified product is dried by heating under vacuum to give 330 g (100% of theory) of 1,5-bis(4'-carboxyphenyl)-3-pentanol as a white, fine, crystalline powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]12[CH2:16][N:15]([C:17]3[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=3)[CH2:14][CH:13]1[CH2:12][S:11][C:10]([NH:24]C(=O)C1C=CC=CC=1)=[N:9]2.[OH-].[Li+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]12[CH2:16][N:15]([C:17]3[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=3)[CH2:14][CH:13]1[CH2:12][S:11][C:10]([NH2:24])=[N:9]2
Reactant: O=C(NC1=NC2(c3ccccc3F)CN(c3ncc(F)cn3)CC2CS1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: NC1=NC2(c3ccccc3F)CN(c3ncc(F)cn3)CC2CS1
Yield: 85.9 %

Procedure:
Racemic N-[7a-(2-fluorophenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (560 mg, 1.24 mmol), methanol (12 ml), and lithium hydroxide (208 mg, 4.95 mmol) is heated to 50° C. for 18 hours under an atmosphere of nitrogen. The methanol is removed to near dryness with a stream of nitrogen. To the reaction is added ethyl acetate (7.5 ml), and water (2.5 ml). The mixture is passed through 10 g diatomaceous earth and the solvent removed under reduced pressure. The filtrate is passed through a 8 g XL-C solid phase extraction column (SPE), the basic methanol wash collected, and the solvent removed under reduced pressure to provide the crude title compound (370 mg, 86%). ES/MS (m/e): 348 (M+H).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[CH2:14]([NH2:16])[CH3:15]>>[CH2:14]([NH:16][CH2:2][C:3]1([OH:1])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1)[CH3:15]
Reactant: CCOC(=O)N1CCC2(CC1)CO2
Reactant: CCN
Product: CCNCC1(O)CCN(C(=O)OCC)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.7 g (30.8 mmol) of ethyl 6-aza-1-oxaspiro[2,5]octane-6-carboxylate are added dropwise to 30 ml of ethylamine solution (50% in water) and the mixture is stirred overnight at room temperature. It is then concentrated and distilled.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:43])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[C:39]([CH3:41])[N:38]=[C:37]([CH3:42])[CH:36]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:42][C:37]1[CH:36]=[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:43])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:22])([F:21])[F:23])[C:12]([N:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[CH3:15])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)[CH:40]=[C:39]([CH3:41])[N:38]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)CC(C)C)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)CC(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from [2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(isobutyl-methyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M303) (0.37 g, 0.60 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (262 mg, 88%).
Reaction SMILES: CO.[NH2:3][C:4]1[C:13]2[N:14]=[C:15]([CH2:22][CH3:23])[N:16]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[C:12]=2[C:11]2[CH:10]=[CH:9][C:8]([CH:24]=[CH:25][C:26]([O:28][CH3:29])=[O:27])=[CH:7][C:6]=2[N:5]=1>[Pd].C(O)C>[NH2:3][C:4]1[C:13]2[N:14]=[C:15]([CH2:22][CH3:23])[N:16]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[C:12]=2[C:11]2[CH:10]=[CH:9][C:8]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:7][C:6]=2[N:5]=1
Reactant: CCc1nc2c(N)nc3cc(C=CC(=O)OC)ccc3c2n1CC(C)(C)O
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CCc1nc2c(N)nc3cc(CCC(=O)OC)ccc3c2n1CC(C)(C)O
Temperature: 50 °C
Reaction time: 18 h
Yield: 88.7 %

Procedure:
A glass Parr vessel was charged with 10% palladium on carbon (1.0 g), methanol (75 mL), ethanol (75 mL) and methyl 3-[4-amino-2-ethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enoate (approximately 4 g, 10.8 mmol). The vessel was evacuated and charged with hydrogen gas (40 psi, 2.8×105 Pa). The mixture was shaken at 50° C. for approximately 18 hours. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure to provide 3.55 g of methyl 3-[4-amino-2-ethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]propanate as an off-white solid. MS (ESI) m/z 371 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[N:5]=[C:4]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[N:3]=1.[CH3:17][O:18][C:19]([C:21]1([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20]>C(O)(C)C>[CH3:17][O:18][C:19]([C:21]1([C:26]2[CH:27]=[CH:28][C:29]([NH:32][C:2]3[C:7]4[CH2:8][CH2:9][CH2:10][C:6]=4[N:5]=[C:4]([CH2:11][CH:12]4[CH2:16][CH2:15][CH2:14][CH2:13]4)[N:3]=3)=[CH:30][CH:31]=2)[CH2:22][CH2:23][CH2:24][CH2:25]1)=[O:20]
Reactant: COC(=O)C1(c2ccc(N)cc2)CCCC1
Reactant: Clc1nc(CC2CCCC2)nc2c1CCC2
Solvent: CC(C)O
Product: COC(=O)C1(c2ccc(Nc3nc(CC4CCCC4)nc4c3CCC4)cc2)CCCC1
Yield: 62.6 %

Procedure:
A mixture of 4-chloro-2-cyclopentylmethyl-6,7-dihydro-5H-cyclopentapyrimidine (0.38 g, 1.6 mmol) and 1-(4-amino-phenyl)-cyclopentane carboxylic acid methyl ester (0.35 g, 1.6 mmol) in anhydrous isopropanol (8 mL) was heated at reflux under nitrogen for 8 to 18 hours. Thereafter, volatiles were evaporated under reduced pressure. The residue was triturated with ether and filtered. The solid was dissolved in ethyl acetate, washed with 5% sodium bicarbonate, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a light yellow powder (0.42 g, 63% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[NH2:15][C:16]1[CH:17]=[C:18]([C:23]2[NH:28][C:27](=[O:29])[C:26]([CH3:30])=[N:25][N:24]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]>C(#N)C>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([NH:6][C:7]([NH:15][C:16]1[CH:17]=[C:18]([C:23]2[NH:28][C:27](=[O:29])[C:26]([CH3:30])=[N:25][N:24]=2)[CH:19]=[CH:20][C:21]=1[Cl:22])=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Reactant: Cc1nnc(-c2ccc(Cl)c(N)c2)[nH]c1=O
Solvent: CC#N
Product: Cc1nnc(-c2ccc(Cl)c(NC(=O)NC(=O)c3cc(F)c(F)cc3Cl)c2)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The solution of equivalent amounts of 2-chloro-4,5-difluorobenzoyl isocyanate was added dropwise to the solution of 60 mg of 3-(3-amino-4-chlorophenyl)-6-methyl-4H-[1,2,4]triazin-5-one in 8 ml of acetonitrile and the mixture was stirred at room temperature for 30 minutes. The solid was filtered off with suction and dried under reduced pressure.
Reaction SMILES: [OH:1][C:2]([CH3:12])([CH2:10][OH:11])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4].[Cl:13][C:14]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:15]=1[CH:16]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:12][C:2]1([C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4])[O:1][CH:16]([C:15]2[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:14]=2[Cl:13])[O:11][CH2:10]1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CCCCOC(=O)C(C)(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCOC(=O)C1(C)COC(c2cc([N+](=O)[O-])ccc2Cl)O1
Yield: 101.6 %

Procedure:
19.4 g of n-butyl 2,3-dihydroxyisobutyrate are added to 18.6 g of 2-chloro-5-nitrobenzaldehyde and 0.5 g of p-toluenesulfonic acid in 250 ml of toluene, and the mixture is refluxed for 5 hours under a water separator. After the mixture has been cooled, the solvent is removed and the residue is dried under greatly reduced pressure. 35 g of 3-(5-methyl-5-n-butoxycarbonyl-1,3-dioxolan-2-yl)-4-chloronitrobenzene (oil) are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([O:11][CH2:10][CH:9]=[CH:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: OCC=Cc1ccc(Br)cc1
Product: CC(=O)OCC=Cc1ccc(Br)cc1
Yield: 88.2 %

Procedure:
3-(4-Bromophenyl)prop-2-en1-ol (2.13 g) (see example 1) was reacted with acetic anhydride (1.2 g) in the usual manner to give 3-(4-bromophenyl)prop-2-enyl acetate (2.25 g) NMR 1H: 7.35(2H,d), 7.08(2H,d), 6.52(1H,d), 6.10(1H,dt), 4.65(2H,d), 2.1(3H,s).
Reaction SMILES: [CH3:1][C:2]([CH:4]=[CH2:5])=[O:3].[CH:6]1[C:16]2[CH2:15][CH2:14][C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[C:11](=[C:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.C1C2CCC3C=CC=CC=3C(=C3CCN(C)CC3)C=2C=CC=1>C(O)C>[CH:6]1[C:16]2[CH2:15][CH2:14][C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[C:11](=[C:21]3[CH2:22][CH2:23][N:24]([CH2:5][CH2:4][C:2](=[O:3])[CH3:1])[CH2:25][CH2:26]3)[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc2c(c1)CCc1ccccc1C2=C1CCNCC1
Reactant: C=CC(C)=O
Agent: CN1CCC(=C2c3ccccc3CCc3ccccc32)CC1
Solvent: CCO
Product: CC(=O)CCN1CCC(=C2c3ccccc3CCc3ccccc32)CC1

Procedure:
5.1 g of methylvinylketone are added dropwise at 70° to a solution of 10 g of 4-(10,11-dihydro-5-dibenzo[a,d]cycloheptenylidene)piperidine [M.P. 113°-114°, produced in a manner analogous to that described in Example 4 (a), from 4-(10,11-dihydro-5-dibenzo[a,d]cycloheptenylidene)-1-methylpiperidine] in 100 cc of ethanol, and the mixture is boiled at reflux for 11/2 hours. The reaction mixture is then concentrated by evaporation in a vacuum, the residue is dissolved in acetone, the solution is made acid with hydrogen chloride in ether, is again concentrated by evaporation, and the residue is crystallized first from acetone/ether and then from isopropanol/ether. The hydrochloride of the title compound has an M.P. over 300°.
Reaction SMILES: [CH3:1][N:2](C=O)C.FC(F)(S(O[C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:31])[NH:26][CH:25]2[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Zn].[C-]#N.[Zn+2].[C-]#N>[CH2:32]([CH:25]1[C:24]2[C:28](=[CH:29][CH:30]=[C:22]([C:1]#[N:2])[CH:23]=2)[C:27](=[O:31])[NH:26]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CN(C)C=O
Reactant: O=C1NC(Cc2ccccc2)c2cc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)ccc21
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(c1)C(Cc1ccccc1)NC2=O
Temperature: 100 °C
Yield: 43 %

Procedure:
To a round bottom flask was added 12 mL of DMF. This was degassed with N2 for 10 min and then added 3-benzyl-1-oxoisoindolin-5-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (609 mg, 1.17 mmol), tris(dibenzylideneacetone)dipalladium(0) (214 mg, 0.23 mmol), 1,1′-bis(diphenylphosphino)ferrocene (142 mg, 0.26 mmol) and zinc (30.6 mg, 0.47 mmol) respectively. This was heated up to 100° C. for 15 min under N2, then added Zinc cyanide (82 mg, 0.70 mmol). This was heated at 100° C. for 2.5 hours, LC/MS showed complete conversion. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate, then filtered through a pad of celite, the filtrate was concentrated down and the residue was purified by flash-chromatography on silica gel with 30-90% ethyl acetate in hexane, 125 mg (43%) of the product was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[C:16]([N:17]=2)=[CH:15][CH:14]=[C:13]([C:18]2([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:20][CH2:19]2)[N:12]=3)=[C:5]([N+:27]([O-:29])=[O:28])[CH:4]=1.Cl.[NH:31]1[CH2:34][CH:33]([C:35]([O:37][CH3:38])=[O:36])[CH2:32]1.C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C.CC(=O)OCC>[N+:27]([C:5]1[CH:4]=[C:3]([CH2:2][N:31]2[CH2:34][CH:33]([C:35]([O:37][CH3:38])=[O:36])[CH2:32]2)[CH:8]=[CH:7][C:6]=1[C:9]1[S:10][C:11]2[C:16]([N:17]=1)=[CH:15][CH:14]=[C:13]([C:18]1([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:20][CH2:19]1)[N:12]=2)([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1cc(CBr)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Reactant: COC(=O)C1CNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)C1CN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c([N+](=O)[O-])c2)C1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-(bromomethyl)-2-nitrophenyl)-5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine (0.363 g, 0.778 mmol), methyl azetidine-3-carboxylate hydrochloride (0.354 g, 2.34 mmol), N,N-diisopropylethylamine (0.812 mL, 4.67 mmol) in 3 mL DMF was heated in a sealed vial to 80° C. for 1 h. The reaction mixture was cooled and allowed to stand overnight. In the morning the reaction mixture was treated with ice, sat'd aq. NaHCO3, and EA. The organic layer was washed with water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography, 40 g, 0-10% MeOH/DCM gave methyl 1-((3-nitro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)azetidine-3-carboxylate as a yellow oil. MS (ESI) m/z: Calculated: 500.2; Observed: 500.7 (M++1).