Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([CH3:14])[C:3](=[O:13])[C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[I-].[NH2:16][N+:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[F:12][C:9]1[CH:10]=[CH:11][C:6]([C:5]2[C:4]([C:3](=[O:13])[CH2:2][CH3:14])=[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][N:17]3[N:16]=2)=[CH:7][CH:8]=1
Reactant: N[n+]1ccccc1
Reactant: CC(Cl)C(=O)C#Cc1ccc(F)cc1
Agent: [I-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCC(=O)c1c(-c2ccc(F)cc2)nn2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 2 %

Procedure:
To a mixture of 8.7 g (38 mmol) of 4-chloro-1-(4-fluorophenyl)pent-1-yn-3-one and 10 g (45 mmol) of N-aminopyridinium iodide in 140 ml of acetonitrile was added dropwise 11 g of DBU in 50 ml of acetonitrile at 0° C. for 20 minutes under a nitrogen atmosphere. The reaction was then stirred at RT overnight. After evaporation of the solvent, the crude mixture was purified on an Al2O3 column, and the desired product recrystallized from ethyl acetate-hexane to obtain 200 mg of 1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)propan-1-one. Compound 1070.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:20][CH3:21])=[O:13]
Reactant: CCO
Reactant: O=C(O)CCCCCCCCCCBr
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCCCCCCCCCBr
Temperature: 25 °C

Procedure:
A solution of 11-bromoundecanoic acid (53 g, 0.2 mol) and concentrated sulphuric acid (1 ml) in ethanol (250 ml) was heated to reflux for 24 hr. After cooling to room temperature, the mixture was concentrated to half its original volume by evaporation under reduced pressure. The residue was poured into water (400 ml) and extracted with diethyl ether (3×300 ml). The combined extracts were then washed with saturated sodium bicarbonate solution (3×200 ml) and water (3×200 ml). After drying over MgSO4 the solvent was evaporated under reduced pressure to give a yellow coil (55.5 g, 95%)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:15][C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22]([N+:24]([O-:26])=[O:25])=[C:21]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:20]=2[CH:33]=1>C(O)C>[N+:24]([C:22]1[O:23][C:19]2[CH:18]=[CH:17][C:16]([CH2:15][O:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=3)=[CH:33][C:20]=2[C:21]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([O-:26])=[O:25]
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: O=[N+]([O-])c1oc2ccc(CBr)cc2c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1ccc(OCc2ccc3oc([N+](=O)[O-])c(-c4ccccc4)c3c2)cc1

Procedure:
To a mixture of 1 g. (0.0066 mole) of 4-hydroxyphenylacetic acid and 0.53 g. of sodium hydroxide in 100 ml. of ethanol is added 2 g. (0.006 mole) of 5-bromomethyl-2-nitro-3-phenylbenzofuran, and the mixture is heated at its reflux temperature for 16 hours. The reaction mixture is evaporated to provide a residue which is extracted thoroughly with chloroform. The residue is separated from chloroform and dissolved in water. The water is acidified to pH 3. The precipitate is separated by filtration, dissolved in dichloromethane, and the dichloromethane solution is dried. The dichloromethane solution is evaporated to provide a yellow solid which is recrystallized from ethanol to provide 4-[(2-nitro-3-phenylbenzofuran-5-yl)methoxy]phenylacetic acid, m.p. 179°-180° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:9]=[C:8]([CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:27]([N:29]3[CH2:34][CH2:33][S:32][CH2:31][CH2:30]3)=[O:28])[CH2:11]2)[O:7][N:6]=1.ClC1C=CC=C(C(OO)=[O:43])C=1>>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:9]=[C:8]([CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([F:25])([F:24])[F:26])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:27]([N:29]3[CH2:34][CH2:33][S:32](=[O:43])[CH2:31][CH2:30]3)=[O:28])[CH2:11]2)[O:7][N:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCCc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1
Product: COCCc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)N3CCS(=O)CC3)C2)n1
Yield: 39.8 %

Procedure:
113 mg (0.227 mmol) of the compound from Example 47A were reacted according to General Method 1 with 70.4 mg (0.204 mmol) of meta-chloroperbenzoic acid. Enantiomer separation of 108 mg of the racemate according to Method 9D gave 37.1 mg of the title compound from Example 46 (Enantiomer 1) and 41.8 mg of the title compound from Example 47 (Enantiomer 2).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:19]=[CH:18][C:11]2[CH2:12][CH2:13][O:14][C:15](=[O:17])[NH:16][C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:27][CH3:28]>CN(C=O)C.O>[C:1]([O:5][C:6]([C:8]1[CH:19]=[CH:18][C:11]2[CH2:12][CH2:13][O:14][C:15](=[O:17])[N:16]([CH2:27][CH3:28])[C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)c1ccc2c(c1)NC(=O)OCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)OCCc2ccc(C(=O)OC(C)(C)C)cc21

Procedure:
A mixture of 6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocycloheptene-3-carboxylic acid tert-butyl ester (1.1 g, 4.18 mmol), potassium carbonate (2.5 g, 18.1 mmol, 4.3 eq.) and iodoethane (1.67 mL, 20.87 mmol, 5 eq.) was stirred in DMF (20 mL) for 16 hours at 60° C. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried (sodium sulfate) and concentrated. Silica gel chromatography (0→20% ethyl acetate in hexanes) provided 5-ethyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocycloheptene-3-carboxylic acid tert-butyl ester as pale solid in quantitative yield: 1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.80 (dd, 1H), 7.28 (d, 1H), 4.48 (t, 2H), 3.91 (q, 2H), 3.00 (t, 2H), 1.59 (s, 9H), 1.23 (t, 3H).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1.C(O)(C)(C)C.[CH:22]1([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[NH:34][C:35]([C:37]3[N:41]4[CH:42]=[CH:43][C:44](F)=[CH:45][C:40]4=[N:39][CH:38]=3)=[O:36])[N:27]([CH2:47][C:48]3[C:49](=[O:55])[N:50]([CH3:54])[CH:51]=[CH:52][CH:53]=3)[N:26]=2)[CH2:24][CH2:23]1>O>[CH:22]1([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[NH:34][C:35]([C:37]3[N:41]4[CH:42]=[CH:43][C:44]([O:16][CH2:15][CH2:14][N:11]5[CH2:12][CH2:13][N:8]([CH3:7])[CH2:9][CH2:10]5)=[CH:45][C:40]4=[N:39][CH:38]=3)=[O:36])[N:27]([CH2:47][C:48]3[C:49](=[O:55])[N:50]([CH3:54])[CH:51]=[CH:52][CH:53]=3)[N:26]=2)[CH2:24][CH2:23]1
Reactant: CN1CCN(CCO)CC1
Reactant: Cn1cccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(F)ccn45)cccc32)c1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CN1CCN(CCOc2ccn3c(C(=O)Nc4cccc5c4c(C4CC4)nn5Cc4cccn(C)c4=O)cnc3c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A one dram vial was charged with solid potassium tert-butoxide (54 mg, 0.48 mmol), 2-(4-methylpiperazin-1-yl)ethanol (0.075 g, 0.52 mmol), and tert-butanol (0.3 mL, 3.4 mmol). The mixture was stirred at ambient temperature for 30 minutes. N-(3-cyclopropyl-1-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide (0.032 g, 0.070 mmol) was added in one portion. The mixture was heated at 88° C. with stirring for 16 hours. The mixture was cooled to ambient temperature and diluted with water until a precipitate formed. The precipitate was isolated by filtration and dried under high vacuum. Purification using silica preparative thin layer chromatography plate (20×20 cm, 0.5 mm) developed in a chamber with 10% methanol/dichloromethane with 0.6% concentrated ammonium hydroxide gave the product. MS (APCI), positive scan, m/z=581.2 (M+).
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.[CH3:9][NH:10][NH2:11]>CC(O)=O>[CH:1]1([C:4]2[CH:5]=[C:6]([NH2:7])[N:10]([CH3:9])[N:11]=2)[CH2:3][CH2:2]1
Reactant: N#CCC(=O)C1CC1
Reactant: CNN
Solvent: CC(=O)O
Product: Cn1nc(C2CC2)cc1N
Temperature: 100 °C
Reaction time: 8 h
Yield: 100.5 %

Procedure:
To a solution of 3-cyclopropyl-3-oxo-propanenitrile (2.22 g, 20.3 mmol) in HOAc (40 mL) was added methylhydrazine (40% [w/w] in water, 2.81 g, 24.4 mmol). The reaction mixture was stirred at 100° C. overnight and then concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM) to give the title compound as yellow oil (2.80 g, 100%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]1.C(=O)([O-])[O-].[K+].[K+].[C:25]1([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1.O>[C:25]1([CH:31]2[CH2:32][CH2:33][N:34]([C:11]([N:9]3[CH2:10][CH:7]([O:6][C:5]4[CH:14]=[CH:15][CH:16]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=4)[CH2:8]3)=[O:12])[CH2:35][CH2:36]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=C(Cl)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(N1CCC(c2ccccc2)CC1)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 37.1 %

Procedure:
A mixture of 2.8 g (0.01 mole) of 3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride and 1.4 g (0.01 mole) of potassium carbonate in 25 ml of tetrahydrofuran was stirred for 10 min then treated with 1.6 g (0.01 mole) of 4-phenylpiperidine. After stirring for 30 min, approximately 2 g of ice was added and stirring continued for 18 hr. The reaction mixture was diluted with 200 ml of water and the oil which separated was extracted into methylene chloride (2×50 ml). The extracts were combined, dried and concentrated in vacuo to yield 4.95 g of crude oil which solidified when cooled to -78° C. Recrystallization from isopropyl ether yielded 1.5 g (37%) of coarse white crystals, m.p. 72°-74° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[NH:19][C:18](=[O:20])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)O1.Cl[C:23]1[N:28]=[C:27]([NH:29][C:30]([C:32]2([C:35]3[CH:45]=[CH:44][C:38]4[O:39][C:40]([F:43])([F:42])[O:41][C:37]=4[CH:36]=3)[CH2:34][CH2:33]2)=[O:31])[CH:26]=[CH:25][C:24]=1[CH3:46].C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[F:43][C:40]1([F:42])[O:39][C:38]2[CH:44]=[CH:45][C:35]([C:32]3([C:30]([NH:29][C:27]4[CH:26]=[CH:25][C:24]([CH3:46])=[C:23]([C:9]5[CH:10]=[CH:11][C:12]([CH:15]6[CH2:16][CH2:17][C:18](=[O:20])[NH:19]6)=[CH:13][CH:14]=5)[N:28]=4)=[O:31])[CH2:34][CH2:33]3)=[CH:36][C:37]=2[O:41]1
Reactant: CC1(C)OB(c2ccc(C3CCC(=O)N3)cc2)OC1(C)C
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
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: [Na+]
Solvent: COCCOC
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(C2CCC(=O)N2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one (43 mg, 0.15 mmol), N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (37 mg, 0.10 mmol) and Pd(PPh3)4 (6 mg, 0.005 mmol) were placed a reaction tube. DME (1 mL) and saturated aqueous Na2CO3 (100 μL) were added and the reaction vial was stirred under N2 atmosphere at 80° C. overnight. The mixture was filtered and concentrated. The residue was dissolved in DMSO and purified by reverse-phase HPLC to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(4-(5-oxopyrrolidin-2-yl)phenyl)pyridin-2-yl)cyclopropanecarboxamide ESI-MS m/z calc. 491.2, found 492.3 (M+1)+. Retention time 1.75 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.12 (s, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.57 (d, J=1.6 Hz, 1H), 7.44-7.34 (m, 6H), 4.71 (t, J=7.1 Hz, 1H), 2.50-2.44 (m, 1H), 2.27-2.23 (m, 5H), 1.81-1.72 (m, 1H), 1.53-1.50 (m, 2H), 1.19-1.16 (m, 2H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:42]=[CH:41][C:24]([C:25]([NH:27][CH:28]6[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]6)=[O:26])=[CH:23][CH:22]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[ClH:43]>C1COCC1.CCOCC>[ClH:43].[NH:31]1[CH2:32][CH2:33][CH:28]([NH:27][C:25](=[O:26])[C:24]2[CH:41]=[CH:42][C:21]([C:18]3[N:17]=[C:16]4[N:12]([CH2:11][C:7]5[CH:6]=[C:5]6[C:10](=[CH:9][CH:8]=5)[N:1]=[CH:2][CH:3]=[CH:4]6)[N:13]=[N:14][C:15]4=[CH:20][CH:19]=3)=[CH:22][CH:23]=2)[CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc(-c3ccc4nnn(Cc5ccc6ncccc6c5)c4n3)cc2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(NC1CCNCC1)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Reaction time: 0.25 h
Yield: 95 %

Procedure:
To a solution of example 29 (0.125 g, 0.222 mmol) in THF (1 ml), ether saturated with HCl (1.5 ml) was added at 0° C. and stirred for 15 min. The precipitate formed was washed with ether and dried under vacuum to afford the title compound as light yellow solid (0.105 g. 95%). M.P.: 220-224° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.14 (d, J=3.6 Hz, 1H), 8.90 (m, 3H), 8.72 (d, J=8.7 Hz, 1H), 8.67 (d, J=7.4 Hz, 1H), 8.33 (d, J=8.5 Hz, 2H), 8.28 (m, 3H), 8.11 (dd, J=8.7, 1.5 Hz, 1H), 8.05 (d, J=8.5 Hz, 2H), 7.89 (dd, J=8.3, 4.8 Hz, 1H), 6.29 (s, 2H), 4.11 (m, 1H), 3.59 (m, 1H), 3.34 (m, 1H), 3.01 (m, 2H), 1.99 (m, 2H), 1.85 (m, 2H).
Reaction SMILES: C([O:3][P:4]([CH2:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)([CH2:6][CH2:7][CH2:8][CH3:9])=[O:5])C>Cl>[ClH:21].[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][NH:13][CH2:12][CH2:11][CH2:10][P:4]([CH2:6][CH2:7][CH2:8][CH3:9])(=[O:3])[OH:5])=[CH:20][CH:19]=1
Reactant: CCCCP(=O)(CCCNCc1ccc(Cl)cc1)OCC
Agent: Cl
Product: CCCCP(=O)(O)CCCNCc1ccc(Cl)cc1

Procedure:
A solution of 1.86 g of 3-(p-chlorobenzylamino)propyl(n-butyl)phosphinic acid ethyl ester in 30 ml of semi-concentrated hyrochloric acid is heated under reflux overnight, a clear solution forming after only 10 minutes. The solution is then cooled to 0°, whereupon a white precipitate forms. The precipitate is filtered off, washed with water and dried under reduced pressure at 60°. Recrystallisation from water and drying yield 3-(p-chlorobenzylamino)propyl(n-butyl)phosphinic acid hydrochloride having a melting point of 212°-214°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:16])=[N:13][C:12](F)=[CH:11][CH:10]=2)=[O:5])[CH3:2].C(OC(C1C=NC2C(C=1O)=CN=C([Cl:34])C=2)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:10]([C:15]=1[Cl:16])=[CH:11][CH:12]=[N:13][C:14]=2[Cl:34])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2ccc(F)nc2c1Cl
Reactant: CCOC(=O)c1cnc2cc(Cl)ncc2c1O
Product: CCOC(=O)c1cnc2c(Cl)nccc2c1Cl

Procedure:
The title compound was prepared following the procedure described for 4a using 8-chloro-4-hydroxy-[1,7]naphthyridine-3-carboxylic acid ethyl ester (11). 1H-NMR (CDCl3) δ (ppm): 1.47 (3H, t, J=7.14 Hz), 4.53 (2H, q, J=7.14 Hz), 8.13 (1H, d, J=5.8 Hz), 8.55 (1H, d, J=5.8 Hz), 9.35 (1H, s). m/z 271.0 (MH+).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].[CH2:19]([O:26][C:27](=[O:31])[C@H:28]([CH3:30])[NH2:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27](=[O:31])[C@H:28]([CH3:30])[NH:29][C:7](=[O:9])[CH:6]([CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)[CH2:5][S:4][C:1](=[O:3])[CH3:2])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Reactant: CC(=O)SCC(C(=O)O)C1CCc2ccccc21
Product: CC(=O)SCC(C(=O)N[C@@H](C)C(=O)OCc1ccccc1)C1CCc2ccccc21
Yield: 72 %

Procedure:
Using the procedure described in Example 60, but starting with 3-acetylthio-2-(1-indanyl)propanoic acid and alanine benzyl ester, N-[3-acetylthio-2-(1-indanyl)-1-oxopropyl)alanine benzyl ester is obtained in a 72% yield in the form of a white solid, having the following characteristics: m.p.: 95° C.; Rf =0.17 [cyclohexane/ethyl acetate (4:1 by volume)].
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][F:9])=[C:6]([F:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[F:13].[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:14][CH:8]([F:9])[C:7]1[C:2]([F:1])=[C:3]([F:13])[C:4]([F:12])=[C:5]([F:11])[C:6]=1[F:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: FCc1c(F)c(F)c(F)c(F)c1F
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1c(F)c(F)c(C(F)Br)c(F)c1F

Procedure:
A mixture of pentafluorobenzyl fluoride (0.37 g), N-bromosuccinimide (0.36 g) and dry carbon tetrachloride (30 ml) was heated under reflux and irradiated with ultra violet light for a period of 4 hr. The reaction mixture was cooled, the insoluble material was removed by filtration and the solvent was removed by distillation under reduced pressure to give α-bromopentafluorobenzyl fluoride. The product was characterised by p.m.r. spectroscopy. Chemical shift δppm (solvent CDCl3): 7.63 (d, J=48 Hz).
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[C:26]([F:29])([F:28])[F:27])([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:33]>CN(C=O)C>[CH3:33][O:9][C:7]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:17][CH:16]=[CH:15][C:14]=2[C:26]([F:29])([F:27])[F:28])([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8]
Reactant: CC(O)(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(C)(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Reaction time: 0.33 h

Procedure:
1-Phenyl-1-[4-phenyl-8-(trifluoromethyl)quinolin-3-yl]ethanol (Example 39, 0.096 g, 0.243 mmol) was taken into DMF (3 mL) then NaH (0.020 g, 0.487 mmol) was added and stirred for 20 minutes. Lastly, iodomethane (0.08 mL, 1.22 mmol) was added and stirring was continued for 30 minutes. The reaction was quenched with water and extracted with ether. The combined organics were dried over magnesium sulfate and concentrated. The resulting material was purified via column chromatography using 5% ethyl acetate in hexane as the eluent. MS (ESI) m/z 408 ([M+H]+); 1H NMR (CDCl3) δ 9.59 (s, 1H), 8.01 (d, J=6.8 Hz, 1H), 7.31 (m, 3H), 7.12 (m, 5H), 7.0 (m, 2H), 6.74 (dd, J=7.5 and 1.2 Hz, 1H), 6.63 (dd, J=7.7 and 1.3 Hz, 1H), 3.06 (s, 3H), 1.8 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:20]I.O>CN(C=O)C>[CH3:20][N:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1)[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)Nc1ccc([N+](=O)[O-])cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])cn1
Reaction time: 0.33 h
Yield: 100 %

Procedure:
To 0.378 g (1.58 mmol) of the above nitro compound in DMF (6 mL) at 0° C. was added 0.067 g (2.80 mmol) of sodium hydride. After 20 min, 0.12 mL (1.93 mmol) of methyl iodide was added, and the mixture was stirred for 2 hrs. Water was added, and the mixture was extracted with EtOAc (×4). The combined organic layer was washed successively with 1M HCl, sat. NaHCO3 solution, and brine, dried (Na2SO4), and concentrated, to give 0.40 g (99% yield) of tert-butyl methyl(5-nitro-2-pyridinyl)carbamate: 1H NMR (CDCl3) δ 9.19 (d, J=2.7 Hz, 1H), 8.36 (dd, J=9.4, 2.7 Hz, 1H), 8.14 (dd, J=9.4, 0.3 Hz, 1H), 3.50 (s, 3H), 1.57 (s, 9H); LCMS (APCI−) m/z: 253 (MH+, 100%).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:13]([C:15]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[NH:20][C:19]2=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=[C:18]2[O:17][CH2:16]1)[CH3:14]>O1CCCC1.C(N(CC)C(C)C)(C)C>[CH2:13]([C:15]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[N:20]2[C:2](=[O:4])[NH:25][C:21]3=[CH:22][CH:23]=[CH:24][C:18](=[C:19]23)[O:17][CH2:16]1)[CH3:14]
Reactant: CCC1(c2ccccn2)COc2cccc(N)c2N1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC1(c2ccccn2)COc2cccc3[nH]c(=O)n1c23
Temperature: 25 °C
Reaction time: 1 h
Yield: 213.3 %

Procedure:
Triphosgene (40 mg, 0.1 mmol) was added to a solution of 3-ethyl-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-5-amine (80 mg, 0.3 mmol) in tetrahydrofuran (5 mL) and N,N-diisopropylethylamine (0.1 mL). The reaction was stirred at room temperature for 1 h and was then partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude 4-ethyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (0.060 g. 60%). LCMS calculated for C16H16N3O2 (M+H)+: m/z=282.1. found: 282.0.
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][NH:6][C:7](=[O:28])[C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[C:11]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:10][CH:9]=2)[CH2:3][CH2:2]1.[NH2:30][OH:31]>CO>[CH:1]1(/[C:4](=[N:30]\[OH:31])/[CH2:5][NH:6][C:7](=[O:28])[C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[C:11]([O:22][CH2:23][C:24]([F:26])([F:25])[F:27])=[N:10][CH:9]=2)[CH2:2][CH2:3]1
Reactant: NO
Reactant: O=C(NCC(=O)C1CC1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(Cl)c2)c1
Solvent: CO
Product: O=C(NC/C(=N/O)C1CC1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(Cl)c2)c1
Reaction time: 18 h
Yield: 90 %

Procedure:
To a solution of 0.100 g N-(2-cyclopropyl-2-oxo-ethyl)-5-(3,4-dichloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinamide in 1.0 ml methanol was added 0.052 g of 50% aqueous hydroxylamine and the mixture was kept at ambient temperature for 18 h. The solvent was evaporated and the residue was purified by chromatography on silica gel with a gradient of heptane:ethyl acetate=9:1 to 1:1 to yield 0.093 g of the title compound as white crystals. MS (EI): 462.0599 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:23])/[CH:5]=[CH:6]/[CH:7]=[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])C.[OH-].[Na+]>CO>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])=[CH:7]/[CH:6]=[CH:5]/[C:4]([OH:23])=[O:3]
Reactant: CCOC(=O)/C=C/C=C(c1ccccc1F)c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C=C/C=C(c1ccccc1F)c1ccccc1F
Yield: 93.7 %

Procedure:
As before. (E)-5.5-bis(2-fluorophenyl)-2,4-pentadienoic acid ethyl ester (1.7 g) in methanol (15 mL) was carried out using 4N sodium hydroxide (2.5 mL). After acidification, the product was extracted into dichloromethane (2×50 mL). The combined extracts were dried and evaporated and the residue crystallized from ether-hexane to provide 1.45 g of (E)-5,5-bis(2-fluorophenyl)-2,4-pentadienoic acid, mp 159°-160° C. Anal. Calculated for C17H12F2O2 : C, 71.32; H, 4.22; F, 13.27 Found: C, 71.09; H, 4.42; F, 13.26.