Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[O:44][N:43]=[CH:42][CH:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:54])C=1.O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[O:44][N:43]=[CH:42][CH:41]=5)=[O:54])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:45]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4ccno4)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4ccno4)cc2)CCN3CC(C)C)cc1
Yield: 50.2 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(isoxazol-5-ylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (200 mg) in dichloromethane (20 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (118 mg) in dichloromethane (20 ml) at −78° C. After finishing the dropping, water was added to the mixture, an aqueous solution of saturated sodium bicarbonate was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=1:1→1:4), and was recrystallized from hexane-ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(isoxazol-5-ylmethyl) sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (103 mg) (Compound 328) as yellow crystals, and was recrystallized from hexane-ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(isoxazol-5-ylmethyl) sulfonyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (72.8 mg) (Compound 329) as yellow crystals.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(=O)([O-])[O-].[K+].[K+].C1(C(C2C=CC=CC=2)[N:18]2[CH2:21][CH:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[CH2:19]2)C=CC=CC=1>C(Cl)Cl>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[O:22][CH:20]1[CH2:21][N:18]([C:1]([Cl:4])=[O:2])[CH2:19]1
Reactant: O=C(Cl)Cl
Reactant: Clc1ccccc1OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(Cl)N1CC(Oc2ccccc2Cl)C1
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
A mixture of 12 g (0.122 mol) of phosgene and 17 g (0.122 mol) of potassium carbonate in 350 ml of methylene chloride was stirred under nitrogen for 30 min then cooled in an ice water bath while 35.6 g (0.102 mol) of 1-(diphenylmethyl)-3-(2-chlorophenoxy)azetidine in 50 ml of methylene chloride was added dropwise. The reaction mixture was removed from the bath and stirred for 3 h; then treated with small pieces of ice to control the decomposition of the excess phosgene. When no further evolution of carbon dioxide was evident, the reaction mixture was treated with 20 ml of water and the methylene chloride solution decanted from the inorganic paste. After concentrating in vacuo, trituration of the residue (51 g) with hexane yielded, upon filtration, 20.7 g (82.5%) of white crystalline product, mp 80°-82° C. A sample was recrystallized from hexane for elemental analysis, mp 80°-82° C.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[Cl:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[CH:18]=[N:17][CH:16]=[C:15]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:14]=3[C:13](=[O:33])[C:12]=2[C:11](F)=[CH:10][CH:9]=1>N1C=CC=CC=1>[Cl:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[CH:18]=[N:17][CH:16]=[C:15]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:14]=3[C:13](=[O:33])[C:12]=2[C:11]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[CH:10][CH:9]=1
Reactant: COc1ccc(COc2cncc3c2C(=O)c2c(F)ccc(Cl)c2C3=O)cc1
Reactant: CN(C)CCN
Solvent: c1ccncc1
Product: COc1ccc(COc2cncc3c2C(=O)c2c(NCCN(C)C)ccc(Cl)c2C3=O)cc1
Reaction time: 3 h

Procedure:
A pyridine solution (0.4 mL) of N, N-dimethylethylenediamine (0.049 g) is added to 9-chloro-6-fluoro-4-(p-methoxybenzyloxy)benzo[g ]isoquinoline-5,10-dione of Preparative Example 29 (0.011 g) and the resultant solution is stirred under a nitrogen atmosphere for 1.75 h at room temperature. The excess amine and pyridine are removed under a slow stream of nitrogen. The residue is placed under vacuun for 3 h and purified by silica gel column chromathography commencing with 1% to 2% methanol in dichloromethane. The removal of the eluents yields 9-chloro-6-[(2-dimethylaminoethyl)amino]-4-(p-methoxybenzyloxy)benzo[g]isoquinoline-5,10-dione as a purple solid (10 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[Br-].[CH2:33]([O:35][C:36](=[O:40])[CH2:37][CH2:38][Zn+])[CH3:34].C1COCC1>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].[OH-].[NH4+]>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([CH2:38][CH2:37][C:36]([O:35][CH2:33][CH3:34])=[O:40])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: COc1ccc2c(Cl)ccnc2c1
Reactant: CCOC(=O)CC[Zn+]
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccnc2cc(OC)ccc12

Procedure:
4-chloro-7-methoxyquinoline (0.35 g, 2 mmol), tri-t-butylphosphonium tetrafluoroborate (0.05 g, 0.2 mmol), and tris(dibenzylideneacetone)dipalladium (0) (0.08 g, 0.09 mmol) were combined. The reaction vessel was purged and flushed with nitrogen three times, followed by addition of 3-ethoxy-3-oxopropylzinc bromide in THF (10 mL, 5 mmol, 0.5 M). The reaction mixture was microwaved at 150° C. for 60 minutes. Upon completion, ammonium hydroxide (10 mL) was added. After 30 minutes the mixture was filtered and the filtrate was partitioned between water and ethyl acetate. Extracted with ethyl acetate (3×20 mL). The organic layers were combined, washed with brine, dried over magnesium sulfate, and concentrated. Purified by MPLC with a gradient of 20 to 50% EtOAc in CH2Cl2. (ESI, pos. ion) m/z: 354.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][C:11]=2[CH3:18])[CH:5]=[CH:6][C:7]=1[CH:8]=[O:9].Cl.[NH+]1C=CC=CC=1.Cl>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=2[CH3:18])[CH:5]=[CH:6][C:7]=1[CH:8]=[O:9]
Reactant: COc1ccc(-c2ccc(C=O)c(Cl)c2)c(C)c1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Product: Cc1cc(O)ccc1-c1ccc(C=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.6 %

Procedure:
3-Chloro-4′-methoxy-2′-methyl-1,1′-biphenyl-4-carbaldehyde (1.0 g, 3.84 mmol) and pyridinium HCl (6 g) in a sealed tube was heated at 195° C. with stirring for 1 hr. The reaction mixture was cooled to room temperature and stirred with 2 N HCl solution and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (×2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporation of the solvent provided (1 g) dark green solid. The product was used without any further purification. An analytical sample was obtained by HPLC purification giving a white solid; mp 125-127° C.; 1H NMR (DMSO-d6): δ 2.21 (3H, s), 6.68-6.72 (2H, m), 7.11 (1H, d, J=8.15 Hz), 7.47 (1H, d, J=7.89 Hz), 7.55 (1H, d, J=1.48 Hz), 7.89 (1H, d, J=7.98 Hz), 9.62 (1H, s), 10.2=35 (1H, s); MS (ESI) m/z 245/247 (M−H)−, 247/249 (M+H)+.
Reaction SMILES: [C:1]([NH2:7])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[N+:8]([C:11]1C=C(C=C[CH:18]=1)C=O)([O-:10])=[O:9].N1CCCCC1.C(O)(=O)C>C(O)(C)C>[C:3](/[C:2](=[C:11](/[N+:8]([O-:10])=[O:9])\[CH3:18])/[C:1]([NH2:7])=[O:6])(=[O:4])[CH3:5]
Reactant: CC(=O)CC(N)=O
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: C1CCNCC1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC(=O)/C(C(N)=O)=C(\C)[N+](=O)[O-]
Yield: 117.5 %

Procedure:
A mixture of 10 g of acetoacetamide and 15 g of 3-nitrobenzaldehyde in 100 ml of isopropanol is stirred at 35° C. for 4 hours in the presence of 0.3 ml of piperidine and 0.5 ml of acetic acid. The precipitated yellow crystals are collected by filtration to give 20 g of α-acetyl-3-nitrocrotonamide, melting at 159°-161° C.
Reaction SMILES: C(Br)C.[Mg].[CH3:5][CH:6]([OH:9])[C:7]#[CH:8].[CH3:10][C:11]([CH3:18])([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH3:12]>O1CCCC1>[C:11]([C:13]([OH:17])([CH2:14][CH2:15][CH3:16])[C:8]#[C:7][CH:6]([OH:9])[CH3:5])([CH3:18])([CH3:12])[CH3:10]
Reactant: CCCC(=O)C(C)(C)C
Reactant: C#CC(C)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCBr
Product: CCCC(O)(C#CC(C)O)C(C)(C)C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
Over a period of 30 min, a solution of 40.7 g (374 mmol) of ethyl bromide in 100 mL of dry tetrahydrofuran was added dropwise to a stirred suspension of 9.08 g (374 mmol) of magnesium turnings in 5 mL of dry tetrahydrofuran, with the reaction being initiated by occasional heating with a heat gun. The reaction mixture was then stirred for additional 3 h at reflux. The reaction was allowed to cool down to room temp., and a solution of 12.6 g (180 mmol) of but-3-yn-2-ol in 80 mL of dry tetrahydrofuran was added dropwise with stirring. The reaction mixture was then again heated to reflux for 4 h, prior to removal of the heating bath. At room temp., a solution of 25.0 g (195 mmol) of 2,2-dimethylhexan-3-one in 90 mL of dry tetrahydrofuran was added with stirring within 35 min, and the reaction mixture was refluxed for another 2 d with stirring. The reaction mixture was then allowed to cool to room temp., and quenched with 500 mL of an aqueous satd. NH4Cl solution. The aqueous layer was extracted three times with 500 mL of ether each, the combined organic extracts were dried with sodium sulfate, and the solvent was evaporated on a rotary evaporator to provide 32.3 g (90%) of crude 5-tert-butyloct-3-yne-2,5-diol as a slightly yellowish oil, which was employed without further purification. A solution of 20.8 g (105 mmol) of this product in 300 mL of ethanol was hydrogenated by stirring at ambient pressure and temp. in an atmosphere of hydrogen in the presence of 3.11 g (2.92 mmol) of 10% palladium on barium sulfate and 300 mg (2.32 mmol) of quinoline. After 10 h of stirring, the catalyst was filtered off over a pad of Celite, and the solvent was removed on a rotary evaporator to provide 20.7 g (99%) of crude (3Z)-5-tert-butyloct-3-ene-2,5-diol, of which 19.6 g (98 mmol) was heated for 45 min in a Kugelrohr apparatus to 155° C./280 mbar in the presence of 2.00 g (14.7 mmol) of KHSO4. The evaporating reaction product was trapped in a bulb at −80° C., and further purified by flash chromatography (400 g of silica-gel, pentane/ether, 98:2) to afford 7.26 g of product. This was then distilled in a Kugelrohr apparatus to furnish at 70-80° C./20 mbar 6.24 g (34%) of the title compound as a colorless odoriferous liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6].C[O:12]C(OC)N(C)C.O.I([O-])(=O)(=O)=O.[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]=[O:12])[C:5]#[N:6]
Reactant: COC(OC)N(C)C
Reactant: Cc1ccc(C#N)cc1F
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C=O)c(F)c1

Procedure:
The reaction was carried out under argon. 3-Fluoro-4-methylbenzonitrile (121 g, 895 mmol) and N,N-dimethylformamide dimethyl acetal (245 g, 2.06 mol) were dissolved in DMF (1.8 liters) and stirred under reflux overnight. The contents of the flask was then poured into water (2 liters), the mixture was extracted twice with ethyl acetate and the combined organic phases were washed with saturated sodium chloride solution. The organic phase was concentrated, and the residue was dissolved again in THF/water (1:1, 2.7 liters). Sodium periodate (503 g, 2.35 mol) was added, and the mixture was stirred at room temperature for one hour. The precipitate was then separated off, and the filtrate was recovered and extracted repeatedly with ethyl acetate. The combined organic phases were washed once with saturated sodium bicarbonate solution and once with saturated sodium chloride solution, dried and concentrated to give an oil. This was purified by column chromatography on silica gel (mobile phase: petroleum ether/dichloromethane 6:4, then 4:6, finally pure dichloromethane). The product fractions were concentrated. This gave 28.0 g (20% of theory) of the target compound as a white crystalline solid.
Reaction SMILES: [C:1]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])(OC(C)(C)C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.OC[CH:40]=[CH:41][C:42]1[CH:64]=[CH:63][C:45]([C:46]([NH:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[NH:55][C:56](=[O:62])[O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:47])=[CH:44][CH:43]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:15]1([CH3:18])[CH:14]=[CH:13][C:12]([S:9]([NH:8][CH2:1][CH:40]=[CH:41][C:42]2[CH:64]=[CH:63][C:45]([C:46]([NH:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=3[NH:55][C:56](=[O:62])[O:57][C:58]([CH3:59])([CH3:60])[CH3:61])=[O:47])=[CH:44][CH:43]=2)(=[O:10])=[O:11])=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C=CCO)cc1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)OC(C)(C)C)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NCC=Cc2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)cc1
Reaction time: 16 h

Procedure:
To a stirred solution of N-Boc-4-tolylsulfonamide (221 mg, 0.81 mmol) and PPh3 (427 mg, 1.63 mmol) in anhydrous THF (4 ml) under nitrogen was successively added a solution of compound XVIII (200 mg, 0.54 mmol) in anhydrous THF (1 ml) and diethyl azodicarboxylate (DEAD) (214 μl, 1.36 mmol). After 16 h, the reaction mixture was quenched with water and diluted with AcOEt. After separation the organic layer was successively washed with water and brine, dried over MgSO4, filtered, and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/hexane:40/60) to afford the title compound XVIIg (337 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C@@H:8]([NH:18][C:19](=[O:31])[CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=3)[NH:23][CH:22]=2)[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[C:5]([C:32]2[CH:33]=[CH:34][C:35](F)=[C:36]([CH:40]=2)[C:37]([NH2:39])=[O:38])=[CH:4][CH:3]=1.NC1N=C(C(NC(=O)CC2C3C(=CC=C(F)C=3)NC=2)CC2C=C(F)C=C(F)C=2)C(Br)=CC=1.CC1(C)C(C)(C)OB(C2C=C(C=CC=2)C(N)=O)O1>>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]([NH:18][C:19](=[O:31])[CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=3)[NH:23][CH:22]=2)[CH2:9][C:10]2[CH:11]=[C:12]([F:17])[CH:13]=[C:14]([F:16])[CH:15]=2)[C:5]([C:32]2[CH:40]=[C:36]([CH:35]=[CH:34][CH:33]=2)[C:37]([NH2:39])=[O:38])=[CH:4][CH:3]=1
Reactant: NC(=O)c1cc(-c2ccc(N)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cc2c[nH]c3ccc(F)cc23)ccc1F
Agent: CC1(C)OB(c2cccc(C(N)=O)c2)OC1(C)C
Agent: Nc1ccc(Br)c(C(Cc2cc(F)cc(F)c2)NC(=O)Cc2c[nH]c3ccc(F)cc23)n1
Product: NC(=O)c1cccc(-c2ccc(N)nc2C(Cc2cc(F)cc(F)c2)NC(=O)Cc2c[nH]c3ccc(F)cc23)c1

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound 1H of Example 1 utilizing 1G and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide. 1H NMR (400 MHz, CDCl3) δ 8.06-7.95 (m, 4H), 7.50-7.38 (m, 2H), 7.26-7.20 (m, 1H), 7.13 (m, 1H), 6.89-6.81 (m, 3H), 6.60 (d, J=8.9 Hz, 1H), 6.50-6.39 (m, 2H), 6.07 (d, J=5.8 Hz, 2H), 5.43 (d, J=8.8 Hz, 1H), 3.59 (s, 2H), 2.88 (dd, J=13.6, 9.3 Hz, 1H), 2.76 (dd, J=13.7, 7.5 Hz, 1H). MS (m/z) 535.4 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=3[N:7]([CH3:19])[C:6]=2[C:5]([C:20]#[N:21])=[CH:4][N:3]=1.[NH4+:22].[OH-]>CCO>[NH2:22][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=3[N:7]([CH3:19])[C:6]=2[C:5]([C:20]#[N:21])=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: Cn1c2cc(C(F)(F)F)ccc2c2c(Cl)ncc(C#N)c21
Agent: [OH-]
Solvent: CCO
Product: Cn1c2cc(C(F)(F)F)ccc2c2c(N)ncc(C#N)c21
Temperature: 145 °C

Procedure:
The product of Step 2 was dissolved in a 2:3 (v/v) mixture of EtOH and conc. NH4OH (0.027 M) in a stainless steel Parr pressure vessel. The vessel was sealed and the reaction was heated for 16 h at 145° C. After cooling to 0° C., the mixture was concentrated to dryness under vacuum and the resulting solid was stirred with 1:10 EtOAc:hexanes containing 10% MeOH to give the title compound as an off-white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[N:19]2[C:14]([CH:15]=[CH:16][CH:17]=[CH:18]2)=[C:13](N=C=O)[CH:12]=1)=[O:10])[C:2]1[CH:7]=CC=CC=1.C(OC(=O)CBr)C=C.[CH2:31]([O:38][C:39](=[O:42])CC)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([O:38][C:39]([C:13]1[CH:12]=[C:11]([C:9]([O:8][CH2:1][CH:2]=[CH2:7])=[O:10])[N:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[CH:18]2)=[O:42])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C=Nc1cc(C(=O)OCc2ccccc2)n2ccccc12
Reactant: CCC(=O)OCc1ccccc1
Agent: C=CCOC(=O)CBr
Product: C=CCOC(=O)c1cc(C(=O)OCc2ccccc2)c2ccccn12

Procedure:
The title compound was prepared using the protocol described in steps A and B for the preparation of 1-isocyanato-indolizine-3-carboxylic acid benzyl ester scheme A6 using bromo-acetic acid allyl ester in step A and propionic acid benzyl ester in step B. TLC, Rf (c-hexane/EtOAc 1:1)=0.8; MS (LC/MS): 336.1 [M+H]+, 358.1 [M+Na]+, 693.2 [2M+Na]+; tR (HPLC conditions a): 4.55 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:5][CH:4]=1.[H][H]>[Pd].C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(C#CCCCO)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(CCCCCO)cc1
Yield: 93.2 %

Procedure:
A solution of 16 (7.1 g, 37 mmol) in 150 dry ethanol (150 mL) was placed in a 0.5 L Parr flask and palladium on carbon (0.92 g, 5% wet. Pd/C) was added as a suspension in ethanol (25 mL). The reaction mixture was shaken at 50 psi of hydrogen pressure at room temperature for 24 hours. After this time, the mixture was filtered through a silica gel pad and the solvent was removed at reduced pressure. The residue was purified by flash chromatography (silica gel, 1:3 ethyl acetate/ hexanes) to provide 17 (6.7 g, 92%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 1.48 (m, 2H), 1.60 (m, 4H), 2.58 (m, 2H), 3.63 (m, 2H) 3.80 (s, 3H), 6.83 (d, 2H), 7.10 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][C:12]#[N:13].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:8][C:7]1[C:2]([CH3:1])=[C:3]([CH2:11][C:12]#[N:13])[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1c(CC#N)cccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1c(N)cccc1CC#N
Yield: 80.6 %

Procedure:
(2-Methyl-3-nitro-phenyl)-acetonitrile (16.6 g ) was dissolved in 400 ml of ethyl acetate and 0.83 g of 10% palladium on carbon (Degussa type) was added; and the reaction mixture was placed under 50 lb/in2 of hydrogen on the Parr shaker for 4 hr. The catalyst was filtered off; the solvent was evaporated; and the residue was purified by flash chromatography on silica gel eluting with ethyl acetate:hexane (2:3), yielding 11.1 g of (3-amino-2-methyl-phenyl)-acetonitrile as a white solid. ##STR119##
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH2:22])[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:12][CH2:11][CH2:10][CH2:9]1.Cl[C:28]1[N:33]=[CH:32][C:31]([C:34]([N:36]2[CH2:41][CH2:40][CH:39]([N:42]([CH3:44])[CH3:43])[CH2:38][CH2:37]2)=[O:35])=[CH:30][CH:29]=1>>[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH:22][C:28]4[CH:29]=[CH:30][C:31]([C:34]([N:36]5[CH2:37][CH2:38][CH:39]([N:42]([CH3:44])[CH3:43])[CH2:40][CH2:41]5)=[O:35])=[CH:32][N:33]=4)[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CN(C)C1CCN(C(=O)c2ccc(Cl)nc2)CC1
Reactant: Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C1CCN(C(=O)c2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nc2)CC1

Procedure:
Compound 364 was prepared as a light yellow solid (TFA salt) from compound 4 and compound 365 using chemistry similar to that described in example 200. 1H NMR (500 MHz, CD3OD) δ ppm 9.57 (1 H, s), 9.27 (1 H, s), 8.56-8.64 (2 H, m), 8.51 (1 H, d, J=1.7 Hz), 8.44 (1 H, d, J=8.8 Hz), 8.02 (1 H, dd, J=8.7, 2.3 Hz), 5.47 (1 H, quin, J=8.9 Hz), 3.49-3.60 (1 H, m, J=12.0, 12.0, 3.8, 3.7 Hz), 2.91 (6 H, s), 2.48-2.61 (2 H, m), 2.02-2.34 (6 H, m), 1.85-1.98 (2 H, m), 1.70-1.85 (2 H, m, J=12.3, 12.3, 12.2, 4.4 Hz). LCMS-ESI (POS), M/Z, M+1: Found 485.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[Br:14][CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH2:17][CH2:16][CH2:15][Br:14]
Reactant: BrCCCBr
Reactant: COC(=O)Cc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)Cc1ccc(OCCCBr)c(F)c1

Procedure:
A solution of methyl 3-fluoro-4-hydroxyphenylacetate (25.545 grams) in 2-butanone (300 mL) was treated with 1,3-dibromopropane (48.79 mL) and potassium carbonate (50.859 grams). The mixture was refluxed for 4 hours. The reaction mixture was partitioned between isopropyl acetate and pH 4 buffer. The organic was washed once with water, then dried over magnesium sulfate. The organic was filtered and evaporated to an oil which was chromatographed over silica gel with hexane/methylene chloride (2:1) to afford the title compound. This compound was taken forward without further purification.
Reaction SMILES: [OH-].[K+].[CH3:3][CH:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1>O>[CH3:3][CH:4]1[CH2:8][CH2:7][C:6](=[CH:15][C:14]2[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][CH:13]=2)[C:5]1=[O:9]
Reactant: CC1CCCC1=O
Reactant: O=Cc1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC1CCC(=Cc2ccc(Cl)cc2)C1=O
Temperature: 120 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
A solution of 16.8 g of 85% strength aqueous potassium hydroxide solution and 1,500 ml of water was charged to a 31 stainless-steel autoclave, 294 g of 2-methylcyclopentanone and 421.8 g of 4-chlorobenzaldehyde were added, and the mixture was then heated to 120° C. under the intrinsic pressure. Stirring was subsequently carried out at this temperature for 3 hours. After cooling to room temperature, the finely particulate yellow product was filtered off with suction, washed to neutrality with water and then dried in a vacuum oven at 60° C. In this way 658.5 g of 2-methyl-5-(4-chlorobenzylidene)-cyclopentanone (93.1% pure) were obtained. This corresponds to a yield of 93% of theory.