Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([F:22])[C:19]([F:21])=[CH:20][C:15]=3[N:14]=[C:13]2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[OH:30])=[CH:7][CH:6]=1.Br[CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH3:1][O:2][C:3](=[O:31])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([F:22])[C:19]([F:21])=[CH:20][C:15]=3[N:14]=[C:13]2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[O:30][CH2:33][CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:7][CH:6]=1
Reactant: BrCC1CCCC1
Reactant: COC(=O)Cc1ccc(Cn2c(-c3ccc(Cl)cc3O)nc3cc(F)c(F)cc32)cc1
Product: COC(=O)Cc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from {4-[2-(4-chloro-2-hydroxy-phenyl)-5,6-difluoro-benzoimidazol-1-ylmethyl]-phenyl}-acetic acid methyl ester and bromomethyl-cyclopentane (CAS Reg. No. 3814-30-0). Brown sticky solid (61%). MS (Turbo Spray): m/z=525.4 (M+H).
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:27][CH2:26][CH2:25][C@H:6]1[C:7]([N:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])(O)=[O:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:43]12([CH2:53][NH2:54])[CH2:52][CH:47]3[CH2:48][CH:49]([CH2:51][CH:45]([CH2:46]3)[CH2:44]1)[CH2:50]2>C(#N)C>[C:43]12([CH2:53][NH:54][C:1]([CH2:4][N:5]3[CH2:27][CH2:26][CH2:25][C@H:6]3[C:7]([N:9]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])=[O:2])[CH2:50][CH:49]3[CH2:48][CH:47]([CH2:46][CH:45]([CH2:51]3)[CH2:44]1)[CH2:52]2
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)NCC12CC3CC(CC(C3)C1)C2
Yield: 10.2 %

Procedure:
Using the procedure described previously, a solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (106 mg, 0.28 mmol), triethylamine (158 uL, 1.13 mmol, 4 eq) in acetonitrile (1.5 mL, was cooled to 0° C. and treated with isobutyl chloroformate (40.5 uL, 0.31 mmol, 1.1 eq) followed by 1-adamantanemethylamine (100 uL, 0.57 mmol, 2 eq). After TLC indicated the reaction was complete, the mixture was purified by HPLC to provide 15 mg (10%) of L-isoleucine, N-[1-(adamant-1-ylmethylcarbamoylmethyl)-L-prolyl] benzylamide.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.O[CH2:31][CH2:32][N:33]([CH3:41])[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37]>>[C:36]([O:35][C:34](=[O:40])[N:33]([CH2:32][CH2:31][N:19]1[C:18](=[O:23])[C:17](=[CH:16][C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[N:7]([CH2:6][C:5]2[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=2[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]3)[S:21][C:20]1=[O:22])[CH3:41])([CH3:39])([CH3:38])[CH3:37]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN(CCN1C(=O)SC(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O)C(=O)OC(C)(C)C

Procedure:
(2-{5-[1-(4-Chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-2,4-dioxothiazolidin-3-yl}ethyl)methylcarbamic acid tert-butyl ester was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and tert-butyl N-(2-hydroxyethyl)-N-methylcarbamate following General Procedure J.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]([C:6]1[N:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:8]2[C:14]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])=[C:13]([F:23])[CH:12]=[CH:11][C:9]=2[N:10]=1)[CH3:5].[NH2:30][C:31]1[C:36]([C:37]#[N:38])=[C:35](Cl)[N:34]=[CH:33][N:32]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:30][C:31]1[C:36]([C:37]#[N:38])=[C:35]([NH:3][C@H:4]([C:6]2[N:7]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:8]3[C:14]([C:15]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)=[O:16])=[C:13]([F:23])[CH:12]=[CH:11][C:9]=3[N:10]=2)[CH3:5])[N:34]=[CH:33][N:32]=1
Reactant: C[C@H](N)c1nc2ccc(F)c(C(=O)N3CCOCC3)c2n1-c1ccccc1
Reactant: N#Cc1c(N)ncnc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(C(=O)N3CCOCC3)c2n1-c1ccccc1
Temperature: 90 °C
Yield: 41.7 %

Procedure:
To a solution of [2-((S)-1-aminoethyl)-5-fluoro-3-phenyl-3H-benzoimidazol-4-yl]-morpholin-4-ylmethanone dihydrochloride (300 mg, 0.69 mmol) in IPA (5 mL) was added 4-amino-6-chloropyrimidine-5-carbonitrile (108 mg, 0.69 mmol) and DIPEA (353 mL, 2.07 mmol) and the reaction mixture heated at 90° C. for 16 h. The reaction mixture was concentrated in vacuo and the resultant residue subjected to flash chromatography (SiO2, eluting with 0-4% methanol in EtOAc). The product was triturated with diethyl ether. The solid obtained was purified by prep HPLC (C18 Phenomenex column, 10-90% MeCN in water 0.1% formic acid, 20 min gradient) to give the title compound as a white solid (140 mg, 42%). 1H NMR 400 MHz δ (DMSO-d6) (mixture of rotamers): 7.80 (0.5H, s), 7.76 (0.5H, s), 7.73 (1H, dd, J=8.8, 4.8 Hz), 7.67 (0.5H, d, J=7.5 Hz), 7.54 (0.5H, d, J=7.2 Hz), 7.50-7.31 (5H, m), 7.19-7.07 (3H, m), 5.28 (0.5H, quin, J=7.1 Hz), 5.21 (0.5H, quin, J=7.0 Hz), 3.48-3.35 (1H, m), 3.34-3.18 (4H, m), 3.10-2.87 (2H, m), 2.56-2.47 (1H, m), 1.47-1.40 (3H, m), LCMS (Method K): RT=2.96 min, [M+H]+=487, RT=3.00 min, [M+H]+=487 (mixture of rotamers)
Reaction SMILES: Br[C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH:7]=[O:8].[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>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:14]1([CH3:13])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH:7]=[O:8]
Reactant: Cc1ccccc1B(O)O
Reactant: O=Cc1sc2ccccc2c1Br
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccccc1-c1c(C=O)sc2ccccc12
Temperature: 130 °C

Procedure:
A mixture of 3-bromobenzo[b]thiophene-2-carbaldehyde (500 mg, 2.07 mmol), 2-methylphenylboronic acid (394 mg, 2.90 mmol), Pd(PPh3)4 (243 mg, 0.21 mmol), Cs2CO3 (2.02 g, 6.21 mmol) in dioxane (12 mL) and water (4 mL) was degassed with a stream of nitrogen and then was heated at 130° C. in a sealed tube using microwave irradiation for 45 min. The reaction mixture was extracted with EtOAc, then the organic layer was washed with water, followed by brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-70% DCM in cyclohexane) affording the title compound (quantitative yield). LCMS: RT 4.16 min.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[N:19]=1>>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:25][CH2:26][N:27]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C:9]([NH:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:5][CH:4]=3)[CH2:28][CH2:29]2)[N:19]=1
Reactant: COc1ccnc(N2CCNCC2)n1
Reactant: CC(=O)NC(C)(C)c1ccc(CCl)cc1
Product: COc1ccnc(N2CCN(Cc3ccc(C(C)(C)NC(C)=O)cc3)CC2)n1

Procedure:
By similar reaction and treatment to that in Example 1(5) using N-(1-(4-chloromethylphenyl)-1-methylethyl)acetamide obtained in Example 95(4) instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(4-methoxypyrimidin-2-yl)piperazine obtained in Example 98(2) instead of phenylpiperazine, the title compound was obtained as white crystals, m.p.=160-162° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[C:29]1([C:35]#[CH:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C.[Al]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:28][N:25]1[CH2:24][CH2:23][N:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15]/[CH:14]=[C:5]3\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]4[C:4]\3=[CH:3][C:2]([C:36]#[C:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:11][CH:10]=4)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1
Reactant: C#Cc1ccccc1
Reactant: CN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Al]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(C#Cc5ccccc5)cc43)cc2)CC1
Temperature: 70 °C
Yield: 53.6 %

Procedure:
A mixture of (4Z)-6-bromo-4-({[4-(4-methylpiperazin-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione (0.10 g, 0.23 mmol), 0.03 mL (0.27 mmol) of phenylacetylene, 0.04 g (0.046 mmol) of dichlorobis(triphenylphosphine)-palladium(II), 0.0043 g (0.023 mmol) of CuI, and 0.12 mL (1.14 mmol) of triethylamine in 2 mL of N,N′-dimethylformamide is added to a 10 mL round bottom flask, sealed with a rubber septum, de-aired and backfilled with nitrogen gas 3 times, and wrapped around with aluminum foil. The reaction mixture is stirred vigorously at 70° C. in an oil bath under nitrogen. Mass spectroscopy suggested the completion of reaction after 45 min. The reaction mixture is filtered through celite, and subsequently evaporated under high-pressure vacuum to brown solid. The solid is dissolved in warm chloroform and ran through a pad of florisil, which is rinsed with 200 mL of warm chloroform. The collected organic portion is evaporated under vacuum to give 0.057 g (54.3% yield) of brown solid: mp 169-170° C.; MS (ESI) m/z 463.1 (M+H)+1
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[Cl:8].C(O)(=[O:12])C>>[Cl:8][C:7]1[C:2](=[O:12])[NH:3][N:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: CC(=O)O
Reactant: Clc1cc(Cl)c(Cl)nn1
Product: O=c1[nH]nc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
3,4,6-Trichloro-pyridazine (34.39 g, 187.5 mmol) in 100 mL acetic acid was heated at reflux for three hours. The resulting mixture was cooled to room temperature and filtered. The filtrate was diluted with ethylacetate. This was washed three times with water, washed with brine, dried over anhydrous MgSO4, concentrated in vacuo, and purified by flash chromatography (30% ethylacetate/hexanes) to yield 4,6-Dichloro-2H-pyridazin-3-one (6.143 g, 37.23 mmol). MS (ESI) 165.0 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([N:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)=[C:4]([C@H:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[F:29][C:30]1[CH:47]=[CH:46][C:33]([CH2:34][CH2:35][O:36][C:37]2[N:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=2)=[CH:32][CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+]>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:17]([O:16][C@@H:10]([C:4]1[C:3]([N:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)=[C:2]([C:40]2[CH:41]=[N:42][C:37]([O:36][CH2:35][CH2:34][C:33]3[CH:32]=[CH:31][C:30]([F:29])=[CH:47][CH:46]=3)=[CH:38][CH:39]=2)[C:7]([CH3:8])=[N:6][C:5]=1[CH3:9])[C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(Br)c1N1CCC(C)(C)CC1
Reactant: OB(O)c1ccc(OCCc2ccc(F)cc2)nc1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCCc3ccc(F)cc3)nc2)c1N1CCC(C)(C)CC1
Temperature: 85 °C
Yield: 9.2 %

Procedure:
To a mixture of (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (30 mg), (6-(4-fluorophenethoxy)pyridin-3-yl)boronic acid (18.9 mg) and Cs2CO3 (42.9 mg) in 1,4-dioxane (2 mL) and water (0.4 mL) was added Pd(PPh3)4 (7.6 mg). The mixture was flushed with nitrogen and then heated at 85° C. for 3 h. The mixture was diluted with water and then extracted with EtOAc (2×20 mL). The organic layers were combined, washed with brine and concentrated to give a residue, which was purified by the preparative HPLC to give (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-6′-(4-fluorophenethoxy)-2,6-dimethyl-[3,3′-bipyridin]-5-yl)acetate (3.6 mg). LCMS (M+H)=592.5.
Reaction SMILES: O.O.Cl[Sn]Cl.Cl.[N+:7]([C:10]1[CH:11]=[C:12]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([N+:24]([O-])=O)[CH:18]=2)[CH:13]=[CH:14][C:15]=1[NH2:16])([O-])=O>>[NH2:7][C:10]1[CH:11]=[C:12]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([NH2:24])[CH:18]=2)[CH:13]=[CH:14][C:15]=1[NH2:16]
Reactant: Nc1ccc(-c2ccc(N)c([N+](=O)[O-])c2)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: Nc1ccc(-c2ccc(N)c(N)c2)cc1N
Yield: 69 %

Procedure:
A 50 ml single neck round bottomed flask equipped with condenser, and stirring magnetic bar were placed SnCl2.2H2O (6 g, 26.5 mmol) and 15 ml concentrated hydrochloric acid and reaction mixture was stirred and than 3,3′-dinitrobenzidine (DNB) formula 2 where in R═CO2H (1.8 g, 5 mmol) was added in small portions over 15 minute to maintain the reaction temperature less than 60° C. The thick slurry was then stirred for additional 2 hours at 40° C. to complete the reduction. The salt of the tetramine was precipitated out, which was neutralized with cold 10% NaOH solution and the solid filtered out, washed with water dried under vacuum to give 3,3′-diaminobenzidine (DAB) in 69% yield (1.035 g).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH2:27][CH2:26][C:21]4([O:25][CH2:24][CH2:23][O:22]4)[CH2:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]>C1(C)C=CC=CC=1.C(O)C.[Pd]>[CH2:1]([CH:4]1[CH2:5][CH2:6][CH:7]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH:18]3[CH2:19][CH2:20][C:21]4([O:22][CH2:23][CH2:24][O:25]4)[CH2:26][CH2:27]3)=[CH:16][CH:17]=2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCCC1CCC(/C=C/c2ccc(C3=CCC4(CC3)OCCO4)cc2)CC1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCC1CCC(CCc2ccc(C3CCC4(CC3)OCCO4)cc2)CC1
Reaction time: 96 h
Yield: 71.4 %

Procedure:
The 8-{4-[(E)-2-(4-propylcyclohexyl)ethenyl]phenyl}-1,4-dioxaspiro[4.5]dec-7-en (6.1 g, 16.64 mmol) was dissolved in a mixture of toluene and ethanol (toluene:EtOH=1:3). Pd/C (0.14 g) was added to 200 mL of the resulting solution and hydrogenated for 4 days. After reaction, Pd/C was removed by filtration, and the residue was purified column chromatography (hexane:ether=8:1) to obtain 8-{4-[2-(4-propylcyclohexyl)ethyl]phenyl}-1,4-dioxaspiro[4.5]decane (4.40 g, 72%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.Cl.[NH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[N:13][OH:14])[CH2:6][CH2:5]2
Reactant: NO
Reactant: O=C1CCc2cc(F)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: ON=C1CCc2cc(F)ccc21
Reaction time: 1 h
Yield: 89.1 %

Procedure:
A solution of 5-fluoroindanone (10 g), hydroxylamine hydrochloride (9 g), potassium carbonate (23 g) and water (3.5 ml) in 96% ethanol (40 ml) was heated to reflux, cooled to ca 45 and additional hydroxylamine hydrochloride (4.5 g) and potassium carbonate (11.5 g) were added and refluxed for an additional 30 min. At this time the mixture was poured into cold water (300 ml) and stirred in an ice bath for one hour; 5-fluoroindanone oxime (9.8 g) was isolated by filtration.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]3[C:17]([CH3:24])=[C:18]([OH:23])[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]=3[O:14][C:13]2([CH3:26])[CH3:25])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].Cl.[Cl:28][CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=1.O>CN(C)C=O>[ClH:28].[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]3[C:17]([CH3:24])=[C:18]([O:23][CH2:29][C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]=4)[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]=3[O:14][C:13]2([CH3:26])[CH3:25])=[CH:8][CH:7]=1)([CH3:5])[CH3:4]
Reactant: ClCc1ccc2ccccc2n1
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C)c2c(c(C)c1OCc1ccc3ccccc3n1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reaction time: 0.17 h
Yield: 71.1 %

Procedure:
Sodium hydride (60% liquid paraffin dispersion, 136 mg, 3.39 mmol) was added to a solution of 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ol (1.0 g, 3.08 mmol) in N,N-dimethylformamide (30 mL) at 0° C., and the mixture was stirred for 10 minutes at the same temperature. To the reaction mixture was added 2-(chloromethyl)quinoline hydrochloride (730 mg. 3.39 mmol) and the mixture was stirred for 30 minutes at 80° C. The reaction mixture was poured into water (40 mL), and extracted twice with ethyl acetate. The organic layers were combined, washed with eater, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. To the residue was added 4 N HCl-ethanol, and the solvent was removed through distillation. The residue was crystallized from ethanol-hexane to obtain the title compound (1.1 g, yield 71%).
Reaction SMILES: [CH3:1]C1(C)CCCC(C)(C)N1.C(=O)=O.[Li]CCCC.[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=1)[C:23]([OH:25])=[O:24].C=O>C1COCC1>[Cl:19][C:20]1[C:21]2[CH2:1][O:24][C:23](=[O:25])[C:22]=2[CH:26]=[CH:27][N:28]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: CC1(C)CCCC(C)(C)N1
Agent: C=O
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1OCc2c1ccnc2Cl
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
A solution of 2,2,6,6-tetramethyl-piperidine (4.05 ml, 24 mmol) in a 100 ml round bottomed flask equipped with a magnetic stirrer, is put under argon atmosphere and 20 ml of dry THF is added. The reaction mixture is cooled to −50° C. by adding a controlled amount of dry ice to an acetone bath. The cooled reaction mixture is treated dropwise with nBuLi solution (8.8 mL of a 2.5 M solution in hexanes, 22 mmol) and the reaction is let stir at −50° C. for 0.5 h. Solid 2-chloro-isonicotinic acid, (1.58 g, 10 mmol) is added as a solid to the reaction mixture at −50° C. The reaction is stirred at −50° C. for 0.5 h. The reaction mixture is treated with paraformaldehyde (7 equivalents) dropwise at −50° C. The reaction is stirred at −50° C. for 2 h and warmed to room temperature overnight. The reaction mixture is concentrated to remove solvent and water and ether are added. The aqueous layer is extracted with ether (6×50 ml). The aqueous phase is treated with aqueous 1N HCl solution, until the pH of aqueous layer is ˜5 and is then extracted with ether (2×40 mL) The aqueous solution is treated with aqueous 1N HCl solution until the pH ˜2. An oily residue separated which from solution is collected to give the title compound as a yellow oil (0.62 g, 36%).
Reaction SMILES: Cl.[NH2:2]O.C(O)C.[C:7]([CH2:13][C:14]([O:16]CC)=O)(=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9].Cl>[OH-].[Na+]>[C:8]([C:7]1[O:12][N:2]=[C:14]([OH:16])[CH:13]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: NO
Reactant: CCOC(=O)CC(=O)C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1cc(O)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
583.7 g of hydroxylamine hydrochloride was dissolved in 2 l of a 4N aqueous solution of sodium hydroxide. 2 l of ethanol was added to the solution under cooling with ice. A 1:1 mixture of a 4N aqueous solution of sodium hydroxide and ethanol was added to the solution so that the pH thereof was adjusted to 10.0. 1,380 g of ethyl pivaloylacetate and a 1:1 mixture of a 4N aqueous solution of sodium hydroxide and ethanol were simultaneously added dropwise to the solution in such a manner that the pH of the reaction solution was 10±0.2 and the temperature thereof was 0° to 5° C. After the dropwise addition was finished, the reaction mixture was stirred at room temperature for 2 hours, and then poured into 6 kg of concentrated hydrochloric acid. The reaction mixture was allowed to stand for 12 hours. The resulting crystal was filtered off, thoroughly washed with water, and then dried. (Yield: 770 g (68.2%); m.p.: 99°-101° C.)
Reaction SMILES: [Na].[C:2]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:6])[CH2:3][CH2:4][CH3:5].[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[CH2:23]Br>C(O)C.C1COCC1>[CH2:11]([O:10][C:8](=[O:9])[CH:7]([C:2](=[O:6])[CH2:3][CH2:4][CH3:5])[CH2:23][C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1)[CH3:12]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: BrCc1ccc2ccccc2c1
Agent: [Na]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCC(=O)C(Cc1ccc2ccccc2c1)C(=O)OCC

Procedure:
Ethyl-α-(2-naphthalenylmethyl)-butyrylacetate was prepared following the procedure of Example 2 from 2.18 g of sodium, 15 g of ethyl butyrylacetate and 21 g of 2-naphthalenylmethyl bromide in 300 mL ethanol-THF (10:1). The crude product was purified by removal of excess starting β-keto ester using a kugelrohr apparatus (oven ≤100° C./0.50 mm).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[C:19]1([SH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C[O-].[Na+].CO.Cl>O.CO>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([S:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:9]=1
Reactant: O=C(O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: Sc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)CCc1oc(Sc2ccccc2)nc1-c1ccc(Cl)cc1
Yield: 89 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid (1.43 g), thiophenol (0.54 ml), sodium methoxide-methanol solution (28%, 2.00 g) and methanol (15 ml) was stirred under reflux for 16 hours. Water was added to the reaction mixture, which was then acidified with 2 N hydrochloric acid. The crystals thus precipitated were collected by filtration to obtain 4-(4-chlorophenyl)-2-phenylthio-5-oxazolepropionic acid (1.60 g, 89%). This was recrystallized from methanol to give colorless needles. mp 156-157° C.