Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C@H:9]([C@H:11]([N:21]1[CH:25]=[C:24]([C:26]([NH2:28])=[O:27])[N:23]=[CH:22]1)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[CH3:10])C1C=CC=CC=1.I[Si](C)(C)C.CO>C(Cl)(Cl)Cl>[OH:8][C@H:9]([C@H:11]([N:21]1[CH:25]=[C:24]([C:26]([NH2:28])=[O:27])[N:23]=[CH:22]1)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[CH3:10]
Reactant: C[C@H](OCc1ccccc1)[C@@H](CCc1ccccc1Cl)n1cnc(C(N)=O)c1
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C[C@H](O)[C@@H](CCc1ccccc1Cl)n1cnc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.7 %

Procedure:
A mixture of 1-[(2S,3R)-2-(benzyloxy)-5-(2-chlorophenyl)-3-pentyl]imidazole-4-carboxamide (obtained in Example 3(9))(40 mg) and iodotrimethylsilane (0.02 ml) in chloroform (1 ml) was stirred at room temperature for 2 hours. The mixture was poured into methanol and the whole was evaporated in vacuo. The residue was taken up in ethyl acetate, washed with water, aqueous sodium bisulfite and sodium bicarbonate, successively, and dried. The residue left after evaporation of solvent was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (20:1) to give a white powder of 1-[(2S,3R)-2-hydroxy-5-(2-chlorophenyl)-3-pentyl]imidazole-4-carboxamide (6.1 mg).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[SH:12][CH2:13][C:14]([OH:16])=[O:15]>>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[S:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: Clc1ccc2ccccc2n1
Reactant: O=C(O)CS
Product: O=C(O)CSc1ccc2ccccc2n1

Procedure:
The present invention provides a single stage method for the production of 2-(quinolylthio)acetic acid by reacting 2-chloroquinoline with mercaptoacetic acid; the desired 2-(quinolylthio)acetic acid is obtained with high purity and yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][N:5]=[C:4]2[N:10]([CH2:13][CH3:14])[N:11]=[CH:12][C:3]=12.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[N:10]([CH2:13][CH3:14])[N:11]=[CH:12][C:3]=12
Reactant: CCn1ncc2c(Cl)c(CO)cnc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCn1ncc2c(Cl)c(C=O)cnc21
Temperature: 4 °C
Reaction time: 1 h

Procedure:
(4-Chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-methanol SAO 33034 (359 mg, 1.70 mmol) was dissolved in anhydrous CH2Cl2 (50 mL) at RT under nitrogen. Dess Martin Periodinane (755 mg, 1.78 mmol) was slowly added portionwise at 4° C. The reaction mixture was stirred for 1 h at 4° C. then overnight at RT. The solid was filtered off and CH2Cl2 (200 mL) was added to the mixture. After separation, the organic layer was washed with brine (20 mL), dried over MgSO4, filtered and evaporated to give 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde SAO 33058 (see table 5) as an off-white solid (711 mg, 100%).
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10]C1CCN(CCC(O)=O)CC1)=[O:9].NCCCCCN(CC1C=CC=CC=1)C[C@@H](C1C=CC(OCC2C=CC=CC=2)=C2C=1C=CC(=O)N2)O[Si](C(C)(C)C)(C)C.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl>O.CN(C)C=O>[C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:9])[OH:10]
Reactant: O=C(O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: CC(C)(C)[Si](C)(C)O[C@@H](CN(CCCCCN)Cc1ccccc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)Nc1ccccc1-c1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 408 %

Procedure:
A mixture of the product of step (e) (3.68 g, 10 mmol) and N,N-dimethylformamide (50 mL) was heated at 60° C. until the solid completely dissolved and then cooled to room temperature. The product of step (d) (6 g, 10 mmol) and diisopropylethylamine (3.5 mL) was added and the reaction mixture was cooled to 0° C. PyBOP (6.25 g, 12 mmol) was added in one portion and the reaction mixture was stirred at 0° C. to room temperature for 2 hours. The reaction mixture was then poured into cold water (500 mL) with stirring and the pH of the resulting mixture was adjusted to about 2 using aqueous 1 M hydrochloric acid. This mixture was stirred for 15 min and then filtered to collect the solid, which was washed with water (100 mL) and dried to afford the title compound (8.7 g, HPLC purity >95%) as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[C:10]([N+:20]([O-])=O)[CH:9]=2)[CH2:4][CH2:3]1.[C:23]([C:25]1[O:29][C:28]([C:30](O)=[O:31])=[CH:27][CH:26]=1)#[N:24].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[C:10]([NH:20][C:30]([C:28]3[O:29][C:25]([C:23]#[N:24])=[CH:26][CH:27]=3)=[O:31])[CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc(N3CCCCC3)c([N+](=O)[O-])c2)CC1
Reactant: N#Cc1ccc(C(=O)O)o1
Agent: [Pd]
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(N3CCCCC3)c(NC(=O)c3ccc(C#N)o3)c2)CC1
Yield: 71 %

Procedure:
The title compound was prepared following the procedure of Example 4, step (c) using 28.1 mg (0.0923 mmol) of 1-methyl-4-(3-nitro-4-piperidin-1-yl-phenyl)-piperazine (as prepared in the previous step), 28 mg of 10% palladium on carbon (Degussa type E101-NE/W, 50% by weight water), 12.7 mg (0.0923 mmol) of 5-cyanofuran-2-carboxylic acid (as prepared in Example 1), 16.2 μL (0.185 mmol) of oxalyl chloride, and 24.1 μL (0.138 mmol) of DIEA. The resulting residue was chromatographed on a 10-g silica SPE column with 1-4% MeOH-dichloromethane to afford 25.8 mg (71%) of the title compound as a beige crystalline solid: 1H-NMR (CDCl3; 400 MHz): δ 9.97 (br s, 1H), 8.18 (d, 1H, J=2.8 Hz), 7.23, 7.25 (AB q, 2H, J=3.7 Hz), 7.11 (d, 1H, J=8.7 Hz), 6.67 (dd, 1H, J=8.7, 2.8 Hz), 3.22-3.25 (m, 4H), 2.75-2.85 (m, 4H), 2.56-2.58 (m, 4H), 2.35 (s, 3H), 1.76-1.81 (m, 4H), and 1.5-1.7 (br m, 2H). Mass spectrum (ESI, m/z): Calcd. for C22H27N5O2, 394.2 (M+H), found 394.2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[F:20][C:21]([F:31])([F:32])[C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=2)[CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[O:30])=[CH:24][CH:23]=1
Reactant: COC(=O)C(Cc1cccc(CCO)c1)C(=O)OC
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Product: COC(=O)C(Cc1cccc(CCOC(=O)Nc2ccc(C(F)(F)F)cc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)benzyl]malonate and α,α,α-trifluoro-p-tolylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH3:23])[CH:14]=1)[CH2:9][C:10](=[O:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[CH3:25][Li].CO>C1COCC1>[C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH3:23])[CH:14]=1)[CH2:9][C:10]([OH:12])([CH3:25])[CH3:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: [Li]C
Reactant: CCOc1cc([C@@H](CC(C)=O)NC(=O)OC(C)(C)C)ccc1OC
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cc([C@@H](CC(C)(C)O)NC(=O)OC(C)(C)C)ccc1OC
Yield: 14.1 %

Procedure:
To a solution of (1R)-[1-(3-ethoxy-4-methoxy-phenyl)-3-oxo-butyl]-carbamic acid tert-butyl ester (1 g, 3 mmol) in THF (10 mL) was added a solution of methyl lithium (4 mL, 3M, 12 mmol) at 0° C. To the mixture was added methanol (5 mL). The residue was extracted with ethyl acetate (50 mL) and NH4Cl (sat, 25 mL). The organic layer was washed with brine (100 mL) and dried over MgSO4. The solvent was removed in vacuo. The residue was purified with preparative HPLC to give (R)-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-3-methyl-butyl]-carbamic acid tert-butyl ester (150 mg, 14% yield).
Reaction SMILES: CC(N)(CO)CO.O=O.CCO[C:13]([C:15]1([CH3:21])[N+:19]([O-:20])=[CH:18][CH2:17][CH2:16]1)=O.[CH3:22][CH2:23][O:24][P:25]([O:34][CH2:35][CH3:36])([C:27]1([CH3:33])[N+:31]([O-:32])=[CH:30][CH2:29][CH2:28]1)=[O:26].O=O.CC(N)(CO)CO>>[CH3:13][C:15]1([CH3:21])[N+:19]([O-:20])=[CH:18][CH2:17][CH2:16]1.[CH3:22][CH2:23][O:24][P:25]([O:34][CH2:35][CH3:36])([C:27]1([CH3:33])[N+:31]([O-:32])=[CH:30][CH2:29][CH2:28]1)=[O:26]
Reactant: CCOC(=O)C1(C)CCC=[N+]1[O-]
Agent: CC(N)(CO)CO
Agent: CCOP(=O)(OCC)C1(C)CCC=[N+]1[O-]
Agent: O=O
Product: CC1(C)CCC=[N+]1[O-]

Procedure:
The nitrone 5-carbamoyl-5-methyl-1-pyrroline N-oxide (AMPO) was successfully synthesized and characterized. Spin trapping by AMPO of hydroxyl, superoxide, C-centered, sulfite, and tert-butoxyl radicals has been demonstrated for the first time by electron paramagnetic resonance (EPR) spectroscopy. Resulting spin adducts for each of these radicals gave unique spectral profiles. Rate of superoxide radical trapping was obtained by competitive trapping by AMPO versus DEPMPO and gave kAMPO=38 M−1 s−1 (based on kDEPMPO=58 M−1 s−1) comparable to that of EMPO kEMPO=44 M−1 s−1. The half-life of AMPO-O2 adduct is about t1/2˜10 minutes similar to that observed from EMPO but significantly shorter than that of DEPMPO-O2 adduct t1/2˜16 minutes. Theoretical analyses using density functional theory calculations at the B3LYP/6-31=G**/B3LYP6-31G* level were performed on AMPO and its corresponding suproxide product. Calculations predicted the presence of intramolecular H-bonding in both AMPO and its superoxide adduct, and these interactions were further confirmed by an X-ray structure (in the case of AMPO) of a novel and the amido nitrone compound 2-amino-5-carbamoyl-5-methyl-1-pyrroline N-oxide (NH2-AMPO). The thermodynamic quantities for superoxide radical trapping by various nitrones have been found to predict favorable formation of certain isomers. The measured partition coefficient in an n-octanol/buffer system of AMPO gave a comparable value to those of DMPO and DEPMPO. This study demonstrates the suitability of AMPO nitrone as spin trap to study radical production in aqueous systems.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[N:5][C:6]([O:19][CH3:20])=[CH:7][C:8]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15](O)=[N:16]2)=[CH:11][CH:10]=1.C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[NH2:56][C:57]1[CH:62]=[CH:61][C:60]([CH:63]2[CH2:68][CH2:67][N:66]([CH2:69][C:70]([NH2:72])=[O:71])[CH2:65][CH2:64]2)=[CH:59][CH:58]=1>>[CH3:1][O:2][C:3]1[N:4]=[N:5][C:6]([O:19][CH3:20])=[CH:7][C:8]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15]([NH:56][C:57]3[CH:62]=[CH:61][C:60]([CH:63]4[CH2:64][CH2:65][N:66]([CH2:69][C:70]([NH2:72])=[O:71])[CH2:67][CH2:68]4)=[CH:59][CH:58]=3)=[N:16]2)=[CH:11][CH:10]=1
Reactant: NC(=O)CN1CCC(c2ccc(N)cc2)CC1
Reactant: COc1cc(-c2ccc3cnc(O)nn23)c(OC)nn1
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(-c2ccc3cnc(Nc4ccc(C5CCN(CC(N)=O)CC5)cc4)nn23)c(OC)nn1
Yield: 15.4 %

Procedure:
7-(3,6-Dimethoxy-pyridazin-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol (70 mg, 0.2 mmol), N-Phenylbis(trifluoromethanesulphonimide) (95.1 mg, 0.266 mmol), N,N-Diisopropylethylamine (0.126 mL, 0.726 mmol), and N,N-Dimethylformamide (2 mL, 30 mmol) and stir at room temperature for half an hour. Add 2-[4-(4-Amino-phenyl)-piperidin-1-yl]-acetamide (90.3 mg, 0.387 mmol) and stir at 60° C. overnight. An LCMS showed product. The reaction was concentrated, DMSO added, filtered and placed onto the Gilson for purification. The most pure fractions were collected, free based with saturated sodium bicarbonate, extracted with DCM, filtered and concentrated to give 2-(4-{4-[7-(3,6-Dimethoxy-pyridazin-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-acetamide as a yellow solid (15 mg, 10%). MP 249-251° C. LCMS (E/I+) 489 (M+H). NMR 1H (DMSO-d6)-9.56 (s, 1H), 9.1 (s, 1H), 8.27 (s, 1H), 7.60 (d, 2H, J=8.30 Hz), 7.40 (d, 2H, J=4.82 Hz), 7.21 (bs, 1H), 7.18 (d, 1H, J=8.42 Hz), 7.13 (bs, 1H), 6.97 (d, 1H, J=4.87 Hz), 4.06 (s, 3H), 4.04 (s, 3H), 2.87-2.96 (m, 4H), 2.40-2.48 (m, 1H), 2.14-2.25 (m, 2H), 1.70-1.78 (m, 4H).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][CH3:18])=[CH:14][C:13]2=[O:19])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[CH:25]=[CH:24][N:23]([CH2:26][C:27]([CH3:30])([OH:29])[CH3:28])[N:22]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C1(C[C@H](N2CC(OC)=CC2=O)C(NC2C=CN(CC(OC)(C)C)N=2)=O)CCCC1>ClCCl>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][CH3:18])=[CH:14][C:13]2=[O:19])[C:9]([NH:20][C:21]2[CH:25]=[CH:24][N:23]([CH2:26][C:27]([OH:29])([CH3:28])[CH3:30])[N:22]=2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: COC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: COC1=CC(=O)N([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(C)(C)OC)n2)C1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)C1

Procedure:
A solution of (S)-3-cyclohexyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid (138 mg, 0.52 mmol), 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 98 mg, 0.63 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (326 mg, 0.75 mmol), N,N-diisopropylethylamine (200 mg, 1.54 mmol) in dichloromethane (10 mL) was stirred for 18 h under nitrogen at 23° C. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium chloride solution and dried. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g silica gel; 0% to 10% methanol/dichloromethane) to afford, (S)-3-cyclopentyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamide (123 mg, 59%) as a white foam, LR-ES-MS m/z calculated for C21H32N4O4 [M]+ 404, observed [M+H]+ 405; 1H NMR (300 MHz, CDCl3) δ ppm 0.78-1.31 (m, 7H) 1.15 (s, 6H) 1.55-1.77 (m, 5H) 1.77-1.95 (m, 2H) 3.82 (s, 3H) 3.87 (d, J=17.8 Hz, 1H) 3.94 (s, 2H) 4.05 (d, J=17.8 Hz, 1H) 4.92 (dd, J=9.5, 5.9 Hz, 1H) 5.14 (s, 1H) 6.67 (d, J=2.1 Hz, 1H) 7.28 (d, J=2.1 Hz, 1H) 8.72 (br. s., 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:21])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1.[H-].[Na+].Cl.Cl[CH2:26][CH2:27][N:28]([CH3:30])[CH3:29]>CN(C)C=O>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:21])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[CH:15]=1
Reactant: CN(C)CCCl
Reactant: Cc1cc(O)c(C(=O)C=Cc2cccc(O)c2)c(=O)n1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(O)c(C(=O)C=Cc2cccc(OCCN(C)C)c2)c(=O)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
To a solution of 0.58 g of 4-hydroxy-3-[3-(3-hydroxyphenyl)-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone in 10 ml of dimethylformamide was added 0.32 g of sodium hydride (60% oily), and this was stirred at room temperature for 1 hour. To the reaction mixture was added 0.25 g of 2-chloroethyldimethylamine hydrochloride, and this was heated at 60° C. for 4 hours. The solvent was distilled off under reduced pressure, and the precipitated crystals were filtered, washed with t-butyl methyl ether, and dried to obtain 0.21 g of 4-hydroxy-3-[3-[3-(2-dimethylaminoethoxy)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (56a)] as a yellow crystal.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([NH:14][NH2:15])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C([O-])(=O)C.[Na+].C(O)(=O)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O>[OH:1][C:2]1[C:3]([C:12]([NH:14][NH:15][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C(Cl)c1ccccc1
Reactant: NNC(=O)c1cc2ccccc2cc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(NNC(=O)c1cc2ccccc2cc1O)c1ccccc1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
A four neck flask (1 liter) equipped with a thermometer and a stirrer was charged with 60.6 g (0.3 mol) of 3-hydroxy-2-naphthohydrazide, 36.9 g (0.45 mol) of sodium acetate and 800 ml of acetic acid and heated to 30° C. Dropwise added thereto was 50.6 g (0.36 mol) of benzoyl chloride in one hour while stirring, and stirring was continued at 30° C. for one hour. After finishing the reaction, the reaction liquid was added to 1.5 liter of deionized water and crystal was filtered off. After washing sufficiently the crystal with 1 liter of deionized water and 500 ml of methanol, it was dried under reduced pressure to obtain slightly brown crystal.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].[CH3:13][C@H:14]1[O:19][C@@H:18]([CH3:20])[CH2:17][NH:16][CH2:15]1>>[Cl:1][C:2]1[C:3]([N:16]2[CH2:15][C@H:14]([CH3:13])[O:19][C@H:18]([CH3:20])[CH2:17]2)=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(F)c(Cl)c1F
Reactant: C[C@@H]1CNC[C@H](C)O1
Product: C[C@@H]1CN(c2c(C(=O)O)ccc(F)c2Cl)C[C@H](C)O1

Procedure:
Starting materials: 3-chloro-2,4-difluorobenzoic acid and cis-2,6-dimethylmorpholine.
Reaction SMILES: [O:1]1[C@@:5]2([CH:10]3[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]3)[CH2:6]2)[CH2:4][NH:3][C:2]1=[O:13].Br[C:15]1[S:16][CH:17]=[C:18]([Br:20])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].C(N)CN>O1CCOCC1.[Cu]I>[Br:20][C:18]1[CH:19]=[C:15]([N:3]2[CH2:4][C@:5]3([CH:10]4[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]4)[CH2:6]3)[O:1][C:2]2=[O:13])[S:16][CH:17]=1
Reactant: O=C1NC[C@@]2(CN3CCC2CC3)O1
Reactant: Brc1csc(Br)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: NCCN
Solvent: C1COCCO1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1cc(Br)cs1
Yield: 63.2 %

Procedure:
(S)-Spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one (471 mg, 2.58 mmol), 2,4-dibromothiophene (1.875 g, 7.75 mmole), copper (I) iodide (492 mg, 2.58 mmol), potassium carbonate (715 mg, 5.17 mmol) and ethylenediamine (170 μL, 2.58 mmol) in 1,4-dioxane (5 mL) were stirred at 110° C. overnight. The solution was allowed to cool, and then filtered, washed with aqueous ammonium hydroxide and evaporated. The residue was purified by flash chromatography using a gradient of ammoniated methanol in chloroform to give the title compound as a yellow solid (560 mg), m/z 343, 345 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:15]([CH2:16][CH2:17][CH3:18])[N:14]=[C:13]([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[C:12]=2[C:26]([F:29])([F:28])[F:27])=[O:10])=[CH:4][C:3]=1[C:30](=[O:37])[NH:31][C:32]1([C:35]#[N:36])[CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:45][CH3:46]>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:45][CH3:46])[C:9]([C:11]2[N:15]([CH2:16][CH2:17][CH3:18])[N:14]=[C:13]([C:19]([F:25])([F:24])[C:20]([F:23])([F:21])[F:22])[C:12]=2[C:26]([F:29])([F:27])[F:28])=[O:10])=[CH:4][C:3]=1[C:30](=[O:37])[NH:31][C:32]1([C:35]#[N:36])[CH2:34][CH2:33]1
Reactant: CCI
Reactant: CCCn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)Nc1ccc(Cl)c(C(=O)NC2(C#N)CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)N(CC)c1ccc(Cl)c(C(=O)NC2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
70 mg (0.13 mmol) of N-{4-chloro-3-[(1-cyanocyclopropyl)carbamoyl]phenyl}-3-(pentafluoroethyl)-1-propyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide and 35 mg (0.14 mmol) of potassium carbonate are suspended in 1.4 ml of N,N-dimethylformamide p.a. Over a period of 16 h, a total of 29 mg (0.19 mmol) of iodoethane are added gradually to the mixture. After the addition has ended, the reaction solution is stirred at room temperature for 20 h. The reaction mixture is diluted with water, and the aqueous phase is extracted three times with ethyl acetate. The combined organic phases are washed twice with saturated sodium chloride solution, dried over sodium sulphate and filtered. The solvents are removed on a rotary evaporator under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18](O)=[O:19].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C.CC1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/CO>ClCCl.CCCCCC.C(OCC)C>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[CH:18]=[O:19]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/CO)C(C)(C)CCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=O)C(C)(C)CCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 129.7 %

Procedure:
Retinoic acid (1.26 g, 0.0042 mol, Basf Co.), dicyclohexylcarbodiimide (DCC) (0.87 g, 0.0042 mol) and catalytic amount of dimethylaminopyridine (DMAP) were added to retinol (1.00 g, 0.0035 mol) dissolved in anhydrous dichloromethane (50 ml) at 0° C. The reaction solution was slowly warmed to room temperature and stirred for 12 hours under nitrogen atmosphere and under the condition for light and moisture to be intercepted. The reaction solution was filtered and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (silica gel 60 for cc part, Merk Co., mesh size 270–400, hexane/diethylether=19/1, v/v) to give 1.55 g (Yield 78%) of the pale yellow title compound.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[OH-].[Na+]>C(O)=O.C(N(CC)CC)C.[C].[Pd]>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][CH2:2]1
Reactant: c1cnc2[nH]ccc2c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O=CO
Product: c1cnc2c(c1)CCN2
Temperature: 70 °C
Reaction time: 87 h
Yield: 21.5 %

Procedure:
1H-Pyrrolo[2,3-b]pyridine (1.00 g, 8.46 mmol) and 10% palladium-carbon (500 mg) were dissolved in a mixture of formic acid (10 mL) and triethylamine (10 mL), and the mixture was stirred at 70° C. for 87 hours. To this reaction mixture was further added 10% palladium-carbon (400 mg), and the solution was stirred for 9.5 hours at 70° C. The reaction mixture was cooled to room temperature, an aqueous solution of 5N sodium hydroxide was added thereto, the solution was extracted with ethyl acetate and tetrahydrofuran, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1), and the title compound (219 mg, 1.82 mmol, 22%) was obtained as a pale yellow solid.