Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15](Br)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[C:31]1(OB(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.O.C(O)C>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)Oc1ccccc1
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(Br)cc12
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
A mixture of tert-butyl(6-bromo-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.48 g, 1 mmol), phenylboric acid (0.15 g, 1.2 mmol), sodium carbonate (0.26 g, 2.5 mmol), toluene (10 ml), ethanol (2 ml) and water (2 ml) was stirred at room temperature under an argon atmosphere for 30 min. To the resulting mixture was added tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol), and then the mixture was refluxed under an argon atmosphere for 10 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl(4-butoxy-2-isobutyl-1-oxo-6-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.42 g, 89.4%) as crystals.
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[CH:8]=[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][CH2:31]O)[CH2:25]3)[CH2:19][CH2:18]2)=[O:16])[CH:10]=[CH:11][C:12]=1[Cl:13].C(N(CC)CC)C.[N-:40]=[N+:41]=[N-:42].[Na+]>ClCCl.O>[N:40]([CH2:31][CH2:30][N:26]1[CH2:27][CH2:28][CH2:29][C@@H:24]([CH2:23][N:20]2[CH2:21][CH2:22][N:17]([C:15]([NH:14][C:9]3[CH:10]=[CH:11][C:12]([Cl:13])=[C:7]([Cl:6])[CH:8]=3)=[O:16])[CH2:18][CH2:19]2)[CH2:25]1)=[N+:41]=[N-:42]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCN(CCO)C2)CC1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: [N-]=[N+]=NCCN1CCC[C@@H](CN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Reaction time: 1 h
Yield: 5.4 %

Procedure:
Methane sulphonyl chloride (0.4 ml) was added to a solution of N-(3,4-dichlorophenyl)-4-{[(3S)-1-(2-hydroxyethyl)piperidin-3-yl]methyl}piperazine-1-carboxamide (1.85 g, 4.45 mmol) in triethylamine (0.75 ml, 5.3 mmol) and dichloromethane (50 ml) at 0° C. under an atmosphere of argon. The reaction mixture was stirred at this temperature for one hour then water (100 ml) was added. The organic layer was separated, dried over magnesium carbonate, filtered then concentrated in vacuo. This material was then dissolved in anhydrous DMF (10 ml). Sodium azide (435 mg, 6.7 mmol) was added and the reaction mixture stirred overnight at 60° C. The reaction mixture was concentrated in vacuo and the residue separated between ethyl acetate (150 ml) and water (150 ml). The organic layer was separated, dried over magnesium carbonate, filtered then concentrated in vacuo onto silica gel (3 g). The resulting powder was subjected to chromatography (SiO2, 20 g) and the product eluted with a gradient of dichloromethane through to 10% methanolic ammonia/dichloromethane to yield the title compound as a white solid (105 mg)
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9]([N:12]([CH2:14][C:15]2[O:19][CH:18]=[C:17]([C:20]([OH:22])=O)[CH:16]=2)[CH3:13])(=[O:11])=[O:10])=[C:4]([CH3:23])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:36]1[CH2:40][CH2:39][N:38]=[C:37]1[C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][NH:49][CH3:50])=[CH:43][CH:42]=1.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9]([N:12]([CH2:14][C:15]2[O:19][CH:18]=[C:17]([C:20]([N:49]([CH2:48][CH2:47][C:44]3[CH:43]=[CH:42][C:41]([C:37]4[NH:38][CH2:39][CH2:40][N:36]=4)=[CH:46][CH:45]=3)[CH3:50])=[O:22])[CH:16]=2)[CH3:13])(=[O:11])=[O:10])=[C:4]([CH3:23])[CH:3]=1
Reactant: CNCCc1ccc(C2=NCCN2)cc1
Reactant: Cc1cc(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)cc1Cl
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)CCc3ccc(C4=NCCN4)cc3)co2)c(C)cc1Cl

Procedure:
5-({[(4-chloro-2,5-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (30 mg, 0.08 mmol) was dissolved in DMF (1 mL) and CDI (20 mg, 0.12 mmol) was added. The mixture was stirred until acid activation was complete. 2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylethanamine.HCl (19 mg, 0.08 mmol) and DIPEA (0.042 mL, 0.24 mmol) were sonicated in DMF (1 mL) for 15 min, 0.5 mL of activated acid solution was added to 0.25 mL of amine solution and the reaction was microwaved (120° C., 200 W) for 20 min, then 2×60 min. A portion of the reaction was concentrated and purified using prep method A.
Reaction SMILES: C([NH:3][C:4]1[N:9]=[C:8]([C:10](=[N:14][O:15][CH3:16])[C:11]([OH:13])=[O:12])[CH:7]=[CH:6][CH:5]=1)=O.Cl>CO>[NH2:3][C:4]1[N:9]=[C:8]([C:10](=[N:14][O:15][CH3:16])[C:11]([OH:13])=[O:12])[CH:7]=[CH:6][CH:5]=1
Reactant: CON=C(C(=O)O)c1cccc(NC=O)n1
Agent: Cl
Solvent: CO
Product: CON=C(C(=O)O)c1cccc(N)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 118.9 %

Procedure:
A mixture of 2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (5.0 g.) and concentrated hydrochloric acid (2.34 g.) in methanol (50 ml.) was stirred for 40 minutes at ambient temperature. After the removal of methanol from the reaction mixture under reduced pressure, the residue was pulverized in diethyl ether, collected by filtration and then dried to give a pale brown powder of 2-(6-aminopyridin-2-yl)-2-methoxyiminoacetic acid hydrochloric (syn isomer) (5.2 g.).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][CH3:12])[CH:5]=1)=O.Cl.[N:14]1[O:15][N:16]=[C:17]2[CH:22]=[C:21]([CH2:23][O:24][NH2:25])[CH:20]=[CH:19][C:18]=12.N1C=CC=CC=1>C(O)C>[N:14]1[O:15][N:16]=[C:17]2[CH:22]=[C:21]([CH2:23][O:24][N:25]=[C:2]([C:4]3[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][CH3:12])[CH:5]=3)[CH3:1])[CH:20]=[CH:19][C:18]=12
Reactant: COc1cc(C(C)=O)ccc1F
Reactant: NOCc1ccc2nonc2c1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: COc1cc(C(C)=NOCc2ccc3nonc3c2)ccc1F
Temperature: 25 °C
Yield: 74.5 %

Procedure:
A solution of 4-fluoro-3-methoxyacetophenone (0.056 g, 0.332 mmol), (benzo[c][1,2,5]oxadiazol-5-yl)methoxyamine hydrochloride (0.072 g, 0.359 mmol) and pyridine (0.10 ml, 1.24 mmol) in ethanol (5 ml) was stirred at reflux under nitrogen for 4 h and cooled to room temperature. The solution was concentrated to a pale yellow oil which was diluted with dichloromethane/water. The resultant mixture was extracted with dichloromethane (×3). The combined organic phases were washed with water and brine, dried over magnesium sulphate, filtered and concentrated to a white solid. The crude product was purified by column chromatography (SiO2), eluting with 9:1 petrol/ethyl acetate, to give a 4′-fluoro-3′-methoxyacetophenone-O-[(benzo[c][1,2,5]oxadiazol-5-yl)methyl]oxime (CP9-129) as a white solid (0.078 g, 74%), m.p. 65°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH:5]=[CH:6][C:7]([NH:9][C:10]1[CH:22]=[CH:21][C:13]([CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:12][CH:11]=1)=[O:8].B([O-])([O-])O[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1(C)C=CC=CC=1.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>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:2]2[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:6][C:7]([NH:9][C:10]2[CH:22]=[CH:21][C:13]([CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:11]=2)=[O:8])=[CH:29][CH:30]=1
Reactant: O=C(C=Cc1cccc(Br)c1)Nc1ccc(CN2CCCCC2)cc1
Reactant: [O-]B([O-])Oc1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(C=Cc1cccc(-c2ccc(F)cc2)c1)Nc1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
A suspension of 1—(4—(3-bromocinnamoylamino)benzyl)piperidine (0.4 g), 4-fluorophenyl borate (0.14 g), 1M potassium carbonate (2 ml) and ethanol (1 ml) in toluene (5 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the suspension was added tetrakistriphenylphosphinepalladium (0.05 g), and the mixture was refluxed over night. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (methanol/triethylamine/ethyl. acetate) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 1—(4—(3—(4-fluoro-phenyl)cinnamoylamino)benzyl)piperidine (Compound 83) (0.35 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1C=C(OCCCCCCCCCCCCCCCCCCCC)C(C(C)C)=C[C:3]=1N.[C:33]([C:36]1C=CC=C(C(=O)C)N=1)(=O)[CH3:34].[CH2:45]([O:65][C:66]1[CH:71]=[CH:70][C:69]([N:72]=[C:73]([C:75]2[CH:80]=[CH:79][CH:78]=[C:77]([C:81](=[N:83][C:84]3[CH:89]=[CH:88][C:87]([O:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][CH2:107][CH2:108][CH2:109][CH3:110])=[CH:86][C:85]=3[CH3:111])[CH3:82])[N:76]=2)[CH3:74])=[C:68]([CH3:112])[CH:67]=1)[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64]>C1(C)C=CC=CC=1>[CH3:112][C:68]1[CH:67]=[C:66]([O:65][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[C:71]([CH:2]([CH3:3])[CH3:1])=[CH:70][C:69]=1[N:72]=[C:73]([C:75]1[CH:80]=[CH:79][CH:78]=[C:77]([C:81](=[N:83][C:84]2[CH:89]=[C:88]([CH:33]([CH3:36])[CH3:34])[C:87]([O:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][CH2:107][CH2:108][CH2:109][CH3:110])=[CH:86][C:85]=2[CH3:111])[CH3:82])[N:76]=1)[CH3:74]
Reactant: CCCCCCCCCCCCCCCCCCCCOc1ccc(N=C(C)c2cccc(C(C)=Nc3ccc(OCCCCCCCCCCCCCCCCCCCC)cc3C)n2)c(C)c1
Reactant: CCCCCCCCCCCCCCCCCCCCOc1cc(C)c(N)cc1C(C)C
Reactant: CC(=O)c1cccc(C(C)=O)n1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCOc1cc(C)c(N=C(C)c2cccc(C(C)=Nc3cc(C(C)C)c(OCCCCCCCCCCCCCCCCCCCC)cc3C)n2)cc1C(C)C

Procedure:
The title compound was prepared by condensation of 2-methyl-4-eicosanoxy-5-isopropylaniline with 2,6-diacetylpyridine in the presence of 4 Å molecular sieves in refluxing toluene for 20 hours, similarly to the preparation of 2,6-bis[1-(4-eicosanoxy-2-methylphenylimino)ethyl]pyridine, described above.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([OH:26])=O)=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[F:31][C:32]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:33]=1[NH2:34].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:34][C:33]3[CH:35]=[CH:36][C:37]([C:39]([F:40])([F:41])[F:42])=[CH:38][C:32]=3[F:31])=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: Nc1ccc(C(F)(F)F)cc1F
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(C(F)(F)F)cc3F)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 11.9 %

Procedure:
The title compound was prepared by following the procedure described for Example-108 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.100 g, 0.266 mmol), thionyl chloride (2.0 mL), 2-fluoro-4-(trifluoromethyl)aniline (0.071 g, 0.396 mmol), THF (10.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on neutral alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.017 g of the desired product. 1HNMR (DMSO-d6): δ 1.56 (s, 6H), 3.14 (s, 2H), 7.33-7.54 (m, 3H), 7.62 (d, J=8.7 Hz, 2H), 7.81 (d, J=11.1 Hz, 1H), 8.73 (t, J=7.8 Hz, 1H), 10.34 (s, 1H), 11.25 (s, 2H); MS [M+H]+: 537.48.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:35])=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].[C:36](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[F:1][C:2]1[C:3]([O:35][CH3:36])=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(O)c(F)c3o2)cc1F
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(F)c(NC(=O)C(C)(C)C)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Yield: 78.2 %

Procedure:
348 mg (0.710 mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl )-7-hydroxy-5-pivaloylamino-4H-1-benzopyran-4-one obtained in Example 86 (3) was dissolved in 35 mL of acetone, 166 mg (1.20 mmol) of potassium carbonate and 0.45 mL (7.1 mmol) of iodomethane were added and the mixture was heated at reflux for 40 minutes. The reaction solution was filtered, the filtrate was concentrated, water was added to the residue and the mixture was extracted once with ethyl acetate. The organic layer was washed twice with a 1N aqueous solution of sodium hydroxide, once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform) to give 280 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methoxy-5-pivaloylamino-4H-1-benzopyran-4-one (yield: 78%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.O.NN>CO.CCOC(C)=O.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Nc1cccc([N+](=O)[O-])c1)N1CCCC1
Agent: [Ni]
Agent: NN
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: Nc1cccc(NC(=O)N2CCCC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 184.8 %

Procedure:
Pyrrolidine-1-carboxylic acid (3-nitro-phenyl)-amide (850 mg, 3.40 mmol) was dissolved in 1:1 MeOH-EtOAc (100 mL). Raney®-Nickel was added (3 full spatulas) followed by hydrazine monohydrate (1.70 g, 34.0 mmol) over a 5 minute period. The reaction mixture was stirred at rt for 16 hours then filtered through celite, washing the precipitate with EtOAc (10×10 mL). The filtrate was evaporated in vacuo and the residue dissolved in EtOAc (50 mL). The solution was washed with saturated brine solution (2×50 mL), dried (Na2SO4), filtered, and the solvent evaporated in vacuo. The crude product was then purified by column chromatography (Flashmaster, 40-63 mesh silica gel, EtOAc→10% MeOH-EtOAc) to provide the title compound as a pale yellow solid (1.29 g, 92%); LC-MS, Rt=0.99 min (MeOH-FA), m/z 206 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:46]=[CH:45][C:6]2[CH:7]([C:17]3[C:18](=[O:44])[NH:19][C:20](=[O:43])[N:21]([C:23]4[CH:28]=[CH:27][N:26]=[C:25](NCC(NC5SC=C(CC(O)=O)N=5)=O)[N:24]=4)[CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2].Cl.[CH3:48][O:49][C:50](=[O:56])[C@@H:51]1[CH2:55][CH2:54][CH2:53][NH:52]1>>[CH2:1]([C:3]1[CH:46]=[CH:45][C:6]2[CH:7]([C:17]3[C:18](=[O:44])[NH:19][C:20](=[O:43])[N:21]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([N:52]5[CH2:53][CH2:54][CH2:55][C@H:51]5[C:50]([O:49][CH3:48])=[O:56])[N:24]=4)[CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(NCC(=O)Nc3nc(CC(=O)O)cs3)n2)c(=O)[nH]c1=O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Product: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(N3CCC[C@H]3C(=O)OC)n2)c(=O)[nH]c1=O

Procedure:
The subtitle compound was prepared from the product of example 15 step (viii) (0.5 g) and L-proline methyl ester hydrochloride (0.265 g) by the method of example 10 step (ii). Purification was by chromatography eluting with 40% ethyl acetate in isohexane. Yield 0.47 g.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[N:6][CH:7]=1.CO.[C:19]1([CH3:28])[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Si:10]([C:9]#[C:8][C:5]1[CH:4]=[CH:3][C:2]([C:22]2[CH:23]=[CH:24][C:19]([CH3:28])=[CH:20][CH:21]=2)=[CH:7][N:6]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)[Si](C)(C)C#Cc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(-c2ccc(C#C[Si](C)(C)C(C)(C)C)nc2)cc1

Procedure:
4.6 g (15.00 mmol) 5-bromo-2-((tert-butyldimethylsilyl)ethynyl)pyridine are added to 12 mL methanol and 50 mL 1,4-dioxane. Then the mixture is charged with 2.40 g (17.3 mmol) p-tolyl-boronic acid, 0.1 g (0.15 mmol) bis(triphenyphosphine)-dichloropalladium and 16.5 mL (33.0 mmol) of a 2N aq. Na2CO3 solution. The reaction mixture is stirred at reflux for 2 h. Then the solvent is removed in vacuo to some extent and the residue is diluted with EtOAc and water. The organic layer is sequently washed with 50 mL half sat. Na2CO3 solution (1×) and 50 mL water (1×). The organic layer is dried with MgSO4 and the solvent is removed in vacuo. The residue is treated with DIPE and PE to receive a precipitate which is filtered and dried to yield the desired product.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[N:15]=[CH:14][C:13]3[C:8](=[CH:9][C:10]([C:17]([OH:19])=O)=[CH:11][C:12]=3[F:16])[N:7]=2)[CH2:3][CH2:2]1.[F:20][C:21]1[CH:22]=[C:23]([C@@H:29]([C:31]2[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=2)[NH2:30])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>>[F:20][C:21]1[CH:22]=[C:23]([C@H:29]([NH:30][C:17]([C:10]2[CH:9]=[C:8]3[C:13]([CH:14]=[N:15][C:6]([NH:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)=[N:7]3)=[C:12]([F:16])[CH:11]=2)=[O:19])[C:31]2[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc([C@H](N)c2cnn(C)c2)cc1F
Reactant: O=C(O)c1cc(F)c2cnc(NCC3CC3)nc2c1
Product: COc1ccc([C@H](NC(=O)c2cc(F)c3cnc(NCC4CC4)nc3c2)c2cnn(C)c2)cc1F

Procedure:
The condensation of 2-(cyclopropylmethylamino)-5-fluoroquinazoline-7-carboxylic acid and (S)-(3-fluoro-4-methoxyphenyl)(1-methyl-1H-pyrazol-4-yl)methanamine (401) to afford I-60 was carried out in accord with the procedure in Example 5.
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=C.S(=O)(=O)(O)O.[C:11]1([CH:18]=[CH:17][C:15]([OH:16])=[CH:14][CH:13]=1)O.[C:19]1(C)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([C:17]2[CH:18]=[CH:11][CH:13]=[CH:14][C:15]=2[OH:16])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:1]1[O:5][CH2:2]1
Reactant: C=CC(=O)O
Reactant: Oc1ccc(O)cc1
Reactant: Cc1ccccc1
Agent: O=S(=O)(O)O
Product: C1CO1
Product: Oc1ccccc1-c1ccccc1

Procedure:
346 parts of a compound represented by formula (8) ##STR10## (produced by Sanyo Chemical Industries, Ltd., reaction product of 1 mol of o-phenylphenol and 4 mol of ethylene oxide, trade name: Newpol OPE-40, OH value 162), 86.5 parts of acrylic acid, 400 parts of toluene, 21 parts of sulfuric acid and 6 parts of hydroquinone were charged and the mixture were heated. The produced water was distilled out together with the solvent, condensed and collected in a separator. When 18 parts of water was collected at the separator, the reaction mixture was cooled. The reaction temperature was 130°-140° C. The reaction mixture was solved in 500 parts of toluene, and 380 parts of an acrylate represented by formula (9) was obtained in the same manner as in Example 1. ##STR11## The viscosity (25° C.) was 120 CPS and refractive index was 1.543. The product was almost odorless.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6](/[N:8]=[C:9]2/[N:10]([C@H:20]3[CH2:25][CH2:24][C@@H:23]([C:26](=[O:31])[NH:27][CH:28]([CH3:30])[CH3:29])[CH2:22][CH2:21]3)[C:11]3[CH:16]=[C:15]([O:17]C)[N:14]=[CH:13][C:12]=3[NH:19]/2)=[O:7])=[CH:4][CH:3]=1.[I-].[Na+].[Si](Cl)(C)(C)C.O>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](/[N:8]=[C:9]2/[N:10]([C@H:20]3[CH2:21][CH2:22][C@@H:23]([C:26](=[O:31])[NH:27][CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:25]3)[C:11]3[CH:16]=[C:15]([OH:17])[N:14]=[CH:13][C:12]=3[NH:19]/2)=[O:7])=[CH:32][CH:33]=1
Reactant: COc1cc2c(cn1)[nH]/c(=N\C(=O)c1ccc(F)cc1)n2[C@H]1CC[C@@H](C(=O)NC(C)C)CC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3cnc(O)cc32)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a RT suspension of (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-methoxy-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide (30 mg, 0.066 mmol) and sodium iodide (69.4 mg, 0.463 mmol) in ACN (0.6 mL) was added TMS-Cl (0.059 mL, 0.463 mmol) and water (10 μL), and the mixture was heated at 60° C. After 2 hours and 4 hours, additional TMS-Cl portions (0.059 mL, 0.463 mmol) were added, and the mixture was stirred at 60° C. for a total reaction time of 20 hours. The material was purified by reverse-phase preparative HPLC using 0.1% TFA in ACN/H2O, gradient 10% to 90% over 15 minutes. The combined fractions were freebased with saturated aqueous NaHCO3 and extracted with 10% IPA/DCM, dried over Na2SO4, filtered and evaporated. The title compound was obtained as a white solid (8 mg, 21% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08 (d, J=8 Hz, 6H) 1.50-1.60 (m, 2H) 1.62-1.82 (m, 2H) 2.05-2.08 (m, 2H) 2.49-2.51 (m, 1H) 2.55-2.74 (m, 2H) 3.97-4.02 (m, 1H) 4.60-4.70 (m, 1H) 6.38 (s, 1H) 7.20-7.30 (m, 2H) 7.48-7.52 (m, 1H) 7.64 (d, J=7.63 Hz, 1H) 8.29 (dd, J=8.22, 5.97 Hz, 2H) 11.10 (br. s., 1H) 12.26 (br. s., 1H). M/Z calc'd for C23H26FN5O3: 439.48. found 440 [M+H].