Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=C[C:4]([CH2:7][C:8](=[O:10])[CH3:9])=CC=1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])C=O.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[F:11][C:12]1[CH:13]=[C:14]([C:25]2[CH:26]=[CH:27][N:22]=[CH:23][C:24]=2[CH2:9][C:8](=[O:10])[CH:7]=[CH2:4])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: C1CCNCC1
Reactant: COc1ccc(C=O)cc1F
Reactant: CC(=O)Cc1ccncc1
Solvent: Cc1ccccc1
Product: C=CC(=O)Cc1cnccc1-c1ccc(OC)c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 393.2 %

Procedure:
A solution of 4-pyridylacetone (1.0 g, 7.4 mmol), 3-fluoro-p-anisaldehyde (1.25 g, 8.1 mmol), and piperidine (0.13 g, 1.5 mmol) in toluene (50 ml) was heated to reflux. After 18 hours, the reaction was cooled to room temperature and the solvent was removed under reduced pressure. The crude product (3.0 g) was purified by column chromatography (silica gel, 65:35 ethyl acetate/hexane) to give 4-(3-fluoro-4-methoxylphenyl)-3-pyridyl-3-butene-2-one as a pale yellow solid (1.60 g, 80%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]([N:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=1)[C:26]([CH:23]1[CH2:25][CH2:24]1)=[O:27])=[O:10]
Reactant: O=C(Cl)C1CC1
Reactant: O=C(Nc1cccc(I)c1)c1ccco1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccco1)N(C(=O)C1CC1)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.2 %

Procedure:
3.19 g of furan-2-carboxylic acid (3-iodo-phenyl)-amide (Example 13bf)) are dissolved in 25 ml of methylene chloride with 2.78 ml of triethylamine and 100 mg of 4-dimethylaminopyridine. 1.60 g of cyclopropanecarbonyl chloride are added thereto and the mixture is stirred at room temperature for 5 hrs. The mixture is concentrated, poured into water and extracted three times with ethyl acetate. Chromatography on silica gel with ethyl acetate/hexane 3:7 gives 1.56 g of cyclopropanecarboxylic acid (furan-2-carbonyl)-(3-iodo-phenyl)-amide as a colourless solid. Yield: 58%. Mass spectrum: peaks inter alia at m/e: 381 (20%), 353 (28%), 313 (86%), 95 (75%), 69 (100%).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C@H:24]2[CH2:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]2)[N:14]=1)(=[O:4])[CH:2]=[CH2:3].FC(F)(F)C(O)=O.CO>C(Cl)Cl>[NH:26]1[CH2:27][CH2:28][CH2:29][C@H:24]([NH:23][C:15]2[N:14]=[C:13]([NH:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[NH:5][C:1](=[O:4])[CH:2]=[CH2:3])[C:18]([C:19]([F:22])([F:20])[F:21])=[CH:17][N:16]=2)[CH2:25]1
Reactant: C=CC(=O)Nc1ccccc1Nc1nc(N[C@H]2CCCN(C(=O)OC(C)(C)C)C2)ncc1C(F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: C=CC(=O)Nc1ccccc1Nc1nc(N[C@H]2CCCNC2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-tert-butyl 3-(4-(2-acrylamidophenylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)piperidine-1-carboxylate (3 g) in DCM (30 ml) was added trifluoroacetic acid (5 ml) at 0° C. for 10 min and stirred at rt for 2 h. TLC showed completion of starting material. (TLC system: 15% methanol in dichloromethane, Rf=0.2). The reaction mixture was concentrated, and the crude was co-distilled with DCM (3×20 mL) and washed with diethyl ether (2×10 mL) to obtain (S)—N-(2-(2-(piperidin-3-ylamino)-5-(trifluoromethyl) pyrimidin-4-ylamino)phenyl)acrylamide as an off white solid. (3 g, 97%). MS: m/z=407.1 (ES+, M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH2:13][C:12](=O)[C:11]=2[C:10]([CH3:25])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([NH:29][NH2:30])([NH2:28])=[NH:27].Cl.Cl.O>C(O)C>[ClH:23].[CH2:1]([N:8]1[C:16]2[CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH2:13][C:12](=[N:30][NH:29][C:26]([NH2:28])=[NH:27])[C:11]=2[C:10]([CH3:25])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nn(Cc2ccccc2)c2c1C(=O)CC(c1ccccc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1nn(Cc2ccccc2)c2c1C(=NNC(=N)N)CC(c1ccccc1Cl)C2
Yield: 195.2 %

Procedure:
A mixture of 1-benzyl-6-(2-chlorophenyl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (0.3 g), aminoguanidine hydrochloride (0.11 g), concentrated hydrochloric acid (0.21 ml), water (0.21 ml) and ethanol (20 ml) was refluxed for 18 hours. Under reduced pressure, the solvent was evaporated, and the resulting crystals were recrystallized from ethanol-water to give 1-benzyl-6-(2-chlorophenyl)-4-guanidinoimino-3-methyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 149) (0.37 g) as colorless crystals.
Reaction SMILES: [N:1]#[C:2][NH2:3].[N:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[C:5]=[S:6].[C:20]([C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[C:25](=[O:28])[CH2:26]Br)#[N:21]>>[NH2:1][C:2]1[N:3]=[C:5]([NH:4][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]3)=[CH:11][CH:12]=2)[S:6][C:26]=1[C:25]([C:24]1[CH:23]=[C:22]([CH:31]=[CH:30][CH:29]=1)[C:20]#[N:21])=[O:28]
Reactant: CN1CCN(c2ccc(N=C=S)cc2)CC1
Reactant: N#Cc1cccc(C(=O)CBr)c1
Reactant: N#CN
Product: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4cccc(C#N)c4)s3)cc2)CC1

Procedure:
This compound was prepared from cyanamide, 1-(4-isothiocyanatophenyl)-4-methylpiperazine (of Example 1) and 3-cyanophenacyl bromide (Maybridge Chemical Co. Ltd.) following the procedure used in Example 24. Mass spectrum (ES) MH+=419.
Reaction SMILES: [F:1]/[CH:2]=[C:3](\[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)/[C:4](OCC)=[O:5].C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O.CO>[F:1]/[CH:2]=[C:3](\[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)/[CH2:4][OH:5]
Reactant: CCOC(=O)/C(=C/F)CCc1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: OC/C(=C/F)CCc1ccc(F)cc1
Temperature: -15 °C
Reaction time: 18 h

Procedure:
Combine ethyl (E)-2-(fluoromethylene)-4-(p-fluorophenyl)butyrate (1.5 g, 6.24 mmol) and toluene (5 mL). Cool to -15° C. Add dropwise, a solution of diisobutylaluminum hydride (10.4 mL, 1.5M in toluene, 15.6 mmol). Warm to ambient temperature. After 18 hours, cool to 0° C. With vigorous stirring add sequentially, methanol (15 mL), an aqueous 5M hydrochloric acid solution (25 mL), and water (35 mL). When gas evolution ceases, extract with toluene. Separate the layers and evaporate organic layer in vacuo to give the title compound. 1H NMR (CDCl3, 300 MHz) δ 2.28 (s, 1H), 2.45 (m, 2H), 2.72 (m, 2H) 3.91 (d, J=3 Hz, 2H), 6.57 (d, J=87 Hz, 1H), 6.96 (m, 2H), 7.13 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26].[Al+3].[Cl-].[Cl-].[Cl-].O>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[CH3:34][O:33][C:29]1[CH:28]=[C:24]([CH:23]=[C:22]([O:21][CH3:20])[C:30]=1[O:31][CH3:32])[C:25]([C:10]1[C:11]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:12]=2[S:13][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:26]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Yield: 125.4 %

Procedure:
2-(4'-methoxyphenyl)-6-methoxybenzo[b]thiophene 5 was prepared according to the procedure of Kost et al. To a well-stirred solution of 5 (0.500 g, 1.85 mmol) and 3,4,5-trimethoxybenzoyl chloride (0.640 g, 2.77 mmol) in CH2Cl2 (20 ml), was added AlCl3 (0.123 g, 0.925 mmol) portion-wise over a 15 minute period. After 5 hours (total reaction time), water was added, and the product was isolated initially by extraction with CH2Cl2 and subsequently by extraction with ethyl acetate (EtOAc). The organic layers were separately washed with brine and then combined and dried over MgSO4. Purification by flash chromatography (silica gel, 60:40 EtOAc/hexane) afforded 3-(3',4',5'-trimethoxybenzoyl)-2-(4'-methoxyphenyl)-6-methoxybenzo [b]thiophene (0.537 g, 1.16 mmol, 63%) as an off-white solid. Recrystallization (hexane/ethanol) afforded a highly pure crystalline sample of the compound with mp 131°-133° C. 1H-NMR (CDCl3, 360 Mhz): δ=7.66 (d,J=8.9 Hz, 1H, ArH)7.32 (d,J=2.4 Hz, 1H, ArH), 7.31 (d,J=8.8 Hz, 2H, ArH), 7.07 (s,2H, ArH), 7.01 (dd,J=8.9,2.4 Hz, 1H, ArH), 6.75 (D,J=8.8 Hz, 2H, ArH), 3.89 (s,3H, --OCH3), 3.83 (s,3H, --OCH3), 3.74 (s,3H, --OCH3), 3.73 (s, 6H, --OCH3); 13C-NMR (CDCl3, 90 Mhz): δ=192.9, 159.9, 157.7, 152.7, 143.7, 142.6, 140.1, 133.9, 132.3, 130.3, 129.9, 126.1, 124.2, 114.9, 114.1, 107.5, 104.4, 60.8, 56.1, 55.6, 55.2 HRMS (EI) M+ calcd for C26H24O6S 464.1294. and Anal. Calcd for C 26H24O6S: C, 67.23; H, 5.21; S, 6.90. Found: C, 67.20; H, 5.26; S, 6.88.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:42][C:43]([N:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:15][CH2:16][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:22]=2[CH2:23]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CCCCC1
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 8.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-chloro-1-piperidin-1-ylethanone (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (1.7 mg) was obtained.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][SH:7].C(N(C(C)C)CC)(C)C.Cl[C:23]1[CH:24]=[C:25]([CH3:33])[C:26]([N+:30]([O-:32])=[O:31])=[CH:27][C:28]=1[CH3:29]>CN1CCCC1=O>[N+:30]([C:26]1[CH:27]=[C:28]([CH3:29])[C:23]([S:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=2)=[CH:24][C:25]=1[CH3:33])([O-:32])=[O:31]
Reactant: FC(F)(F)c1cccc(CS)c1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])c(C)cc1SCc1cccc(C(F)(F)F)c1
Temperature: 130 °C

Procedure:
A mixture of 3-trifluoromethylbenzyl mercaptan (3.42 g), diisopropylethylamine (2.3 g) and 3-chloro-6-nitro-p-xylene (3.0 g) in dry N-methylpyrrolidinone (20 ml) was heated at 130° C. for 6 hours. On cooling, the mixture was poured into ice-water and the resulting mixture was filtered to give a solid which was washed with ice-water and then air dried. The solid was purified by silica gel chromatography eluting with light petroleum (60-80° C.)/ethyl acetate (9:1) to give the title product as a solid, m.p. 85-7° C.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[I:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1>CN(C)C=O>[CH2:1]([C:5]1[N:6]([CH2:24][C:23]2[CH:26]=[CH:27][C:20]([I:19])=[CH:21][CH:22]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccc(I)cc1
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-butyl-4-chloro-1H-imidazole-5-carboxaldehyde (4.0 g; preparable as described in Drugs of the Future (1991), Vol. 16, p 305), potassium carbonate (2.94 g) and dry dimethylformamide (50 ml) was stirred for 15 minutes at ambient temperature. 4-Iodobenzyl bromide (6.34 g) was added to the resulting mixture and stirring was continued for approximately 17 hours. The solvent was then evaporated under reduced pressure at 80° C. Water (200 ml) was added to the resulting residue which was then extracted with diethyl ether (2×100 ml). The combined extracts were washed with water (50 ml) and dried over magnesium sulphate. The solvent was evaporated. The resulting residue was purified by flash chromatography on silica gel (eluting with dichloromethane/methanol (80:1)) to give the intermediate compound 2-butyl-4-chloro-1-(4-iodobenzyl)-1H-imidazole-5-carboxaldehyde as an oil (6.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH2:10][C:9]=2[CH:16]([OH:18])[CH3:17])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][C:12]([CH3:14])([CH3:15])[CH2:11][CH2:10][C:9]=2[C:16](=[O:18])[CH3:17])=[CH:6][CH:7]=1
Reactant: CC(O)C1=C(c2ccc(Cl)cc2)CC(C)(C)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)C1=C(c2ccc(Cl)cc2)CC(C)(C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of EXAMPLE 253A (1.18 g) in dichloromethane (20 ml) was slowly added Dess-Martin Periodinane (2.457 g). The reaction mixture was stirred at room temperature for 3 hours and diluted with ether. The resulting mixture was washed with aqueous NaOH and water. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography, eluting with 0-100% dichloromethane in hexane to provide the title compound.
Reaction SMILES: [C@H:1]1(F)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3].[N-:13]=[N+:14]=[N-:15].[Na+]>C(#N)C>[C@H:1]1([N:13]=[N+:14]=[N-:15])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: [N-]=[N+]=[N-]
Reactant: OC[C@H]1O[C@H](F)[C@@H](O)[C@@H](O)[C@@H]1O
Agent: [Na+]
Solvent: CC#N
Product: [N-]=[N+]=N[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O

Procedure:
12 g of α-mannosyl fluoride were heated with 4.7 g of sodium azide in 100 ml of acetonitrile for 80 hours at the reflux temperature. After the mixture had been worked up as in Example 1, 10.3 g of a syrup containing 92% of α-azidomannose were obtained.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([S:18][CH:19]1[N:22]([CH2:23][C:24](=[O:33])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21](=[O:34])[CH2:20]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>ClCCl.CCOCC>[CH2:12]([S:18]([CH:19]1[N:22]([CH2:23][C:24](=[O:33])[CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21](=[O:34])[CH2:20]1)=[O:9])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCSC1CC(=O)N1CC(=O)CCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCCS(=O)C1CC(=O)N1CC(=O)CCc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of m-chloroperbenzoic acid (2.48 g, 0.0144 mol) in dichloromethane (50 ml) was added dropwise to a stirred solution of 4-hexylthio-1-(4-phenyl-2-oxobutyl)azetidin-2-one (4.0 g, 0.012 mol) in dichloromethane (50 ml) at -60° C. Stirring was continued at -60° C. for 30 minutes then the mixture was poured into an aqueous solution of sodium hydrogen carbonate and sodium sulphite. The layers were separated and the aqueous was extracted with dichloromethane. The combined extracts were dried (MgSO4) and evaporated to give a solid which was slurried in ether, filtered, washed with ether and petrol. The solid was recrystallised from ethyl acetate to give the title compound as white crystals, 920 mg, (22%), m.p. 154-5° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([N:26]([CH3:42])[C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1)[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:30]5[CH:29]=[N:28][C:27]([N:26]([CH2:24][CH3:25])[CH3:42])=[CH:32][CH:31]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CCN(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CCN(C)c1ccc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cn1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and ethyl-methyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-amine (stage 98.1.1) to give the title compound as a white solid. (HPLC: tR 2.18 min (Method A); M+H=428 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.90 (s, 1H), 8.26-8.24 (m, 1H), 8.14-8.12 (m, 1H), 8.04-8.01 (m, 1H), 7.88-7.84 (m, 1H), 7.57-7.52 (m, 1H), 7.43-7-40 (m, 1H), 6.73-6.69 (m, 1H), 3.93 (s, 3H), 3.62-3.53 (m, 51-1), 3.01 (s, 3H), 1.96 (s, 3H), 1.07 (t, 3H))
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[N:3]=1.C([OH:23])CCC>Cl.O>[Cl:1][C:2]1[CH:7]=[C:6]([OH:23])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[N:3]=1
Reactant: CCCOc1ccccc1-c1nc(Cl)cc(Cl)n1
Reactant: CCCCO
Agent: Cl
Solvent: O
Product: CCCOc1ccccc1-c1nc(O)cc(Cl)n1

Procedure:
A stirred solution of 4,6-dichloro-2-(2-propoxyphenyl)pyrimidine (16.68 g) in concentrated hydrochloric acid (40 ml), n-butanol (80 ml) and water (40 ml) was heated under reflux for 3 hours. The cooled reaction mixture was evaporated under reduced pressure to yield a residue which was washed with water and diethyl ether and recrystallised from isopropanol to yield the title compound, 8.46 g, m.p. 115.5°-11 6.5° C. A sample (1 g) of this material was recrystallised twice from isopropanol to yield the pure title compound, 0.42 g, m.p. 118°-118.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Li]C(C)(C)C.CCCCC.[C:20](#N)[C:21]1[C:22](=[CH:24][CH:25]=[CH:26][CH:27]=1)[NH2:23].C1C[O:32]CC1>>[NH2:23][C:22]1[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=1[C:20]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([O:8][CH3:9])[CH:2]=1)=[O:32]
Reactant: COc1ccccc1Br
Reactant: N#Cc1ccccc1N
Reactant: C1CCOC1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Product: COc1cccc(C(=O)c2ccccc2N)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 14 %

Procedure:
To a solution of bromoanisole 91 (1.38 mL, 10.7 mmol) in THF (5 mL) at 78° C. and under nitrogen atmosphere, was added 1.2 M t-BuLi in pentane (18.2 mL, 21.9 mmol) dropwise. After stirring for 20 min, anthranilonitrile 92 (0.63 g, 5.3 mmol) was added. The reaction was warmed to rt and stirred overnight. The reaction was cooled to 0° C. and quenched with 3N HCl. After stirring 30 min at rt, the acidic extracts were washed with EtOAc (3×12 mL). The aqueous layer was made basic (pH>10) using 6N NaOH and extracted with CH2Cl2. The organic extracts were washed with sat. NaCl, dried over NaSO4, filtered, and concentrated to give a crude mixture containing 93. The crude oil was purified by chromatography on silica to provide pure 93 (0.17 g, 14%) as a yellow oil; 1H NMR (500 MHz, DMSO-d6) δ 7.40–7.43 (m, 1H), 7.27–7.30 (m, 1H), 7.07–7.17 (m, 4H), 6.86–6.88 (m, 1H), 6.49–6.52 (m, 1H), 3.81 (s, 3H); CI MS m/z=228 [C14H13NO2+H]+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[CH3:27][C:28]1[O:29][C:30]2[C:31](=[C:33]([C:37](O)=[O:38])[CH:34]=[CH:35][CH:36]=2)[N:32]=1.[OH-].[Na+]>O.CO>[CH3:26][CH:6]1[CH2:5][C@H:4]2[C@H:8]([CH2:9][N:10]([C:11]([C:13]3[N:14]=[C:15]([CH3:25])[S:16][C:17]=3[C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:12])[C@@H:3]2[CH2:2][NH:1][C:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:30]3[O:29][C:28]([CH3:27])=[N:32][C:31]=23)=[O:38])[CH2:7]1
Reactant: Cc1nc2c(C(=O)O)cccc2o1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2cccc3oc(C)nc23)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2-methyl-benzoxazole-4-carboxylic acid which was synthesised by saponification of the corresponding methyl ester derivative (Goldstein S et al. J. of Heterocyclic. Chem. 1990, 27, 2, 335-336) with NaOH in a mixture water/MeOH.
Reaction SMILES: [C:1]1(=[O:7])O[CH:4]([CH3:5])[CH2:3][CH2:2]1.[CH2:8]([NH2:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].CCCCCC.C(OCC)(=[O:24])C>C1(C)C=CC=CC=1>[CH2:8]([NH:15][C:5](=[O:24])[CH2:4][CH2:3][CH2:2][CH2:1][OH:7])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CC1CCC(=O)O1
Reactant: CCOC(C)=O
Reactant: CCCCCCCN
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCCCCCCNC(=O)CCCCO
Temperature: 25 °C

Procedure:
Part A. A solution of γ-valerolactone (25.0 g, 0.249 mol) in toluene (50 mL) and n-heptylamine (35.96 g, 0.312 mol) was heated to reflux for 18 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool to ambient temperature, diluted with ethyl acetate (300 mL) and washed with 1 N aqueous HCl (50 mL), water and brine. The organic layer was dried over magnesium sulfate and then concentrated to give a white solid. The product was crystallized from ethyl ether:hexane to give N-heptyl-5-hydroxypentanamide (41.8 g, 0.194 mol) as white plates, mp 55°-56°. 1H NMR (CDCl3) δ6.06 (bs,1H), 3.61 (t,2H,J=7.3 Hz), 3.24 (quartet,2H,J=8.4 Hz), 3.19 (bs,1H), 2.19 (t,2H,J=8.3 Hz), 1.80-1.23 (m,14H), 0.86 (t,3H,J=6.0 Hz).
Reaction SMILES: CC[C@@H]1[C@@H]2C[C@@H]([C@H](O)C3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)N=CC=3)N(CC2)C1.[OH-:23].[Na+].[CH:25]([OH:28])(C)C>C[N+](C)(C)C.[Cl-]>[CH3:25][O:28][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][C:21]1=[O:23]
Reactant: [OH-]
Reactant: CC[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccccc12
Reactant: CC(C)O
Agent: C[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Product: COC1CCCCC1=O

Procedure:
Example 1 is repeated, except that isopropanol is used as solvent, 10 mg of hydrocinchonidine are used as modifier and 100 mg of catalyst are used. In addition, 800 mg of Amberlite IRA-900 (strongly basic anion exchanger, activated using NaOH) are added. The yield is 0.36 g of product of 95% purity containing 5% solvent (44%).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[NH:8][CH2:7][CH2:6]2.[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][N:16]=1>CN1CCCC1=O>[ClH:14].[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][N:16]=[C:15]2[N:8]1[C:9]2[C:5](=[CH:4][C:3]([OH:2])=[C:11]([CH3:12])[C:10]=2[CH3:13])[CH2:6][CH2:7]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Cc1c(O)cc2c(c1C)NCC2
Agent: Cl
Solvent: CN1CCCC1=O
Product: COc1cc2ncnc(N3CCc4cc(O)c(C)c(C)c43)c2cc1OC
Yield: 40 %

Procedure:
Utilizing a procedure analogous to that described in Example 47 this product (with conversion to the HCl salt as outlined for Example 2) was prepared in 40% yield from 5-hydroxy-6,7-dimethyl-indoline (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in N-methyl-pyrrolidinone. (M.P. 207°-209° C. (dec); LC-MS: 352 (MH+); anal. RP18-HPLC RT: 3.48 min.).