Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].C([N+]1(C)[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10]1)C1C=CC=CC=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[NH2:26].C(=O)([O-])[O-].[K+].[K+]>O.C(O)C>[CH2:16]([CH:11]1[C:12](=[O:15])[CH2:13][CH2:14][N:26]([C:25]2[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:23]([O:22][CH3:21])[CH:24]=2)[CH2:10]1)[CH2:17][CH2:18][CH3:19]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: CCCCC1C[N+](C)(Cc2ccccc2)CCC1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCCC1CN(c2cc(OC)c(OC)c(OC)c2)CCC1=O
Yield: 204.8 %

Procedure:
A slurry of 1-benzyl-3-butyl-1-methyl-4-oxo-piperidinium iodide (306 mg) in water (2 ml) was added in one portion to a refluxing solution of 3,4,5-trimethoxy aniline (929 mg) and anhydrous potassium carbonate (33 mg) in ethanol (4 ml). The dark solution was heated to reflux for three hours. Water was added and the reaction was extracted twice with DCM. The combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated to leave a dark oil, which was purified by flash chromatography (ethyl acetate/hexanes 1:1) to give the product as a colorless oil (520 mg). MS (ESI): 322.4 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH:14]=[C:13]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=[CH:11]2)=[O:4].C(CN)[OH:22]>C(OC(C)=O)(C)C>[OH:22][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH:14]=[C:13]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=[CH:11]2)=[O:4]
Reactant: NCCO
Reactant: CS(=O)(=O)Oc1ccc2cccc(NC(=O)CCl)c2c1
Solvent: CC(=O)OC(C)C
Product: CS(=O)(=O)Oc1ccc2cccc(NC(=O)CO)c2c1
Reaction time: 18 h

Procedure:
To a solution of ester from Step B (11.0 g, 39.5 mmol) in 150 mL of i-PrOAc at room temperature was added ethanolamine (12.0 mL, 199 mmol). After 18 hours, the reaction was partitioned between EtOAc and water, and the organic layer was extracted with saturated brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide a dark oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1.[O-2].[Mg+2]>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1ccc(N)cc1
Agent: [Mg+2]
Agent: [O-2]
Solvent: O
Product: Cc1ccc(Nc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 200 °C
Reaction time: 48 h
Yield: 47 %

Procedure:
To a mixture of 4-nitro-fluorobenzene (250 mg, 1.77 mmol) and 4-amino-toluene (195 mL, 1.77 mmol) in 4 mL of water in a sealed tube was added magnesium oxide (86 mg, 2.126mmol). The suspension was stirred at 200° C. for 2 days. The reaction was cooled to ambient temperature and the suspension was diluted with water and filtered to remove insoluble material. The aqueous layer was extracted 3 times with ethyl acetate (50 mL) and the combined organic layers were washed with boronic acid (5%, 50 mL) and water, dried over magnesium sulfate and concentrated in vacuo to provide (4-nitro-phenyl)-p-tolyl-amine (190 mg, 47% yield). ). API MS: 229.20 (M+1).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][C:2]1=[O:11].C(N(C(C)C)CC)(C)C.[C:21](OC(=O)C)(=[O:23])[CH3:22]>ClCCl>[C:21]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:1][C:2](=[O:11])[CH2:3]1)(=[O:23])[CH3:22]
Reactant: O=C1CNc2ccccc2N1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CC(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold (0° C.) solution of 3,4-dihydroquinoxalin-2(1H)-one (1.0 g, 6.7 mmol; J. Med. Chem. 758, 1994) and N,N-diisopropyl-N-ethylamine (1.7 mL, 10.1 mmol) in dichloromethane (30 mL) under an atmosphere of nitrogen, acetic anhydride (0.76 mL, 8.1 mmol) was added and stirred at room temperature overnight. The resultant solution was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 1% methanol in chloroform. Collection and concentration of appropriate fractions provided the acetylation product.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.I[C:22]1[NH:26][C:25]([CH3:27])=[N:24][C:23]=1[CH3:28].C(Cl)Cl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:22]1[NH:26][C:25]([CH3:27])=[N:24][C:23]=1[CH3:28]
Reactant: Cc1nc(C)c(I)[nH]1
Reactant: COC(=O)c1ccc(Cl)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(Cl)c(-c2[nH]c(C)nc2C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.5 %

Procedure:
To methyl 4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 50.2, 600 mg, 2.02 mmol) in dioxane (20 mL) was added 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5, 538 mg, 2.42 mmol) and Pd(dppf)Cl2.DCM (165 mg, 0.20 mmol). The mixture was degassed with argon and stirred for 10 minutes at room temperature, then an aqueous potassium carbonate solution (1M, 10 mL) was added and the mixture was stirred at 90° C. for 18 h. The mixture was cooled and diluted with EtOAc, then filtered through Celite®. The filtrate was washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2; 0-100% EtOAc in hexanes) to yield 270 mg (50%) of the title compound as a foam. m/z (ES+) 265 (M+H)+. 1H NMR (400 MHz, Chloroform-d) δ 8.07 (d, J=2.2 Hz, 1H), 7.90 (dd, J=8.4, 2.2 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 3.91 (s, 3H), 2.40 (s, 3H), 2.19 (s, 3H).
Reaction SMILES: C(OC([C:6]1([NH:17]C(=O)C)[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:16])=O)C>Cl>[NH2:17][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:16]
Reactant: CCOC(=O)C1(NC(C)=O)Cc2ccccc2NC1=O
Agent: Cl
Product: NC1Cc2ccccc2NC1=O
Temperature: 25 °C

Procedure:
A mixture of 81 in 6 M HCl was refluxed for a time sufficient for reaction completion. After cooling to rt, the mixture was rotary evaporated and dried under vacuum to give 82 as its hydrochloride salt.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:32][CH2:33][CH2:34][C:35]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:36]=1[CH2:37][C:38](=[O:44])[NH:39]2.[C:45]1([C:51]2[CH:52]=[C:53](O)[CH:54]=[CH:55][CH:56]=2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>O1CCCC1>[C:45]1([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:50]=[CH:49][CH:48]=[C:47]([O:32][CH2:33][CH2:34][C:35]2[CH:43]=[CH:42][CH:41]=[C:40]3[C:36]=2[CH2:37][C:38](=[O:44])[NH:39]3)[CH:46]=1
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: Oc1cccc(-c2ccccc2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1Cc2c(CCOc3cccc(-c4ccccc4)c3)cccc2N1
Reaction time: 0.25 h
Yield: 36.1 %

Procedure:
Diethyl azodicarboxylate (1.58 mL, 10 mmol) was added to a solution of triphenylphosphine (2.62 g, 10 mmol) in tetrahydrofuran (20 mL) under nitrogen atmosphere. The mixture was stirred for 15 minutes. To it was then added 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (1.77 g, 10 mmol) followed by 3-phenylphenol (1.7 g, 10 mmol). The mixture was stirred at room temperature for one day and the solvent was evaporated. The residue was dissolved in ethyl acetate (150 mL) and the organic solvent was washed with 2 N hydrochloric acid (3×50 mL), saturated sodium bicarbonate solution and brine. The residue was chromatographed on silica gel eluting with ethyl acetate: hexane 2:8 to give 1.19 g (36%) of 4-[2-(biphenyl-3-yloxy)-ethyl]-1,3-dihydro-indol-2-one.
Reaction SMILES: Cl.[OH:2]/[N:3]=[C:4](/[C:10]1[N:11]=[C:12]([NH:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:13][CH:14]=1)\[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:42][F:43]>CS(C)=O.C(Cl)Cl>[F:43][CH2:42][O:2]/[N:3]=[C:4](/[C:10]1[N:11]=[C:12]([NH:15][C:16]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:13][CH:14]=1)\[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: FCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)/C(=N\OCF)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
Ethyl (Z)-2-hydroxyimino-2-(2-triphenylmethylaminothiazol-4-yl)acetate, hydrochloride salt (8.7 g) was stirred with potassium carbonate (15.35 g) in dimethyl sulphoxide (30 ml) under nitrogen at 21° . Bromofluoromethane (ca 3 g) was added. The nitrogen flow was stopped and the stirring continued for two hours. The mixture was poured into an ice-water mixture with stirring and the solid was collected by filtration and washed with water. The solid was dissolved in methylene chloride and the organic layer was separated and dried with magnesium sulphate. Evaporation gave a foam. This was dissolved in methylene chloride and pre-absorbed onto Kieselgel 60 (50 g). This was added to the top of a column of similar silica (125 g) set up in 10% ethyl acetate in cyclohexane. The column was eluted successively with 10%, 20% and 33% ethyl acetate in cyclohexane. After combination of appropriate fractions, evaporation gave the title compound (8.06 g) as a foam; λmax (EtOH) 302 nm (E1 cm1% 92), λinfl include 227.5 nm (E1 cm1% 546) and 259 nm (E1 cm1% 221), νmax (CHBr3) 3400 (NH), 1739 (ester) and 1533 cm-1 (C=N).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>CC(CC)=O.O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH2:22][C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([F:18])[CH:20]=1
Reactant: Fc1cccc(CBr)c1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(F)c1
Reaction time: 8 h

Procedure:
A mixture of 10.0 g (63.7 mmol) 2-fluoro-4-nitrophenol, 17.6 g (127 mmol) potassium carbonate and 13.24 g (70.0 mmol) 3-fluorobenzyl bromide in 200 ml ethyl methyl ketone is hold overnight at 80° C. The reaction mixture is diluted with water and extracted with ethyl acetate. Crystallisation from diethyl ether/n-hexane gives 12.68 g (75%) of a slightly yellow solid. MS: m/e=265.1 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]2[CH:37]=[CH:36][C:35]([CH:38]=[O:39])=[CH:34][CH:33]=2)=[CH:4][N:3]=1.[BH4-].[Na+].CO>CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+]>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]2[CH:33]=[CH:34][C:35]([CH2:38][OH:39])=[CH:36][CH:37]=2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(-c4ccc(C=O)cc4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(-c2csc3c(-c4ccc(CO)cc4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.7 %

Procedure:
N-{4-[4-amino-7-(4-formylphenyl)thieno[3,2-c]pyridin-3-yl]-2-methoxyphenyl}-1-methyl-1H-indole-2-carboxamide (Example 2, 0.030 g, 0.056 mmol) was dissolved in N,N-dimethylformamide (0.5 mL). Sodium borohydride (0.006 g, 0.167 mmol) and methanol (0.5 mL) were added, and the reaction mixture was stirred at ambient temperature for 16 h. The mixture was diluted with aqueous sodium carbonate (1 M, 10 mL) and the product was extracted with methanol dichloromethane (1:33, 3×20 mL). The organic fractions were combined, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel, using ethyl acetate-heptane (3:1) as the mobile phase, to afford the title compound (0.011 g, 0.020 mmol) as a white powder. 1H NMR (DMSO-d6, 400 MHz) δ 9.53 (s, 1H), 8.00 (d, 1H), 7.92 (s, 1H), 7.71 (s, 1H), 7.62 (m, 1H), 7.59 (s, 1H), 7.56 (m, 2H), 7.49 (t, 1H), 7.36 (s, 1H), 7.32 (m, 3H), 7.16 (d, 1H), 7.12 (m, 1H), 5.61 (br, 2H), 5.31 (t, 1H), 4.61 (d, 2H), 4.05 (s, 3H), 3.92 (s, 3H); MS: (M−H)− 533.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[C:4](=[O:6])[CH3:5])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[C:17]([CH2:19][C@@H:20]([OH:27])[CH2:21][C:22](OCC)=[O:23])#[N:18].Cl>O1CCCC1.O1CCCC1.CCCCCCC>[C:17]([CH2:19][C@@H:20]([OH:27])[CH2:21][C:22](=[O:23])[CH2:5][C:4]([N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])=[O:6])#[N:18]
Reactant: CCOC(=O)C[C@H](O)CC#N
Reactant: CCN(CC)C(C)=O
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CCN(CC)C(=O)CC(=O)C[C@H](O)CC#N
Reaction time: 0.5 h

Procedure:
To a stirred -10° C. solution of N,N-diethylacetamide (prepared from N,N-diethylamine and acetyl chloride by refluxing for 2 hours in toluene) (28.75 g, 0.25 mol) in tetrahydrofuran (0.25 L) is slowly added a solution of lithium diisopropylamide in tetrahydrofuran-heptane (0.125 L of 2M) while maintaining the temperature between -10° C. to -5° C., and the mixture is stirred at -20° C. to 0° C. for 30 minutes. (R)-4-cyano-3-hydroxybutyric acid, ethyl ester (Brower, supra) (10 g, 0.06 mol) as a solution in 200 mL of tetrahydrofuran is added to the previously prepared mixture. The reaction mixture is stirred for 30 minutes at -5° C. to -20° C., and transferred to a 2.2N aqueous hydrochloric acid solution (0.25 L). The aqueous layer is extracted with 300 mL of ethyl acetate, the aqueous layer is separated and reextracted with 50 mL of ethyl acetate, the extracts are combined and concentrated in vacuo to afford crude (R)-6-cyano-N,N-diethyl-5-hydroxy-3-oxohexanamide as an oil; Molecular weight: 226. GC/MS m/e 226, 157, 140, 114, 72, 58, 32.
Reaction SMILES: [CH3:1][O:2][C@H:3]([C@@H:8]([CH3:15])[C@@H:9]([O:13][CH3:14])/[CH:10]=[CH:11]/[CH3:12])[C@@H:4]([CH3:7])[CH2:5][OH:6].[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>N1C=CC=CC=1>[CH3:1][O:2][C@H:3]([C@@H:8]([CH3:15])[C@@H:9]([O:13][CH3:14])/[CH:10]=[CH:11]/[CH3:12])[C@@H:4]([CH3:7])[CH2:5][O:6][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C/C=C/[C@H](OC)[C@H](C)[C@@H](OC)[C@@H](C)CO
Solvent: c1ccncc1
Product: C/C=C/[C@H](OC)[C@H](C)[C@@H](OC)[C@@H](C)COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (E)-(2S,3S,4S,5S)-3,5-Dimethoxy-2,4-dimethyl-oct-6-en-1-ol (1.5 g, 6.94 mmol) in anhydrous pyridine (20 ml) at 0° C. and under an atmosphere of nitrogen was added pivaloyl chloride (1.33 ml, 10.7 mmol). The reaction was warmed to room temperature and stirred for 2 hours, after which it was quenched with saturated ammonium chloride and extracted with dichloromethane (2×). The combined organic layers were dried by passing through a hydrophobic frit and concentrated in vacuo. The product was purified by flash chromatography (SiO2, iHex/EtOAc, 20:1 then 1:1) to afford 2.0 g (100%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 5.67 (dq, J=15.3 Hz, 6.6 Hz, 1H), 5.21 (m, 1H), 4.23 (dd, J=10.6 Hz, 3.3 Hz, 1H), 4.1 (dd, J=10.6 Hz, 6.0 Hz, 1H), 3.52 (dd, J=10.0 Hz, 2.0 Hz, 1H), 3.42 (s, 3H), 3.34 (t, J=9.3 Hz, 1H), 3.25 (s, 3H), 1.96 (m, 1H), 1.78 (dd, J=6.4 Hz, 1.5 Hz, 3H), 1.68 (m, 1H), 1.24 (s, 9H), 0.90 (d, J=7.1 Hz, 3H), 0.76 (d, J=7.1 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5]1.C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:19]>O1CCCC1>[CH2:21]([O:20][C:18]([N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]1[CH2:3][CH2:2][OH:1])=[O:19])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCOC(=O)Cl
Reactant: OCCC1CCCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCOC(=O)N1CCCCC1CCO

Procedure:
6.5 g (0.05 mol) of 2-(2-hydroxyethyl)-piperidine and 10 ml of triethylamine are dissolved in 300 ml of tetrahydrofuran, and 7.5 g (0.55 mol) of butyl chloroformate are added at -20° C.
Reaction SMILES: [CH2:1]([C:4]1[C:19]([OH:20])=[C:18]([N+:21]([O-:23])=[O:22])[CH:17]=[CH:16][C:5]=1[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:32])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCCl>[OH:32][CH2:3][CH:2]1[CH2:1][C:4]2=[C:5]([C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[C:19]2[O:20]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1c(C(=O)OCc2ccccc2)ccc([N+](=O)[O-])c1O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(OCc1ccccc1)c1ccc([N+](=O)[O-])c2c1CC(CO)O2
Temperature: 70 °C
Reaction time: 3 h
Yield: 30.4 %

Procedure:
Benzyl 2-allyl-3-hydroxy-4-nitro-benzoate 29c (1.36 g, 4.30 mmol) was dissolved in 100 mL of 1,2-dichloroethane followed by the addition of m-chloroperbenzoic acid (1.18 g, 4.77 mmol). The reaction solution was heated to 70° C. and stirred for 3 hours. The resulting solution was cooled down to room temperature, added with 20 mL of saturated sodium thiosulfate solution, stirred for 30 minutes and extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with water (20 mL), saturated sodium chloride solution (20 mL) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound benzyl 2-(hydroxymethyl)-7-nitro-2,3-dihydrobenzofuran-4-carboxylate 29d (430 mg, yield: 30.1%) as a light yellow solid.
Reaction SMILES: CN(C)/[CH:3]=[C:4]1\[CH2:5][CH2:6][CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]\1=O.[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[NH:22])=[CH:19][CH:18]=1>CCO>[CH2:12]([O:11][C:8]1[C:9]2[N:23]=[C:21]([C:20]3[CH:24]=[CH:25][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)[N:22]=[CH:3][C:4]=2[CH2:5][CH2:6][CH:7]=1)[CH3:13]
Reactant: CCOC1=CCC/C(=C\N(C)C)C1=O
Reactant: COc1ccc(C(=N)N)cc1
Solvent: CCO
Product: CCOC1=CCCc2cnc(-c3ccc(OC)cc3)nc21

Procedure:
6-[1-Dimethylamino-meth-(E)-ylidene]-2-ethoxy-cyclohex-2-enone (WO 2004/104007) (1 g; 5 mmol) and 4-methoxybenzamidine (0.92 g; 6.1 mmol) are refluxed in EtOH (20 ml) for 14 hours. The reaction mixture is evaporated to dryness, taken up in CH2Cl2 and purified via chromatography (SiO2; acetone/hexanes 5:95) to yield the title compound as yellow resin. 1H-NMR (400 MHz; DMSO-d6): 8.58 (s, 1H); 8.31 (d, 2H); 7.07 (d, 2H); 5.64 (t, 1H); 3.93 (q, 2H); 3.84 (s, 3H); 2.78 (t, 2H); 2.40 (m, 2H); 1.40 (t, 3H). MS (m/z) ES+: 283 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[CH:14]=[CH:13][NH:12][N:11]=1.[OH-].[K+].[CH3:17]I.O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[CH:14]=[CH:13][N:12]([CH3:17])[N:11]=1
Reactant: COc1ccccc1Nc1cc[nH]n1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccccc1Nc1ccn(C)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The pyrazole from Example 5 (b) (4.0 g) was added to a mixture of crushed potassium hydroxide pellets (4.7 g) in dry dimethylsulphoxide, which had previously been stirred for 5 minutes under nitrogen at room temperature. After stirring for 0.75 hours, methyl iodide (3.1 g) was added to the red solution and stirring was maintained for a further 0.75 hours. The reaction mix was poured into water, extracted with ethyl acetate, the organic layer washed, dried, evaporated and chromatographed to give a light brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([C:13](O)=O)[C:9]2=[O:16])=[CH:4][CH:3]=1.[CH3:17][O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C=O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:24]3[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][O:18][CH3:17])[CH2:22][CH2:23]3)[C:9]2=[O:16])=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCN(c2ccc(Cl)cc2)C1=O
Reactant: COCCN1CCNCC1
Agent: C=O
Solvent: CO
Product: COCCN1CCN(CC2CCN(c3ccc(Cl)cc3)C2=O)CC1
Temperature: 25 °C
Yield: 77.6 %

Procedure:
3.0 g of 1-(4-chlorophenyl)-3-carboxy-2-pyrrolidinone and 2.32 g of 4-(2-methoxyethyl)piperazine were mixed with 6 ml of methanol. Thereto was added 0.465 g of 80% paraformaldehyde. The mixture was subjected to a reaction for 10.5 hours under refluxing and then cooled to room temperature. Thereto was added 10 ml of methanol, and the insolubles were removed by filtration. The filtrate was concentrated under reduced pressure. The residue was mixed with 15 ml of water. The resulting crystals were collected by filtration and washed with 3 ml of 95% aqueous methanol twice to obtain 3.42 g of 1-(4-chlorophenyl)-3-[4-(2-methoxyethyl)piperazine-1-yl]methyl-2-pyrrolidinone.
Reaction SMILES: CO[CH:3](OC)[CH2:4][N:5]([CH2:12][CH2:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22])[C:6](=[O:11])[C:7]([F:10])([F:9])[F:8].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O>ClC1C=CC=CC=1>[F:22][C:15]1[C:14]2[CH2:13][CH2:12][N:5]([C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])[CH:4]=[CH:3][C:19]=2[C:18]([O:20][CH3:21])=[CH:17][CH:16]=1
Reactant: COc1ccc(F)c(CCN(CC(OC)OC)C(=O)C(F)(F)F)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: Clc1ccccc1
Product: COc1ccc(F)c2c1C=CN(C(=O)C(F)(F)F)CC2
Yield: 73 %

Procedure:
Dissolve N-(2,2-dimethoxy-ethyl)-2,2,2-trifluoro-N-[2-(2-fluoro-5-methoxy-phenyl)-ethyl]-acetamide (5 g, 14.2 mmol) in chlorobenzene (100 mL). Add polyphosphoric acid (5 g) and P2O5 (2.5 g) and heat at 80° C. for 2 h. Add water to the hot mixture, cool to room temperature and extract with DCM. Dry the organic extracts over Na2SO4 and concentrate in vacuo to obtain the desired intermediate (3.0 g, 73%). MS (ES+) m/z: 290 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[C:5]([Cl:15])[CH:6]=[CH:7][C:8]=2[F:14])[N:3]=1.C([Sn](CCCC)(CCCC)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)CCC>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[C:5]([Cl:15])[CH:6]=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2c(Cl)ccc(F)c2c1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2c(Cl)ccc(F)c2c1Cl

Procedure:
The Stille coupled product was prepared according to Procedure E using 2,4,8-trichloro-5-fluoro-3-methylquinoline (0.61 g, 2.306 mmol), 2-(tributylstannyl)-pyridine (0.89 g, 2.42 mmol), palladium tetrakistriphenylphosphine (0.27 g, 0.23 mmol) in toluene (2 mL) to give 4,8-dichloro-5-fluoro-3-methyl-2-(pyridin-2-yl)-quinoline as a white solid. Mass Spectrum (ESI) m/e=307.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C(N=C=NCCCN(C)C)C.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]([N:39]3[CH2:38][CH2:37][N:36]([C:33]4[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=4)[CH2:41][CH2:40]3)=[O:15])=[C:11]([CH3:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: Cc1onc(-c2cccc(F)c2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1onc(-c2cccc(F)c2)c1C(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 72.3 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 3-(3-fluorophenyl)-5-methylisoxazol-4-carboxylic acid (407 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(4-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (511 mg, 1.33 mmol, 72%) was obtained.