Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: C1CCNC1
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: Brc1ccc(-c2nsc3cc(OCCCCN4CCCC4)ccc23)cc1

Procedure:
According to the method in example 4, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and pyrrolidine were converted to yield 3-(4-Bromo-phenyl)-6-(4-pyrrolidin-1-yl-butoxy)-benzo[d]isothiazole, MS: 432 (MH+, 1Br).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[CH:16][C:17]4[S:22][CH:21]=[C:20]([C:23]5[CH:34]=[CH:33][C:26]([CH2:27]CS([O-])(=O)=O)=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:41]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH3:42]>CN(C)C=O.C(OCC)(=O)C>[CH2:41]([N:43]1[CH2:48][CH2:47][N:46]([CH2:27][C:26]2[CH:25]=[CH:24][C:23]([C:20]3[C:18]4[N:19]=[C:14]([NH:13][C:10]5[CH:11]=[N:12][C:7]([N:4]6[CH2:5][CH2:6][O:1][CH2:2][CH2:3]6)=[CH:8][CH:9]=5)[N:15]=[CH:16][C:17]=4[S:22][CH:21]=3)=[CH:34][CH:33]=2)[CH2:45][CH2:44]1)[CH3:42]
Reactant: O=S(=O)([O-])CCc1ccc(-c2csc3cnc(Nc4ccc(N5CCOCC5)nc4)nc23)cc1
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN1CCN(Cc2ccc(-c3csc4cnc(Nc5ccc(N6CCOCC6)nc5)nc34)cc2)CC1
Temperature: 80 °C
Yield: 71.1 %

Procedure:
4-(2-(6-Morpholinopyridin-3-ylamino)thieno[3,2-d]pyrimidin-7-yl)benzylmethanesulfonate (30 mg, 0.06 mmol) was dissolved in N,N-dimethylformamide (1 mL) and potassium carbonate (17 mg, 0.12 mmol) and 1-ethylpiperazine (38 μL, 0.30 mmol) were added. The reaction mixture was stirred at 80° C. for a day, diluted with ethyl acetate, and washed with brine. The organic layer was dried with magnesium sulfate, filtered with celite, and then concentrated. Purification by chromatography (5% methanol/dichloromethane) yielded the target compound (22 mg, 70% yield).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C:12]([N:15]1[C:19]2=[N:20][CH:21]=[N:22][C:23]([NH2:24])=[C:18]2[C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:16]1)([CH3:14])[CH3:13])C1C=CC=CC=1.[BrH:32].CCOCC>C(O)(=O)C>[BrH:32].[NH2:10][CH2:11][C:12]([N:15]1[C:19]2=[N:20][CH:21]=[N:22][C:23]([NH2:24])=[C:18]2[C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:16]1)([CH3:14])[CH3:13]
Reactant: CC(C)(CNC(=O)OCc1ccccc1)n1nc(-c2ccccc2)c2c(N)ncnc21
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(C)(CN)n1nc(-c2ccccc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 1D (85 mg, 0.2 mmol) was treated with 1 mL of 33% solution of HBr in glacial acetic acid. The reaction was stirred at room temperature for 1 hour. Dry ether was then added to the mixture leading to the formation of a precipitate. It was collected by filtration, rinsed thoroughly with Et2O and dried. 50 mg of the compound were redissolved in 50 mL of water and freeze dried for two days. A white solid was obtained. 1H NMR (ppm, DMSO-d6): δ 1.73 (s, 6H), 2.34 (s, 3H), 3.59 (br q, J=5.67 Hz, 2H), 7.33 (d, J=7.89 Hz, 2H), 7.53 (d, J=8.07 Hz, 2H), 7.95 (br s, 3H), 8.40 (s, 1H). 13C NMR (ppm, DMSO-d6): δ 20.93, 24.83, 46.51, 61.41, 98.47, 128.33, 128.76, 129.80, 138.82, 144.85, 149.49, 152.83, 154.21. LCMS (+esi): 297 (M-Br−).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:49])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([N:30]2[CH2:35][CH2:34][N:33]([CH2:36][C:37]([NH:39][CH2:40][CH2:41][C@H:42]3[CH2:46][O:45]C(C)(C)[O:43]3)=[O:38])[CH2:32][CH2:31]2)=[O:29])[CH:5]=[CH:6][CH:7]=1>O1CCOCC1.Cl>[Cl:1][C:2]1[C:3]([F:49])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10][C@H:9]2[C:28]([N:30]2[CH2:35][CH2:34][N:33]([CH2:36][C:37]([NH:39][CH2:40][CH2:41][C@H:42]([OH:43])[CH2:46][OH:45])=[O:38])[CH2:32][CH2:31]2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)N2CCN(CC(=O)NCC[C@H]3COC(C)(C)O3)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)N2CCN(CC(=O)NCC[C@H](O)CO)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of rac 2-{4-[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperazin-1-yl}-N-[2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-acetamide (32 mg, 0.0445 mmol) in 1,4-dioxane (5 mL), 4 M HCl (2 mL) was added and the mixture was stirred at rt for 4 hrs. The mixture was concentrated and the residue was dissolved in a mixture of 1,4-dioxane and freeze dried to give a white solid. 31 mg.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([NH2:14])[CH:12]=[CH2:13]>O1CCCC1>[C:4]1([CH:3]=[CH:2][CH2:1][NH:14][CH2:11][CH:12]=[CH2:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCC=Cc1ccccc1
Reactant: C=CCN
Solvent: C1CCOC1
Product: C=CCNCC=Cc1ccccc1
Reaction time: 20 h
Yield: 82 %

Procedure:
A solution of cinnamyl bromide (10 g, 50.7 mmol) in 250 mL tetrahydrofuran was added dropwise to a solution of allyl amine (38 ml, 507 mmol) in 50 mL tetrahydrofuran at 0° C. the mixture was allowed to slowly come to room temperature then stirred 20 hours. The tetrahydrofuran was removed in-vacuo, and the residue was partitioned between 500 mL of ethyl acetate and 200 ml of water. The layers were separated, the organic phase was washed with water followed by brine, then dried over sodium sulfate and concentrated to an amber oil. The oil was purified by flash chromatography on an 8×15 cm silica column, eluting with 5% methanol/chloroform followed by 10% methanol/chloroform. Obtained 7.2 g of an amber oil as product. Yield=81%. NMR (300 MHz, CDCl3) δ 7.39-7.20 (m, 5H), 6.54 (d, 1H, J=16 Hz), 6.35-6.26 (m, 1H), 6.01-5.87 (m, 1H), 5.24-5.14 (m, 2H), 3.43 (d, 2H, J=7 Hz), 3.31 (d, 2H, J=6 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[N:6]([C:7](Cl)=[O:8])[CH2:5][C:4]([CH3:11])([CH3:10])[O:3]1.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][C:2]1([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[N:6]([C:7]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[O:8])[CH2:5][C:4]([CH3:11])([CH3:10])[O:3]1
Reactant: c1c[nH]cn1
Reactant: CCCCCCC1(C)OC(C)(C)CN1C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCC1(C)OC(C)(C)CN1C(=O)n1ccnc1
Yield: 92 %

Procedure:
A mixture comprising 2.6 g (0.01 mole) of 2-methyl-2-n-hexyl-3-chlorocarbonyl-5,5-dimethyl-1,3-oxazolidine, 1.0 g (0.015 mole) of imidazole and 2.1 g (0.015 mole) of potassium carbonate was stirred with 30 ml of dimethylformamide (DMF) as the solvent at 50° C. to 60° C. for one hour. After completion of the reaction, water was added and then the mixture was extracted with toluene. The toluene layer was washed with water, dried and condensed, and then purified by a column chromatography, thereby obtaining 2.7 g of the title compound having pale yellow color.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@H:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[C@@H:3]1[C:9](Cl)=[O:10].[Cl:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[CH2:22][OH:23])=[CH:16][CH:15]=1.N1C=CC=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[C@H:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[C@@H:3]1[C:9]([O:23][CH2:22][C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([O:18][C:17]2[CH:27]=[CH:28][C:14]([Cl:13])=[CH:15][CH:16]=2)[CH:20]=1)=[O:10]
Reactant: OCc1cccc(Oc2ccc(Cl)cc2)c1
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)OCc1cccc(Oc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
In 20 ml of dry benzene was dissolved 2.28 g of cis-2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropanecarbonyl chloride, followed by addition of 2.34 g of 3-(4-chlorophenoxy)benzyl alcohol and 1.58 g of pyridine. The mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was washed with dilute hydrochloric acid and water, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove a low-boiling fraction, whereby an oily product was obtained as a residue. This oil was purified by preparative liquid chromatography [column: Waters Associates' Prep LC/System 500, Prep PAK® 500/SILICA; solvent system: diisopropyl ether:n-hexane=6:94, v/v]. The above procedure yielded 3.91 g of 3-(4-chlorophenoxy)benzyl cis-2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropanecarboxylate (yield 92%).
Reaction SMILES: C[Si]([N:5]=[N+]=[N-])(C)C.[N:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[C:10]([O:12][C:13]2=[O:18])=[O:11].C(O)C>C(Cl)(Cl)Cl>[NH:5]1[C:9]2[N:8]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13](=[O:18])[O:12][C:10]1=[O:11]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: O=C1OC(=O)c2ncccc21
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2ncccc2c(=O)o1
Temperature: 25 °C

Procedure:
Trimethylsilylazide (89.1 ml) was added dropwise, with stirring, to a suspension of quinolinic anhydride (100.0 g) in dry chloroform (450 ml) under nitrogen. The mixture was stirred until nitrogen evolution had subsided (around 30 minutes) and then boiled under reflux with stirring for 45 minutes to give a solution. The mixture was cooled to ambient temperature and ethanol (40.0 ml) was added. The mixture was stirred for 20 minutes and a precipitate was collected by filtration and dried under vacuum overnight. The solid was stirred in cold acetonitrile (850 ml) and filtered. The filtrate was boiled under reflux for 15 minutes with stirring and then cooled in ice and filtered to give 4H-pyrido[2,3-d] [1,3]oxazine-2,4(1H)-dione, m.p. 213°-215° C. (with decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([OH:12])=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.[OH-].[Na+]>CC(C)=O>[C:13]([C:4]1[CH:3]=[C:2]([NH:1][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[CH:7]=[C:6]([C:8]([CH3:9])([CH3:10])[CH3:11])[C:5]=1[OH:12])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)Nc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1

Procedure:
To a solution of 11.05 grams (0.05 mole) of 4-amino-2,6-di-tert-butylphenol in 50 ml of acetone was added with mixing 9.5 grams (0.05 mole) of p-toluenesulfonyl chloride. After the slight exotherm subsided, 10 ml of 5N sodium hydroxide solution was added. During this addition, an oil separated which eventually solidified. An additional 50 ml of water was added, and the product was separated by filtration. The crude product weighed 12.88 grams and melted at 160°-180° C. After recrystallization from methanol/water and ethanol/water, the melting point was 180°-182° C. (Compound 1)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-])=[O:10])[C:6]([NH:12][C:13]([C:15](OCC)=[O:16])=[O:14])=[CH:5][C:4]=1[C:20]([F:23])([F:22])[F:21])#[N:2].C(O)(=O)C>C(O)C.[Pd]>[C:1]([C:3]1[CH:8]=[C:7]2[C:6]([NH:12][C:13](=[O:14])[C:15](=[O:16])[N:9]2[OH:10])=[CH:5][C:4]=1[C:20]([F:23])([F:22])[F:21])#[N:2]
Reactant: CCOC(=O)C(=O)Nc1cc(C(F)(F)F)c(C#N)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2O
Yield: 80.4 %

Procedure:
To a solution of 10.5 g (31.7 mmol) 2-cyano-5-ethoxalylamino-4-nitrobenzotrifluoride in 450 ml ethanol was added 45 ml glacial acetic acid. The mixture was hydrogenated at atm. pressure by using 0.2 g 5% Pd-C as a catalyst. The filtered and evaporated reaction product was recrystallized (ethylacetate-light petroleum) to give 6.91 g (81%) of 7-cyano-1-hydroxy-6-trifluoromethyl-quinoxaline-2,3(1H,4H)-dione. M.p. 180° C. decomp. 1H-NMR (DMSO-d6): 7.93 (1H, s), 7.53 (1H, s). MS (m/e): 271 (M+, 70%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:25])([CH3:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:26][N:27]([CH3:54])[CH2:28][CH2:29][CH2:30][N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([CH3:40])[CH:38]=2)[C:33]([Sn](CCCC)(CCCC)CCCC)=[N:32]1>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I>[Si:17]([O:16][CH2:15][C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:33]3[C:34]4[C:39](=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)[N:31]([CH2:30][CH2:29][CH2:28][N:27]([CH3:54])[CH3:26])[N:32]=3)[N:3]=2)[NH:8][CH:9]=1)=[O:12])([CH3:25])[CH3:24])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)c1c[nH]c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(CCCN(C)C)c2cc(C)ccc12
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)c4n3)nn(CCCN(C)C)c2c1
Temperature: 85 °C
Yield: 253.4 %

Procedure:
A mixture of 2-bromo-N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (300 mg, 0.7 mmol) and N,N-dimethyl-3-(6-methyl-3-(tributylstannyl)-1H-indazol-1-yl)propan-1-amine (1.4 g, 2.76 mmol) with tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.087 mmol), copper iodide (10 mg, 0.52 mmol) in 15 mL of dry DMF was heated to 85° C. overnight under N2. The reaction mixture was cooled to room temperature, diluted with 50 mL of water and the formed solid was separated by filtration. The solid was washed with 2-methoxy-2-methylpropane (5 mL) to give N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(1-(3-(dimethylamino)propyl)-6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (1 g, crude) which was used in the next step directly without further purification. LCMS: (M+H)+=564.
Reaction SMILES: C([CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([B:15]2[O:19][C:18]([CH3:21])([CH3:20])[C:17]([CH3:23])([CH3:22])[O:16]2)=[CH:11][CH:10]=1)=[O:7])(C)(C)C.[CH3:24]C(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>N1C=CC=CC=1.CCOC(C)=O>[CH3:24][N:8]([C:9]1[CH:14]=[CH:13][C:12]([B:15]2[O:16][C:17]([CH3:23])([CH3:22])[C:18]([CH3:21])([CH3:20])[O:19]2)=[CH:11][CH:10]=1)[C:6](=[O:7])[CH3:5]
Reactant: CC(C)(C)CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)N(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 77 %

Procedure:
A mixture of tert-butyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide (100 mg, 0.429 mmol) in pyridine (1 mL) was added acetic anhydrate (1 mL) and stirred at room temperature for 23 hours. The mixture was diluted with AcOEt, washed with 1N HCl, brine, dried over Na2SO4, then filtrated through Celite pad. The filtrate was concentrated to afford the desired product (91 mg, 77%) as a dark brown solid. 1HNMR (CDCl3) 400 MHz δ: 7.85 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 3.27 (s, 3H), 1.88 (s, 3H), 1.35 (s, 12H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH3:23][NH2:24]>C(Cl)Cl>[CH3:23][NH:24][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCCCCCc1ccccc1
Reactant: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CNC(=O)CCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 8-phenyl octanoic acid (28.6 g, 129.8 mmol, 1 eq) in CH2Cl2 (100 mL) cooled to 0° C. was added oxalyl chloride (17 mL, 195 mmol, 1.5 eq) dropwise via an addition funnel over 30 minutes. Upon the completion of the addition, the ice bath was removed and the reaction was stirred at rt for 2 h. It was then heated at reflux for 30 minutes. The reaction was cooled to rt and concentrated in vacuo to afford a yellow oil. It was added as a solution in EtO (100 mL) to a solution of condensed methyl amine (-20 mL) in EtO (200 mL) at −78° C. Immediately, a white precipitate formed. The cold bath was removed and the reaction was allowed to stir overnight warming to rt under a stream of N2. The residue was washed with Et2O and concentrated to afford N-methyl-8-phenyloctanamide (25.2 g, 83%) as a yellow-white solid. 1H NMR (CDCl3) δ 7.68-7.10 (m, 5H); 5.42 (bs, 1H); 3.80 (m, 3H); 2.60 (m, 2H); 2.18 (m, 2H); 1.60 (m, 4H); 1.30 (m, 8H).
Reaction SMILES: [CH2:1]([C:5]1[CH:21]=[CH:20][C:8]([O:9][CH2:10][C:11]2[O:15][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[C:2]([CH3:4])=O.[OH:22][CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)[CH2:24][NH2:25].O>C1C=CC=CC=1>[Cl:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH:23]([OH:22])[CH2:24][NH:25][CH:2]([CH3:4])[CH2:1][C:5]1[CH:21]=[CH:20][C:8]([O:9][CH2:10][C:11]2[O:15][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(COc2ccc(CC(C)=O)cc2)o1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)c1ccc(COc2ccc(CC(C)NCC(O)c3cccc(Cl)c3)cc2)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 5-[4-acetonylphenoxymethyl]furan-2-carboxylate (1.76 g) and 2-hydroxy-2-(3-chlorophenyl) ethanamine (1.05 g) in dry benzene (100 ml) was heated under reflux with azeotropic removal of water, for 2 hr. The solvent was evaporated and sodium borohydride (2 g) added, in portions, to a stirred solution of the residual oil in methanol (80 ml) with cooling in ice. The mixture was stirred at ambient temperature for 3 hr. the solvent was evaporated and the residue was partitioned between water and dichloromethane. The organic layer was dried (MgSO4) and evaporated to an oil which was purified by column chromatography on silica gel. Elution with methanol:chloroform (4:96) gave an oil which was crystallised from n-hexane to give methyl 5-[4-[2-[(3-chloro-β-hydroxyphenethyl)amino]propyl]phenoxymethyl]furan-2-carboxylate, m.pt 75°-86° C., as a 19:81 mixture of diastereoisomers. The mother liquor was evaporated; crystallisation from Petroleum ether (60:80)--ether gave a second crop, m.pt. 75°-83° C., as a 55:45 mixture of diastereoisomers.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH2:17][CH2:18][CH3:19])[C:4]([NH:6][C:7]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[O:9][N:8]=1)=[O:5])[CH3:2].[CH3:20]I>>[CH2:1]([N:3]([CH2:16][CH2:17][CH2:18][CH3:19])[C:4]([N:6]([CH3:20])[C:7]1[CH:11]=[C:10]([C:12]([CH3:13])([CH3:15])[CH3:14])[O:9][N:8]=1)=[O:5])[CH3:2]
Reactant: CI
Reactant: CCCCN(CC)C(=O)Nc1cc(C(C)(C)C)on1
Product: CCCCN(CC)C(=O)N(C)c1cc(C(C)(C)C)on1

Procedure:
The reaction is effected as in Example 171 by using 1-ethyl-1-butyl-3-(5-t-butyl-3-isoxazolyl)urea and methyl iodide to give 1-ethyl-1-butyl-3-methyl-3-(5-t-butyl-3-isoxazolyl)urea as an oil boiling at 140° to 145° C (bath temperature)/0.67 mm Hg.
Reaction SMILES: [CH:1]([C:3]1[C:4]([F:15])=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13][CH3:14])[CH:9]=[CH:8]2)=[CH2:2].[H][H]>CCO.[Pd]>[CH2:1]([C:3]1[C:4]([F:15])=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13][CH3:14])[CH:9]=[CH:8]2)[CH3:2]
Reactant: [H][H]
Reactant: C=Cc1c(F)cnc2ccc(OC)nc12
Agent: [Pd]
Solvent: CCO
Product: CCc1c(F)cnc2ccc(OC)nc12
Yield: 103 %

Procedure:
8-Ethenyl-7-fluoro-2-(methoxy)-1,5-naphthyridine (for a synthesis see WO2004/058144 Example 53(h)) (1.0 g, 4.90 mmol) was stirred in EtOH (50 ml) with 10% palladium on carbon (0.2 g) and the resulting suspension was hydrogenated under 1 atmosphere of hydrogen pressure for 3 h. The mixture was filtered with suction through celite and the solids were washed with MeOH (500 ml). The combined filtrate plus washings were concentrated to give the title compound as a clear oil (1.045 g, 103%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.CN(C)/[CH:17]=[C:18](/[C:24](=[O:33])[C:25]1[CH:30]=[C:29]([I:31])[CH:28]=[CH:27][C:26]=1F)\[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>O>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][N:1]2[C:26]3[C:25](=[CH:30][C:29]([I:31])=[CH:28][CH:27]=3)[C:24](=[O:33])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17]2)[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cn(C[C@H]2CCN(C(=O)OC(C)(C)C)C2)c2ccc(I)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-3-(Aminomethyl)-1-N-Boc-pyrrolidine (994 mg, 4.86 mmol) was added to the stock solution of (Z)-ethyl 3-(dimethylamino)-2-(3-iodobenzoyl)acrylate (Intermediate 24, 0.34M, 13 mL, 4.42 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dried in a vacuum oven for 1.5 h. The resulting residue was then dissolved in dimethylformamide (8 mL) and potassium carbonate powder (670 mg, 4.86 mmol) was added. The reaction mixture was heated at 60° C. for overnight then cooled to room temperature. Water (50 mL) was added and the suspension was extracted with ethyl acetate (3×50 mL). The organic layers were dried over sodium sulfate, and the solvent was removed in vacuo to give quantitative (R)-ethyl 1-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methyl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate as a brown sticky solid.
Reaction SMILES: [O:1]=[C:2]1[S:6][C:5]([C:7](=[N:13][O:14][CH3:15])[C:8]([O:10]CC)=[O:9])=[CH:4][S:3]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[O:1]=[C:2]1[S:6][C:5]([C:7](=[N:13][O:14][CH3:15])[C:8]([OH:10])=[O:9])=[CH:4][S:3]1
Reactant: CCOC(=O)C(=NOC)c1csc(=O)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CON=C(C(=O)O)c1csc(=O)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.8 %

Procedure:
To a solution of thus obtained ethyl 2-(2-oxo-1,3-dithiol-4-yl)-2-methoxyiminoacetate (anti isomer, 1.7 g.) in ethanol (20 ml.) was added dropwise a solution of sodium carbonate 10 hydrate (2.2 g.) in water (10 ml.) and the mixture was stirred at room temperature for 3 hours. After removing ethanol from the resultant solution in vacuo, the residue was acidified with hydrochloric acid and extracted with diethyl ether. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated in vacuo to give oily product The oil was allowed to stand in a refrigerator to give 2-(2-oxo-1,3-dithiol-4-yl)-2-methoxyiminoacetic acid (anti isomer, 0.75 g.).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([N:11]3[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18](=[O:20])[OH:19])[CH2:12]3)=[C:5]2[NH:4][C:3]1=[O:21].Br[CH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1>>[C:24]([O:20][C:18](=[O:19])[NH:17][C@@H:13]1[CH2:14][CH2:15][CH2:16][N:11]([C:10]2[CH:9]=[CH:8][N:7]=[C:6]3[N:2]([CH3:1])[C:3](=[O:21])[N:4]([CH2:23][C:24]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=4)[C:5]=23)[CH2:12]1)([CH3:31])([CH3:25])[CH3:23]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Cn1c(=O)[nH]c2c(N3CCC[C@@H](NC(=O)O)C3)ccnc21
Product: Cn1c(=O)n(Cc2ccc(C#N)cc2)c2c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)ccnc21
Yield: 126.1 %

Procedure:
The specific operation referred to the step (5) described in Example 1 for details. 347 mg (R)-1-(3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)piperidin-3-yl carbamic acid ter.-butyl ester (1 mmol) and 235 mg 4-(bromomethyl)benzonitrile (1.2 mmol) were charged. A column chromatography was performed to afford 350 mg titled product with a yield of 75.6%.