Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([SH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[NH2:9][C:10]1[C:15](Br)=[N:14][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][N:11]=1>C(#N)C>[NH2:9][C:10]1[C:15]([S:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:14][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][N:11]=1
Reactant: Nc1ncc(-c2ccccc2)nc1Br
Reactant: SC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Nc1ncc(-c2ccccc2)nc1SC1CCCC1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 67.6 %

Procedure:
To a solution of cyclopentanethiol (0.18 g, 1.80 mmol) in dry acetonitrile (20 mL), sodium hydride (NaH) (0.04 g, 1.80 mmol) was added the resulting mixture was stirred for 15 min. After this time 2-amino-3-bromo-5-phenylpyrazine 17b (0.15 g, 0.6 mmol) was added and the mixture heated at 80° C. for 2 h, cooled and quenched with water. Then EtOAc was added and the organic layer was anidrified over Na2SO4, filtered and the solvent removed under reduced pressure to get a crude that was purified by flash chromatography using dichloromethane-EtOAc (9:1 v/v) as eluent, to obtain 0.11 g of the title compound 18n as a yellow solid (mp 92-94° C., 67% yield). 1H-NMR (CDCl3): 1.68-1.83 (m, 6H), 2.28-2.31 (m, 2H), 4.21-4.28 (m, 1H), 4.93 (br s, 2H), 7.32-7.35 (m, 1H), 7.41-7.45 (m, 2H), 7.91-7.93 (m, 2H), 8.20 (s, 1H). MS (ESI): m/z 272 (Mile).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:18]([O:20][CH:21]([O:26][CH2:27][CH3:28])[CH2:22][CH2:23][CH2:24]Cl)[CH3:19].O>CN(C)C=O>[CH2:18]([O:20][CH:21]([O:26][CH2:27][CH3:28])[CH2:22][CH2:23][CH2:24][N:8]1[C:7]2[C:16](=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:15](=[O:17])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)[CH3:19]
Reactant: CCOC(CCCCl)OCC
Reactant: O=c1c2ccccc2[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(CCCn1c2ccccc2c(=O)c2ccccc21)OCC
Reaction time: 2 h

Procedure:
A suspension of 1.44 g of sodium hydride in 100 ml of dimethylformamide is treated within 10 minutes with 9.75 g of 9-acridanone and held at 50° for 2 hours. At 120° there are then added 9.5 g of 4,4-diethoxybutyl chloride. After 16 hours, the mixture is cooled, poured into water and extracted with dichloromethane. The extract is dried over sodium sulfate and evaporated. The residue is extracted with hexane and crystallized twice from hexane. There is obtained 10-(4,4-diethoxybutyl)-9-acridanone of metling point 73°-74.5°.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.S([O-])([O-])(=O)=O.[Mg+2]>CCCCCC>[CH:6]1([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C1CCCCCCC1
Reactant: C1CCNC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCCCCC
Product: C1CCCC(N2CCCC2)CCC1

Procedure:
A three-neck 3000 ml. flask was charged with 75 gm. (1.05 moles) of pyrrolidine, 51 gm. cyclooctanone (0.4 mole) and 80 ml. anhydrous hexane. To the resulting solution, 80 gm. (0.8 mole) of anhydrous magnesium sulfate was added and the mixture was mechanically stirred and heated at reflux (the reaction was monitored by NMR analysis) for 108 hours. The reaction mixture was filtered through a fritted glass funnel. The filtrate was concentrated at reduced pressure on a rotary evaporator to give 70.5 gm. of a clear (yellow-tinted) oily substance. 1H-NMR and 13C-NMR spectra were acceptable for the desired product, 1-(1-pyrrolino)cyclooctene. Saturation of the 1-(1-pyrrolino)cyclooctene to give N-cyclooctylpyrrolidine was accomplished in 98% yield by catalytic hydrogenation in ethanol at a 55 psi pressure of hydrogen gas in the presence of 10% Pd on activated carbon.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[C:9]([OH:15])=[CH:10][CH:11]=[CH:12][C:13]=2[F:14])[CH:7]=1.[CH3:17][C@@H:18](O)[CH2:19][CH:20]=[CH2:21].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[C:9]([O:15][C@H:20]([CH2:19][CH:18]=[CH2:17])[CH3:21])=[CH:10][CH:11]=[CH:12][C:13]=2[F:14])[CH:7]=1
Reactant: Oc1cccc(F)c1-c1cc(Br)ccc1F
Reactant: C=CC[C@@H](C)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC[C@H](C)Oc1cccc(F)c1-c1cc(Br)ccc1F
Reaction time: 8 h
Yield: 77.8 %

Procedure:
5′-Bromo-2′,6-difluoro-[1,1′-biphenyl]-2-ol (520 mg, 1.82 mmol., 1.0 equiv) were mixed with (R)-pent-4-en-2-ol (314 mg, 3.65 mmol, 2.0 equiv) and Ph3P (957 mg, 3.65 mmol, 2.0 equiv) in THF (6 mL). To this solution was added DEAD (1661 μl, 3.65 mmol, 2.0 equiv) dropwise and stirred overnight. The solution was mixed with silica gel and concentrated and purified by 40 g ISCO column with 0-10% EtOAc/hexane to afford 5-bromo-2,2′-difluoro-6′-((S)-pent-4-en-2-yloxy)-1,1′-biphenyl (500 mg, 78%). 1H NMR (400 MHz, CDCl3) δ 7.52-7.42 (m, 2H), 7.34-7.28 (m, 1H), 7.03 (t, J=9.0 Hz, 1H), 6.81-6.74 (m, 2H), 5.81-5.62 (m, 1H), 5.12-4.96 (m, 2H), 4.41 (dq, J=11.7, 5.9 Hz, 1H), 2.44-2.18 (m, 2H), 1.23 (dd, J=7.3, 6.3 Hz, 3H). LCMS (M+1)=353.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=[O:14])[S:5][C:6]=1[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][CH:8]=1.[Cl:16]N1C(=O)CCC1=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=[O:14])[S:5][C:6]=1[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][C:8]=1[Cl:16]
Reactant: Cn1nccc1-c1sc(C(=O)O)cc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: Cn1ncc(Cl)c1-c1sc(C(=O)O)cc1Cl
Reaction time: 4 h
Yield: 98.1 %

Procedure:
A solution of 4-chloro-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (121 mg, 0.5 mmol) and N-chlorosuccinimide (67 mg, 0.5 mmol) in THF (5 mL) was stirred in a sealed tube at 70° C. After 4 hrs, the solution was concentrated and partitioned between DCM and H2O. The aqueous layer was extracted several times with DCM. The organic fractions were combined, concentrated and azeotropically dried with toluene to give the title compound as a brown oil (136 mg, 98%): LC-MS (ES) m/z=278 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1)=[O:4].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.C1C=CC=CC=1>O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([Cl:12])[CH:14]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(N)cn1
Reactant: O=Cc1cccc(Cl)c1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)c1ccc(N=Cc2cccc(Cl)c2)cn1

Procedure:
The starting material is prepared as follows: the mixture of 30.44 g of 5-aminopyridine-2-carboxylic acid methyl ester, 30.9 g of m-chlorobenzaldehyde, and 400 ml of benzene is refluxed for 3 days on a water-separating trap. The initial suspension eventually becomes a pale yellow solution, which is evaporated. The residual yellow solid is recrystallized from benzene-ethyl acetate-diethyl ether, to yield the 5-(m-chlorobenzylideneamino)-pyridine-2-carboxylic acid methyl ester melting at 139°-142°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.[N:36]1([C:42](Cl)=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[N:36]1([C:42]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[CH:11]=[C:10]([C:12]4[CH:17]=[N:16][N:15]5[C:18]([C:21]6[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:33])([F:35])[F:34])=[O:29])[CH:24]=[CH:25][CH:26]=6)=[CH:19][N:20]=[C:14]5[CH:13]=4)[CH:9]=[N:8]3)[CH2:3][CH2:2]2)=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCNCC5)c4)cnn23)c1
Reactant: O=C(Cl)N1CCOCC1
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCN(C(=O)N6CCOCC6)CC5)c4)cnn23)c1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 30 (Step 6) starting from N-{3-[7-(1-piperidin-4-yl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea and morpholine-4-carbonyl chloride (Aldrich, Cat. No. 348295). LCMS (M+H)+: m/z=598.2.
Reaction SMILES: [C:1]1([CH:11]=[C:12]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[C:13]([OH:15])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>C(OC(=O)C)(=O)C>[C:1]1([CH:11]=[C:12]2[CH2:16][CH2:17][C:18](=[O:19])[O:20][C:13]2=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCC(=Cc1cccc2ccccc12)C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1CCC(=Cc2cccc3ccccc23)C(=O)O1
Temperature: 60 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
100 ml of acetic anhydride were added to 10 g (37 mmole) of 2-(1-naphthylmethylene)glutaric acid (prepared as described above), and the mixture was stirred at 60° C. for 1 hour. At the end of this time, the solvent was removed by distillation under reduced pressure, and then a 1: 1 by volume mixture of benzene and hexane was added to the residue to precipitate crystals, which were collected by filtration to give 8.1 g of 2-(1-naphthylmethylene)glutaric anhydride.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[CH:4]=NO.Cl.C=[O:16].O>O1CCCC1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[CH:4]=[O:16]
Reactant: C=O
Reactant: Cc1cccc([N+](=O)[O-])c1C=NO
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc([N+](=O)[O-])c1C=O

Procedure:
At 65° C., 14 g of 2-methyl-6-nitrobenzaldoxime (80 mmol) are stirred in a mixture of 55 ml of 5% strength hydrochloric acid, 37 g of a 37% strength solution of formaldehyde, 50 ml of water and 100 ml of tetrahydrofuran for 24 hours. The phases are subsequently separated, and the dark phase is extracted with methylene chloride/water. The organic phase is dried with sodium sulfate and concentrated. This gives 10.1 g of crude product which is purified by filtration over silica gel using toluene as mobile phase.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[CH:5]=[C:4]([CH3:16])[N:3]=1.[B-](F)(F)(F)[F:18].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(#N)C>CO>[F:18][C:5]1[C:6]2[C:11](=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=2)[C:2]([OH:1])=[N:3][C:4]=1[CH3:16]
Reactant: F[B-](F)(F)F
Reactant: COC(=O)c1ccc2cc(C)nc(O)c2c1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CO
Solvent: CC#N
Product: COC(=O)c1ccc2c(F)c(C)nc(O)c2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 42.3 %

Procedure:
A mixture of methyl 1-hydroxy-3-methylisoquinoline-7-carboxylate (120 mg), Selectfluor (registered trademark) (215 mg), acetonitrile (2 mL), and methanol (2 mL) was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with water. Then, the precipitate was collected by filtration to obtain methyl 4-fluoro-1-hydroxy-3-methylisoquinoline-7-carboxylate (55 mg).
Reaction SMILES: [S:1](Cl)(Cl)=O.C(OC([NH:10][N:11]=[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[CH3:13])=O)C>>[C:15]1([CH3:20])[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:12]1[N:11]=[N:10][S:1][CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)NN=C(C)c1ccccc1C
Product: Cc1ccccc1-c1csnn1
Temperature: 60 °C

Procedure:
To thionyl chloride (1 ml), cooled to 0° C. was added N′-(1-o-tolyl-ethylidene)-hydrazinecarboxylic acid ethyl ester. The reaction mixture was heated to 60° C. for 1 h. Solvent evaporation gave 4-o-tolyl-[1,2,3]thiadiazole; 1H NMR (CDCl3, 400 MHz) δ8.51 (s, 1H), 7.65 (d, 1H, J=7.3 Hz), 7.36 (m, 3H), 2.46 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[CH:7][C:8]=1[Cl:9])[CH3:2].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(Cl)Cl>>[Cl:9][C:8]1[CH:7]=[CH:6][C:5]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cc(O)ccc1Cl
Reactant: OB(O)c1ccccc1
Solvent: ClCCl
Product: CCc1cc(Oc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-ethyl-4-chlorophenol (2.0 g, 0.013 mol), phenylboronic acid (4.7 g, 0.038 mol), TEA (11 mL, 0.077 mol), cupric acetate (4.2 g, 0.023 mol) and DCM (60 mL, 0.9 mol) were added to a 100 mL oven dried flask and the reaction was stirred at rt for 24 h. The solvent was then removed under reduced pressure and the resulting residue was purified by flash chromatography (5% EtOAc in Hexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][C@H:12]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:13]([CH3:17])[C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[O:36][NH2:37]>C(Cl)Cl>[OH:36][NH:37][C:14](=[O:15])[C@@H:13]([CH3:17])[C@H:12]([S:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(S[C@H](CCCCc2ccccc2)[C@H](C)C(=O)O)cc1OC
Reactant: C[Si](C)(C)ON
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(S[C@H](CCCCc2ccccc2)[C@H](C)C(=O)NO)cc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
(2R,3R)-3-(3,4-Dimethoxyphenylsulfanyl)-2-methyl-7-phenylheptanoic acid (0.33 g, 0.85 mmol) is dissolved in CH2Cl2 (4 mL) and cooled to 0° C. and to this is added 2 M oxalyl chloride in CH2Cl2 (1.3 mL, 2.6 mmol) over 3 minutes. After 10 minutes the ice bath is removed and the reaction is stirred at room temperature for 2 hours. The reaction is concentrated in vacuo and azeotroped with chloroform twice. The residue is dissolved in CH2Cl2 (4 mL), cooled in ice and O-trimethylsilylhydroxylamine (0.32 mL, 2.6 mmol) is added over 2 minutes. After 10 minutes the reaction is concentrated in vacuo. The residue is dissolved in CH2Cl2 (50 mL) and washed with 1 N HCl (20 mL). The organic layer is dried over MgSO4 and the solvent removed in vacuo to give (+)-(2R,3R)-3-(3,4-Dimethoxyphenylsulfanyl)-2-methyl-7-phenylheptanoic acid hydroxyamide (0.27 g, 79%): [a]D23 +40° (c=1.0, CHCl3); 1H NMR (300 MHz, CD3OD) δ 7.25-7.20 (m, 2H), 7.13-7.11 (m, 3H), 7.00-6.96 (m, 2H), 6.88 (d, J=8.0 Hz, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.01-2.95 (m, 1H), 2.57-2.55 (m,1H), 2.23-2.15 (m, 1H), 1.71-1.41 (m, 6H), 1.34 (d, J=6.9 Hz, 3H); MS (FAB) m/e 404 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[O:11][C:12]([CH:27]([CH3:29])[CH3:28])=[C:13]([CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[CH:20]=2)=[O:18])[N:14]=1.B(Cl)(Cl)Cl.C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[O:11][C:12]([CH:27]([CH3:29])[CH3:28])=[C:13]([CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[CH:20]=2)=[O:18])[N:14]=1
Reactant: COc1cc(Cl)ccc1-c1nc(CCC(=O)c2ccc(O)c(C)c2)c(C(C)C)o1
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1cc(C(=O)CCc2nc(-c3ccc(Cl)cc3O)oc2C(C)C)ccc1O
Temperature: 0 °C
Reaction time: 72 h
Yield: 64.2 %

Procedure:
The obtained 3-[2-(2-methoxy4-chlorophenyl)-5-isopropyl-4-oxazolyl]-1-(3-methyl-4-hydroxyphenyl)propan-1-one (621 mg, 1.50 mmol) was suspended in methylene chloride (30 mL) and cooled with ice. To the suspension, a 1M methylene chloride solution of boron trichloride (BCl3) (3.0 mL, 3.00 mmol) was dropwise added for 1 minute. The mixture was allowed to room temperature, stirred for 72 hours, and poured into ice water. Chloroform and saturated sodium hydrogen carbonate were added to the mixture. The organic layer was washed with water, and a saline, dried over anhydrous sodium sulfate. The chloroform was removed under reduced pressure. The residue was purified by column chromatography on silica gel with hexane/ethyl acetate (3/1) to give the desired compound (385 mg) as colorless oil (yield 64%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[N:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]=3[NH:9][C:8]2=[O:20])[CH2:3][CH2:2]1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([C:30]2[CH:39]=[C:38]([CH3:40])[C:33]3[NH:34][C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:40][C:38]1[C:33]2[NH:34][C:35](=[O:37])[O:36][C:32]=2[CH:31]=[C:30]([C:28]([C:24]2[N:25]=[CH:26][N:27]=[C:22]([N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[C:11]5[CH:12]=[N:13][C:14]6[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=6[C:10]=5[NH:9][C:8]4=[O:20])[CH2:5][CH2:6]3)[CH:23]=2)=[O:29])[CH:39]=1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Reactant: O=c1[nH]c2c3ccccc3ncc2n1C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5c6ccccc6ncc54)CC3)ncn2)cc2oc(=O)[nH]c12

Procedure:
134 mg (0.500 mmol) 3-piperidin-4-yl-1,3-dihydroimidazo[4,5-c]quinolin-2-one, 145 mg (0.500 mmol) 6-(6-chloropyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one and 0.174 mL (1.00 mmol) DIPEA were stirred overnight in 5 mL DMF at RT. The mixture was purified by preparative HPLC-MS. The fractions containing the product were combined, the organic solvent was eliminated i. vac. and the aqueous phase remaining was neutralised with a 4N aqueous NaOH solution. The precipitate was suction filtered, washed with water and dried in the CAD.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)CCC.[ClH:20].Br[C:22]1[CH:23]=[CH:24][C:25]2[N:31]([CH2:32][C:33]3[N:34]=[CH:35][NH:36][CH:37]=3)[CH2:30][CH2:29][N:28]([C:38]([C:40]3[C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[CH:43]=[CH:42][CH:41]=3)=[O:39])[CH2:27][C:26]=2[CH:50]=1>>[ClH:20].[ClH:20].[ClH:20].[NH:36]1[CH:37]=[C:33]([CH2:32][N:31]2[C:25]3[CH:24]=[CH:23][C:22]([C:6]4[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=4)=[CH:50][C:26]=3[CH2:27][N:28]([C:38]([C:40]3[C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[CH:43]=[CH:42][CH:41]=3)=[O:39])[CH2:29][CH2:30]2)[N:34]=[CH:35]1
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(Br)cc2C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: Cl
Product: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(-c3cccnc3)cc2C1
Yield: 8 %

Procedure:
Example 67 was prepared as a yellow solid in 8% yield from Compound A of Example 37 and 3-(tributylstannyl)pyridine as described for Compound B of Example 37.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:30]1[CH2:31][C@@H:32]([OH:33])[C@H:28]([NH:27][C:25]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:8]4[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:16]=3[NH:23][C:22]=2[CH3:24])=[O:26])[CH2:29]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@@H]4CNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)c1
Agent: Cl
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@@H]4CN(C(C)=O)C[C@H]4O)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f22) and commercially acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:25]=[CH:24][C:15]([C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:17])=[CH:14][CH:13]=2)=[N:2]1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[CH3:56][O:57][CH2:58][CH2:59][O:60][CH2:61][C:62](O)=[O:63]>>[CH3:56][O:57][CH2:58][CH2:59][O:60][CH2:61][C:62]([N:21]1[CH2:22][CH2:23][N:18]([C:16](=[O:17])[C:15]2[CH:14]=[CH:13][C:12](/[CH:11]=[CH:10]/[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[CH:25][CH:24]=2)[CH2:19][CH2:20]1)=[O:63]
Reactant: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCNCC1
Reactant: COCCOCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Product: COCCOCC(=O)N1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Yield: 4.1 %

Procedure:
The crude product obtained using Compound 18 (200 mg, 0.602 mmol), N-methylmorpholine (0.132 mL, 1.20 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (161 mg, 0.842 mmol), 1-hydroxybenzotriazole monohydrate (106 mg, 0.783 mmol) and 2-methoxyethoxyacetic acid (0.0674 mL, 0.722 mmol) in a similar manner to Example 5, was purified by silica gel column chromatography (chloroform/methanol=80/20) to obtain Compound 127 (0.011 g, 4%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].Cl.N1C=CC=CC=1.[OH:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[CH3:31])[NH2:27]>C(OCCO)C>[OH:23][C:24]1[CH:25]=[C:26]([NH:27][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: COc1cccc2c(Cl)c(C#N)cnc12
Reactant: Cc1ccc(N)cc1O
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cccc2c(Nc3ccc(C)c(O)c3)c(C#N)cnc12
Temperature: 100 °C
Yield: 89 %

Procedure:
Using an analogous procedure to that described in Example 274. A reaction mixture of 328.0 mg (1.5 mmol) of 4-chloro-8-methoxy -3-quinolinecarbonitrile, 173.3 mg (1.5 mmol) of pyridine hydrochloride and 203.2 mg (1.7 mmol) of 3-hydroxy-4-methyl-aniline in 15 mL of 2-ethoxyethanol was heated at 100° C. for 1.5 hr. After the work up, 407.7 mg (89.4%) of the product was obtained as a yellow solid, m.p. 148-150° C., mass spectrum (electrospray, m/e): M+H 306.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:6][NH:7][C:8](=[O:24])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21].CO[C:32](OC)([CH3:34])[CH3:33].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:6][NH:7][C:8](=[O:24])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][CH:19]1[CH2:22][O:23][C:32]([CH3:34])([CH3:33])[O:21][CH2:20]1
Reactant: COC(C)(C)OC
Reactant: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2NC(CO)CO)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2NC2COC(C)(C)OC2)cc1OC
Reaction time: 0.5 h

Procedure:
To a solution of N-(3,4-dimethoxybenzyl)-2-[2-hydroxy-1-(hydroxymethyl)ethylamino]-5-nitrobenzamide (117 mg) in dichloromethane (5.0 mL) were added 2,2-dimethoxypropane (0.36 mL) and 4-toluenesulfonic acid (10 mg), and the mixture was stirred for 30 minutes under reflux. The resulting mixture was diluted with ethyl acetate and washed successively with diluted sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was triturated with diethyl ether to give N-(3,4-dimethoxybenzyl)-2-(2,2-dimethyl-1,3-dioxan-5-ylamino)-5-nitrobenzamide (105 mg) as a solid substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=3)[N:11]=[C:10]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:9]=2)=[CH:4][CH:3]=1>O.C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=3)[N:11]=[C:10]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)c1cc(-c2ccc(N)cc2)c2cc(Cl)ccc2n1
Solvent: CCO
Solvent: O
Product: CCN(CC)C1=Nc2ccc(Cl)cc2C(c2ccc(N)cc2)C1

Procedure:
5.49 g of sodium/mercury amalgam were added over the course of 5 hours to a solution of 250 mg of 4-(4-aminophenyl)-6-chloro-2-diethylaminoquinoline in 2.5 ml of water and 16 ml of ethanol while stirring. The mixture was stirred overnight and decanted to remove the Hg precipitate, and the solvent was distilled under reduced pressure. The residue was mixed with water and extracted with ethyl acetate. The solid product as pale residue was dissolved in a little ethyl acetate, acidified with ethereal HCl, stirred at room temperature and filtered with suction.