Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(S[CH:5]1[N:8]([C:9](=[C:23]([O:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:41])[CH2:6]1)C=C.[Cl:42]Cl>ClCCl.C(Cl)(Cl)(Cl)Cl>[Cl:42][CH:5]1[N:8]([C:9](=[C:23]([O:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:41])[CH2:6]1
Reactant: ClCl
Reactant: C=CCSC1CC(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Oc1cccc2ccccc12)C(=O)C(C)(C)C
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)C(Oc1cccc2ccccc12)=C(C(=S)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1Cl
Temperature: 25 °C
Yield: 73.7 %

Procedure:
To a solution of 7.1 g of 4-nitrobenzyl 2-(4-allylthioazetidin-2-on-1-yl)-3-(1-naphthyloxy)-3-trimethylacetylthiopropenate in dichloromethane at -20° was added a solution of 23 mmol of chlorine in carbon tetrachloride. After 30 minutes the mixture was warmed to room temperature, evaporated in vacuo, and the residual oil was chromatographed over silica gel. Elution with hexane-ethyl acetate mixtures afforded 4.898 g of the title compound as a pale yellow foam (75% of the theoretical yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C:30]2[C:35]([C:36]3[CH:41]=[CH:40][N:39]=[N:38][CH:37]=3)=[CH:34][C:33]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[CH:43]=3)=[C:32]([Cl:49])[CH:31]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.FC(F)(F)C(O)=O.CO>ClCCl>[Cl:1][C:2]1[C:3]([O:29][C:30]2[C:35]([C:36]3[CH:41]=[CH:40][N:39]=[N:38][CH:37]=3)=[CH:34][C:33]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[CH:43]=3)=[C:32]([Cl:49])[CH:31]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3cc(Cl)c(-c4cccc(F)c4)cc3-c3ccnnc3)cc2F)c(OC)c1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Oc2cc(Cl)c(-c3cccc(F)c3)cc2-c2ccnnc2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 13 %

Procedure:
5-Chloro-4-(2-chloro-3′-fluoro-5-(pyridazin-4-yl)biphenyl-4-yloxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 66, 165 mg, 0.22 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL) was added. The reaction was stirred at room temperature for 3 hours. Methanol (5 mL) was added to quench the reaction and the suspension stirred vigorously for 18 hours. The mixture was diluted with dichloromethane (5 mL) and the resulting precipitate was filtered through Celite™ and washed with dichloromethane (2×5 mL) and the filtrate concentrated in vacuo. The residue was dissolved in dichloromethane and methanol and passed through a short silica plug eluting with dichloromethane/methanol (98:2). The material obtained was further purified by silica gel column chromatography using (dichloromethane/methanol/acetic acid 97:3:0.5) to give the title compound (17 mg, 13%) as a white solid.
Reaction SMILES: C([O:7][CH2:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:13][C:12]2([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[O:11]1)(=O)C(C)(C)C.C(OCC[C@@H]1[C@@H](C2C=CC=CC=2)OC2(CCCC2)O1)(=O)C(C)(C)C>>[C:15]1([C@H:14]2[O:13][C:12]3([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[O:11][C@@H:10]2[CH2:9][CH2:8][OH:7])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)C(=O)OCC[C@H]1OC2(CCCCC2)O[C@@H]1c1ccccc1
Agent: CC(C)(C)C(=O)OCC[C@H]1OC2(CCCC2)O[C@@H]1c1ccccc1
Product: OCC[C@H]1OC2(CCCCC2)O[C@@H]1c1ccccc1
Yield: 80 %

Procedure:
The substantially same method as described in Example 293 was conducted, except that 2-((2R,3R)-3-phenyl-1,4-dioxaspiro[4.5]decan-2-yl)ethyl pivalate (Preparation example 294) was used instead of that 2-((2R,3R)-3-phenyl-1,4-dioxaspiro[4.4]nonan-2-yl)ethyl pivalate (Preparation example 292), to obtain the title compound (1.2 g, 80˜95%)
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[CH:25])=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2].[Br:26][C:27]1[CH:28]=[C:29]([CH:35]=[C:36](I)[CH:37]=1)[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>C1COCC1.C(O)(C(F)(F)F)=O.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:26][C:27]1[CH:37]=[C:36]([C:25]#[C:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:18]2[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[C:7]([CH:15]=[CH:16][CH:17]=2)[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:35]=[C:29]([C:30](=[O:31])[N:32]([CH3:33])[CH3:34])[CH:28]=1
Reactant: CN(C)C(=O)c1cc(Br)cc(I)c1
Reactant: C#CCCCCCc1cccc(OCCCC(=O)O)c1CCC(=O)O
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)c1cc(Br)cc(C#CCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)c1
Temperature: 70 °C
Yield: 65.8 %

Procedure:
To a solution of 4-[2-(2-carboxy-ethyl)-3-hept-6-ynyl-phenoxy]-butyric acid (900 mg, 2.6 mmol), 3-bromo-5-iodo-N,N-dimethyl-benzamide (1.0 g, 2.8 mmol), CuI (20 mg, 0.11 mmol) in THF (10 mL) and TEA (10 mL) was added bis(triphenylphosphine) palladium(II) dichloride (75 mg, 0.11 mmol). The reaction mixture was heated at 70° C. for 5 h. Then the reaction mixture was cooled to room temperature, a few drops of TFA were added and the resulting mixture was concentrated under reduced pressure. The crude material was purified by column chromatography (Isco™ 120 g) using ethyl acetate as eluting solvent to give the title compound (980 mg, 65%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13](N)=[C:12]([CH3:17])[CH:11]=1.N(OCCC(C)C)=O.[I:26]I>C(Cl)(Cl)Cl>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([C:10]2[CH:15]=[CH:14][C:13]([I:26])=[C:12]([CH3:17])[CH:11]=2)=[C:2]([F:1])[CH:7]=1
Reactant: COc1ccc(-c2ccc(N)c(C)c2)c(F)c1
Reactant: II
Agent: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2ccc(I)c(C)c2)c(F)c1

Procedure:
2′-fluoro-4′-methoxy-3-methylbiphenyl-4-amine (190 mg, 0.822 mmol), 3-methylbutyl nitrite (144.4 mg, 1.233 mmol), iodine (251 mg, 0.986 mmol) and chloroform (7 ml) were refluxed in an oil bath for 3.5 hours then allowed to cooled to ambient overnight. Reaction crude was purified by flash chromatography (SiO2, Biotage 40+M cartridge) eluted with a EtOAc/hexanes gradient mixture. Related fractions were pooled and concentrated in vacuo to afford the title compound. LCMS was showing the solid to be about 70 A % pure. LCMS (ESI) calc.=LCMS (ESI) calc.=341.99; found=341.94 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:23][CH3:24])=[CH:5][C:6]2[CH2:7][CH:8]3[CH2:22][NH:21][CH2:20][CH2:19][N:9]3[CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]=2[CH:12]=1.C(N(CC)CC)C.[CH2:32]([O:39][CH2:40][C:41](Cl)=[O:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([O:23][CH3:24])=[CH:5][C:6]2[CH2:7][CH:8]3[CH:22]([C:41](=[O:42])[CH2:40][O:39][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[NH:21][CH2:20][CH2:19][N:9]3[CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]=2[CH:12]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)N1CCNCC1C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C(c1ccccc1)N1CCNC(C(=O)COCc3ccccc3)C1C2
Reaction time: 0.5 h

Procedure:
8,9-Dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinoline (the compound obtained in Example 1-(6)) (1.6 g) is dissolved in methylene chloride (10 ml), and thereto are added triethylamine (0.8 ml) and benzyloxyacetyl chloride (0.8 ml) under ice-cooling, and the mixture is stirred for 30 minutes. The reaction solution is washed with a saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography on silica gel (eluent; chloroform:ethyl acetate=9:1) to give 8,9-dimethoxy-2-benzyloxyacetyl-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinoline (1.1 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH:6]([CH2:8][OH:9])[CH2:5][CH2:4][O:3]1.N1C=CC=CC=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:9][CH2:8][CH:6]2[CH2:5][CH2:4][O:3][C:2]([CH3:10])([CH3:1])[CH2:7]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)CC(CO)CCO1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCOC(C)(C)C2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (2,2-dimethyltetrahydro-2H-pyran-4-yl)methanol (1 g, 6.93 mmol) in DCM (5 mL) and pyridine (5 mL, 61.8 mmol) was added para-toluenesulfonyl chloride (1.586 g, 8.32 mmol) and DMAP (0.042 g, 0.347 mmol). The mixture was stirred for 18 hr at ambient temperature. The reaction mixture was concentrated in vacuo and the resulting residue was diluted with water and DCM. The separated organic layer was washed with 0.2N aqueous HCl (1×), 1N aqueous HCl (2×), brine, dried over sodium sulfate, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, 40 g, EtOAc/hexane=0/100 to 50/50; 25 min] providing (R/S)-(2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Yield: 2.05 g. LCMS (m/z): 299.1 [M+H]+; Retention time=0.96 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16]Cl)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CCCCl)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(N2CCCC2=O)C1
Reaction time: 2 h
Yield: 35.4 %

Procedure:
A solution of 3-(4-chlorobutyrylamino)azetidine-1-carboxylic acid tert-butyl ester (1.04 g, 3.76 mmol) in DMF (15 mL) was cooled to 0° C. before the addition of NaH (180 mg, 4.51 mmol). The resulting mixture was allowed to stir for 2 h then quenched with H2O and extracted with EtOAc. The organic phase was washed with H2O and brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 20-100%) affording 3-(2-Oxopyrrolidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester as a brown oil (320 mg, 35%). 1H NMR (CDCl3, 300 MHz): δ 4.99 (m, 1 H), 4.15 (m, 2 H), 3.97 (m, 2 H), 3.57 (t, J=7.0 Hz, 2 H), 2.42 (t, J=8.1 Hz, 2 H), 2.15-2.02 (m, 2 H) and 1.45 (s, 9 H)
Reaction SMILES: [C:1]1([CH:7]2[O:12][C:11](=[O:13])[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[NH:21][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])O.[Na+].Cl[CH2:35][O:36][CH2:37][CH3:38].O>C(#N)C>[C:1]1([CH:7]2[O:12][C:11](=[O:13])[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:21]([CH2:35][O:36][CH2:37][CH3:38])[S:22]([C:25]([F:26])([F:27])[F:28])(=[O:23])=[O:24])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOCCl
Reactant: O=C1OC(c2ccccc2)CCN1Cc1ccccc1NS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOCN(c1ccccc1CN1CCC(c2ccccc2)OC1=O)S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Yield: 75 %

Procedure:
6-Phenyl-3-[2-(trifluoromethanesulfonylamino)benzyl]-[1,3]-oxazinan-2-one (0.20 g, 0.48 mmol) and sodium hydrogen carbonate (0.08 g, 0.85 mmol) were suspended in acetonitrile (10 ml), added with chloromethylethyl ether (0.07 g, 0.83 mmol) and heated to reflux for three hours. After cooling to room temperature, the reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with a saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 6-phenyl-3-{2-[N-(ethoxymethyl)-N-(trifluoromethanesulfonyl)amino]benzyl)-[1,3]-oxazinan-2-one (0.17 g).
Reaction SMILES: [NH:1]([C:3]1[C:8]([C:9]([O:11]CC)=O)=[CH:7][N:6]=[C:5]2[N:14]([CH2:17][C:18]3[O:22][CH:21]=[CH:20][CH:19]=3)[N:15]=[CH:16][C:4]=12)[NH2:2].C([N:25]1[C:29]2=NC=[C:32](C(OCC)=O)[C:33](NN)=[C:28]2C=N1)C>>[CH2:17]([N:14]1[C:5]2[N:6]=[CH:7][C:8]3[C:9](=[O:11])[NH:25][C:29]4[N:1]([N:2]=[C:33]([CH3:32])[CH:28]=4)[C:3]=3[C:4]=2[CH:16]=[N:15]1)[C:18]1[O:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccco2)c1NN
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1NN
Product: Cc1cc2[nH]c(=O)c3cnc4c(cnn4Cc4ccco4)c3n2n1

Procedure:
By substituting 4-hydrazino-1-furfurylpyrazolo-[3,4-b]pyridine-5-carboxylic acid, ethyl ester for the 1-ethyl-4-hydrazino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester in Example 1 a and proceeding as in parts a and b, 8-furfuryl-2-methyl-4H-pyrazolo[1,5-a]pyrazolo-[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one is obtained. This compound is now processed as in Example 1, part c, substituting bromobenzene for the methyl iodide. A small amount of copper catalyst is added to obtain 1-furfuryl-2-methyl-4-phenyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido-[3,4-e]pyrimidin-5(8H)-one.
Reaction SMILES: [C:1]1([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([C:35]3[O:39][N:38]=[C:37]([CH:40]([CH3:42])[CH3:41])[N:36]=3)[CH2:31][CH2:30]2)=[CH:23][CH:22]=1>>[CH3:42][CH:40]([C:37]1[N:36]=[C:35]([N:32]2[CH2:31][CH2:30][CH:29]([CH2:28][O:27][C:24]3[CH:23]=[CH:22][C:21]([C:14]4[CH:15]=[CH:16][C:11]([C:9]([NH:8][CH2:7][C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[O:10])=[CH:12][CH:13]=4)=[CH:26][CH:25]=3)[CH2:34][CH2:33]2)[O:39][N:38]=1)[CH3:41]
Reactant: O=C(NCc1ccccc1)c1ccc(B(O)O)cc1
Reactant: CC(C)c1noc(N2CCC(COc3ccc(Br)cc3)CC2)n1
Product: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc(C(=O)NCc5ccccc5)cc4)cc3)CC2)n1
Yield: 2 %

Procedure:
The title compound (2 mg, 2%) was prepared from (4-{[(phenylmethyl)amino]carbonyl}phenyl)boronic acid (51 mg, 0.2 mmol) and 4-{[(4-bromophenyl)oxy]methyl}-1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]piperidine (prepared as in Example 24, Step 1, 76 mg, 0.2 mmol) in a manner similar to Example 1, Step 1, and worked up in a manner similar to Example 9, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.83 (d, 2H, J=8.6 Hz), 7.61 (d, 2H, J=8.6 Hz), 7.54 (d, 2H, J=8.9 Hz), 7.39-7.28 (m, 5H), 6.97 (d, 2H, J=8.8 Hz), 6.41 (t, 1H, J=5.7 Hz), 4.68 (d, 2H, J=5.5 Hz), 4.26-4.16 (m, 2H), 3.88 (d, 2H, J=6.4 Hz), 3.18-3.06 (m, 2H), 2.96-2.85 (m, 1H), 2.13-2.01 (m, 1H), 2.02-1.92 (m, 2H), 1.55-1.40 (m, 2H), 1.29 (d, 6H, J=7.0 Hz); LRMS (ESI), m/z 511 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[O:17]>C(C(C)=O)C>[O:13]([CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Oc1ccccc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(COc1ccccc1)c1ccc(Cl)cc1
Yield: 50.4 %

Procedure:
To 28.4 g (213 mmole) of anhydrous potassium carbonate suspended in 100 ml of methyl ethyl ketone was added 20 g (213 mmole) of phenol and 47 g (201 mmole) of 2-bromo-4'-chloroacetophenone. The reaction mixture was refluxed for 2.5 hours, cooled, concentrated in vacuo, partitioned between diethyl ether and water, washed with dilute aqueous sodium hydroxide, washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to yield 25 g of 2-phenoxy-4'-chloroacetophenone, a white solid, mp 80°-83° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:15])[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.Br[C:17]1[C:18]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[N:19][CH:20]=[CH:21][CH:22]=1.CC(C)([O-])C.[Na+].F[B-](F)(F)F.[H+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[Cl-].[NH4+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1COCC1.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([C:17]3[C:18]([O:23][CH2:24][C:25]4[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:19][CH:20]=[CH:21][CH:22]=3)[C:9](=[O:15])[C:10]2([CH3:13])[CH3:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(COc2ncccc2Br)cc1
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(COc2ncccc2C2Cc3ccc(OC)cc3C(C)(C)C2=O)cc1
Temperature: 90 °C
Yield: 8.1 %

Procedure:
To 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 845 mg), 3-bromo-2-(4-methoxy-benzyloxy)-pyridine (Compound GT15-15, 1.46 g), sodium t-butoxide (597 mg), palladium acetate (18.6 mg) and tri-tert-butylphosphine tetrafluoroboric acid (21 mg), toluene (10 ml) and THF (2 ml) were added and the mixture was stirred and heated at 90° C. for 2.5 hrs under nitrogen atmosphere. After cooling, the reaction mixture was added with saturated aqueous solution of ammonium chloride, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and the residues obtained after concentration under reduced pressure were purified by silica gel column (ethyl acetate/hexane) to obtain the title compound (140 mg, 8%).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][N:3]=1.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([F:27])=[CH:23][C:24]=2[F:26])[N:19]=[C:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:17]=1[CH3:34].C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:26][C:24]1[CH:23]=[C:22]([F:27])[CH:21]=[C:20]2[C:25]=1[C:16]([NH:8][C:7]1[C:2]([F:1])=[N:3][CH:4]=[C:5]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[CH:6]=1)=[C:17]([CH3:34])[C:18]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)=[N:19]2
Reactant: Nc1cc(N2CCOCC2)cnc1F
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1F
Temperature: 90 °C
Reaction time: 21.5 h

Procedure:
A mixture of 2-fluoro-5-morpholinopyridin-3-amine (0.12 g, 0.60 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.261 g, 0.90 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.055 g, 0.060 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl (0.058 g, 0.121 mmol), and sodium tert-butoxide (0.176 g, 1.83 mmol) in dry toluene (5.0 mL) was degassed by nitrogen. The mixture was heated to 90° C. After 21.5 h, the reaction was cooled to rt, then treated with water. After extracting twice with EtOAc, the organics were combined and dried over anhydrous magnesium sulfate. After filtration and concentration the residue was purified on basic alumina (0-60% EtOAc in hexanes) to afford an light yellow solid as 5,7-difluoro-N-(2-fluoro-5-(4-morpholinyl)-3-pyridinyl)-3-methyl-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (500 MHz, CDCl3) δ ppm 8.71 (1H, d, J=4.6 Hz), 7.93 (2H, m), 7.70 (1H, m), 7.42 (1H, d, J=2.7 Hz), 7.32 (1H, m), 7.15 (1H, m), 7.01 (1H, m), 6.58 (1H, d, J=7.1 Hz), 3.88 (4H, m), 3.16 (4H, m), 2.23 (3H, s). Mass Spectrum ESI (pos.) m/e: 452.2 (M+H)+.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:16][CH2:17][CH:18]([OH:20])[CH3:19]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:13][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:12]1[N:16]([CH2:17][CH:18]([OH:20])[CH3:19])[CH:2]=[CH:3][C:4]=1[CH2:5]2
Reactant: O=CCC1Cc2ccc(Cl)cc2C1=O
Reactant: CC(O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(O)Cn1ccc2c1-c1ccc(Cl)cc1C2
Reaction time: 0.58 h
Yield: 80 %

Procedure:
A solution of 2 g of (RS)-2-(2-oxoethyl)-6-chlor-1-indanone and 100 mg of p-toluenesulfonic acid in 90 ml of anhydrous toluene was heated on a water separator. A solution of 2.88 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 35 minutes, during which the solvent was reduced to a volume of 30 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). There were obtained 1.9 g (80%) of (RS)-1-(6-chloro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol as a brown oil which was used directly in the next reaction.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>O>[N+:12]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[C:17]([C:16]([F:15])([F:24])[F:25])[CH:18]=1)([O-:14])=[O:13]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1cccc2c(Cl)ccnc12
Solvent: O
Product: O=[N+]([O-])c1cccc2c(Nc3cccc(C(F)(F)F)c3)ccnc12
Temperature: 150 °C
Yield: 156.3 %

Procedure:
A mixture of 4-chloro-8-nitroquinoline (step-2, Intermediate-11, 100 mg, 0.48 mmol) and 3-(trifluoromethyl)aniline (309 mg, 1.92 mmol) was heated at 150° C. for 20 minutes in microwave. Then water was added to the reaction mixture and it was extracted with CHCl3. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 250 mg of the title product.
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:7][C:6]([Cl:18])=[N:5][C:4]=2[CH:3]=1.C([Li])CCC.CN(C)[CH:26]=[O:27]>C1COCC1>[Cl:18][C:6]1[N:7]=[C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[N:10]=[CH:11][C:2]([CH:26]=[O:27])=[CH:3][C:4]=2[N:5]=1
Reactant: Clc1nc(N2CCOCC2)c2ncc(Br)cc2n1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cnc2c(N3CCOCC3)nc(Cl)nc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
To a 50 mL round bottom flask, 4-(7-bromo-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine (3.0 g, 0.0091 mol—Preparation 3) and dry THF (15 mL) were added under nitrogen atmosphere and then cooled to −78° C. To the reaction flask, 2.5 M n-butyl lithium (4.4 mL, 0.0109 mol) was slowly added and the reaction mixture was stirred at −78° C. for 30 minutes. To the reaction mixture, N,N-dimethylformamide (1.27 mL, 0.0164 mol) was added and the reaction mixture allowed to warm to 0° C. The reaction mass was quenched with 10% aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated to provide the crude product. The crude product was purified by column chromatography (60-120 silica gel, 10-40% ethyl acetate) to provide the title compound as a light yellow solid (0.8 g, 31%). 1H NMR (300 MHz, CDCl3): δ 10.24 (s, 1H), 9.11 (d, J=2.1 Hz, 1H), 8.41 (d, J=2.1 Hz, 1H), 3.91 (t, J=4.8 Hz, 8H): LC-MS (ESI): Calculated mass. 278.06, Observed mass [M+H]+: 279.0 (RT=0.66 min).
Reaction SMILES: [CH2:1]([N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:7]=[CH:6]1)[CH:2]([CH3:4])[CH3:3].C(OC(=O)C)(=[O:21])C>>[OH:21][C:9]1[C:8]2[N:7]=[CH:6][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CC(C)Cn1cnc2c[n+]([O-])c3ccccc3c21
Reactant: CC(=O)OC(C)=O
Product: CC(C)Cn1cnc2c(O)nc3ccccc3c21

Procedure:
Using the method of Example 133, 1-isobutyl-1H-imidazo[4,5-c]quinolin-5-oxide (from Example 74) was reacted with acetic anhydride to provide 4-hydroxy-1-isobutyl-1H-imidazo[4,5-c]quinoline, m.p. >300° C. after recrystallization from N,N-dimethylformamide. Analysis: Calculated for C14H15N3O: %C, 69.7; %H, 6.3; %N, 17.4; Found: %C, 69.8; %H, 6.4: %N, 17.6.