Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[C:13]1[N:18]=[C:17]([O:19][C:20]2[C:25]([CH3:26])=[CH:24][C:23]([NH2:27])=[C:22]([CH3:28])[CH:21]=2)[CH:16]=[CH:15][N:14]=1.O>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:13]1[N:18]=[C:17]([O:19][C:20]2[C:25]([CH3:26])=[CH:24][C:23]([NH2:27])=[C:22]([CH3:28])[CH:21]=2)[CH:16]=[CH:15][N:14]=1
Reactant: Cc1cc(Oc2ccnc(Cl)n2)c(C)cc1N
Reactant: Cc1c(O)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Oc2ccnc(Oc3cccc(Cl)c3C)n2)c(C)cc1N
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A solution of 1.43 g (10 mmol) 3-chloro-2-methyl-phenol and 0.4 g sodium hydride (60% in paraffine, 10 mmol) in 20 ml THF were stirred for 30 min at ambient temperature. After adding 1.25 g (5 mmol) 4-(2-chloro-pyrimidin-4-yloxy)-2,5-dimethyl-phenylamine the mixture was stirred for 20 hrs at 60° C. After cooling down to ambient temperature 20 ml water was added and the organic layer was separated, dried over magnesium sulfate, concentrated in vacuo, column chromatography (cycclhexane/ethyl acetate, 2:1) and a second column chromatography (dichloromethane) yielded 640 mg (30%) with a purity of 85%; log P (pH=2.3)=2.81.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[Cl:24][CH2:25][CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29]>O1CCCC1>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][NH:16][S:28]([CH2:27][CH2:26][CH2:25][Cl:24])(=[O:30])=[O:29])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(CCNS(=O)(=O)CCCCl)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-Boc-4-(2-aminoethyl)-piperazine (1.26 g, 6.8 mmol, Aldrich) and triethylamine (1 mL) in tetrahydrofuran (10 mL), 3-chloro-propylsulfonyl chloride (0.68 mL, 6.94 mmol, Aldrich) was added slowly at room temperature. The mixture was stirred for 30 min at room temperature and the reaction was quenched with water. It was extracted with ethyl acetate and the extracts were combined and dried over anhydrous sodium sulfate. The solids were filtered off, and the filtrate was concentrated in vacuo to give 4-[2-(3-chloro-propane-1-sulfonylamino)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester. It was taken in tetrahydrofuran (20 mL), and cesium carbonate (500 mg) sodium iodide (80 mg) were added and the mixture was stirred at reflux overnight. The mixture was cooled to room temperature and poured into water. It was extracted with ethyl acetate (3×15 mL), and the extracts were combined and dried over anhydrous sodium sulfate. The solids were filtered off, and the filtrate was concentrated in vacuo to give 2.01 g of 4-[2-(1,1-dioxo-isothiazolidine-2-yl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester as a solid. LR-MS: 334 [(M+H)+]
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]=1)=[O:4]>CO.[Pd]>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:15])([CH3:1])[CH3:16])=[N:7][CH:8]=1
Reactant: CC(C)(C)C(=O)Nc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)C(=O)Nc1ccc(N)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,2-dimethyl-N-(5-nitropyridin-2-yl)propanamide (300 mg, 1.34 mmol) from Step 1 of this example was dissolved with stirring in MeOH (4.5 ml). Palladium on carbon (10%, 75 mg) was added and the slurry degassed, placed under an atmosphere of hydrogen (3×) and stirred at RT for 30 minutes. The mixture was filtered through CELITE, the filter cake washed with EtOAc (3×100 ml), the filtrates combined and the volatiles removed in vacuum to give the titled compound.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]([CH3:27])([O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][CH2:18][CH3:19])[C:12]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[C:11]2[CH3:26])[CH3:6])C.[ClH:29]>>[ClH:29].[CH3:6][C:5]([O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][CH2:18][CH3:19])[C:12]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[C:11]2[CH3:26])([CH3:27])[C:4]([OH:28])=[O:3]
Reactant: CCCn1c(-c2ccncc2)c(C)c2cc(OC(C)(C)C(=O)OCC)ccc21
Agent: Cl
Product: CCCn1c(-c2ccncc2)c(C)c2cc(OC(C)(C)C(=O)O)ccc21

Procedure:
The above compound was prepared from 2-methyl-2-[3-methyl-1-propyl-2-(4-pyridyl)-1H-indole-5-yloxy]propanoic acid ethylester by hydrolysis with diluted hydrochloric acid at the boiling temperature. After the hydrochloric acid was distilled off in vacuo, the reaction product was recrystallized from acetone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[CH2:13][OH:14].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]=[CH:17][N:18]([CH3:20])[CH3:19])(=[O:11])=[O:10])=[CH:5][C:4]=1[CH2:13][OH:14]
Reactant: COC(OC)N(C)C
Reactant: COc1ccc(S(N)(=O)=O)cc1CO
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N=CN(C)C)cc1CO
Temperature: 80 °C
Reaction time: 1 h

Procedure:
The mixture consisting of 1 g of 4-methoxy-3-hydroxymethylphenylsulfonamide, 0.66 g of dimethylformamide dimethyl acetal and 5 ml of dimethylformamide is stirred at 80° C. for one hour and then concentrated in vacuo. The residue is an oil which gradually solidifies and which is used without further purification for the following chlorination.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[NH2:23][C:24]1[C:25]([CH3:30])=[CH:26][CH:27]=[CH:28][CH:29]=1>>[CH3:13][C:12]1[C:7]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Cc1ccccc1N
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1ccccc1Nc1nc(NCc2ccccn2)nc(C)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using o-toluidine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.08 (s, 3H), 2.27 (s, 3H), 2.34 (s, 3H), 4.66 (d, J=3.2 Hz, 2H), 5.70 (bs, 1H), 6.14 (s, 1H), 7.01 (t, J=6.3 Hz, 1H), 7.13 (t, J=6.3 Hz, 2H), 7.18 (d, J=7.5 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.84 (d, J=7.8 Hz, 1H), 8.54 (d, J=4.8 Hz, 1H); MS (ESI) m/z 320.7 (M+1)+.
Reaction SMILES: C(OC([N:8]1[CH:14]2[CH2:15][CH2:16][CH:9]1[CH2:10][N:11]([C:18]1[CH:19]=[N:20][C:21]([NH:24][C:25]3[N:26]=[CH:27][C:28]4[CH:33]=[C:32]([C:34](=[O:38])[N:35]([CH3:37])[CH3:36])[N:31]([CH:39]5[CH2:43][CH2:42][CH2:41][CH2:40]5)[C:29]=4[N:30]=3)=[CH:22][CH:23]=1)[C:12](=[O:17])[CH2:13]2)=O)(C)(C)C.C(OCC)(=O)C.Cl>O1CCOCC1>[CH3:36][N:35]([CH3:37])[C:34]([C:32]1[N:31]([CH:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)[C:29]2[N:30]=[C:25]([NH:24][C:21]3[CH:22]=[CH:23][C:18]([N:11]4[C:12](=[O:17])[CH2:13][CH:14]5[NH:8][CH:9]([CH2:16][CH2:15]5)[CH2:10]4)=[CH:19][N:20]=3)[N:26]=[CH:27][C:28]=2[CH:33]=1)=[O:38]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC5CCC(CC4=O)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC5CCC(CC4=O)N5)cn3)nc2n1C1CCCC1
Temperature: 25 °C
Yield: 45 %

Procedure:
To 0.55 grams (0.96 mmoles) of 3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylic acid tert-butyl ester was added 15 ml of ethyl acetate. The mixture was stirred at room temperature under N2 and cooled to ice bath temperature. To this mixture was added 5 mls 4N HCl in dioxane. The resultant mixture was allowed to stir until all starting material was consumed. The resultant mixture was stirred until all starting material was consumed as determined by HPLC-MS. To this mixture was added 50 ml of a 1:1 mixture of ethyl acetate/diethyl ether to precipitate solids. The solids were filtered and washed with excess 1:1 mixture of ethyl acetate/diethyl ether and dried under vacuum to a constant weight to yield 7-Cyclopentyl-2-[5-(4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide as the di-hydrochloride salt, 0.213 grams (45% yield). MS m/z 489 (M+H)+. 1H NMR (400 MHz, D6 DMSO) δ 10.2 (s, 1H, broad), 9.05 (s, 1H, broad), 8.35 (s, 1H), 8.0 (d, 1H), 7.7 (d, 1H), 6.9 (s, 1H), 4.82 (m, 1H, broad), 4.6 (d, 1H), 4.25 (s, 1H, broad), 4.15 (s, 1H, broad), 3.82 (m, 1H, broad), 3.5 (d, 1H), 3.05 (s, 6H), 2.82 (m, 1H), 2.3 (m, 2H), 2.2-1.95 (m, 10H, broad), 1.89 (m, 1H), 1.65 (m, 2H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[CH2:22]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37](Cl)=[O:38])=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)[CH2:23][CH3:24]>C(Cl)Cl>[CH2:22]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([N:7]3[C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[CH2:10][N:4]4[CH:3]=[CH:2][CH:1]=[C:5]4[CH2:6]3)=[O:38])=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)[CH2:23][CH3:24]
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: CCCc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1ccc(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2.0 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 30 ml of methylene chloride, under nitrogen, while cooling to 0° C. is added dropwise 30 ml of triethylamine followed by a solution of 4'-(propyl) [1,1'-biphenyl]-4-carbonyl chloride in 10 ml of methylene dichloride. The reactants are stirred at room temperature for 16 hours. The reaction mixture is poured in ice water and extracted with methylene chloride (3×50 ml) The organic layer is, washed with water, 2N citric acid, saturated aqueous NaHCO3, water and dried(MgSO4) and evaporated in vacuo to give a residue which is purified by column chromatography on silica gel with ethyl acetate-hexane to give 1.4 g of the desired product as a crystalline solid, m.p. 118°-120° C. MS(M+H=407.3; M+Na=429.3)
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+].[F:26][C:27]([F:31])([F:30])[CH2:28]O>>[F:26][C:27]([F:31])([F:30])[CH2:28][O:13][C:12](=[O:14])[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:10][CH:9]=1
Reactant: CC(C)Cc1ccc(CC(=O)O)cc1
Reactant: OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)Cc1ccc(CC(=O)OCC(F)(F)F)cc1
Temperature: 0 °C

Procedure:
A mixture of 1.9 g of p-isobutylphenylacetic acid, 10 ml of 2,2,2-trifluoroethanol and 1 ml of concentrated sulfuric acid was refluxed for 5 hours. After the reaction was complete, the mixture was poured into ice-water. The resulting mixture was neutralized with adding 5% sodium carbonate solution, and then extracted with ether. The ether layer separated was dehydrated and concentrated to leave an oily residue. The residue was distilled in vacuo to yield 2.3 g of p-isobutylphenylacetic acid-2,2,2-trifluoroethyl ester as a colorless liquid, boiling at 78°-79° C./1 mmHg. Analysis-Calculated for C14H17F3O2 : C, 61.30; H, 6.25. Found: C, 61.01; H, 6.15. Mass spectrum: parent ion 274 m/e.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH3:7])[CH3:6])=[O:4].Cl.Cl.[Cl:10][C:11]1[C:12]([F:37])=[C:13]([CH:34]=[CH:35][CH:36]=1)[NH:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:32][CH3:33])=[C:22]([O:25][CH:26]3[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]3)[CH:23]=2)[N:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:10][C:11]1[C:12]([F:37])=[C:13]([CH:34]=[CH:35][CH:36]=1)[NH:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:32][CH3:33])=[C:22]([O:25][CH:26]3[CH2:31][CH2:30][CH2:29][N:28]([CH2:2][C:3](=[O:4])[N:5]([CH3:7])[CH3:6])[CH2:27]3)[CH:23]=2)[N:18]=[CH:17][N:16]=1
Reactant: CN(C)C(=O)CCl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCN(CC(=O)N(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
2-Chloro-N,N-dimethylacetamide (105 mg) was added to a mixture of 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline dihydrochloride (250 mg) and potassium carbonate (1.19 g) in DMF (5 ml). The mixture was stirred at room temperature for 30 mins, filtered and the solvent evaporated. Purification by flash column chromatography eluting with methylene chloride/methanol (96/4) gave a foam. This was triturated with diethyl ether and isohexane to give the title product as a white solid (105 mg); 1H NMR. Spectrum: (DMSO d6) 1.45 (m, 1H), 1.61 (m, 1H), 1.78 (m, 1H), 2.10 (m, 1H), 2.26 (m, 1H), 2.38 (m, 1H), 2.65-2.77 (m, 1H), 2.75 (s, 3H), 2.99 (s, 3H), 3.04 (m, 1H), 3.22 (s, 2H), 3.94 (s, 3H), 4.62 (m, 1H), 7.21 (s, 1H), 7.29 (m, 1H), 7.47-7.55 (m, 2H), 7.88 (s, 1H), 8.38 (s, 1H), 9.59 (s, 1H); Mass Spectrum: (M+H)+ 488.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]1[N:22]3[CH2:23][CH2:24][CH2:25][NH:26][CH2:27][C:21]3=[N:20][C:12]=1[C:13]([NH2:19])=[N:14]2.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>CN(C=O)C>[CH3:28][S:29]([N:26]1[CH2:25][CH2:24][CH2:23][N:22]2[C:11]3[C:10]4[C:15](=[CH:16][CH:17]=[CH:18][CH:9]=4)[N:14]=[C:13]([NH2:19])[C:12]=3[N:20]=[C:21]2[CH2:27]1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1nc2ccccc2c2c1nc1n2CCCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCCn2c(nc3c(N)nc4ccccc4c32)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (2.32 mL, 16.7 mmol) was added to a suspension of 9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine hydrochloride (1.61 g, 5.56 mmol, Example 7 Part A) in DMF (20 mL). The mixture was sonicated for ten minutes at 80° C., and methanesulfonyl chloride (764 mg, 6.67 mmol) was slowly added. The mixture was stirred at ambient temperature overnight. The solvent was removed under reduced pressure. Unsuccessful attempts were made to purify the product, and ultimately, the product was isolated by filtration to provide 894 mg of 9-(methylsulfonyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine containing some impurities.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:52]=[CH:51][C:6]([C:7]([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@:25]2([CH2:39]OS(C2C=CC(C)=CC=2)(=O)=O)[OH:38])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[N-:53]=[N+:54]=[N-:55].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@:25]2([CH2:39][N:53]=[N+:54]=[N-:55])[OH:38])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:52][CH:51]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@]2(O)COS(=O)(=O)c2ccc(C)cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@]2(O)CN=[N+]=[N-])(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 91 %

Procedure:
A slurry of 5′-O-(4,4′-dimethoxytrityl)-3′-p-toluensulfonyloxymethylthymidine (0.40 g; 0.55 mmol) and NaN3 (0.11 g; 1.65 mmol) in anhydrous DMF (3 ml) was heated at 50° C. for 3 days. The reaction mixture was cooled to room temperature, diluted with EtOAc (30 ml), and washed with water (3×40 ml), then with 10% NaHCO3 (3×40 ml). The organic layer was dried over Na2SO4, concentrated and purified by chromatography on silica (EtOAc-Hexanes, 1:1) to yield 0.30 g (92%) of 5′-O-(4,4′-dimethoxytrityl)-3′-C-azidomethylthymidine as a colorless powder.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([C:31]#[CH:32])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N+:37]([CH2:40][CH2:41][O:42]C1CCCCO1)([O-])=[O:38].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C.C1(C)C=CC=CC=1>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]([CH3:33])([CH3:34])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([C:31]3[O:38][N:37]=[C:40]([CH2:41][OH:42])[CH:32]=3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:35])[F:36])[CH:8]=1
Reactant: O=[N+]([O-])CCOC1CCCCO1
Reactant: C#Cc1cc(-c2ccccc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccccc1-c1cc(-c2cc(CO)no2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 70 h
Yield: 15.3 %

Procedure:
To a solution of 200 mg (0.396 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-ethynyl-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramide (Example 66), 0.182 ml (1.19 mmol) 2-(2-nitroethoxy)tetrahydropyran and 5 mg (0.04 mmol) 4-N,N-dimethylaminopyridine in 3 ml acetonitrile a solution of 260 mg (1.19 mmol) di-tert-butyl dicarbonate in 2 ml toluene was added, and the mixture was stirred at room temperature for 70 h. Quenching with water was followed by extraction with two portions of ethyl acetate. The combined organic extracts were dried with sodium sulfate and concentrated. The residue was dissolved in 1.5 ml methanol and treated with 4 mg (0.02 mmol) 4-toluenesulfonic acid monohydrate. After stirring for 1.5 h at room temperature the solvent was evaporated. The residue was dissolved in ethyl acetate. Washing with saturated sodium bicarbonate solution was followed by drying with sodium sulfate and concentration. Column chromatography afforded 35 mg (15%) of the title compound as a viscous orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[C:17]([OH:22])[CH:18]=[CH:19][CH:20]=3)[C:15](=[O:23])[N:14]2[CH3:24])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:25]([NH:28][C:29]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:27])[CH3:26]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[C:17]([OH:22])[CH:18]=[CH:19][CH:20]=3)[C:15](=[O:23])[N:14]2[CH3:24])[CH2:10][CH2:11][N:32]2[CH2:33][CH2:34][C:29]([NH:28][C:25](=[O:27])[CH3:26])([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:30][CH2:31]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)NC1(c2ccccc2)CCNCC1
Reactant: CN1C(=O)c2c(O)cccc2C1C(CC=O)c1ccc(Cl)c(Cl)c1
Product: CC(=O)NC1(c2ccccc2)CCN(CCC(c2ccc(Cl)c(Cl)c2)C2c3cccc(O)c3C(=O)N2C)CC1
Product: Cl

Procedure:
3-(3,4-Dichlorophenyl)-3-(4-hydroxy-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.2.0 g) was coupled to 4-acetamido-4-phenylpiperidine (0.14 g) by a method similar to that described in Example 8. The reaction product was purified by chromatography and converted to the corresponding hydrochloride salt as described in the Example 8 to afford the title compound (0.27 g); mp 185°-205° C.; MS: m/z=566(M+1); NMR(CD3SOCD3): 2.88 (m,1), 2.96 (s,3), 4.79 (d,1, J=3.5), 6.86 (m,2), 7.09 (d,1, J=1.8), 7.20-7.47 (m,8). Analysis for C31H33Cl2N3O2.1.0 HCl.1.5 H2O: Calculated: C, 59.10; H, 5.91, N, 6.67; Found: C, 59.51; H, 5.63; N, 6.23.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH2:10].[CH3:11][C:12]1[N:16]([CH2:17][C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)[C:15]2[CH:27]=[CH:28][CH:29]=[CH:30][C:14]=2[N:13]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][C:22](=[O:23])[C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:16]2[C:15]3[CH:27]=[CH:28][CH:29]=[CH:30][C:14]=3[N:13]=[C:12]2[CH3:11])=[CH:26][CH:25]=1
Reactant: NCCc1ccccc1F
Reactant: Cc1nc2ccccc2n1Cc1ccc(C(=O)O)cc1
Product: Cc1nc2ccccc2n1Cc1ccc(C(=O)NCCc2ccccc2F)cc1

Procedure:
The title compound was prepared in analogy to example 1c, but using 2-(2-fluoro-phenyl)-ethylamine and 4-(2-methyl-benzoimidazol-1-ylmethyl)-benzoic acid as coupling components. MS (ISP): 388.2 ((M+H)+.).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1I.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[N:47]([CH:49]=[O:50])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:49]([NH2:47])=[O:50]
Reactant: CN(C)C=O
Reactant: COc1cc2ncc(I)c(Cl)c2cc1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Product: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Temperature: 100 °C

Procedure:
A stainless steel cylinder was charged with 4-chloro-3-iodo-6,7-dimethoxyquinoline (0.200 g, 0.572 mmol), palladium (II) acetate (0.013 g, 0.057 mmol), 1,3-bis(diphenylphosphino)propane (0.047 g, 0.11 mmol), DMF (2 mL), and 1,1,1,3,3,3-hexamethyldisilazane S (0.37 g, 0.48 mL, 2.3 mmol). The cylinder was sealed and pressurized with CO gas at 30 psi. The system was heated at 100° C. for 1.5 h and then cooled to RT. The mixture was concentrated to afford an orange solid. This material was triturated with dichloromethane and the resulting precipitate was filtered and dried to afford 4-chloro-6,7-dimethoxyquinoline-3-carboxamide as an off-white solid. MS (ESI, pos. ion) m/z: 267.0 (M+H). Mass Calc'd for Cl2H11ClN2O3: 266.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])/[CH:10]=[CH:11]/[C:12]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH2:29][N:30]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:31][Si](C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.CCOC(C)=O.COCN(CC1C=CC=CC=1)C[Si](C)(C)C.FC(F)(F)C(O)=O>[CH2:36]([N:30]1[CH2:31][C@@H:11]([C:12]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[C:13]=2[C:14]([O:16][CH3:17])=[O:15])[C@H:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:26])[CH2:29]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)c1c(/C=C/C(=O)OCc2ccccc2)cccc1C(F)(F)F
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c([C@@H]2CN(Cc3ccccc3)C[C@H]2C(=O)OCc2ccccc2)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.5 %

Procedure:
To a solution of (E)-methyl 2-(3-(benzyloxy)-3-oxoprop-1-enyl)-6-(trifluoromethyl)benzoate (5.83 g, 16.0 mmol) in 60 mL of CH2Cl2 was added N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (4.0 g, 16.8 mmol) and trifluoroacetic acid (0.25 mL, 3.2 mmol). The solution was allowed to stir at ambient temperature for 18 h. Starting material still remained by TLC analysis and so additional N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (0.25 g, 1.05 mmol) and trifluoroacetic acid (0.05 mL, 0.65 mmol) were added and the reaction was stirred at 40° C. for an additional 2 h. The reaction was allowed to cool and was diluted with EtOAc, washed with sat'd aq NaHCO3 and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography (4:1 hexane/EtOAc) to afford 7.6 g (95%) of the title compound as an oil. LRMS (ES)+: 498.32 (M+H)+.