Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][C:5](=O)[CH:4]=[CH:3]1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C>C(O)C.[Pt]=O>[CH3:1][C:2]1([CH3:8])[CH2:3][CH2:4][CH:5]([NH:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6]1
Reactant: CC1(C)C=CC(=O)C1
Reactant: NCc1ccccc1
Agent: O=[Pt]
Solvent: CCO
Product: CC1(C)CCC(NCc2ccccc2)C1
Reaction time: 24 h
Yield: 83.5 %

Procedure:
4,4-Dimethyl-2-cyclopenten-1-one (804 mg, 7.30 mmol) and benzylamine (877 μL, 8.03 mmol) were dissolved in 15 mL of ethanol. Charcoal (400 mg) and platinum oxide (Adams' catalyst, 331 mg, 1.46 mmol) were added and the mixture was stirred under hydrogen (balloon) for 24 hours. The reaction was purged with argon and diluted with ethyl acetate. The mixture was loaded onto silica gel and purified by flash chromatography on silica gel eluted with 5% triethylamine and hexane to provide 1.24 g (84%) of a clear colorless oil.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:26](Cl)=[N:25][S:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CC(C)([O-])C.[K+].C(O)(C)(C)C.[Cl:41][C:42]1[CH:47]=[C:46]([CH2:48][OH:49])[CH:45]=[CH:44][N:43]=1>CO>[F:28][C:2]([F:1])([F:29])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:26]([O:49][CH2:48][C:46]4[CH:45]=[CH:44][N:43]=[C:42]([Cl:41])[CH:47]=4)=[N:25][S:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nsnc2Cl)CC1
Reactant: OCc1ccnc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)(C)O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nsnc2OCc2ccnc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.1 %

Procedure:
To a solution of 4-(4-chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide (103.7 mg, 0.226 mmol, prepared in Example 10b) and 1M solution of potassium tert-butoxide in tert-butanol (0.70 mL, 0.70 mmol) was added 2-chloro-4-pyridinemethanol (64.5 mg, 0.448 mmol, prepared in Example 16a). The resulting suspension was stirred at room temperature for 2 h. The crude reaction mixture was diluted with methanol and purified by preparative HPLC (0.1% TFA in water, 0.1% TFA in acetonitrile). The pure fractions were combined and the acetonitrile/TFA was removed in vacuo. The remaining aqueous solution was made basic with NaHCO3 and the free based product was extracted into EtOAc. The organic phase was concentrated in vacuo yielding pure product N-[3,5-bis(trifluoromethyl)phenyl]-4-(4-{[(2-chloropyridin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)piperazine-1-carboxamide (33.4 mg, 26.1% yield). 1H NMR (CDCl3) 8.43 (d, 1H), 7.90 (s, 2H), 7.55 (s, 1H), 7.38 (s, 1H), 6.68 (s, 1H), 5.49 (s, 2H), 3.66 (d, 8H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:28])[C:17]1[CH:22]=[CH:21][C:20](C2NN=NN=2)=[CH:19][CH:18]=1)([O-])=O.[CH3:29]O.[C:31](OCC)(=[O:33])C>>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]([CH3:29])=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:28])[C:17]1[CH:18]=[CH:19][C:20]([O:33][CH3:31])=[CH:21][CH:22]=1
Reactant: O=C(Nc1cc(-c2cccs2)ccc1[N+](=O)[O-])c1ccc(-c2nnn[nH]2)cc1
Reactant: CCOC(C)=O
Reactant: CO
Product: COc1ccc(C(=O)Nc2cc(-c3ccc(C)s3)ccc2N)cc1
Yield: 26 %

Procedure:
Following the same procedure as described in Example 48, step 3 (scheme 36) but substituting compound 171 for compound 94dd and using ethyl acetate as a solvent instead of methanol, the title compound 302 was obtained in 26% yield. 1H NMR: (400.2 MHz, DMSO) δ (ppm): 9.60 (s, 1H), 7.96 (d, J=8.0, Hz, 2H); 7.36 (d, J=2.1 Hz, 1H); 7.20 (dd, J=2.1, 8.3 Hz, 1H); 7.03 (d, J=8.0, Hz, 2H); 7.00 (d, J=3.5 Hz, 1H); 6.78 (d, J=8.3 Hz, 1H), 6.70 (dd, J=1.1, 3.5 Hz, 1H); 3.83 (s, 3H); 2.42 (d, J=1.1 Hz, 3H). MS: calc: 338.4; found: 338.4 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([S:22](C)=O)[N:14]=[C:13]2[CH2:25][CH2:26][CH3:27])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([SH:22])[N:14]=[C:13]2[CH2:25][CH2:26][CH3:27])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: CCCc1nc(S(C)=O)c(C(=O)OCC)n1Cc1cc2c(cc1Cl)OCO2
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc(S)c(C(=O)OCC)n1Cc1cc2c(cc1Cl)OCO2
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
800 mg of the product obtained in Stage 5 above is introduced into 16 ml of methylene chloride and 0.54 ml of trifluoroacetic anhydride is added. Agitation is carried out for 30 minutes, followed by evaporation to dryness and the residue is taken up in 10 ml of methanol and 4 ml of triethylamine. After agitation for 30 minutes, extraction is carried out with chloroform, the extracts are washed with a saturated solution of ammonium chloride, dried and evaporated to dryness. In this way 720 mg of expected product is obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=O.O.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(Cl)(=O)C([Cl:39])=O>O1CCOCC1.O.CN(C=O)C>[C:10]1([C:7]2[NH:6][C:5]([C:3]([Cl:39])=[O:2])=[CH:9][CH:8]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(-c2cccc3ccccc23)[nH]1
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1COCCO1
Product: O=C(Cl)c1ccc(-c2cccc3ccccc23)[nH]1

Procedure:
5-Naphthalen-1-yl-1H-pyrrole-2-carboxylic acid methyl ester was diluted with 1:1 dioxane-water (30 ml), and treated with lithium hydroxide hydrate (24.4 mmol, 1.02 g), then heated to reflux for 15 min. The solution was acidified with 20% aqueous citric acid (30 ml), then extracted with ethyl acetate (75 ml). The organics were washed with brine (2×20 ml), then concentrated under reduced pressure. The residue was diluted with CH2Cl2, (30 ml), and treated with oxalyl chloride (24.0 mmol, 2.10 ml), and DMF (one drop), then heated to reflux for 30 min. The solution was concentrated under reduced pressure to provide 1.95 g of 5-naphthalen-1-yl-1H-pyrrole-2-carboxylic acid chloride.
Reaction SMILES: [C:1]([O-:7])([O-])([O:3][CH2:4][CH3:5])[CH3:2].[CH3:8][C:9]([CH3:23])=[CH:10][CH2:11][CH2:12]/[C:13](/[CH3:22])=[CH:14]/[CH2:15][CH2:16][C:17](O)([C:19]#[CH:20])[CH3:18].[C:24](O)(=O)CC>>[CH3:8][C:9]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:22])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:18])[CH2:19][CH3:20])=[C:23]=[CH:24][CH2:2][C:1]([O:3][CH2:4][CH3:5])=[O:7]
Reactant: CCOC(C)([O-])[O-]
Reactant: CCC(=O)O
Reactant: C#CC(C)(O)CC/C=C(\C)CCC=C(C)C
Product: CCOC(=O)CC=C=C(C)CCC=C(C)CCC=C(C)CC
Yield: 96 %

Procedure:
In the same manner as in the preceeding Examples, 32.4 g of ethyl ortho-acetate, 22 g of dehydronerolidol and 1.5 g of propionic acid were reacted at 135 to 140°C. for 6 hours and the resulting reaction mixture was subjected to distillation under reduced pressure. Ethyl 5,9,13-trimethyl-3,4,8,12-pentadecatetraenoate was obtained in a yield of 96% from a fraction boiling at 144 to 146°C. under 0.025 mm Hg.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:9]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[C:10]2[C:15]([C:16]=1[N:17]=[C:18]=[O:19])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][O:35][C:36]([C:38]1[C:42]([NH2:43])=[CH:41][S:40][CH:39]=1)=[O:37].C(OCC)(=O)C>FC(C1C=CC=CC=1)(F)F>[C:1]([O:5][C:6]([C:8]1[N:9]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[C:10]2[C:15]([C:16]=1[NH:17][C:18]([NH:43][C:42]1[C:38]([C:36]([O:35][CH3:34])=[O:37])=[CH:39][S:40][CH:41]=1)=[O:19])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1c(N=C=O)c2cc(C(F)(F)F)ccc2n1C(=O)OCc1ccccc1
Reactant: COC(=O)c1cscc1N
Solvent: FC(F)(F)c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cscc1NC(=O)Nc1c(C(=O)OC(C)(C)C)n(C(=O)OCc2ccccc2)c2ccc(C(F)(F)F)cc12
Temperature: 150 °C
Yield: 74.6 %

Procedure:
To a solution of 1-benzyloxycarbonyl-3-isocyanato-5-trifluoromethylindole-2-carboxylic acid tert-butyl ester 5E (˜4.10 mmol) in trifluoromethylbenzene (10 mL) was added 4-aminothiophene-3-carboxylic acid methyl ester 5F (1.30 g, 8.28 mmol). The reaction mixture was heated in a microwave reactor at 150° C. for 30 minutes. Ethyl acetate (100 mL) was added and the organic layer was washed with 1 N hydrochloric acid and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to provide 1-benzyloxycarbonyl-3-[3-(4-methoxycarbonylthiophen-3-yl)-ureido]-5-trifluoromethyl-1H-indole-2-carboxylic acid tert-butyl ester 5G (1.89 g, 3.06 mmol).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[CH2:6]2.C(N(CC)CC)C.[N:28]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(#N)C>[O:20]=[C:14]1[CH:13]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][NH:1][C:34]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:35])[CH:4]=3)[C:8]2=[O:12])[CH2:18][CH2:17][C:16](=[O:19])[NH:15]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3cc(CNC(=O)N4CCOCC4)ccc3C2=O)C(=O)N1
Reaction time: 4 h
Yield: 20.7 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.37 g, 1 mmol) and triethylamine (0.30 mL, 2.2 mmol) in acetonitrile (10 mL) was added morpholine-4-carbonyl chloride (012 mL, 1.05 mmol) at room temperature under nitrogen. After 4 h, the reaction mixture was filtered and rinsed with acetonitrile (30 mL) and the filtrate was concentrate on the rota-vap. The residue was stirred with 20 mL of acetonitrile and water mixture (1:1). The resulted suspension was filtered to give morpholine-4-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.08 g, 20% yield): HPLC: Waters Nova-Pak C18 column, 3.9×150 mm, 4 μm; gradient CH3CN/0.1% aq H3PO4, 10 min, 1.0 mL/min, 4.8 min (96%); mp: 208-210° C.; 1H NMR (DMSO-d6) δ 1.92-2.07 (m, 1H, CHH), 2.39 (qd, J=4.4, 13.3 Hz, 1H, CHH), 2.55-2.66 (m, 1H, CHH), 2.84-2.99 (m, 1H, CHH), 3.27-3.32 (m, 4H, CH2+CH2), 3.52-3.59 (m, 4H, CH2+CH2), 4.25-4.49 (m, 4H, CH2+CH2), 5.11 (dd, J=5.0, 13.3 Hz, 1H, CHN), 7.22 (t, J=5.8 Hz, 1H, Ar), 7.40 (d, J=7.9 Hz, 1H, Ar), 7.47 (s, 1H, NH), 7.67 (d, J=7.9 Hz, 1H, Ar), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.51, 31.20, 43.54, 43.86, 47.10, 51.56, 65.92, 121.88, 122.77, 126.89, 130.11, 142.23, 145.28, 157.57, 168.02, 171.01, 172.86; LCMS: MH=387; Anal Calcd for C19H22N4O5+0.6H2O: C, 57.45; H, 5.89; N, 14.10. Found: C, 57.10; H, 6.07; N, 13.97.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=[O:5])C.CO.C1COCC1.CO.[N+:37]([C:40]1[NH:41][CH:42]=[C:43]([CH2:45][N:46]2[CH2:51][CH2:50][NH:49][C:48](=[O:52])[CH2:47]2)[N:44]=1)([O-])=O>[Ni].C(Cl)Cl.CO>[O:52]=[C:48]1[NH:49][CH2:50][CH2:51][N:46]([CH2:45][C:43]2[N:44]=[C:40]([NH:37][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=4[F:22])=[CH:14][CH:15]=3)=[O:5])[NH:41][CH:42]=2)[CH2:47]1
Reactant: O=C1CN(Cc2c[nH]c([N+](=O)[O-])n2)CCN1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Agent: [Ni]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3nc(CN4CCNC(=O)C4)c[nH]3)c3nccnc23)c1F

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2, and 4-(2-nitro-1H-imidazol-4-ylmethyl)-piperazin-2-one (Step 142.1) instead of 2-nitroimidazole in Step 14.3. Title compound: ESI-MS: 524.1 [M+H]+; tR=3.10 min (System 1); TLC: Rf=0.23 (DCM/MeOH, 9:1).
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.[N+:12]([O-])([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O>[ClH:1].[N+:12]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[CH2:11][CH:3]([NH2:2])[CH2:4]2)([O-:14])=[O:13]
Reactant: NC1Cc2ccccc2C1
Reactant: O=[N+]([O-])[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Product: NC1Cc2ccc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2-aminoindane hydrochloride (19.11 g, 0.112 mol) at 0° C. was added sulfuric acid (60 ml) followed by potassium nitrate (11.84 g, 0.117 mol). The mixture was allowed to warm to room temperature, stirred for an additional 2 hr, then dumped onto ice/50% NaOH (500 ml total). The mixture was extracted with ether (3×200 ml) and the combined extracts were washed with water, dried over magnesium sulfate, filtered, and concentrated to an oil which was converted to the hydrochloride salt. Recrystallization from isopropanol/methanol afforded 5-nitro-2-aminoindane hydrochloride: (14.58 g, 60%); m.p. >300° C.
Reaction SMILES: [CH:1]([O:6][CH3:7])(OC)OC.[C:8]1(=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C:10](=[O:18])[NH:9]1>C(OC(=O)C)(=O)C.CN(C)C=O>[CH3:7][O:6][CH:1]=[C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8](=[O:19])[NH:9][C:10]1=[O:18]
Reactant: O=C1Cc2ccccc2C(=O)N1
Reactant: COC(OC)OC
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: COC=C1C(=O)NC(=O)c2ccccc21
Temperature: 125 °C

Procedure:
Trimethyl orthoformate (5.648 mL, 51.56 mmol) is added to a solution of 4H-Isoquinoline-1,3-dione (4 g, 24.82 mmol) in acetic anhydride (41.6 mL) and N,N-dimethylformamide (10.4 mL). After it is heated at 125° C. for 50 min, it is cooled and filtered to collected 3.698 g (73%) of the title compound as a yellow solid. mp 260-261° C.; MS (ESI) m/z 204.04 (M+1). Found: C, 58.34; H, 3.63; N, 10.21.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].[CH3:12][NH2:13]>C1COCC1>[NH2:11][C:3]1[C:2]([CH3:1])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH:13][CH3:12])=[O:6]
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(C)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
3-Methyl-2-aminobenzoic acid (3.43 g, 22.7 mmol) and N,N′-carbonyldiimidazole (4.05 g, 24.9 mmol) were stirred in THF at 40° C. for 3 hours. After cooled to room temperature, methylamine (2.0 M in THF, 22.7 ml) was added thereto, and further stirred for 1 hour at room temperature. The solvent was evaporated off under reduced pressure, and the residue was purified through silica gel column chromatography (chloroform/methanol=9/1) to obtain the intended compound (3.43 g, yield 92%) as a milky white solid.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])[CH2:4]C)C.[P:8]([Cl:18])(Cl)(=[O:16])[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.C[O:21][C:22](=[O:26])[C@H](C)N>C(Cl)Cl>[P:8]([Cl:18])(=[O:16])([O:26][C:22](=[O:21])[C@H:6]([CH3:7])[NH:3][CH3:4])[O:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)[C@H](C)N
Reactant: O=P(Cl)(Cl)Oc1ccccc1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Product: CN[C@@H](C)C(=O)OP(=O)(Cl)Oc1ccccc1
Temperature: -50 °C
Reaction time: 5 h

Procedure:
A solution of triethylamine (1 ml- 7.17 mmol) in 15 ml of dry CH2Cl2 was added dropwise to a mixture of phenyl phosphorodichloridate (757.4 mg, 3.59 mmol) and L-alanine methyl ester hydrochloride (500 mg, 3.58 mmol) in 50 ml of dry CH2Cl2 at −80° C. in one hour. The mixture was then stirred vigorously at −50° C. during five hours and CH2Cl2 evaporated. 25 ml of dry ether was added and precipitate filtered off under nitrogen. Evaporation of ether gave a colourless oil which was used without further purification for the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][NH:39][CH2:40][C:41]#[CH:42]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:39]([CH3:38])[CH2:40][C:41]#[CH:42])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: C#CCNC
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: C#CCN(C)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and methyl-prop-2-ynylamine according to conditions described in general procedure C. Mp: 116-117° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.58-1.61 (m, 6 H), 2.85 (m, 3 H), 3.27-3.30 (m, 5 H), 4.22 (s, 2 H), 6.30 (d, J=5.5 Hz, 1 H), 6.94-6.98 (m, 1 H), 7.15 (d, J=8.8 Hz, 1 H), 7.43 (d, J=8.0 Hz, 1H), 7.46 (s, 1 H), 7.55-7.60 (m, 3 H), 7.82-7.84 (m, 1 H), 7.98 (d, J=7.4 Hz, 1 H), 8.30 (d, J=5.5 Hz, 1 H), 10.44 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@H:21]([CH3:29])[C:22](OC(C)(C)C)=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2.FC(F)(F)C(O)=O.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[NH:60]1[CH2:65][CH2:64][CH2:63][CH:62]([NH:66][C:67](=[O:74])[C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[CH2:61]1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@H:21]([CH3:29])[C:22]([N:60]3[CH2:65][CH2:64][CH2:63][CH:62]([NH:66][C:67](=[O:74])[C:68]4[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=4)[CH2:61]3)=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: O=C(NC1CCCNC1)c1ccccc1
Reactant: C[C@H](C(=O)OC(C)(C)C)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](C(=O)N1CCCC(NC(=O)c2ccccc2)C1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.3 %

Procedure:
A solution of tert-butyl (2R)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate (0.025 g) in DCM (1 ml) was treated with trifluoroacetic acid (1 ml) and stirred at room temperature for 2 h. The mixture was then concentrated under reduced pressure to give an oil which was subsequently treated with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.013 g), HOBT (0.009 g) and triethylamine (0.023 ml). After stirring at room temperature for 1 h, N-piperidin-3-ylbenzamide (0.015 g) was added and stirring was continued for 48 h. The reaction mixture was partitioned between DCM and water. The organic extract was concentrated under reduced pressure and the residue purified using SPE (silica, eluting with cyclohexane:ethyl acetate 5:1, 3:1, 1:1, 1:3 and ethyl acetate) to give the title compound (0.012 g) as a colourless gum.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:31][CH2:32][C:33](Cl)=O>ClCCl>[Cl:31][CH2:32][C:33]1[N:19]([CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)NCCCNc1c(N)cnc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCn1c(CCl)nc2cnc3ccccc3c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
Triethylamine (20.4 g, 202 mmol) was added to a solution of tert-butyl 3-[(3-aminoquinolin-4-yl)amino]propylcarbamate (42.52 g, 134.4 mmol) in dichloromethane (500 mnL). Chloroacetyl chloride (16.7 g, 148 mmol) was added dropwise, and the reaction was stirred overnight at ambient temperature. The reaction mixture was filtered to remove a solid; the filtrate was concentrated under reduced pressure and mixed with ethyl acetate. The resulting mixture was filtered to remove a solid, washed sequentially with brine (3×) and dilute aqueous sodium bicarbonate, concentrated under reduced pressure, and dried under high vacuum to provide 41.9 g of tert-butyl 3-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.I[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH3:18][C:19]([N+:22]([O-])=[O:23])([CH3:21])[CH3:20]>>[CH2:11]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N+:22]([C:19]([CH3:21])([CH3:20])[CH3:18])[O-:23])=[CH:4][CH:3]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CC(C)(C)[N+](=O)[O-]
Reactant: CCCCCCCI
Reactant: O=Cc1ccc(O)cc1
Product: CCCCCCCOc1ccc(C=[N+]([O-])C(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 2 using 4-hydroxybenzaldehyde, 1-iodoheptane and 2-methyl-2-nitropropane. The title compound was isolated in 60% overall yield as a solid, m.p. 68.5° C.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][C@@H:6]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[C@H:7]1[OH:20])#[N:2].[CH3:23][NH:24][CH3:25]>>[C:1]([N:3]=[C:4]([N:24]([CH3:25])[CH3:23])[NH:5][C@@H:6]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[C@H:7]1[OH:20])#[N:2]
Reactant: CNC
Reactant: CSC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Product: CN(C)C(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O

Procedure:
A mixture of (3S,4R)-4-(3-cyano-2-methyl-1-isothioureido)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (16.3 g) and 50% aqueous dimethylamine solution (81.5 ml) was stirred under reflux for 1.5 hours to form white precipitates. These precipitates were collected by filtration, washed with cold water, and recrystallized from ethanol to give (3S,4R)-4-(2-cyano-3,3-dimethylguanidino)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (12.05 g).
Reaction SMILES: O[C:2]1([C:8]([OH:10])=O)[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1.C(N(C(C)C)CC)(C)C.Cl.[CH3:21][NH:22][O:23][CH3:24].F[P-](F)(F)(F)(F)F.N1([O:41][P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:24][O:23][N:22]([CH3:21])[C:8]([C:2]1[C:7]([OH:41])=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:10]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CNOC
Reactant: O=C(O)C1(O)C=CC=CN1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ncccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.6 %

Procedure:
2-Hydroxypicolinic acid (9.80 g, 70.45 mmol), N,N-dimethylformamide (150 ml), di-iso-propylethylamine (31 ml, 181.58 mmol), and N,O-dimethylhydroxylamine hydrochloride (7.21 g, 73.92 mmol), were stirred at 0° C. (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (38.44 g, 73.87 mmol) was added and the reaction mixture was slow warmed to room temperature. The reaction was stirred 18 hours. The mixture was concentrated and 20% 2-propanol in dichloromethane added. The mixture was washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, and concentrated. The crude material was purified by flash chromatography (0 to 50% ethyl acetate in hexanes) to give 5.21 g (41%) of 3-hydroxy-pyridine-2-carboxylic acid methoxy-methyl-amide. 1H NMR (250 MHz, CDCl3) δ 11.73 (s, 1H), 8.11 (t, J=2.9 Hz, 1H), 7.32-7.28 (m, 2H), 3.87 (s, 3H), 3.77 (s, 3H).