Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:33][C:34]1[CH:39]=[CH:38][C:37](Br)=[CH:36][N:35]=1>>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20]([C:37]2[CH:36]=[N:35][C:34]([CH3:33])=[CH:39][CH:38]=2)=[CH:19][CH:18]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1ccc(Br)cn1
Product: Cc1ccc(-c2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)cn1
Yield: 45.6 %

Procedure:
Using an analogous procedure to that described in Method 4, N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Method 13, 1.20 g, 2.74 mmol) was reacted with 2-methyl-5-bromopyridine (505 mg, 2.94 mmol). The crude residue was purified by flash chromatography on silica (90 g), eluting with ethyl acetate/isohexane (40-100%) to give the title compound (504 mg, 46%); NMR Spectrum: (DMSO-d6) 1.46 (s, 9H), 2.51 (s, 3H), 7.19 (m, 2H), 7.40 (d, 1H), 7.58 (m, 2H), 7.91 (d, 2H), 8.08, (d, 3H), 8.66 (s, 1H), 8.86 (d, 1H), 9.89 (s, 1H); Mass Spectrum: M+H+ 404.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[C:6]([C:8]1[CH:34]=[CH:33][C:11]([C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([CH3:32])=[C:19]([NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([CH2:29]Cl)=[CH:25][CH:24]=3)[CH:20]=2)=[O:13])=[CH:10][CH:9]=1)#[N:7].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([CH3:32])=[C:19]([NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([CH2:29][NH:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:25][CH:24]=3)[CH:20]=2)=[O:13])=[CH:33][CH:34]=1)#[N:7]
Reactant: COCCN
Reactant: Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1NC(=O)c1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCNCc1ccc(C(=O)Nc2cc(NC(=O)c3ccc(C#N)cc3)ccc2C)cc1
Temperature: 55 °C
Reaction time: 96 h
Yield: 59 %

Procedure:
2-Methoxyethylamine (0.019 ml) was added to a stirred solution of N-[5-(4-cyanobenzamido)-2-methylphenyl]-4-(chloromethyl)benzamide (0.060 g) and potassium carbonate (0.041 g) in acetone (5 ml) and the reaction mixture was heated to 55° C. overnight. Further portions of 2-methoxyethylamine and potassium carbonate (same quantities as before) were added and the reaction mixture was stirred at 55° C. for a further 4 days. The reaction mixture was evaporated and the residue was triturated with water. The resultant solid was isolated and dried under vacuum at 55° C. to give the title compound as a solid (0.039 g, 59%); NMR Spectrum: (CDCl3) 2.27 (s, 3H), 2.83 (m, 2H), 3.37 (m, 4H), 3.56 (t, 2H), 3.91 (s, 2H), 7.19 (d, 1H), 7.49 (d, 2H), 7.77 (m, 7H), 7.95 (d, 2H), 8.13 (s, 1H), 8.3 (s, 1H); Mass Spectrum: M−H− 441.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[S:7](=[O:9])(=[O:8])[C@@H:6]2[CH2:10][C:11]([CH3:23])([CH3:22])[O:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=3[C@@:5]2([CH3:24])[N:4]=[C:3]1[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29].N#N.[H][H]>C1COCC1.[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][C:11]([CH3:23])([CH3:22])[CH2:10][C@H:6]3[S:7](=[O:8])(=[O:9])[C:2]([CH3:33])([CH3:1])[C:3]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[N:4][C@:5]3([CH3:24])[C:14]=2[CH:15]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc([N+](=O)[O-])ccc3OC(C)(C)C[C@H]2S(=O)(=O)C1(C)C
Reactant: [H][H]
Agent: [Pd]
Agent: N#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(N)ccc3OC(C)(C)C[C@H]2S(=O)(=O)C1(C)C

Procedure:
Solution of tert-butyl ((4aR,11bR)-3,3,6,6,11b-pentamethyl-10-nitro-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (56 mg, 0.116 mmol) in THF (1.1 ml) was purged with N2, and hydrogenated under hydrogen balloon in the presence of palladium 10 wt. % Pd on activated carbon (37.1 mg, 0.035 mmol) for 4.5 h. The mixture was filtered through the plug of Celite, and the filter cake was washed with ethyl acetate. The combined filtrate was concentrated to afford the crude tert-butyl ((4aR,11bR)-10-amino-3,3,6,6,11b-pentamethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate which was used for next step directly. MS m/z=452.1 (M+H).
Reaction SMILES: ClC1C=C(C2ON=C(C3C=CC4OC(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)=CC=4C=3)N=2)C=CC=1OCCC.[Cl:42][C:43]1[C:67]([C:68]2[N:72]=[C:71]([C:73]3[CH:78]=[CH:77][C:76]([CH2:79][CH2:80][CH3:81])=[CH:75][CH:74]=3)[O:70][N:69]=2)=[CH:66][C:46]2[CH:47]=[C:48]([C:50]3([NH:58]C(=O)OC(C)(C)C)[CH2:55][O:54]C(C)(C)[O:52][CH2:51]3)[O:49][C:45]=2[CH:44]=1>>[NH2:58][C:50]([C:48]1[O:49][C:45]2[CH:44]=[C:43]([Cl:42])[C:67]([C:68]3[N:72]=[C:71]([C:73]4[CH:74]=[CH:75][C:76]([CH2:79][CH2:80][CH3:81])=[CH:77][CH:78]=4)[O:70][N:69]=3)=[CH:66][C:46]=2[CH:47]=1)([CH2:51][OH:52])[CH2:55][OH:54]
Reactant: CCCc1ccc(-c2nc(-c3cc4cc(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)oc4cc3Cl)no2)cc1
Agent: CCCOc1ccc(-c2nc(-c3ccc4oc(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)cc4c3)no2)cc1Cl
Product: CCCc1ccc(-c2nc(-c3cc4cc(C(N)(CO)CO)oc4cc3Cl)no2)cc1
Yield: 40 %

Procedure:
When tert-butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate was replaced with the tert-butyl 5-(6-chloro-5-(5-(4-propylphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (obtained as crude via a process as described in Example 36, Step D) the similar procedure as in Example 36, Step E gave the title compound (0.006 g, 40%) as white solid. 1H NMR (CD3OD) 8.12 (d, 2H, J=8.28 Hz); 8.12 (s, 1H); 7.75 (s, 1H); 7.43 (d, 2H, J=8.31 Hz); 6.9 (s, 1H); 3.88 (d, 2H, J=10.9 Hz); 3.78 (d, 1H, J=10.9 Hz); 2.7 (t, 2H, J=7.41 Hz); 1.76-1.64 (m, 2H); 0.97 (t, 3H, J=7.32 Hz).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C@@H:7]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[NH:6][C:5]1=[O:14])[CH3:3].C([Li])CCC.CCCCCC.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>O1CCCC1.O.C(OCC)(=O)C>[Si:26]([N:6]1[C@H:7]([C:8]#[C:9][Si:10]([CH3:12])([CH3:11])[CH3:13])[C@H:4]([C@H:2]([OH:1])[CH3:3])[C:5]1=[O:14])([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: C[C@@H](O)[C@@H]1C(=O)N[C@@H]1C#C[Si](C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[C@@H](O)[C@@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1C#C[Si](C)(C)C
Temperature: -70 °C
Yield: 32.5 %

Procedure:
Cis-3-[(R)-1-hydroxyethyl]-4-trimethylsilylethynyl-2-azetidinone (0.8 g) is dissolved in dry tetrahydrofuran (15 ml) in an argon stream, and the solution is cooled to -70° C. followed by dropwise addition of n-butyllithium (1.6M)-hexane (4.8 ml) while carefully maintaining the temperature so as not to exceed -65° C. To the mixture is added dropwise a solution of tert-butyldimethylsilyl chloride (0.86 g) in dry tetrahydrofuran (5 ml) at -70° C. or lower, and the resulting mixture is stirred at the same temperature for an hour and then poured into a mixture of ethyl acetate (100 ml) and water (100 ml). The organic layer is separated, washed with aqueous sodium chloride and dried over magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to silica gel column chromatography (eluent: 1:9 ethyl acetate-n-hexane mixture) to give 0.40 g of cis-1-(tert-butyldimethylsilyl)-3-[(R)-1-hydroxyethyl]-4-trimethylsilylethynyl-2-azetidinone.
Reaction SMILES: C(O[CH:6](N(C)C)[N:7]([CH3:9])[CH3:8])(C)(C)C.[CH3:13][C:14]1[N:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([NH:24][C:25](=[O:34])[C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)=[N:21]2)=[CH:16][CH:15]=1.CN(C)C=O.Cl>C(O)C.C(OCC)C.C(Cl)(Cl)(Cl)Cl.O>[CH3:6][N:7]([CH3:9])[CH:8]=[CH:13][C:14]1[N:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([NH:24][C:25](=[O:34])[C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)=[N:21]2)=[CH:16][CH:15]=1
Reactant: COc1ccc(C(=O)Nc2ccc3ccc(C)nc3n2)cc1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccc3ccc(C=CN(C)C)nc3n2)cc1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
Tert-butoxybis(dimethylamino)methane (28 g) is added to a suspension composed of N-(7-methyl-1,8-naphthyridin-2-yl)-4-methoxybenzamide (12 g) and anhydrous dimethylformamide (12 cc). The mixture is stirred for 3 hours at 130° C. The solution obtained is poured into water (100 cc) and the mixture extracted with methylene chloride (200 cc). The organic extracts are washed with water (2×100 cc), dried over magnesium sulphate and concentrated to dryness at 50° C. under reduced pressure (0.5 kPa). The amorphous residue obtained is dissolved in boiling carbon tetrachloride (100 cc). A solid is precipitated by slowly adding isopropyl ether (150 cc). The crystallized solid obtained is separated by filtration, washed with isopropyl ether (30 cc) and dried in the air. The base obtained (9.2 g; m.p. approximately 110° C.) is dissolved in ethanol (150 cc) and a 4.7N solution (20 cc) of hydrochloric acid in ethyl ether is added. The precipitate obtained is separated by filtration, washed with ethyl ether (3×30 cc) and dried at 25° C. under reduced pressure (4 kPa). The crude hydrochloride obtained is purified by recrystallization in ethanol (160 cc). N-[7-(2-Dimethylaminovinyl)-1,8-naphthyridin-2-yl]-4-methoxybenzamide in the hydrochloride state (6 g), m.p. 240° C., is thereby obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=1.Cl.[CH3:13][NH:14][O:15][CH3:16].C(N1C=CN=C1)(N1C=CN=C1)=O>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:14]([O:15][CH3:16])[CH3:13])=[O:9])=[CH:5][N:4]=1
Reactant: CNOC
Reactant: COc1ccc(C(=O)O)cn1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Product: COc1ccc(C(=O)N(C)OC)cn1

Procedure:
In analogy to example 158, step 3, 6-methoxynicotinic acid was reacted with N,O-dimethylhydroxylamine hydrochloride and 1,1′-carbonyldiimidazole to give the title compound as a colorless oil, MS (ESI+): m/z=197.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[H][H]>C(O)C.[Pd].C>[CH:8]1([C:4]2[C:3]([CH3:14])=[C:2]([Cl:1])[CH:7]=[CH:6][CH:5]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: Cc1c(Cl)cccc1C1=CCCCC1
Agent: [Pd]
Solvent: CCO
Product: Cc1c(Cl)cccc1C1CCCCC1
Reaction time: 8 h
Yield: 49.8 %

Procedure:
103 g of 1-(3'-chloro-2'-methylphenyl)-cyclohexene is dissolved in 1,200 ml of ethanol; 5 g of Pd/charcoal is then added. Hydrogenation is then carried out for 8 hours at room temperature and a hydrogen pressure of 80 bar. The catalyst is filtered off and the remaining solution is evaporated down. Fractional distillation gives 51.8 g of 3-cyclohexyl-2-methylchlorobenzene.
Reaction SMILES: [CH3:1][CH:2]([CH2:23][CH3:24])[CH2:3][O:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[C:10]([O:20][CH3:21])[N:11]2C2CCCCO2)=[C:7]([NH2:22])[N:6]=1.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>CO>[F:28][C:27]([F:30])([F:29])[C:25]([OH:31])=[O:26].[CH3:1][CH:2]([CH2:23][CH3:24])[CH2:3][O:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[C:10]([O:20][CH3:21])[NH:11]2)=[C:7]([NH2:22])[N:6]=1
Reactant: CCC(C)COc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCC(C)COc1nc(N)c2nc(OC)[nH]c2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-[(2-methylbutyl)oxy]-8-methoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (199 mg) in dry MeOH (1.99 mL) was added TFA (0.199 mL). The mixture was stirred at room temperature for 24 h. The reaction was concentrated in vacuo to give a yellow residue. The residue was triturated with Et2O and was filtered to give the title compound as an off-white solid (111 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1.ClCCl>[O:12]=[C:8]1[CH2:7][CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([NH:1][C:13](=[O:15])[CH3:14])[CH:11]=[CH:10][C:9]1=2
Reactant: Nc1ccc2c(c1)CCCC2=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc2c(c1)CCCC2=O
Reaction time: 1 h

Procedure:
To a solution of 6-amino-3,4-dihydro-2H-naphthalen-1-one (CAS#3470-53-9, 0.875 g, 5.44 mmol) in pyridine (5 mL) is added acetic anhydride (0.83 g, 8.16 mmol). After 1 hour, the solution is diluted with dichloromethane and washed with water and 1M aqueous HCl. The organic phase is dried over sodium sulfate, filtered, and concentrated to give N-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetamide; 1H NMR (400 MHz, CDCl3) δ ppm 2.09-2.16 (m, 2 H), 2.22 (s, 3 H), 2.59-2.67 (m, 2 H), 2.95 (t, J=6.1 Hz, 2 H), 7.21 (dd, J=8.3, 2.1 Hz, 1 H), 7.42 (br. s., 1 H), 7.70 (br. s., 1 H), 8.00 (d, J=8.3 Hz, 1 H).
Reaction SMILES: C([Li])CCC.O1CCCCC1OC1CCCCO1.[CH:19]#[C:20][CH:21]([OH:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C[Si](C)(C)[O:30][C:31]1([CH3:45])[CH2:36][CH:35]([O:37][Si](C)(C)C)[CH2:34][C:33]([CH3:43])([CH3:42])[C:32]1=[O:44].[Cl-].[NH4+]>C1COCC1.CCCCCC>[OH:44][C:32]1([C:19]#[C:20][CH:21]([OH:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:33]([CH3:43])([CH3:42])[CH2:34][CH:35]([OH:37])[CH2:36][C:31]1([OH:30])[CH3:45]
Reactant: CC1(C)CC(O[Si](C)(C)C)CC(C)(O[Si](C)(C)C)C1=O
Reactant: C#CC(O)CCCCC
Agent: C1CCC(OC2CCCCO2)OC1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCC(O)C#CC1(O)C(C)(C)CC(O)CC1(C)O
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To 2.8 ml of a 1.6M n-hexane solution of n-butyl lithium was added 10 ml of anhydrous THF at -78° C. (bath temperature) in a nitrogen atmosphere, and 1.1 g of a tetrahydropyranyl ether of 1-octyn-3-ol was added dropwise thereto under the same conditions. After the addition, the mixture was stirred for 30 minutes. Then, 15 ml of an anhydrous THF solution containing 1.4 g of 2,4-bis(trimethylsiloxy)-2,6,6-trimethylcyclohexanone was added dropwise to the mixture under the same conditions over 20 minutes. After the dropwise addition, the mixture was stirred for 5 hours. A saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The diethyl ether was removed from the extract by distillation, and a 1N hydrochloric acid aqueous solution and methanol were added to the residue, followed by stirring at room temperature for 6 hours. The methanol was removed by distillation under reduced pressure, and the residue was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, and the solvent, etc. were removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.1 g (yield: 85%) of 1-(1,2,4-trihydroxy-2,6,6-trimethylcyclohexyl)oct-1-yn-3-ol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])=[CH:20][CH:19]=3)[CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:7]([CH3:35])[C:6]=2[CH:36]=1.C(N(CC)CC)C.[CH2:44]([N:46]=[C:47]=[O:48])[CH3:45]>O1CCCC1>[CH:11]1([CH:10]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])=[CH:20][CH:19]=2)[C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:47](=[O:48])[NH:46][CH2:44][CH3:45])=[CH:36][C:6]=3[C:7]=2[CH3:35])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(N)cc3c2C)C2CCCCC2)cc1
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ccc2oc(C(Nc3ccc(C(=O)N(C)CCC(=O)OCC)cc3)C3CCCCC3)c(C)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
To a solution (10 mL) of ethyl 3-{[(4-{[(5-amino-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl](methyl)amino}-propanoate (280 mg) synthesized in Example A110(5) in tetrahydrofuran were added triethylamine (95 μL) and ethyl isocyanate (54 μL), and the mixture was stirred at room temperature for 1 day. Triethylamine (95 μL) and ethyl isocyanate (54 μL) were additionally added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (60-100% ethyl acetate/hexane) to give the title object compound (304 mg, 95%) as a colorless oil.
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:24])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][OH:23])=[CH:16][CH:15]=1.O.Cl>C(O)C>[OH:23][CH2:22][CH2:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]([OH:24])=[O:4])=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccccc1COc1ccc(CCCO)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccccc1COc1ccc(CCCO)cc1
Yield: 86.8 %

Procedure:
A stirring solution of 127.1 g of potassium hydroxide in 500 ml of 95% ethanol was treated portion wise over several minutes with 59.4 g of 2- [[4-(3-hydroxypropyl)phenoxy]methyl]benzoic acid methyl ester. The resulting solution was allowed to reflux overnight with continued stirring. The product solution was poured into 900 ml of water and the solution was acidified to below pH 2 approximately 200 ml of concentrated hydrochloric acid. The resulting suspension was transferred to a separatory funnel and was partitioned against a total of 1000 ml of ethyl acetate. The primary aqueous phase was discarded and the organic phase was washed with several 500 ml aliquots of water until the pH of the final aqueous phase was neutral. The dried (Na2SO4) organic phase was concentrated in vacuo to a solid which was recrystallized from ethanol/water to give 49.13 g of 2-[[4-(3-hydroxypropyl)phenoxy]methyl]benzoic acid, m.p. 139°-140° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-])=O)[NH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[NH2:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[C:2]([Cl:1])=[CH:3][NH:4]2
Reactant: O=[N+]([O-])c1cccc2[nH]cc(Cl)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cccc2[nH]cc(Cl)c12
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 55 %

Procedure:
Stannous chloride (4.59 g, 20.36 mmol) is added to a solution of 3-chloro-4-nitroindole in 50 mL of ethanol. The reaction is heated to 45° C. and stirred for 1.5 hours. The reaction is cooled to room temperature and treated with 1 M aqueous sodium hydroxide solution. This mixture is extracted with ethyl acetate. The combined organic extracts are dried over magnesium sulfate, filtered and the solvents removed by rotary evaporation. The crude residue is purified via silica gel column chromatography using 15% ethyl acetate/hexanes as the eluent. The appropriate fractions are combined and the solvents removed by rotary evaporation to yield 0.466 g of 4-amino-3-chloroindole as an off-white solid (55% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[CH2:25]([O:29][NH2:30])[CH:26]([CH3:28])[CH3:27]>C(O)C>[CH2:25]([O:29][N:30]=[C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: O=C(Cc1cccnc1)c1ccc(Cl)cc1Cl
Reactant: CC(C)CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)CON=C(Cc1cccnc1)c1ccc(Cl)cc1Cl
Reaction time: 4 h

Procedure:
A solution of 4.65 g of 2',4'-dichloro-2-(3-pyridyl)acetophenone in 25 ml of ethanol is treated with 2.70 g of anhydrous sodium carbonate and 2.63 g of O-isobutylhydroxylamine hydrochloride and the reaction mixture is then heated to reflux temperature with stirring. After 4 hours, it is poured onto ice and extracted with ethyl acetate. The organic phase is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 2',4'-Dichloro-2-(3-pyridyl)acetophenone O-isobutyloxime is obtained as an E/Z isomer mixture in the form of a brownish oil. In the chromatographic separation on silica gel using n-hexane/ethyl acetate (7:3), the E isomer [1H-NMR (CDCl3, 200 MHz): 2.055 ppm (heptet, HC(CH3)2)] is eluted first and then the Z isomer [1H-NMR (CDCl3, 200 MHz): 1.928 ppm (heptet, HC(CH3)2)].
Reaction SMILES: [CH3:1][NH:2][C:3](=[N:6][N+:7]([O-:9])=[O:8])SC.[NH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[N:16][CH:17]=1>C(O)C>[Cl:18][C:15]1[N:16]=[CH:17][C:12]([CH2:11][NH:10][C:3]([NH:2][CH3:1])=[N:6][N+:7]([O-:9])=[O:8])=[CH:13][CH:14]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: CNC(=N[N+](=O)[O-])SC
Solvent: CCO
Product: CNC(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Yield: 34 %

Procedure:
A mixture of 0.45 g of 1,2-dimethyl-3-nitroisothiourea, 0.43 g of 5-(aminomethyl)-2-chloropyridine and 25 ml of ethanol was refluxed for 6 hours and concentrated. The residue was purified by a column chromatography [developing solvent: chloroform-ethanol (5:1)] to afford 0.25 g of 1-(6-chloro-3-pyridylmethyl)-3-methyl-2-nitroguanidine (Compound No. 5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([NH2:11])=[CH:9][N:10]=2)[N:7]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([NH:11][C:19](=[O:21])[CH3:20])=[CH:9][N:10]=2)[N:7]=1
Reactant: Nc1cnc2ccc(Cl)nn12
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cnc2ccc(Cl)nn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution 6-chloroimidazo[1,2-b]pyridazin-3-amine and triethylamine (0.8 mL, 6.0 mmol) in DCM (25 mL) was added acetyl chloride dropwise and stirred at rt for overnight. The mixture was concentrated and purified by ISCO column chromatography (10% MeOH/DCM) to give not very pure N-(6-chloroimidazo[1,2-b]pyridazin-3-yl)acetamide (500 mg, 95% yield). 60 mg of non-pure material was further purified by Prep HPLC (neutral) to give pure N-(6-chloroimidazo[1,2-b]pyridazin-3-yl)acetamide. 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.01 (d, J=9.35 Hz, 1H), 7.94 (s, 1H), 7.26 (d, J=9.35 Hz, 1H), 2.29 (s, 3H); LRMS (ESI) m/e 210.9 [(M+H)+, calcd for C8H8ClN4O 211.6].
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6](Cl)[C:5]=2[N:15]=1.[NH3:28]>CO>[NH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:3]1[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:28])[C:5]=2[N:15]=[C:2]1[NH2:1]
Reactant: N
Reactant: CC(C)(C)OC(=O)NCCCCn1c(N)nc2c(Cl)nc3ccccc3c21
Solvent: CO
Product: NCCCCn1c(N)nc2c(N)nc3ccccc3c21
Temperature: 170 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-(2-amino-4-chloro-1H-imidazo[4,5-c]quinolin-1-yl)butylcarbamate (5.5 g, 14 mmol) and ammonia (50 mL of a 7 N solution in methanol) were added to a high-pressure vessel, which was sealed and heated in an oven at 170° C. for two days. The resulting solution was allowed to cool to room temperature and concentrated under reduced pressure. The resulting dark oil was partially dissolved in methanol, and diethyl ether was added. The mixture was stirred for one hour, and a solid was isolated by filtration. The solid was washed sequentially with diethyl ether and 90:10 dichloromethane:methanol (100 mL) and dried on the filter funnel for 30 minutes. The resulting green solid (2.52 g) was purified by automated flash chromatography on silica gel (eluting with aqueous ammonium hydroxide:methanol:dichloromethane in a gradient from 0:0:100 to 2.5:47.5:50) to provide 167 mg of 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinoline-2,4-diamine as a dark green solid.