Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[N:36][C:37](=[O:45])[C:38]1[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH2:32][CH2:33][OH:34])[C:24]=2[F:35])[C:11]2[NH:15][C:14](=[O:16])[N:13]([C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:12]=2)=[CH:5][CH:4]=1.C(=O)([O-])O.[K+].[CH3:51][C@@H:52]1[CH2:57][CH2:56][CH2:55][CH2:54][C@H:53]1[O:58][C:59](=[O:64])[O:60][CH:61](Cl)[CH3:62]>CN(C=O)C>[CH3:51][C@@H:52]1[CH2:57][CH2:56][CH2:55][CH2:54][C@H:53]1[O:58][C:59](=[O:64])[O:60][CH:61]([O:16][C:14]1[N:13]([C:17]2[N:18]=[CH:19][CH:20]=[CH:21][N:22]=2)[N:12]=[C:11]([CH:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([NH2:1])=[N:36][C:37](=[O:45])[C:38]3[CH:39]=[CH:40][C:41]([CH3:44])=[CH:42][CH:43]=3)=[CH:8][CH:7]=2)[C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH2:32][CH2:33][OH:34])[C:24]=2[F:35])[N:15]=1)[CH3:62]
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccc(C)cc3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Reactant: CC(Cl)OC(=O)O[C@@H]1CCCC[C@H]1C
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccc(C)cc3)cc2)c2nc(OC(C)OC(=O)O[C@@H]3CCCC[C@H]3C)n(-c3ncccn3)n2)c1
Temperature: 55 °C
Reaction time: 48 h
Yield: 43.2 %

Procedure:
To a mixture of N-[1-amino-1-(4-{[[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]amino}phenyl)methylidene]-4-methylbenzamide (230 mg) and DMF (3 mL), potassium hydrogen carbonate (113 mg) and carbonic acid 1-chloroethyl ester (1R,2R)-2-methylcyclohexyl ester (250 mg) were sequentially added, and the resulting mixture was stirred at 55° C. for 24 hours and at room temperature for another 2 days. The reaction solution was purified by reverse phase silica gel column chromatography (mixed solvent of acetonitrile-water) to obtain the captioned compound (129.2 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:27][CH2:28][CH2:29][CH3:30])[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C)[C:10]=2[C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[OH-].[Na+]>Cl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:27][CH2:28][CH2:29][CH3:30])[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[C:10]=2[C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Temperature: 25 °C
Yield: 90.9 %

Procedure:
A suspension of 1,1-dimethylethyl N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate (13.8 g) in 1N hydrochloric acid (140 mL) was heated on a steam bath for 1.5 hours. The reaction mixture was allowed to cool to ambient temperature and then it was made basic (pH>11) with 50% sodium hydroxide. The resulting precipitate was isolated by filtration, washed with water and then dried to provide 9.5 g of 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine as a white solid, m.p. 212-213° C. Analysis: Calculated for C17H24N6: %C, 65.36; %H, 7.74; %N, 26.90; Found: %C, 65.16; %H, 7.65; %N, 27.29.
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.ClC([O:11][CH2:12][CH:13]([CH3:15])C)=O.[CH3:16][C:17]([CH3:30])([CH2:28][CH3:29])[C:18](=[O:27])[C:19]([CH:21]1[CH2:26][CH2:25][CH2:24][NH:23][NH:22]1)=[O:20]>C(Cl)Cl>[CH3:16][C:17]([CH3:30])([CH2:28][CH3:29])[C:18](=[O:27])[C:19]([CH:21]1[CH2:26][CH2:25][CH2:24][NH:23][N:22]1[C:12](=[O:11])[CH2:13][CH2:15][CH2:24][CH2:25][CH2:26][C:7]1[CH:6]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:20]
Reactant: CCN(CC)CC
Reactant: CC(C)COC(=O)Cl
Reactant: CCC(C)(C)C(=O)C(=O)C1CCCNN1
Solvent: ClCCl
Product: CCC(C)(C)C(=O)C(=O)C1CCCNN1C(=O)CCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 103.5 %

Procedure:
To a solution of 5-phenylvalaric acid (0.2 g, 1.1 mmol) in 3 ml CH2Cl2 was added triethylamine (0.15 ml, 1.1 mmol), followed by isobutyl chloroformate (0.15 g, 1.1 mmol) at 0° C. After stirring for 5 minutes, a solution of 3,3-dimethyl-1-perhydropyridazinylpentane-1,2-dione (0.212 g, 1 mmol) in 1 ml CH2Cl2 was added. The reaction was gradually warmed up to room temperature. The crude material was subject to silica gel purification to yield final product as clear oil (0.20 g, 55%). Rf=0.58 (33% EtOAc/hexane). 1H NMR (CDCl3, 400 MHz): δ 0.89 (t, 3H, J=7.5); 1.24 (s, 6H); 1.37 (m, 2H); 1.68 (m, 6H); 1.74 (m, 4H); 2.23 (m, 2H); 2.62 (t, 2H, J=7.60); 2.80 (m, 2H); 4.53 (m, 2H); 7.21 (m, 5H). Anal. Calcd. for C23H24N2O3: C, 71.47; H, 8.87; N, 7.25. Found: C, 71.54; H, 8.80; N, 7.32.
Reaction SMILES: [O:1]([CH3:13])[C@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[C:14](O)(=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[C:14]([O:12][CH2:11][C@H:9]1[O:10][C@H:2]([O:1][CH3:13])[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]1[OH:8])(=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCC(=O)O
Reactant: CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Product: CCCCCCCC(=O)OC[C@H]1O[C@H](OC)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 36 h
Yield: 33.4 %

Procedure:
Methyl α-D-glucopyranoside (20.0 g, 0.10 mol, prepared according to Example 6), was esterified with octanoic acid (29.7 g, 0.21 mol) by the procedure described in Example 1 using 6.0 g of an immobilized lipase (from Candida antarctica) as a catalyst. After 36 hours HPLC analysis showed 77% conversion (65% monoester, 12% diester). The reaction was stopped by filtering off the enzyme. Part of the crude product was purified by chromatography yielding 10.7 g (32.4%) of the title compound which was identified by NMR spectroscopy.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[CH3:29][C:30]([CH3:35])([CH3:34])[C:31](Cl)=[O:32]>>[CH3:29][C:30]([CH3:35])([CH3:34])[C:31]([N:25]([CH2:24][C:15]1[CH:16]=[C:17]([C:20]([F:21])([F:23])[F:22])[CH:18]=[CH:19][C:14]=1[C:8]1[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:3])=[O:28])[CH:7]=1)[CH2:26][CH3:27])=[O:32]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: CC(C)(C)C(=O)Cl
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)C(C)(C)C

Procedure:
(2′-{[(2,2-Dimethyl-propionyl)-ethyl-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (Compound 1-245) was prepared using the procedures of Example 1 and using (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and trimethylacetyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:24])[C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[F:23])[N:11]=[N:10][CH:9]=[C:8]2Cl)=[O:4].[NH3:26]>CO.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:24])[C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[F:23])[N:11]=[N:10][CH:9]=[C:8]2[NH2:26])=[O:4]
Reactant: N
Reactant: COC(=O)c1cc2c(Cl)cnnc2c(F)c1Nc1ccc(Br)cc1F
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc2c(N)cnnc2c(F)c1Nc1ccc(Br)cc1F
Temperature: 25 °C

Procedure:
A solution of 7-(4-bromo-2-fluorophenylamino)-4-chloro-8-fluoro-cinnoline-6-carboxylic acid methyl ester (1.00 equiv.) in saturated NH3 in MeOH is refluxed for 16 hours. Additional saturated NH3 in MeOH is added as the reaction progresses if necessary. The reaction mixture is cooled to room temperature and diluted with EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude product that is purified by trituration or flash column chromatography to afford the desired product as necessary.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)=[O:11])[CH2:6][CH2:5]1.[NH:22]1[CH:26]=[C:25]([CH2:27][C:28](O)=[O:29])[N:24]=[N:23]1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:22]1[CH:26]=[C:25]([CH2:27][C:28]([NH:1][CH2:2][CH2:3][CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=3)=[O:11])[CH2:6][CH2:5]2)=[O:29])[N:24]=[N:23]1
Reactant: O=C(O)Cc1c[nH]nn1
Reactant: NCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1c[nH]nn1)NCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1

Procedure:
A mixture comprising of 3,5-dichlorobenzyl 4-(2-aminoethyl)piperidine-1-carboxylate (Example 3, step 1) (100 mg, 0.302 mmol), 2-(1H-1,2,3-triazol-4-yl)acetic acid (57.6 mg, 0.453 mmol), 1-propanephosphonic anhydride solution (0.353 mL, 0.604 mmol) and Huenig's Base (0.105 mL, 0.604 mmol) in DMF (1 mL) was stirred at room temperature for 18 hours, and then concentrated under reduced pressure. The mixture was diluted with water and extracted with EtOAc. The organic portion was dried over MgSO4, filtered and the solvent concentrated under pressure. Further purification was carried out using preparative LC-MS. The resulting product fractions were concentrated under reduced pressure to give an aqueous solution and then extracted with EtOAc. The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:13]=[C:12]([C:14](=[O:20])[N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])[CH:11]=[C:7]([C:8]([OH:10])=O)[CH:6]=1)[CH3:2].Cl.CN(C)CCCN=C=[N:30][CH2:31][CH3:32].C1COCC1.[F-].C([N+:44](CCCC)(CCCC)CCCC)CCC>ClCCl>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:6]=[C:7]([C:8]2[O:10][N:44]=[C:31]([CH3:32])[N:30]=2)[CH:11]=[C:12]([C:14]([N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])=[O:20])[CH:13]=1)[CH3:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CCCN(C)C(=O)c1cc(C(=O)O)cc(C(=O)OCC)c1
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(C(=O)OCC)cc(-c2nc(C)no2)c1
Yield: 36 %

Procedure:
Stir a solution of 5-(methyl-propyl-carbamoyl)-isophthalic acid monoethyl ester (330 mg, 1.13 mmol), acetamideoxime (117 mg, 1.58 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (303 mg, 1.58 mmol) in dichloromethane (20 mL) at room temperature overnight. Concentrate and purify (silica gel chromatography, eluting with 2:98 methanol:dichloromethane). Concentrate and add THF (30 mL) and 1 N tetrabutylammonium fluoride in THF (43 μL, 0.043 mmol). Reflux the solution for 30 min and concentrate. Add ethyl acetate, extract with saturated aqueous sodium chloride, dry (magnesium sulfate) concentrate and purify (silica gel chromatography, eluting with 50:50 ethyl acetate:hexanes) to give the title compound (135 mg, 36%).
Reaction SMILES: [Na].[Br:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5](F)[CH:4]=1.[CH2:15]([OH:17])[CH3:16]>>[CH2:10]([O:9][C:7](=[O:8])[C:6]1[CH:12]=[CH:13][C:3]([Br:2])=[CH:4][C:5]=1[O:17][CH2:15][CH3:16])[CH3:11]
Reactant: CCO
Reactant: CCOC(=O)c1ccc(Br)cc1F
Agent: [Na]
Product: CCOC(=O)c1ccc(Br)cc1OCC
Temperature: 0 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
Sodium (1.815 g, 78.9 mmol, Aldrich) was cut into small pieces and added to ethanol (100 mL). After all the pieces were dissolved, the clear solution was added to a solution of ethyl 4-bromo-2-fluoro-benzoate (13 g, 52.6 mmol) in ethanol (20 mL) cooled to 0° C. The ice bath was then removed and the mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated in vacuo, and the residue was taken in water and 20% ethyl acetate-hexane. The organic layer was washed with saturated solution of sodium bicarbonate, brine, and dried over anhydrous sodium sulfate. The solids were filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (120 g of silica gel, eluting with 10-15% ethyl acetate in hexane) gave 4-bromo-2-ethoxy-benzoic acid ethyl ester as white solids (11.020 g, 77%).
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[CH2:8][O:7]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][CH:26]([NH2:28])[CH3:27])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>S1(CCCC1)(=O)=O.CCOCC>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][CH:26]([NH:28][CH2:8][CH:6]([OH:7])[CH2:5][O:4][C:3]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:2]=2[I:1])[CH3:27])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(I)c(OCC2CO2)c1
Reactant: COc1ccc(CC(C)N)cc1OC
Solvent: O=S1(=O)CCCC1
Solvent: CCOCC
Product: COc1ccc(I)c(OCC(O)CNC(C)Cc2ccc(OC)c(OC)c2)c1
Yield: 73.6 %

Procedure:
A solution of 5.6 g (0.018 mole) of [(2-iodo-5-methoxyphenoxy)methyl]oxirane, the product of Example 5b. and 3.25 g (0.016 mole) of 2-(3,4-dimethoxyphenyl)-alphamethylethylamine in 15 ml of sulfolane was heated at 80° C. for one hour and at 110° for six hours. The mixture was dissolved in ether and the ether washed with water and brine. The ether layer was dried (K2CO3) and the solvent evaporated in vacuo. The residue was flash chromatographed on SiO2 using MeOH:CHCl3, 1:30 as the eluant. The major compound bearing fractions were pooled and the solvent evaporated in vacuo. There was obtained 5.9 g (71% yield) of 1-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]-3-(2-iodo-5-methoxyphenoxy)-2-propanol as a yellow oil.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([O:29][CH3:30])=[O:28])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][C:16](=O)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.CCOC(C)=O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([O:29][CH3:30])=[O:28])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH:16]([N:35]2[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]2)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCNCC1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)COc1ccccc1-3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(N1CCN(C)CC1)COc1ccccc1-3
Reaction time: 0.08 h

Procedure:
To a solution of methyl 14-cyclohexyl-7-oxo-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (prepared as described in Example 9, Step 4) in DCM (0.04 M), were added 3.0 eq of 1-methylpiperazine and 4.5 eq acetic acid, followed by 1.5 eq. of solid sodium triacetoxyborohydride. NaOH (20 eq, 1 N) was added after 2 h, and after stirring for 5 min the mixture was taken into EtOAc and washed with water and brine. Drying over sodium sulfate and concentration in vacuo gave the crude product, which was used without any further purification; MS (ES+) m/z 488 (M+H)+.
Reaction SMILES: [Li]CCCC.Br[C:7]1[S:11][CH:10]=[N:9][CH:8]=1.[Sn:12](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16].Cl>C1COCC1.CCCCCC>[CH2:21]([Sn:12]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:17][CH2:18][CH2:19][CH3:20])[C:7]1[S:11][CH:10]=[N:9][CH:8]=1)[CH2:22][CH2:23][CH3:24]
Reactant: Brc1cncs1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cncs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.7 %

Procedure:
A hexane solution of n-BuLi (4.14 mL, 10 mmol) was added dropwise to an anhydrous tetrahydrofuran solution of 5-bromothiazole (0.46 mL, 5.0 mmol) at −78° C. under nitrogen atmosphere over a period of 30 minutes, and the mixture was stirred for 1 hour. A solution of n-Bu3SnCl (1.41 mL, 5.0 mmol) in THF was then added dropwise over a period of 30 minutes at −78° C., and after stirring for 2 hours, the mixture was raised to room temperature and stirred for another hour. Three drops of a 1N HCl solution were added, and the organic layer was extracted from the aqueous layer twice with 10 mL of ether. The solvent was distilled away to yield the title compound (650 mg, 35 mL).
Reaction SMILES: C(O[C@H]1C[C@@H](C2C=CN=CC=2)OC2(CCNCC2)C1)C.CCN=C=NCCCN(C)C.[CH:32]([O:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][C:37]=1[CH3:45])([CH3:34])[CH3:33].CCN(C(C)C)C(C)C>ClCCl>[CH:32]([O:35][C:36]1[CH:44]=[CH:43][C:39]([CH:40]=[O:41])=[CH:38][C:37]=1[CH3:45])([CH3:34])[CH3:33]
Reactant: Cc1cc(C(=O)O)ccc1OC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CCO[C@H]1C[C@@H](c2ccncc2)OC2(CCNCC2)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C=O)ccc1OC(C)C
Reaction time: 16 h
Yield: 146.5 %

Procedure:
A solution of cis-8-ethoxy-10-(4-pyridyl)-11-oxa-3-azaspiro[5.5]undecane (50 mg, 0.18 mmol), EDCI (38 mg, 0.20 mmol) and 4-isopropoxy-3-methyl-benzoic acid (35 mg, 0.18 mmol) in dichloromethane (0.9 mL) was treated with DIPEA (94 μL, 0.54 mmol) and stirred for 16 h. The reaction mixture was filtered and purified by reverse phase HPLC (1-100% ACN/water) to afford cis-8-ethoxy-10-(2-pyridyl)-11-oxa-3-azaspiro[5.5]undecan-3-yl)(4-isopropoxy-3-methyl-phenyl)methanone (47 mg, 57.58%). ESI-MS m/z calc. 452.27, found 453.2 (M+1)+; Retention time: 1.059 minutes (3 min run).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[CH3:34][O:35][CH2:36][CH2:37][NH:38][CH3:39]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][N:38]([CH2:37][CH2:36][O:35][CH3:34])[CH3:39])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: CNCCOC
Product: COCCN(C)CCCS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3c(OC)ccc(F)c3F)c(N)n2)CC1

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226) and N-(2-methoxyethyl)methylamine (TCI America) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C24H35N6O5SF2 [(M+H)+] 557.2352, observed 557.2357.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>C(OC(=O)C)(=O)C>[N+:13]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[C:11]([OH:12])[C:2]([OH:1])=[CH:3]2)([O-:15])=[O:14]
Reactant: Oc1cc2ccccc2cc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1cccc2cc(O)c(O)cc12
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A suspension of 5.0 g of 2,3-Dihydroxynaphthalene dimesitylate in 50 ml of acetic anhydride was treated with 12 ml of 70% HNO3 at such a rate as to keep the temperature between 37-40° C. A cooling bath should be kept under the flask, ready to be raised if necessary, as the temperature should not be allowed to exceed 45° C. The 12.0 ml of nitric acid was added to the reaction mixture over a period of 1-2 h. After 2 h, the reaction mixture was cooled to 5° C. in an ice bath and the precipitate was collected by filtration and washed with ether. Yield 5-Nitro-2,3-dihydroxynaphthalene dimesitylate 70%; mp 199-201° C., 1H NMR (DMSO-d6) δ 3.58 (s, 6H), 7.76 (t, J=8.0 Hz, 1H), 8.25-8.65 (m, 4H)
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18](=O)[CH3:19])[N:9]=1.C(N(CC)CC)C.C(OC([N:35]1[C@@H:43]2[C@@H:38]([CH2:39][CH2:40][CH2:41][CH2:42]2)[CH2:37][C@H:36]1[CH2:44][NH2:45])=O)(C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:60][O:61][C:62]1[C:67]2[O:68][C:69]([CH3:72])([CH3:71])[O:70][C:66]=2[CH:65]=[C:64]([C:73](Cl)=[O:74])[CH:63]=1>ClCCl>[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([CH:18]([N:45]([CH2:44][C@@H:36]2[CH2:37][C@H:38]3[C@H:43]([CH2:42][CH2:41][CH2:40][CH2:39]3)[NH:35]2)[C:73]([C:64]2[CH:63]=[C:62]([O:61][CH3:60])[C:67]3[O:68][C:69]([CH3:72])([CH3:71])[O:70][C:66]=3[CH:65]=2)=[O:74])[CH3:19])[N:9]=1
Reactant: CC(C)(C)OC(=O)N1[C@H](CN)C[C@@H]2CCCC[C@@H]21
Reactant: CC(=O)c1cc2ccccc2cn1
Reactant: COc1cc(C(=O)Cl)cc2c1OC(C)(C)O2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N(C[C@@H]2C[C@@H]3CCCC[C@@H]3N2)C(C)c2cc3ccccc3cn2)cc2c1OC(C)(C)O2
Yield: 5.4 %

Procedure:
Experimental conditions analogous to Example 1, from 0.19 g (0.68 mmol) of 1-isoquinolin-3-yl-ethanone trifluoroacetic acid salt (neutralized in situ with 95 μL (0.68 mmol) of triethylamine, 0.20 g (0.82 mmol) of (2S,3aS,7aS)-2-aminomethyl-octahydro-indole-1-carboxylic acid tert-butyl ester, 6 mL dichloromethane, and 0.21 g (1.02 mmol) of sodium triacetoxyborohydride. The benzoylation/deprotection steps were done using 284 μL (2.04 mmol) of triethylamine and 0.15 g (0.61 mmol) of 7-methoxy-2,2-dimethyl-benzo[1,3]dioxole-5-carbonyl chloride. The residue from the organic layer was purified using reverse phase HPLC, mobile phase with a gradient 15-80% acetonitrile in 50 min. The residue was dissolved in dichloromethane, washed with aqueous sodium bicarbonate, dried with anhydrous magnesium sulfate and evaporated in vacuum to yield 17 mg of the product as the free base mixture of diastereoisomers. LC-MSD, m/z for C31H37N3O4 [M+H]+: 516.7, [M+2H]2+: 258.9. 1H NMR (400 MHz, CDCl3): δ 1.2-2.1 (m, 20 H), 3.0-4.0 (m, 7 H), 5.4-5.5 (m, 1 H), 6.7-6.8 (m, 1 H), 7.0-7.1 (m, 1 H), 7.4-7.9 (m, 4 H), 7.9-8.0 (m, 1 H), 9.2-9.3 (m, 1 H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:24]([CH3:25])[C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[N:21]=3)[CH:15]=2)[CH2:10][CH2:9]1)(C)(C)C.[Cl:31]CCl>CO.Cl.CCOCC>[ClH:31].[CH3:25][N:24]1[C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[N:21]=[C:20]1[C:16]1[CH:15]=[C:14]([N:11]2[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]2)[CH:19]=[CH:18][CH:17]=1
Reactant: ClCCl
Reactant: Cn1c(-c2cccc(N3CCC(NC(=O)OC(C)(C)C)CC3)c2)nc2ccccc21
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cn1c(-c2cccc(N3CCC(N)CC3)c2)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of {1-[3-(1-Methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidin-4-yl}-carbamic acid tert-butyl ester (2.00 g, 4.93 mmol) in dichloromethane (2 mL) and methanol (1 mL), 2M HCl in Et2O (25 mL) was added and the resulting mixture was stirred overnight at room temperature.
Reaction SMILES: [C:1]([N:4]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[C:5](=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:7]=1)(=[O:3])[CH3:2].[CH3:37][I:38]>>[I-:38].[C:1]([N:4]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N+:32]=1[CH3:37])[C:5](=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CI
Reactant: CCCCCCCCCCCCCCOc1cc(C(=O)N(Cc2ccccn2)C(C)=O)ccc1OC
Product: CCCCCCCCCCCCCCOc1cc(C(=O)N(Cc2cccc[n+]2C)C(C)=O)ccc1OC
Product: [I-]

Procedure:
The title compound is prepared by the procedure of Example 28 using 0.421 g of product from Example 44 and 2.64 ml of methyl iodide. The residue is recrystallized from methyl alcohol to give 0.541 g of the desired product as yellow crystals.