Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([N:10]([CH3:12])[CH3:11])[N:3]=1.[CH3:13][C:14](OC(C)=O)=[O:15]>N1C=CC=CC=1>[C:14]([O:9][CH2:8][C:6]1[CH:5]=[C:4]([N:10]([CH3:12])[CH3:11])[N:3]=[C:2]([Cl:1])[CH:7]=1)(=[O:15])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)c1cc(CO)cc(Cl)n1
Solvent: c1ccncc1
Product: CC(=O)OCc1cc(Cl)nc(N(C)C)c1
Reaction time: 12 h

Procedure:
To a stirring solution of (2-chloro-6-(dimethylamino)pyridin-4-yl)methanol in 7 mL of pyridine was added 1.2 mL of Ac2O. After the solution was stirred for 12 h, the solution was concentrated, and saturated NaHCO3 solution was added to pH=7. The aqueous layer was extracted with EtOAc, and the organic layer was washed with H2O (15 mL) and brine (15 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (15% EtOAc/hexanes) provided (2-chloro-6-(dimethylamino)pyridin-4-yl)methyl acetate as a yellow oil with some impurity.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16]=1[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])[CH:6]=[CH:5]2.C([O-])(=O)C.[K+].[Br:32]Br.O>C(O)(=O)C>[Br:32][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:12]1[O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16]=1[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:8]2
Reactant: CCCCC(=O)c1c(-c2ccc3cc(O)ccc3c2)oc2ccccc12
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCC(=O)c1c(-c2ccc3c(Br)c(O)ccc3c2)oc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.6 %

Procedure:
To an ice-cooled mixture of 1-[2-(6-hydroxy-2-naphthyl)-1-benzofuran-3-yl]-1-pentanone (1.59 g, 4.62 mmol) in glacial acetic acid (50 mL) was added potassium acetate (4.54 g, 46.2 mmol). The mixture was stirred at room temperature for 15 minutes and then chilled again in an ice bath. Bromine (0.27 mL, 5.3 mmol) in acetic acid (6 mL) was added dropwise. The mixture was stirred at room temperature for 15 minutes. It was poured into excess water and filtered. The precipitate was dissolved in ethyl acetate, with some warming, and dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to dryness to afford 1-[2-(5-bromo-6-hydroxy-2-naphthyl)-1-benzofuran-3-yl]-1-pentanone as a yellow solid (1.85 g), mp 171-172° C. Mass spectrum (+APCl, [M+H]+) m/z 423. 1HNMR (400 MHz, DMSO-d6): δ10.95 (s, 1H), 8.4 (d, 1H, J=1.7 Hz), 8.15 (d, 1H, J=9.0 Hz), 8.05-8.1 (m, 2H), 7.95 (dd, 1H, J=8.8 Hz and 2.0 Hz), 7.7-7.75 (m, 1H), 7.35-7.45 (m, 3H), 2.75 (t, 2H, J=7.3 Hz), 1.5-1.6 (m, 2H), 1.1-1.2 (m, 2H), and 0.7 ppm (t, 3H, J=7.3 Hz). Elemental Analysis for C23H19BrO3. 0.25 H2O: Calculated: C, 64.57; H, 4.59; N, 0.00. Found: C, 64.19; H, 4.26; N, 0.05.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[S:3]([N:6]1[CH:10]=[C:9]([C:11](=[O:21])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=2)[N:8]=[CH:7]1)(=[O:5])=[O:4].[NH4+].[Cl-]>O.C(O)C.[Fe]>[NH2:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[C:11]([C:9]1[N:8]=[CH:7][N:6]([S:3]([N:2]([CH3:22])[CH3:1])(=[O:4])=[O:5])[CH:10]=1)=[O:21]
Reactant: CN(C)S(=O)(=O)n1cnc(C(=O)c2cccc([N+](=O)[O-])c2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CN(C)S(=O)(=O)n1cnc(C(=O)c2cccc(N)c2)c1
Yield: 101.9 %

Procedure:
To a mixture of Example 55B (3.24 g, 10 mmol) and NH4Cl (540 mg, 10 mmol) in water (15 mL) and ethanol (35 mL) was added iron powder (3.92 g, 70 mmol) and the mixture was refluxed for 1 hour. The mixture was filtered, the solid was washed with THF, and the combined filtrate and washings were removed under vacuum to provide 3 g (˜100%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][OH:23])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]3[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:6]=1.[OH:24][CH2:25][CH2:26][N:27]([CH2:46][CH2:47][OH:48])[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[NH:35][C:36]3[CH:42]=[C:41]([C:43]([O-])=[O:44])[CH:40]=[CH:39][C:37]=3[N:38]=2)=[CH:30][CH:29]=1>>[OH:24][CH2:25][CH2:26][N:27]([CH2:46][CH2:47][OH:48])[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[NH:35][C:36]3[CH:42]=[C:41]([C:43]([NH:20][C:18]4[CH:17]=[CH:16][C:14]5[NH:15][C:11]([C:8]6[CH:9]=[CH:10][C:5]([N:4]([CH2:21][CH2:22][OH:23])[CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=6)=[N:12][C:13]=5[CH:19]=4)=[O:44])[CH:40]=[CH:39][C:37]=3[N:38]=2)=[CH:30][CH:29]=1
Reactant: Nc1ccc2nc(-c3ccc(N(CCO)CCO)cc3)[nH]c2c1
Reactant: O=C([O-])c1ccc2nc(-c3ccc(N(CCO)CCO)cc3)[nH]c2c1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(N(CCO)CCO)cc3)nc2c1)c1ccc2nc(-c3ccc(N(CCO)CCO)cc3)[nH]c2c1

Procedure:
Compound 289 was prepared according to the procedure similar to that described in Scheme V from 2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5-aminobenzimidazole and 2-(4-(bis(2-hydroxyethyl)amino)phenyl)benzimidazole-5-carboxylate. [M+H]+ calcd for C35H37N7O5: 636.29; found: 636.06.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:9]([O:11][C:12]1[CH:21]=[C:20]([O:22][CH:23]2[CH2:40][CH:39]3[CH:25]([C:26](=[O:46])[N:27]([CH3:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH:33][CH:34]4[C:36]([C:42]([OH:44])=[O:43])([NH:37][C:38]3=[O:41])[CH2:35]4)[CH2:24]2)C2C(=C(C)C(OC)=CC=2)N=1)[CH3:10]>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[C:12]([O:11][CH2:9][CH3:10])[CH:21]=[C:20]2[O:22][CH:23]1[CH2:40][CH:39]2[CH:25]([C:26](=[O:46])[N:27]([CH3:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH:33][CH:34]3[C:36]([C:42]([OH:44])=[O:43])([NH:37][C:38]2=[O:41])[CH2:35]3)[CH2:24]1
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1
Reactant: Nc1ccccc1Cl
Product: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2cccc(Cl)c2n1

Procedure:
The title compound (10) was prepared from 2-chloroaniline following the procedure (Steps A-J) reported for synthesis of 17-[2-ethoxy-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (2): m/z=556 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([N:12]1[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]1)(=[O:11])=[O:10].[C:19](N1C=CN=C1)([N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)=[O:20]>CN(C)C=O>[CH3:8][S:9]([N:12]1[CH2:13][CH2:14][CH:15]([NH:18][C:19]([N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)=[O:20])[CH2:16][CH2:17]1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCC(NC(=O)n2ccnc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a mixture of 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoro-acetic acid (229.4 mg, 0.785 mmol, US20060014708) in N,N-dimethyl formamide (4.0 mL) was added TEA (101 mg, 1.004 mmol) and 1,1′-carbonyldiimidazole (Aldrich, 134 mg, 0.826 mmol). After it was stirred at rt for 2 hrs, the solvent was removed and the reaction mixture was extracted with EtOAc, and washed with water (2×), and saturated NaCl. The organic phase was separated, dried over Na2SO4, filtered and concentrated to give imidazole-1-carboxylic acid (1-methanesulfonyl-piperidin-4-yl)-amide (150.7 mg, 70.5%) which was used without further purification.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH2:7]([CH2:9][NH2:10])[OH:8].O>ClCCl>[OH:8][CH2:7][CH2:9][NH:10][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1]
Reactant: C=C1CC(=O)O1
Reactant: NCCO
Solvent: O
Solvent: ClCCl
Product: CC(=O)CC(=O)NCCO
Reaction time: 2 h

Procedure:
To a solution of diketene (42.1 g, 0.5 mol) in dichloromethane (100 ml), ethanolamine (30.5 g, 0.5 mol) was added dropwise at 10°-20.C with stirring, and the reaction was carried out at room temperature for 2 hrs. After pouring H2O (200 ml) into the reaction solution, an aqueous layer was separated, washed thrice with dichloromethane and was obtained N-(2-hydroxyethyl)-3-oxobutanamide as an aqueous solution.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:20])[N:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])[C:10]=1[CH3:11])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[N:9]1[C:10]([CH3:11])=[C:6]([CH2:4][OH:3])[N:7]=[C:8]1[CH3:20]
Reactant: CCOC(=O)c1nc(C)n(-c2ccc(F)cc2F)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(CO)c(C)n1-c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 81.9 %

Procedure:
1-(2,4-Difluoro-phenyl)-2,5-dimethyl-1H-imidazole-4-carboxylic acid ethyl ester (0.5 g, 2 mmol) was dissolved in 15 mL dry THF and cooled to 0° C. Lithium aluminum hydride (2.0 mL, 1M in THF, 2 mmol) was added dropwise and stirred for 45 min at 0° C. The reaction mixture was quenched successively with 76 μl water, 76 μl 15% sodium hydroxide and 230 μl water. Sodium sulfate was added, stirred for 10 min, filtered and evaporated to dryness to obtain the desired compound as a white solid (0.39 g, 92%), MS: m/e=239.2 (M+H+).
Reaction SMILES: [C:1]([NH:7][C:8](=[O:30])[NH:9][C:10]1[N:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=O)[O:25]C(C)=C)[CH:18]=2)=[CH:12][CH:11]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.[NH:32]1[CH2:35][CH2:34][CH2:33]1.CN1CCCC1>O1CCOCC1>[C:1]([NH:7][C:8](=[O:30])[NH:9][C:10]1[N:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]([N:32]3[CH2:35][CH2:34][CH2:33]3)=[O:25])[CH:18]=2)=[CH:12][CH:11]=1)(=[O:6])[C:2]([CH3:4])([CH3:3])[CH3:5]
Reactant: C1CNC1
Reactant: C=C(C)OC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C(C)(C)C)nc2)ccn1
Agent: CN1CCCC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)N3CCC3)c2)cn1
Temperature: 25 °C
Yield: 26.5 %

Procedure:
A mixture of Example C2 (0.265 g, 0.641 mmol), azetidine hydrochloride (0.120 g, 1.282 mmol) and N-methylpyrrolidine (0.065 g, 0.769 mmol) in dioxane (6 mL) was heated at 80° C. overnight, cooled to RT, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The material was further purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA); the organics were removed under reduced pressure and the aqueous residue was treated with satd. NaHCO3, extracted with EtOAc (4×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)azetidine-1-carboxamide (70 mg, 25%). 1H NMR (400 MHz, DMSO-d6): δ 11.21 (s, 1H), 10.43 (s, 1H), 9.09 (s, 1H), 8.23 (d, J=2.9 Hz, 1H), 8.11-8.06 (m, 2H), 7.71 (dd, J=9.0, 2.9 Hz, 1H), 7.48 (d, J=2.4 Hz, 1H), 6.59 (dd, J=5.7, 2.4 Hz, 1H), 3.92 (t, J=7.5 Hz, 4H), 2.12-2.10 (m, 2H), 1.21 (s, 9H); MS (ESI) m/z: 413.2 (M+H+).
Reaction SMILES: [Na].Br.[CH2:3]1[C:5]2([CH2:10][NH:9][C:8]([NH2:11])=[N:7][CH2:6]2)[CH2:4]1.[C:12](OCC)(=[O:17])[CH2:13][C:14]([O-])=[O:15]>CO>[OH:17][C:12]1[N:11]=[C:8]2[NH:9][CH2:10][C:5]3([CH2:4][CH2:3]3)[CH2:6][N:7]2[C:14](=[O:15])[CH:13]=1
Reactant: NC1=NCC2(CC2)CN1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Br
Agent: [Na]
Solvent: CO
Product: O=c1cc(O)nc2n1CC1(CC1)CN2
Temperature: 100 °C
Yield: 60 %

Procedure:
1.1 g of sodium are added in a fractionated way to 15 mL of MeOH. After total dissolution, 1.6 g of 5,7-diazaspiro[2.5]oct-5-en-6-amine hydrobromide solubilized beforehand in 5 mL of MeOH, and then 8 mL of ethyl malonate are added. The mixture is heated to 100° C., after 4 h of heating, the medium is dry concentrated. The obtained oil is taken up in ether. The precipitate is filtered and then the residue is taken up in 7 mL of H2O and acidified with concentrated HCl up to pH 3-4. The formed precipitate is filtered, washed with ether and dried in the oven in vacuo. 1.5 g (yield=60%) of 8′-hydroxy-1′,2′-dihydro-spiro[cyclopropane-1,3′-pyrimido[1,2-a]pyrimidin]-6′-one are obtained as a beige solid used as such.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH:8]([F:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:7][O:6]1)=[O:4].[OH-].[Na+:24].O1CCCC1>C(O)C>[Na+:24].[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH:8]([C:5]2([C:3]([O-:4])=[O:2])[CH2:7][O:6]2)[F:22])=[CH:16][CH:17]=1
Reactant: COC(=O)C1(C(F)CCCCCOc2ccc(Cl)cc2)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C([O-])C1(C(F)CCCCCOc2ccc(Cl)cc2)CO1
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
To a suspension of 1.79 g (5.41 mmol) of 2-[6-(4-chlorophenoxy)-1-fluorohexyl]-2-oxiranecarboxylic acid methyl ester (isomer A) of Example 3 in 5.14 ml of absolute ethanol is added at room temperature 5.14 ml (5.14 mmol) of 1N aqueous sodium hydroxide. After 30 minutes, 4.0 ml of tetrahydrofuran is aded to achieve total dissolution and stirring is maintained for 1.25 hours. Evaporation of the solvents and trituration with pentane and isopropyl ether gives 1.46 g (79.7%) of the title compound: m.p. 112°-125° C.; IR (KBr) 1640, 1608 cm-1 ; NMR (d6 -DMSO) δ 1.47 (4H, m), 1.74 (4H, m), 2.63 (1H, dd, J=8, 3 Hz), 2.73 (1H, d, J=8 Hz), 3.98 (2H, t, J=9 Hz), 5.19 (1H, ddd, J=48, 10, 2 Hz), 6.98 (2H, d, J=8 Hz).
Reaction SMILES: Br[C:2]1[C:11]([C@H:12]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:23])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:24])=[N:7]2.CC1(C)C(C)(C)OB([C:33]2[CH:42]=[CH:41][C:40]3[O:43][CH2:44][CH2:45][N:38]4[C:39]=3[C:34]=2[CH2:35][CH2:36][CH2:37]4)O1.C(COC)OC.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:19]([O:18][C@@H:12]([C:11]1[C:2]([C:33]2[CH:42]=[CH:41][C:40]3[O:43][CH2:44][CH2:45][N:38]4[C:39]=3[C:34]=2[CH2:35][CH2:36][CH2:37]4)=[C:3]2[C:8](=[CH:9][C:10]=1[CH3:23])[N:7]=[C:6]([CH3:24])[CH:5]=[CH:4]2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C)ccc2c1Br
Reactant: CC1(C)OB(c2ccc3c4c2CCCN4CCO3)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C)ccc2c1-c1ccc2c3c1CCCN3CCO2
Temperature: 80 °C

Procedure:
Preparation of (2S)-ethyl 2-tert-butoxy-2-(2,7-dimethyl-5-(3,5,6,7-tetrahydro-2H-[1,4]oxazino[2,3,4-ij]quinolin-8-yl)quinolin-6-ypacetate: A Smith process vial was charged with (S)-ethyl 2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetate (52 mg, 0.133 mmol, 1 eq.), 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,5,6,7-tetrahydro-2H-[1,4]oxazino[2,3,4-ij]quinoline (48 mg, 0.159 mmol.), Pd(PPh3)4 (15 mg, 10%) and flushed with nitrogen. Dimethoxyethane (1.6 mL) and 2 M K2CO3 (0.24 mL, 0.48 mmol) was added. The reaction was heated in oil bath at 80° C. for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give (2S)-ethyl 2-tert-butoxy-2-(2,7-dimethyl-5-(3,5,6,7-tetrahydro-2H-[1,4]oxazino[2,3,4-ij]quinolin-8-yl)quinolin-6-yl)acetate as atropisomer mixture (39 mg, 60%). LCMS-ESI+: calcd for C30H37N2O4: 489.52 (M+H+). Found: 489.3.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[S:18][C:19]([N+:22]([O-])=O)=[CH:20][CH:21]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C1(N2CCC3C=[CH:37][C:38]([O:40]C4SC(NC(=O)C)=CN=4)=CC=3CC2)CCC1>>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[S:18][C:19]([NH:22][C:38](=[O:40])[CH3:37])=[CH:20][CH:21]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)Nc1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)s1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)s1
Product: CC(=O)Nc1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)s1

Procedure:
Example 212 (E212) was prepared from 3-cyclobutyl-7-[(5-nitro-2-thienyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E211) using an analogous method to that described for Example 210 (E210); MS (ES+) m/e 357 [M+H]+.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:9])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].C[O:11][C:12](=O)/[CH:13]=[CH:14]/C(=C(/N)\C)/C(=O)CCC>CN(C=O)C.C(OCC)(=O)C>[OH:11][C:12]1[CH:13]=[CH:14][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([CH3:9])[N:1]=1
Reactant: CCOC(=O)/C=C(/C)N
Reactant: CCCC(=O)C(/C=C/C(=O)OC)=C(/C)N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(O)nc1C

Procedure:
Stoichiometric amounts (0.04 mol) of methyl proplolate and ethyl 3-aminocrotonate were heated to 140° C. for 1 h. 1 g of the crude (2E,4Z)-methyl-4-(1-aminoethylidene)-5-oxooct-2-enoate in 4 mL of DMF was heated to 230° C. in a sealed microwave reactor for 40 min. The reaction mixture was diluted with ethyl acetate, washed with H2O, dried (MgSO4) and evaporated to afford crude ethyl 6-hydroxy-2-methylnicotinate. A mixture of 800 mg of crude ethyl 6-hydroxy-2-methylnicotinate in 4 mL of phosphorus oxychloride was heated to 150° C. in a sealed microwave reactor for 15 min. The reaction mixture was poured into ice/water, extracted with diethyl ether. The combined organic layers were dried (MgSO4) and evaporated. Purified by silica gel chromatograph (0-20% ethyl acetate/hexane) to yield ethyl 6-chloro-2-methylnicotinate. 400 mg of ethyl 6-chloro-2-methylnicotinate was hydrolyzed via Procedure M to give 6-chloro-2-methylnicotinic acid. 300 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-chloro-2-methylnicotinic acid via Procedure G. The reaction mixture was diluted with ethyl acetate, washed with 0.1 N sodium hydroxide and brine, dried (MgSO4) and evaporated to afford 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide. Procedure F was performed using 100 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 128 mg of 2,6-dimethylpiperazine in 1 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-((3S,5R)-3,5-dimethylpiperazin-1-yl)-2-methylnicotinamide. MS (Q1) 436.3 (M)+.
Reaction SMILES: [CH3:1][C:2]1([CH2:5][CH2:6][C:7]([OH:9])=O)[CH2:4][CH2:3]1.C(Cl)(=O)C([Cl:13])=O>ClCCl>[CH3:1][C:2]1([CH2:5][CH2:6][C:7]([Cl:13])=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(CCC(=O)O)CC1
Solvent: ClCCl
Product: CC1(CCC(=O)Cl)CC1
Reaction time: 8 h

Procedure:
3-(1-Methylcyclopropyl)propionic acid (1.752 mmol, 0.2 g) was stirred in dichloromethane at 0° C. Oxalyl chloride (8.76 mmol, 0.752 mL, 1.112 g) was added and the reaction stirred overnight. The reaction mixture was concentrated under vacuum to give the intermediate 3-(1-methylcyclopropyl)propanoyl chloride. A mixture of 3-(1-methyl-cyclopropyl)propanoyl chloride (0.813 mmol, 0.119 g), (4-aminophenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-1-yl)methanone (0.542 mmol, 0.25 g) and triethylamine (1.084 mmol, 0.151 mL, 0.110 g) were stirred in dichloromethane at 0° C. for 1 hour. The reaction mixture was allowed to warm to room temperature. The reaction mixture was washed with water, concentrated under vacuum and purified by acidic prep HPLC to afford the title compound (67 mg). MS (ESI) m/z 572.3 [M+H]+
Reaction SMILES: Cl.CO.[CH2:4]([NH2:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:12][C:13]1([C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.C([BH3-])#N.[Na+].Cl>CO>[CH2:4]([NH:11][CH:16]1[CH2:17][CH2:18][C:13]([CH3:12])([C:20]([O:22][CH3:23])=[O:21])[CH2:14][CH2:15]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)C1(C)CCC(=O)CC1
Reactant: NCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(C)CCC(NCc2ccccc2)CC1

Procedure:
5N hydrochloric acid-methanol was added to a solution of 19.6 ml of benzylamine in 75 ml of methanol under ice-cooling, neutralizing the solution. Then, 5.1 g of methyl 1-methyl-4-oxo-1-cyclohexanecarboxylate and 1.13 g of sodium cyanoborohydride were added to the mixture solution. The solution was reacted at room temperature for 26 hours. After reaction, concentrated hydrochloric acid was added to the reaction solution, adjusting the pH value to 2 or less. The solution was washed three times with 30 ml of methylene chloride. Further, a 2N aqueous sodium hydroxide solution was added to the aqueous layer formed, adjusting the pH value to 10 or more. The solution was extracted three times with 30 ml of ethyl acetate. The organic layer obtained was washed twice with an aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed in vacuo. The oily substance, thus obtained, was subjected to column chromatography using 50 g of silica gel. From the fraction eluted with hexane and ethyl acetate=4:1, the solvent was removed in vacuo, yielding 3.1 g of methyl 4-(N-benzylamino)-1-methyl-1-cyclohexanecarboxylate as a colorless oil, which had the following physiochemical properties:
Reaction SMILES: Br[C:2]1[C:3](=[O:34])[N:4]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:33]=[CH:32][C:19]3[N:20]([CH2:30][CH3:31])[C:21](=[O:29])[C:22]([CH3:28])([CH3:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]=3[CH:17]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[CH2:30]([N:20]1[C:21](=[O:29])[C:22]([CH3:28])([CH3:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]2[CH:17]=[C:16]([O:15][CH2:14][CH2:13][CH2:12][N:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:11]=[C:2]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:3]3=[O:34])[CH:33]=[CH:32][C:19]1=2)[CH3:31]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCn3c(=O)c(Br)cc4ccccc43)ccc21
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCn3c(=O)c(-c4ccccc4)cc4ccccc43)ccc21
Temperature: 25 °C
Yield: 68.4 %

Procedure:
7-[3-(3-Bromo-2-oxo-2H-quinolin-1-yl)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(0.5 g), phenylboronic acid(0.12 g), tetrakis(triphenyl phosphine)palladium (0) (0.11 g), and potassium carbonate(0.39 g) were added to dioxane(5 ml). The mixture was heated under reflux for 2 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature. Water was added thereto, followed by extraction by ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane=1:1→3:1). The purified product was condensed to dryness under reduced pressure, thereby obtaining the title compound(0.34 g) as a white amorphous solid.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3](=[O:28])[NH:4][C:5]1[C:13]([CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][C:19]([O:21]C)=[O:20])=[C:12]([O:24][CH3:25])[C:11]([CH3:26])=[C:10]2[C:6]=1[C:7](=[O:27])[O:8][CH2:9]2.O.O.[OH-].[Li+]>CO>[CH3:29][N:2]([CH3:1])[C:3](=[O:28])[NH:4][C:5]1[C:13]([CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[C:12]([O:24][CH3:25])[C:11]([CH3:26])=[C:10]2[C:6]=1[C:7](=[O:27])[O:8][CH2:9]2
Reactant: COC(=O)CC/C(C)=C/Cc1c(NC(=O)N(C)C)c2c(c(C)c1OC)COC2=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1c(C)c2c(c(NC(=O)N(C)C)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Yield: 94.6 %

Procedure:
To a solution of 0.3 g (0.74 mmol) of methyl (E)-6-[1,3-dihydro-4-(3,3-dimethylureido)-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoate in 7.4 ml of 4:1 methanol:water was added 0.13 g (2.96 mmol) of lithium hydroxide monohydrate. The solution was heated at 50°-60° C. for 4 hours. Upon cooling, the reaction was partitioned between aqueous sodium hydrogen sulfate and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to (E)-6-[1,3- dihydro-4-(3,3-dimethylureido)-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]- 4-methyl-4-hexenoic acid. Recrystallization from hexane-ethyl acetate gave 0.27 g (0.7 mmol) of (E)-6-[1,3-dihydro-4-(3,3-dimethylureido)-6-methoxy-7-methyl -3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoic acid, mp 170 °-190° C.