Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[Cl:2][C:3]1[N:4]=[N:5][C:6](Cl)=[CH:7][CH:8]=1.[CH3:10][OH:11]>>[Cl:2][C:3]1[N:4]=[N:5][C:6]([O:11][CH3:10])=[CH:7][CH:8]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CO
Agent: [Na]
Product: COc1ccc(Cl)nn1

Procedure:
Sodium (4.8 g, 0.21 mol) is added portion-wise to MeOH (200 ml) with stirring. After a clear solution is formed, it is added slowly to a solution of 3,6-dichloro-pyridazine (29.6 g, 0.2 mol) in MeOH (200 ml). After addition, the mixture is heated at reflux for 3 h, then cooled and concentrated under reduced pressure. EtOAc and water are added. The organic layer is separated, dried and concentrated under reduced pressure to give 26.4 g of 3-chloro-6-methoxy-pyridazine as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]([OH:27])=[O:26])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]([O:27][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:26])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(Cc3cccc(C(=O)O)n3)c(-c3ccccc3)[nH]c2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(Cc3cccc(C(=O)OCc4ccccc4)n3)c(-c3ccccc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 6-(6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxylic acid (3.00 g) in N,N-dimethylformamide (16.8 mL) were added potassium carbonate (1.39 g) and benzyl bromide (0.996 mL) successively, and this mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (3.06 g). 1H-NMR (CDCl3) δ ppm: 3.85 (3H, s), 4.54 (2H, s), 5.48 (2H, s), 6.72 (1H, dd, J=2.2, 8.5 Hz), 6.91 (1H, d, J=2.2 Hz), 7.16-7.23 (1H, m), 7.27-7.44 (7H, m), 7.47-7.57 (4H, m), 7.60 (1H, t, J=7.8 Hz), 7.90-7.97 (1H, m), 8.10 (1H, br s).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C@H:11]2[CH3:23])[CH3:9])=[CH:4][CH:3]=1.O1CCCC1.C([Li])CCC.[B:34](OC(C)C)([O:39]C(C)C)[O:35]C(C)C.[OH-].[Na+]>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][N:10]([CH:8]([C:5]2[CH:4]=[C:3]([B:34]([OH:39])[OH:35])[C:2]([F:1])=[N:7][CH:6]=2)[CH3:9])[C@H:11]([CH3:23])[CH2:12]1)=[O:17])([CH3:21])([CH3:20])[CH3:22]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(c1ccc(F)nc1)N1CCN(C(=O)OC(C)(C)C)C[C@H]1C
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(c1cnc(F)c(B(O)O)c1)N1CCN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: -78 °C
Yield: 73.4 %

Procedure:
To a 150-mL round-bottomed flask was added (3R)-tert-butyl 4-(1-(6-fluoropyridin-3-yl)ethyl)-3-methylpiperazine-1-carboxylate (3.0 g, 9.28 mmol), and tetrahydrofuran (100 mL, 9.28 mmol). The solution was stirred at −78° C. and treated dropwise via syringe with butyllithium solution, 2.5 m in hexanes (4.08 mL, 10.20 mmol) (Aldrich). The solution was stirred at −78° C. for 1 hr and treated in one portion with triisopropyl borate (2.55 mL, 11.13 mmol) (Aldrich). The mixture was stirred at −78° C. for 1 hour. NaOH (1.0 N (30 mL) was added and the solution was stirred at room temperature for 30 minutes. The aqueous layer was separated and the organic layer was extracted with additional NaOH (1.0N, 30 mL). The combined aqueous layer was carefully acidified with 5N HCl (12 mL) to a final pH of about 4 to 5. The reaction mixture was extracted with EtOAc (3×100 mL) and the organic extract was dried over sodium sulfate, filtered and concentrated under a vacuum to give 5-(1-((R)-4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)ethyl)-2-fluoropyridin-3-ylboronic acid (2.5 g, 6.81 mmol, 73.4% yield).
Reaction SMILES: [CH3:1][N:2]([CH:4]=[O:5])[CH3:3].[CH3:6][CH2:7][OH:8].[CH:9]1([N:15]=C=NC2CCCCC2)CCCC[CH2:10]1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][N:2]([CH3:3])[C:4]([C@@H:9]1[CH2:10][O:8][CH2:7][CH2:6][NH:15]1)=[O:5]
Reactant: CCO
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CN(C)C=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H]1COCCN1
Reaction time: 18 h

Procedure:
A mixture of 8 g of the compound obtained in the preceding stage in 40 ml of DCM and 2 ml of DMF is cooled to 4° C., 10 ml of EtOH, 1 g of 4-dimethylaminopyridine and 15 g of 1,3-dicyclohexylcarbodiimide are successively added, and then the reaction mixture is left stirring for 18 hours at AT. The insoluble material is filtered off and the filtrate is concentrated under vacuum. The residue is taken up in DCM and the insoluble material is again filtered off. The resulting organic phase is washed with an aqueous 5% KHSO4 solution, with an aqueous 5% NaHCO3 solution, dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, elution being carried out with a DCM/AcOEt (95/5; v/v) mixture. 8 g of the expected product are obtained.
Reaction SMILES: [OH:1][CH2:2][C:3](=[CH2:7])[C:4]([O-:6])=[O:5].[Li+].Cl.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C=O)C>[Si:15]([O:1][CH2:2][C:3](=[CH2:7])[C:4]([OH:6])=[O:5])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=C(CO)C(=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=C(CO[Si](C)(C)C(C)(C)C)C(=O)O
Reaction time: 8 h

Procedure:
To lithium 2-(hydroxymethyl)prop-2-enoate (926 mg, 8.57 mmol) was added DMF (17.0 mL), HCl (1.07 mL, 4 M in dioxanes, 4.28 mmol) and imidazole (700 mg, 10.3 mmol), followed by TBS-Cl (2.84 g, 18.9 mmol) at 25° C. The reaction was stirred overnight, then quenched by pouring into a separatory funnel containing water. The aqueous layer was brought to pH˜3 with 1 N HCl and was extracted with ethyl acetate (×3). The organic layers were combined and dried with Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography using MPLC using 5-80% EtOAc/hexanes. The monoprotected product was collected and concentrated in vacuo to afford a clear oil. 1H NMR (600 MHz, DMSO-D6) δ 12.67 (s, 1H), 6.13 (s, 1H), 5.80 (s, 1H), 4.31 (s, 2H), 0.92 (s, 9H), 0.09 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.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>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: C1CCOC1
Product: Brc1cccc(-c2ccccc2)n1
Temperature: 25 °C
Yield: 4.4 %

Procedure:
A degassed solution of 2,6-dibromopyridine (4.0 g, 16.5 mmol) and phenylboronic acid (2.1 g, 16.7 mmol) in dry tetrahydrofuran (30 ml) was stirred under an atmosphere of nitrogen then sodium carbonate (3.55 g, 33.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.95 g, 5 mol %) added. This mixture was heated to reflux for 18 h. After cooling to ambient temperature, solvent was removed in vacuo, the residue dissolved in dichloromethane, washed with water and saturated brine, then dried over magnesium sulfate, filtered and evaporated in vacuo to give a solid. Purification by chromatography on silica gel eluting with dichloromethane gave 2-bromo-6-phenylpyridine (0.17 g) as a white solid: δH (400 MHz, CDCl3) 7.45 (4H, m), 7.60 (1H, dd, J 8 and 8), 7.70 (1H, d, J 8), 7.99 (2H, d, J 8); m/z (ES+) 233/235 (M++H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:12][C:13](=[O:16])[CH2:14]Cl)([CH3:11])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[K].CCSC(N(CC(C)C)CC(C)C)=O.CO>CC(O)(CC)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:11])[NH:12][C:13](=[O:16])[CH2:14][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(CO)(NC(=O)CCl)c1cccc(Br)c1
Agent: CCSC(=O)N(CC(C)C)CC(C)C
Agent: [K]
Solvent: CO
Solvent: CCC(C)(C)O
Product: CC1(c2cccc(Br)c2)COCC(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A solution of (RS)-N-[1-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide (5.36 g, 17 mmol) in 2-methyl-2-butanol (100 ml) was treated in one portion with potassium tent-butylate (6.66 g, 58 mmol). Initially, the temperature rose to 30° C.; the reaction mixture was left to cool to room temperature and stirring was continued for one hour. For the workup, the reaction mixture was treated with methanol (50 ml), then evaporated at reduced pressure. The residue was purified by chromatography on silica gel using a gradient of dichloromethane/methanol=100/0 to 75/25 as the eluent. There were obtained 4.18 g (88% of theory) of (RS)-5-(3-bromo-phenyl)-5-methyl-morpholin-3-one as a white solid. Mass (calculated) C11H12BrNO2 [270.128]; (found) [M+H]+=270, [M+2-H]+==272.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:28])[C:13]2[NH:19][C:18]3[C:20]([Cl:24])=[CH:21][CH:22]=[CH:23][C:17]=3[CH2:16][S:15](=[O:26])(=[O:25])[C:14]=2[CH:27]=1)=[O:9].[N+:29]([O-])([OH:31])=[O:30]>O>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:28])[C:13]2[NH:19][C:18]3[C:20]([Cl:24])=[CH:21][C:22]([N+:29]([O-:31])=[O:30])=[CH:23][C:17]=3[CH2:16][S:15](=[O:25])(=[O:26])[C:14]=2[CH:27]=1)=[O:9]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cccc(Cl)c1N2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc([N+](=O)[O-])cc(Cl)c1N2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Cooled sulfuric acid (1 mL) was added to a solution of compound of Example 37e (0.3 g, 0.85 mmol) in concentrated nitric acid (10 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1.5 h. The reaction mixture was slowly poured in cold water (100 mL), solid obtained was filtered, washed with water till pH was neutral. Solid obtained was crystallized using ethyl acetate/pet. ether 60-80° C. to obtain the title compound. Yield: 0.31 g, (91.70%); 1H NMR (DMSO-d6, 300 MHz): δ 2.70 (s, 3H, CH3), 3.90 (s, 3H, OCH3), 5.30 (s, 2H, CH2), 8.10 (s, 1H, Ar), 8.15 (s, 1H, Ar), 8.35 (s, 1H, NH), 8.55 (s, 2H, Ar); MS: m/e (El) 396 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:14]([NH:17][CH2:18][CH2:19][NH:20][CH:21]([CH3:23])[CH3:22])([CH3:16])[CH3:15].C(N(CC)CC)C>C(Cl)Cl>[CH3:15][CH:14]([N:17]([CH2:18][CH2:19][NH:20][CH:21]([CH3:23])[CH3:22])[S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11])[CH3:16]
Reactant: CC(C)NCCNC(C)C
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)NCCN(C(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
p-Nitrobenzenesulfonyl chloride (22.1 g, 0.1 mole) in methylene chloride (150 ml) was added dropwise with stirring to N,N'-diisopropyl ethylene diamine (14.4 g, 0.1 mole) and triethylamine (10.1 g, 0.1 mole) in methylene chloride (400 ml). The reaction was stirred one hour at room temperature, washed with water and the solvent removed. The residue dissolved in diethyl ether precipitated the unwanted "bis" byproduct which was filtered and discarded. Chromatography of the filtrate on Dry Column Silica Gel (500 g) with ethyl acetate provided pure product free base as a gum (14.31 g). Conversion, using isopropanol/HCl, to the hydrochloride salt provided the title compound as the hydrochloride salt (14.85 g) m.r. 219°-222° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCCn2ccnn2)c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.1 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product as a yellow solid 2-[4-(4-fluoro-phenyl) 2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)amide (74.3 mg, 65%).
Reaction SMILES: [O:1]1[C:5](=[O:6])[CH2:4][CH:3]2[CH2:7][CH:8]=[CH:9][CH:2]12.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1>C1COCC1>[CH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[CH2:21][CH:4]1[C:5](=[O:6])[O:1][CH:2]2[CH:9]=[CH:8][CH2:7][CH:3]12
Reactant: O=C1CC2CC=CC2O1
Reactant: BrCc1ccc2ccccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1OC2C=CCC2C1Cc1ccc2ccccc2c1

Procedure:
Analogously to the procedure of Example 1, the title compound was prepared from 0.31 g (2.5 mmol) of 3,3a,4,6a-tetrahydro-cyclopenta[b]furan-2-one, 2.5 ml of a 1 molar lithium bis-(trimethylsilyl)-amide solution in THF and 0.55 g (2.5 mmol) of 2-(bromomethyl)-naphthalene in 10 ml of THF. Yield: 498 mg (75.4%) of a pale yellow oil (Example 21). Diastereomer mixture: 94:6 (HPLC) MS (EI): m/e=264 [M+] The separation into the diastereomers and enantiomers is carried out using preparative HPLC: Example 22, 23, 24 and 25.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:3][CH:2]=1.Br[CH2:22][C:23]([NH2:25])=[O:24]>>[OH2:24].[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][C:8]2([CH2:22][C:23]([NH2:25])=[O:24])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]3[C:20]2=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:5][CH:6]=1.[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][C:8]2([CH2:22][C:23]([NH2:25])=[O:24])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]3[C:20]2=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:5][CH:6]=1
Reactant: NC(=O)CBr
Reactant: c1ccc2c(c1)-c1ccccc1C2Cc1ccncc1
Product: NC(=O)CC1(Cc2ccncc2)c2ccccc2-c2ccccc21
Product: O
Yield: 45 %

Procedure:
By substituting 9-(4-pyridinylmethyl)-9H-fluorene and α-bromoacetamide in Ex. 1, the desired product was isolated in 45% yield; mp 156°-158° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C@@H:12]1([OH:19])[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]1[OH:18].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([O:18][C@@H:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C@@H:12]2[OH:19])[CH:7]=1
Reactant: O[C@@H]1CCCC[C@@H]1O
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1O[C@@H]1CCCC[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2,4-Difluoronitrobenzene (0.549 ml) and cis-1,2-cyclohexanediol (0.581 g) in THF (10.0 ml), cooled with an ice-bath, was added lithium bis(trimethylsilyl)amide (1 mol/1 solution in THF; 5.00 ml). The mixture was stirred overnight at rt, and then evaporated to dryness. The residue was taken up in ethyl acetate, extracted once with hydrochloric acid (1 mol/l) and twice with NaOH solution (1 mol/l), dried with magnesium sulphate, filtered and evaporated to dryness. The residue was purified by column chromatography (silica; methylene chloride/methanol 100:0=>97:3) to yield a yellowish oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](CC(O)=O)=[CH:4][C:3]=1[N+:12]([O-])=O.[CH2:15]([OH:17])[CH3:16]>[Pd]>[CH:5]1[CH:4]=[C:3]([NH2:12])[C:2]([NH:1][C:15]([C:16]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)=[O:17])=[CH:7][CH:6]=1
Reactant: Nc1ccc(CC(=O)O)cc1[N+](=O)[O-]
Reactant: CCO
Agent: [Pd]
Product: Nc1ccc(C(=O)Nc2ccccc2N)cc1

Procedure:
4-Amino-3-nitrophenylacetic acid (0.97 g) and the product from Example 15 (1.0 g) were treated by the procedure described in Example 19. The intermediate product was hydrogenated over palladium in ethanol to yield the intermediate dianiline. Treatment of this intermediate with 2,3-dihydroxy-1,4-dioxane, followed by conversion to the methanesulfonate addition salt yielded 0.88 g. of the desired product. m.p. 192° C. 1H NMR (DMSO-d6, 300 MHz) δ1.7-2.0 (m, 4H), 2.3 (s, 3H), 2.4-3.6 (m, 9H), 3.03 (d, 3H), 3.79 (s, 3H), 6.84 (d, 1H), 6.90 (d, 1H), 7.16 (t, 1H), 7.85 (dd, 1H), 8.1 (m, 2H), 8.96 (m, 2H), 9.1 (bs, 1H). Anal calcd for C24H31N3O4S: C, 62.99; H, 6.83; N, 9.18. Found: C, 62.79; H, 6.96; N, 9.00.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CCN(CC)CC.[C:20]1([CH2:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:27](=[O:28])[CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Br)ccc1NC(=O)Cc1ccccc1
Reaction time: 27 h

Procedure:
To a mixture of methyl 2-amino-5-bromobenzoate (9.00 g, 39.1 mmol) and Et3N (7.6 mL, 54.8 mmol) in CH2Cl2 (90 mL) was added 2-phenylacetyl chloride (7.26 g, 46.9 mmol) at 4° C. dropwise. After completion of the addition, the cooling bath was removed and the mixture was stirred for 27 hours. TLC showed some of the starting material methyl 2-amino-5-bromobenzoate still remained. More 2-phenylacetyl chloride (1.88 g, 12.2 mmol) and Et3N (2.2 mL, 15.9 mmol) were added, and the mixture was stirred overnight. K2CO3 (aqueous) was added, the organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water, dried (Na2SO4), filtered, and concentrated in vacuo. CH3CN (100 mL) was added, and the precipitated solid was filtered, washed with Et2O, and dried to give the title compound. The filtrate was concentrated in vacuo, and the solid was filtered, washed with Et2O, and dried to give more title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[N:11][CH:10]=[C:9]2[C:4]=1[C:5]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C@@H:21]([NH:26]C(=O)OC(C)(C)C)[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:15][C:6]=1[N:7]([CH3:14])[C:8]2=[O:13].[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[NH2:26][C@@H:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:20][O:19][C:16]1[CH:17]=[CH:18][C:5]2[C:4]3[C:9](=[CH:10][N:11]=[CH:12][C:3]=3[O:2][CH3:1])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=2[CH:15]=1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]
Reactant: COc1cncc2c(=O)n(C)c3cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc3c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cncc2c(=O)n(C)c3cc(OC[C@@H](N)CC(C)C)ccc3c12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To the solution of (S)-tert-butyl (1-((1-methoxy-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (40 mg, 0.041 mmol) in DCM (0.9 mL) cooled to 0° C., TFA (0.2 mL, 2.60 mmol) was added dropwise and stirred for 5 min. The reaction mixture was warmed to rt and stirred for 3 h. The volatiles were removed under reduced pressure. The crude product was purified by prep HPLC using (0.1% TFA in ACN:water) to afford (S)-8-((2-amino-4-methylpentyl)oxy)-1-methoxy-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one, 2 TFA (17.11 mg, 0.028 mmol, 69% yield) as white solid. LC/MS (ESI) m/e 356.0 [(M+H)+, calcd for C20H26N3O3 356.2]; LC/MS retention time (method C): tR=1.82 min; HPLC retention time (method A): tR=9.44 min; HPLC retention time (method B): tR=9.78 min; 1H NMR (400 MHz, METHANOL-d4) δ ppm 9.17 (s, 1H), 9.14 (d, J=9.0 Hz, 1H), 8.54 (s, 1H), 7.09 (d, J=2.5 Hz, 1H), 7.02 (dd, J=9.0, 2.5 Hz, 1H), 4.21 (s, 3H), 4.19-4.15 (m, 1H), 4.04-3.95 (m, 2H), 3.78 (s, 3H), 1.97-1.80 (m, 1H), 1.51-1.42 (m, 2H), 1.04 (d, J=6.5 Hz, 3H), 1.02 (d, J=6.5 Hz, 3H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][C@H:12]([OH:14])[CH:11]=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:22](OC=C)(=[O:24])[CH3:23].C(Cl)(Cl)Cl>COC(C)(C)C>[Si:1]([O:8][CH:9]1[CH2:13][CH:12]([O:14][C:22](=[O:24])[CH3:23])[CH:11]=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C=C[C@@H](O)C1
Reactant: C=COC(C)=O
Solvent: COC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)OC1C=CC(O[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 51.1 %

Procedure:
Cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol (10.0 g, 46.6 mmol, prepared in example 3a) is dissolved in tert-butyl methyl ether (60 mL, anhydrous). To the solution is added triethylamine (4.5 mL, 32.3 mmol), pancreatin (30 g, available from Sigma Chemical Company), and vinyl acetate (22 mL, 239 mmol). The reaction is allowed to stir for 7 hours at room temperature. The reaction is then filtered through diatomaceous earth and the filtrate is concentrated under vacuum. The products are separated by chromatography on silica gel (5% to 20% ethyl acetate/hexane) to provide (-)-acetic acid 4-tert-butyldimethylsilyloxy-cyclopent-2-enyl ester (B. 6.1 g, 51% yield, 99% ee), [α]D -0.2°, (c=0.52, chloroform) as a yellow oil and (-)-cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol (A, 4.7 g, 47% yield, >99% ee), [α]D -18.6°, (c=1.01, chloroform) as a yellow oil.
Reaction SMILES: [OH:1]S(O)(=O)=O.[CH2:6]([N:13]1[CH2:30][CH2:29][CH2:28][C:16]2([CH:21](C#N)[C:20](=[O:24])N[C:18](=[O:25])[CH:17]2C#N)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-:31].[Na+].Cl>O>[CH2:6]([N:13]1[CH2:30][CH2:29][CH2:28][C:16]([CH2:17][C:18]([OH:25])=[O:1])([CH2:21][C:20]([OH:24])=[O:31])[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=S(=O)(O)O
Reactant: [OH-]
Reactant: N#CC1C(=O)NC(=O)C(C#N)C12CCCN(Cc1ccccc1)CC2
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)CC1(CC(=O)O)CCCN(Cc2ccccc2)CC1
Temperature: 25 °C

Procedure:
65% H2SO4 (17.5 ml) was added to a solid powder of 9-benzyl-2,4-dioxo-3,9-diazaspiro[5.6]dodecane-1,5-dicarbonitrile (3.5 g, 10.4 mmol) and the reaction mixture was heated at reflux for 2 h. Then the reaction mixture was cooled to RT, water (6.1 ml) was added and it was again heated at reflux for 20 h. After cooling to 0° C., the reaction mixture was first basified to pH ˜10-12 using 40% NaOH solution and then acidified to pH ˜2-3 using 2 N HCl solution. The solvent was removed under reduced pressure and the residue was dried by azeotropic distillation with benzene. Residual benzene was removed under reduced pressure to afford the dry solid product which was used in the next step without further purification.