Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.[CH:15]1(Br)[CH2:19][CH2:18][CH2:17][CH2:16]1>C(#N)C>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:9]=1
Reactant: BrC1CCCC1
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1cccc(OC2CCCC2)c1
Temperature: 25 °C

Procedure:
Potassium carbonate (400 mg, 2.8 mmol) was added to 3-Bromophenol (500 mg, 2.8 mmol) dissolved in acetonitrile and the mixture was refluxed for 1 h and cooled to RT. cyclopentyl bromide (430 mg, 2.8 mmol) was added and the mixture refluxed again overnight. Work up (H2O/EtOAc) and purification afforded the title compound as a pale-yellow liquid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.11 (t, J 8.3, 1H), 7.05-7.00 (m, 2H), 6.82-6.76 (m, 1H), 4.76-4.68 (m, 1H), 1.94-1.73 (m, 6H), 1.65-1.54 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9](=O)[CH:10]([CH3:12])[CH3:11].[N:14]([O-])=O.[Na+].O.O.[Sn](Cl)Cl.[OH-].[Na+]>O.Cl>[OH:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[NH:1][N:14]=[C:9]2[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)C(=O)c1cc(O)ccc1N
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CC(C)c1n[nH]c2ccc(O)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
A solution of 900 mg (5.02 mmol) of 1-(2-amino-5-hydroxyphenyl)-2-methyl-1-propanone in 30 ml of half-conc. hydrochloric acid is treated slowly at −5° C. with a solution of 364 mg (5.27 mmol) of sodium nitrite in 15 ml of water and, after addition is complete, stirred at this temperature for 30 min. A solution of 2.266 g (10.04 mmol) of tin(II) chloride dihydrate in 15 ml of conc. hydrochloric acid is then added dropwise to the reaction mixture at −5° C. and the reaction is slowly warmed to room temperature. The mixture is neutralized using 45% strength sodium hydroxide solution, filtered off through kieselguhr, washed with ethyl acetate, and the organic phase is dried over sodium sulphate, concentrated in vacuo and dried. 370 mg (36%) of 5-hydroxy-3-isopropyl-1H-indazole are obtained.
Reaction SMILES: [CH2:1]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:16][C:17]([O:20][C:21](ON=C(C1C=CC=CC=1)C#N)=[O:22])([CH3:19])[CH3:18]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[O:20]([C:21]([NH:13][C:12]1[CH:14]=[CH:15][C:9]([CH2:1][C:2]2[CH:3]=[CH:4][C:5]([NH2:6])=[CH:7][CH:8]=2)=[CH:10][CH:11]=1)=[O:22])[C:17]([CH3:19])([CH3:18])[CH3:16]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: Nc1ccc(Cc2ccc(N)cc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccc(Cc2ccc(N)cc2)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 553 %

Procedure:
This synthesis again starts with a monoprotected diamine. To a solution consisting of 8.0 g (40 mmol) 4,4'-methylenedianiline in 60 ml dry chloroform and 0.85 ml triethylamine is added dropwise a solution of 1 g BOC-ON dissolved in 20 ml chloroform. This reaction is allowed to stir at room temperature for 6 days. The reaction mixture is then filtered and the filtrate evaporated to a solid. This solid is then purified by silica gel column chromatography (70% petroleum ether/30% ethyl acetate as eluant) to give 6.7 g (55%) of N-(t-butoxylcarbonyl)-4,4'methylenedianiline.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH3:15])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:15][C:10]1[CH:9]=[C:8]([NH:7][C:6](=[O:16])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:13]=[CH:12][C:11]=1[O:14][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)ccc1O
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)OC(C)(C)C)ccc1Oc1ccc([N+](=O)[O-])cn1
Temperature: 80 °C
Reaction time: 4 h
Yield: 78.1 %

Procedure:
To a DMF (50 ml) solution of tert-butyl(4-hydroxy-3-methylphenyl)carbamate (5.00 g) was added 2-chloro-5-nitropyridine (3.91 g) and potassium carbonate (4.64 g). After stirring at 80° C. for 4 hours, the mixture was concentrated under reduced pressure. The residue was diluted in AcOEt and water, and extracted with AcOEt. The organic layer was washed with water, saturated aqueous NaCl, dried over anhydrous Na2SO4 and concentrated under reduced pressure. To the residue were added Et2O and the mixture was stirred at room temperature for 2 hours. The resulting precipitate was collected by filtration to afford the title compound (6.04 g) as a brown powder.
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[CH:11]=[C:10]([C:12]([OH:14])=O)[N:9]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:8]=1.N1C=CC=C(C)C=1.[Cl:29][C:30]1[CH:41]=[C:40]([CH3:42])[C:33]2[NH:34]C(=O)[O:36][C:37](=O)[C:32]=2[CH:31]=1>C(#N)C.O>[Br:6][C:7]1[CH:11]=[C:10]([C:12]2[O:14][C:37](=[O:36])[C:32]3[CH:31]=[C:30]([Cl:29])[CH:41]=[C:40]([CH3:42])[C:33]=3[N:34]=2)[N:9]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:8]=1
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: Cc1cc(Cl)cc2c(=O)oc(=O)[nH]c12
Agent: CS(=O)(=O)Cl
Solvent: Cc1cccnc1
Solvent: CC#N
Solvent: O
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Temperature: -2.5 °C
Reaction time: 0.08 h
Yield: 86.7 %

Procedure:
To a solution of methanesulfonyl chloride (5.0 mL, 7.4 g, 65 mmol) in acetonitrile (55 mL) at −5° C. was added dropwise a solution of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (see WO 03/015519 for preparation) (93.6% purity, 16.16 g, 50.0 mmol) and 3-picoline (8.3 mL, 7.9 g, 85 mmol) in acetonitrile (50 mL) over five minutes while maintaining the temperature at about −5 to 0° C. A slurry formed during the addition. The mixture was stirred for 5 minutes at this temperature, and then 6-chloro-8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (99.0% purity, 11.22 g, 52.5 mmol) was added all at once, and the residue was rinsed with acetonitrile (10 mL). To the reaction mixture was added 3-picoline (8.3 mL, 7.9 g, 85 mmol) dropwise in 5 minutes at −5 to 0° C. After stirring for 15 minutes at −5 to 0° C., the reaction mixture was heated to 50° C. and stirred 4 hours. Then the reaction mixture was cooled to room temperature, water (30 mL) was added dropwise and the mixture was stirred 15 minutes. The mixture was filtered, and the solids were re-slurried sequentially with 4:1 acetonitrile-water (2×40 mL) and acetonitrile (3×40 mL), and then dried under nitrogen to afford the title product as a light yellow powder, 20.95 g (93.6% purity by HPLC, 86.7% yield calculated based on the purity).
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.[NH2:13][C@@H:14]1[C:32](=[O:33])[N:16]2[C:17]([C:29]([OH:31])=[O:30])=[C:18]([CH:21]([S:23][C:24]3[NH:28][N:27]=[N:26][N:25]=3)[CH3:22])[CH2:19][S:20][C@H:15]12>CO>[C:2]1([CH:12]([O:30][C:29]([C:17]2[N:16]3[C:32](=[O:33])[C@@H:14]([NH2:13])[C@H:15]3[S:20][CH2:19][C:18]=2[CH:21]([S:23][C:24]2[NH:25][N:26]=[N:27][N:28]=2)[CH3:22])=[O:31])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.09 g of p-toluenesulphonic acid monohydrate are added to a suspension of 5.0 g of 7β-amino-3-(1-methyl-5-tetrazolylthiomethyl)-3-cephem-4-carboxylic acid (U.S. Pat. No. 3,516,997) in 200 ml of methanol, whilst stirring; this slowly produces a clear solution, which is concentrated under reduced pressure. Diethyl ether is added and the p-toluenesulphonic acid salt of 7β-amino-3-(1-methyl-5-tetrazolylthiomethyl)-3-cephem-4carboxylic acid is filtered off. The salt is dissolved in 100 ml of dioxane and 2.5 g of diphenyldiazomethane are added in portions to the solution. The mixture is stirred for 18 hours at room temperature and concentrated under reduced pressure; 100 ml of an 0.1 N aqueous sodium bicarbonate solution are added to the residue and the mixture is extracted with twice 100 ml of ethyl acetate. The organic extracts are washed successively with water and with a saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. The crystallisation from diethyl ether gives 7β-amino-3-(1-methyl-5-tetrazolylthiomethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester, thin layer chromatogram (silica gel): Rf=0.21 (system: chloroform/ethyl acetate/acetic acid, 80:19:1); ultraviolet absorption spectrum (ethanol): λmax =269 mμ (ε=6,400); infrared absorption spectrum (in methylene chloride); characteristic bands at 2.93μ, 5.60μ and 6.15μ.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[N:18][CH:19]=[C:20](Br)[CH:21]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].[C:25]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([C:32]3[CH:33]=[CH:34][C:29]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:30][CH:31]=3)[CH:21]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cncc(Br)c1)N2
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
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: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cncc(-c3ccc(C(C)(C)C)cc3)c1)N2
Yield: 99.4 %

Procedure:
To a mixture of 2-(5-bromo-pyridin-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (778 mg, 2 mmol), 4-tert-butylphenylboronic acid (358 mg, 2 mmol) and tetrakis(triphenylphosphine)palladium(0) (232 mg, 0.2 mmol) in dioxane (10 mL) was added 2 M sodium carbonate solution in water (2 mL). The resulting mixture was subjected to microwave irradiation for 1 h at 110° C. The mixture was diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL×2), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-[5-(4-tert-butyl-phenyl)-pyridin-3-yl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (880 mg, 99%) as a yellow solid: LC/MS m/e calcd for C29H34N2O2 (M+H)+: 443.61, observed: 443.2.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:15]=[C:14](F)[CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].[CH2:17]([O:24][C:25]1[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([O:24][C:25]1[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=1)[O:31][C:14]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([Cl:7])[CH:15]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Oc1cccc(OCc2ccccc2)c1
Reactant: O=Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2cccc(OCc3ccccc3)c2)cc1Cl
Temperature: 150 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
Potassium carbonate (5.53 g) was added to a DMF solution (70 ml) of 2-chloro-4-fluorobenzaldehyde (3.35 g) and 3-benzyloxyphenol (4.23 g) and the solution was stirred for 3 hours while heated to 150° C. The reaction mixture was decanted into water and was extracted with ethyl acetate. The organic phase was sequentially washed with water and a saturated aqueous solution of sodium chloride and was dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1). In this manner, the desired product (6.73 g) was obtained as a colorless powder.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:31]=[CH:30][C:7](/[CH:8]=[C:9]2/[C:10](=[O:29])[N:11]([CH2:15][C:16]3[CH:28]=[CH:27][C:19]([C:20]([O:22]C(C)(C)C)=[O:21])=[CH:18][CH:17]=3)[C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2].NCCN1C(=O)C(CC2C=CC(OCC)=CC=2)SC1=O>>[CH2:1]([O:3][C:4]1[CH:31]=[CH:30][C:7](/[CH:8]=[C:9]2/[C:10](=[O:29])[N:11]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:27][CH:28]=3)[C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(/C=C2\SC(=O)N(Cc3ccc(C(=O)OC(C)(C)C)cc3)C2=O)cc1
Agent: CCOc1ccc(CC2SC(=O)N(CCN)C2=O)cc1
Product: CCOc1ccc(/C=C2\SC(=O)N(Cc3ccc(C(=O)O)cc3)C2=O)cc1
Yield: 96.4 %

Procedure:
The title compound 28q was prepared by deprotection of tert-butyl group of compound 28p (100 mg, 0.23 mmol). Deprotection following the procedure of compound 6 gave the title compound 28q as a white solid (85 mg, 97.3%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:9][CH2:10][C:11]([O-])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(C)(C)C)=O>C(OCC)(=O)C.CCCCCCC>[C:1]([O:5][C:6]([N:8]([CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)[CH2:9][CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCC(=O)[O-])C1CCCC1
Agent: CC(C)(C)OC=O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CCCO)C1CCCC1

Procedure:
This compound was prepared from N-tert-butoxycarbonyl-3-cyclopentylamino-propanoate (3a, 2.28 g, 8.0 mmol) using the procedure described in Example 2b. Yield: 1.34 g (69%). ESI-MS: 244.2 (M+H)+, 266.3 (M+Na)+, 188.2 (M+H—C4H8)+, 144.2 (M+H-Boc)+. Rf (silica gel; ethyl acetate/heptane, 1:4, v/v): 0.30.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.[N:11]([O-])=[O:12].[Na+]>C(O)(=O)C.O>[N:11]([N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:1][CH2:2][CH2:3]1)=[O:12]
Reactant: O=N[O-]
Reactant: c1ccc2c(c1)NCCS2
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=NN1CCSc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 101.1 %

Procedure:
To a solution of 3,4-dihydro-2H-1,4-benzothiazine (50.0 g, 330.8 mmol) in acetic acid (170 mL.), cooled at −10° C. in an ice/acetone bath, was added sodium nitrite (27.4 g, 397.1 mmol) in 75 mL of water over 35 min. After the addition, the mixture was warmed to room temperature and stirred for additional 1.5 hours. Cold water (150 mL) was added and the resulting mixture was extracted with dichloromethane (4×250 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give 4-nitroso-3,4-dihydro-2H-1,4-benzothiazine as a semi-solid (60.26 g, 101%), which was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ2.99-3.05 (m, 2H), 4.16-4.24 (m, 2H), 7.15-7.31 (m, 3H), 7.88-7.97 (m, 1H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:10]([CH3:12])([CH3:11])[C:9](=[O:13])[N:8]2[CH:14]2[CH:21]3[CH2:22][C:17]4([C:24](O)=[O:25])[CH2:18][CH:19]([CH2:23][CH:15]2[CH2:16]4)[CH2:20]3)=[CH:4][CH:3]=1.O.OC1C2N=N[NH:36]C=2C=CC=1.CCN=C=NCCCN(C)C.Cl.N>ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:10]([CH3:12])([CH3:11])[C:9](=[O:13])[N:8]2[CH:14]2[CH:21]3[CH2:22][C:17]4([C:24]([NH2:36])=[O:25])[CH2:18][CH:19]([CH2:23][CH:15]2[CH2:16]4)[CH2:20]3)=[CH:27][CH:28]=1
Reactant: CC1(C)C(=O)N(C2C3CC4CC2CC(C(=O)O)(C4)C3)N1Cc1ccc(F)cc1
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: ClCCl
Product: CC1(C)C(=O)N(C2C3CC4CC2CC(C(N)=O)(C4)C3)N1Cc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 24.9 %

Procedure:
A solution of 4-[2-(4-fluorobenzyl)-3,3-dimethyl-4-oxo-1,2-diazetidin-1-yl]adamantane-1-carboxylic acid (20.0 mg, 0.0520 mmol) prepared in Example 90 in dichloromethane (1 mL) was added with hydroxybenzotriazole monohydrate (12.0 mg, 0.0890 mmol), WSC.HCl (20.0 mg, 0.100 mmol), 30% aqueous solution of ammonia (0.1 mL) at room temperature, and the resultant was stirred at the same temperature for 30 minutes. The reaction solution was added with water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The obtained residue was purified using Preparative Thin-Layer chromatography (ethyl acetate), and the title compound (5.00 mg, 24.9%) was obtained as a white crystalline powder.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH2:31]([NH:33][CH2:34][CH2:35][CH3:36])[CH3:32]>>[CH2:31]([N:33]([CH2:34][CH2:35][CH3:36])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)[CH3:32]
Reactant: CCCNCC
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Product: CCCN(CC)CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1

Procedure:
The product from Example 44E and ethyl(propyl)amine were processed as described in Example 1D to provide the titled compound. 1HNMR (300 MHz, CD3OD) δ8.70 (m, 1H), 8.23 (d, J=1.8 Hz, 1H), 7.98 (m, 3H), 7.58 (d, J=8.7 Hz, 1H), 6.85 (s, 1H), 3.2-3.8 (m, 14H), 3.20 (m, 2H), 1.80 (m, 2H), 1.38 (t, J=7.5 Hz, 3H), 1.05 (t, J=7.5 Hz, 3H); MS (DCI) m/z 422 (M+H)+;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26][NH2:27])=[CH:23][CH:24]=2)[CH:19]=[CH:18][N:17]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[NH2:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26][NH:27][C:12]([C@@H:9]3[CH2:10][CH2:11][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:14])=[CH:23][CH:24]=2)[CH:19]=[CH:18][N:17]=1
Reactant: NCc1ccc2c(N)nccc2c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Yield: 97.2 %

Procedure:
2.00 g 1-Tert.butoxycarbonyl-azetidin-2(S)-carboxylic acid, 1.70 g 1-amino-6-aminomethyl-isoquinolin, 3.50 g TBTU were dissolved in 40 mL DMF. 3.55 mL N-methylmorpholin was added slowly with stirring. The solution was applied to a reversed-phase chromatography column (length 100 mm, diameter 14 mm; Merck Lichroprep RP-18, 15-25 μ). Elution was started with 25 mL of methanol/water containing 0.3% acetic acid (10:90), then a linear gradient to pure methanol over a period of 75 mL was applied followed by 50 mL of pure methanol. Fraktions of 5 mL each were sampled. The solvent was evaporated to give 3.4 g of the tile compound. MS: 357.
Reaction SMILES: F[B-](F)(F)F.C(N(C(C)C)[CH:10]=[N+:11]([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])(C)C.CC(C)([O-])C.[K+].[C:27]([O:31][C:32]([N:34]1[C:38](=[O:39])[CH2:37][CH2:36][C@H:35]1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:43][CH:42]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28].C(OC(C)C)(=O)C>C1COCC1>[C:27]([O:31][C:32]([N:34]1[C@H:35]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)=[CH:45][CH:46]=2)[CH2:36]/[C:37](=[CH:10]\[N:11]([CH:12]([CH3:13])[CH3:14])[CH:15]([CH3:16])[CH3:17])/[C:38]1=[O:39])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)N(C=[N+](C(C)C)C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: F[B-](F)(F)F
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)C
Product: CC(C)N(/C=C1\C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O)C(C)C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
N,N,N′,N′-tetraisopropylformamidinium tetrafluoroborate (2.13 g, prepared according to Example 11) is added to a 1 M solution of potassium-tert-butoxide in THF (5.69 ml). The resulting mixture is then stirred for 1 h at 50° C. (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (8-a, R1=Boc) (500 mg) is then added and the mixture stirred at 60° C. for 1 h. The mixture is then cooled to room temperature and diluted by addition of 10 ml isopropyl acetate. The mixture is then filtered through silica and concentrated in vacuo to afford (R)-5-biphenyl-4-ylmethyl-3-[1-diisopropylamino-meth-(E)-ylidene]-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (7-a, R1=Boc, R6=iPr, R7=iPr). Spectroscopic data as for Example 19, Method 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1.FC1C=C(NC2CCNCC2)C=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2F)CC1
Agent: Fc1cccc(NC2CCNCC2)c1
Product: Fc1ccccc1NC1CCNCC1

Procedure:
The title compound was prepared from 1,1-dimethylethyl 4-[(2-fluorophenyl)amino]-1-piperidinecarboxylate (D15) using a method similar to that described for D4 in Description 4.
Reaction SMILES: C([N:3]([C:29](=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.Cl[CH2:39][C:40]([NH:42][CH:43]1[CH2:45][CH2:44]1)=O>>[CH:43]1([NH:42][CH2:40][CH2:39][O:10][C:8]2[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:29][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[CH:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:6][CH:7]=2)[CH2:45][CH2:44]1
Reactant: O=C(CCl)NC1CC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCNC3CC3)cc2)c1
Yield: 32.2 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N-cyclopropylacetamide (13 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (3.9 mg) was obtained.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([C:10]1[C:15]([NH:16][C:17]([C:19]2[S:20][CH:21]=[C:22]([CH:24]=[CH2:25])[N:23]=2)=O)=[C:14]([Cl:26])[C:13]([O:27][CH3:28])=[CH:12][CH:11]=1)(=[O:9])[CH3:8]>C(O)(C)(C)C.C(OCC)C>[Cl:26][C:14]1[C:13]([O:27][CH3:28])=[CH:12][CH:11]=[C:10]2[C:15]=1[N:16]=[C:17]([C:19]1[S:20][CH:21]=[C:22]([CH:24]=[CH2:25])[N:23]=1)[CH:8]=[C:7]2[OH:9]
Reactant: C=Cc1csc(C(=O)Nc2c(C(C)=O)ccc(OC)c2Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: C=Cc1csc(-c2cc(O)c3ccc(OC)c(Cl)c3n2)n1
Temperature: 100 °C
Yield: 73 %

Procedure:
Potassium tert-butoxide (2.13 g, 2.2 eq.) was added to a suspension of compound 272 (2.91 g, 1 eq.) in tert-butanol (30 mL). The reaction mixture was heated to 100° C. for 5 hrs. After one night at room temperature, the mixture was diluted with diethyl ether and the precipitate filtered, washed with diethyl ether, and solubilized in water. The pH was adjusted to 6-7 by addition of 1N HCl and the precipitate was filtered, washed with water, and triturated with diethyl ether to yield compound 273 in 73% yield. 1H NMR (CDCl3, 400 MHz): δ (ppm) 4.06 (s, 3H), 5.54 (d, J=10.82 Hz, 1H), 6.25 (d, J=17.31 Hz, 1H), 6.74 (s, 1H), 6.79 (dd, J=17.31 and 10.82 Hz, 1H), 7.06 (d, J=9.10 Hz, 1H), 7.32 (s, 1H), 8.28 (d, J=9.10 Hz, 1H), 9.97 (br s, 1H).