Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:25]([C:27]([CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1)=[O:28])[NH2:26].[CH2:42]([O:49][N:50]1[C:56](=[O:57])[N:55]2[CH2:58][C@H:51]1[CH2:52][CH2:53][C@H:54]2[C:59](O)=[O:60])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:42]([O:49][N:50]1[C:56](=[O:57])[N:55]2[CH2:58][C@H:51]1[CH2:52][CH2:53][C@H:54]2[C:59]([NH:26][NH:25][C:27]([CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1)=[O:28])=[O:60])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
HATU (3.3 g, 8.7 mmol) and tert-butyl 4-(hydrazinecarbonyl)piperidine-1-carboxylate (2.29 g, 9.42 mmol) were added to a 0° C. solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (2 g, 7.25 mmol) in CH2Cl2 (50 mL), followed by the addition of DIPEA (2.8 g, 21.8 mmol). The reaction mixture was stirred at 0° C. for 12 hrs then washed with water and saturated sodium chloride, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (gradient elution 1%-10% MeOH/CH2Cl2) to give tert-butyl 4-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinecarbonyl)piperidine-1-carboxylate as a white solid. (2.2 g, 62%). ESI-MS (EI+, m/z): 502.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:5]=[C:6]([Cl:23])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1.CI.[C:32](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:5]=[C:6]([Cl:23])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:32])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=1
Reactant: O=C([O-])[O-]
Reactant: FC(F)(F)c1ccc(NCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(CCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)c1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 68.3 %

Procedure:
A mixture of 0.37 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(4-(trifluoromethyl) phenylamino)propyloxy)benzene, 0.1 ml of methyl iodide, 0.12 g of potassium carbonate and 10 ml of N,N-dimethylformamide was stirred at 50° C. for 3 hours. After cooling to room temperature, the reaction mixture was poured into ice-water, and extracted twice with 50 ml of ethyl acetate. The combined ethyl acetate layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.26 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(methyl(4-(trifluoromethyl)phenyl)amino)propyloxy)benzene (68% yield), nD25.5 1.5593.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:25][C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][CH:27]=2)[C:9]2[S:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[N:13]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:58][O:59][C:60](=[O:64])[CH2:61][CH2:62][NH2:63]>CN(C=O)C.C(OCC)(=O)C>[CH3:58][O:59][C:60](=[O:64])[CH2:61][CH2:62][NH:63][C:30](=[O:32])[C:29]1[CH:33]=[CH:34][C:26]([CH2:25][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[S:10][CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:24])[F:23])=[CH:18][CH:19]=3)[N:13]=2)=[CH:27][CH:28]=1
Reactant: COC(=O)CCN
Reactant: O=C(O)c1ccc(CN(c2ccc(Cl)cc2)c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCNC(=O)c1ccc(CN(c2ccc(Cl)cc2)c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 109.3 %

Procedure:
4-({(4-Chlorophenyl)-[4-(4-trifluoromethoxyphenyl)thiazol-2-yl]amino}methyl)benzoic acid (47 g, 93 mmol) was dissolved in DMF (500 mL) and 1-hydoxybenzotriazole (18.9 g, 140 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (26.7 g, 140 mmol) were added and the mixture was stirred at room temperature for 1.5 hours. Di PEA (i 9.1 mL, 111 mmol) and 3-aminopropionic acid methyl ester hydrochloride (15.5 g, 111 mmol) were added to the mixture and the resulting mixture was stirred at room temperature for 16 hours. Ethyl acetate (500 mL) was added and the mixture was washed with water (500 mL). The aqueous phase was extracted with ethyl acetate (500 mL). The combined organic phases were washed with water (2×500 mL) and saturated aqueous ammonium chloride (2×300 mL), dried (Na2SO4) and concentrated in vacuo to afford 60 g (quant.) of crude 3-[4-({(4-chlorophenyl)-[4-(4-trifluoromethoxyphenyl)thiazol-2-yl]amino}methyl)benzoylamino]propionic acid methyl ester as a solid. Recrystallisation from ethanol afforded 31.2 g (55%) pure product.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(C)(C)C.C(N(CC)CC)C.C([Li])CCC.[CH3:37][C@H:38]1[C@@H:42]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[O:41][C:40](=[O:49])[NH:39]1.C(OC(=O)C(C)(C)C)(=O)C(C)(C)C>C1COCC1>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]([N:39]2[C@@H:38]([CH3:37])[C@@H:42]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[O:41][C:40]2=[O:49])=[O:17])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Reactant: O=C(O)Cc1ccc(Oc2ccccc2)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: CC(C)(C)C(=O)OC(=O)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1C(=O)Cc1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
To a solution containing 4-phenoxyphenylacetic acid (10.0 g, 43.8 mmol) in THF (62.6 mL) at -78° C. was added pivaloyl chloride (5.49 g, 45.6 mmol) followed by triethylamine (4.61 g, 45.6 mmol). The mixture was stirred at -78° C. for 15 minutes, at 0° C. for 1 hour, then recooled to -78° C. In a separate flask, 2.5M n-butyllithium (20 mL, 50 mmol) was added to a solution of (4S,5R)-(-)-4-methyl-5-phenyl-2-oxazolidinone (8.86 g, 50 mmol) in THF (100 mL) at -78° C., stirred for 15 minutes, then transferred to the flask containing pivalic anhydride via cannula. The mixture was stirred 15 minutes at -78° C. then at room temperature for 18 hours. The solvent was removed, and the residue was partitioned between diethyl ether (500 mL) and 1N HCl (500 mL). The organic layer was dried (MgSO4), filtered and concentrated to provide a light yellow solid. The solid was chromatographed with 10% ethyl acetate in hexane to yield 10.9 g (64%) of the title compound as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[N:9]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([CH:34]3[CH2:36][CH2:35]3)=[CH:26][CH:25]=2)[C:10]([S:13][C:14]([CH3:23])([CH3:22])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:11][N:12]=1.[C:37]1(B(O)O)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C1(C)C=CC=CC=1.C1COCC1.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>[CH:34]1([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]([N:9]3[C:8]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[N:12][N:11]=[C:10]3[S:13][C:14]([CH3:23])([CH3:22])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:25][CH:26]=2)[CH2:36][CH2:35]1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
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
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nnc(-c2ccccc2)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 90 °C
Yield: 73.7 %

Procedure:
Aqueous sodium carbonate solution (1M, 614 μL, 0.614 mmol) was added to a solution of tert-butyl 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoate (60 mg, 0.123 mmol), phenylboronic acid (17 mg, 0.135 mmol) and Pd(PPh3)4 (28 mg, 0.024 mmol) in toluene (2 mL) and THF (1 mL). The mixture was bubbled under nitrogen for 5 mins and then heated to 90° C. under nitrogen for 20 hours. After cooling to room temp, water (20 mL) was added and the aqueous layer extracted with dichloromethane (2×20 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, concentrated and purified by column chromatography (40% EtOAc/hexanes) to give tert-butyl 2-(4-(4-cyclopropylnaphthalen-1-yl)-5-phenyl-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoate as a brown oil (44 mg, 73%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[S:5]1(=[O:7])=[O:6].Cl[CH2:17][C:18]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[O:19]>CN(C)C=O>[OH:15][C:14]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[S:5](=[O:7])(=[O:6])[N:4]([CH3:3])[C:17]=1[C:18]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[O:19]
Reactant: CN1C(=O)c2ccccc2S1(=O)=O
Reactant: COCCOC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Reaction time: 2 h

Procedure:
In a manner similar to Example 1B, 1.0 g. of 91% sodium hydride was added over a period of one hour to a solution of 3.0 g. (0.015 mole) of N-methylsaccharin and 2.6 g. (0.017 mole) of 2-methoxyethyl chloroacetate in 15 ml. of dimethylformamide at 35° C. The exothermic reaction (55° C.) was allowed to stir for 2 hours after the addition was complete, and was then quenched in 5% hydrochloric acid solution and the product extracted with methylene chloride. The residue, remaining after the solvent was removed, was dissolved in 10 ml. of warm dimethylformamide and added to 100 ml. of 2% hydrochloric acid. The cooled suspension was stirred for 30 minutes and filtered. Drying of the filtered material gave 1.12 g. (24%) of the product identical with that prepared in Example 1B.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[S:3]([N:6]1[CH:10]=[C:9]([CH:11]([OH:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=[C:7]1[Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])(=[O:5])=[O:4].[H-].[Na+].[CH3:30]I>C1COCC1.CCOC(C)=O>[CH3:27][N:2]([CH3:1])[S:3]([N:6]1[CH:10]=[C:9]([CH:11]([O:19][CH3:30])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:8]=[C:7]1[Si:20]([C:23]([CH3:24])([CH3:26])[CH3:25])([CH3:21])[CH3:22])(=[O:4])=[O:5]
Reactant: CI
Reactant: CN(C)S(=O)(=O)n1cc(C(O)Cc2ccccc2)nc1[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(Cc1ccccc1)c1cn(S(=O)(=O)N(C)C)c([Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-(tert-butyl-dimethyl-silanyl)-4-(1-hydroxy-2-phenyl-ethyl)-imidazole-1-sulfonic acid dimethylamide (160 mg) at r.t. in THF (5 ml) under an argon atmosphere was added NaH (18 mg; 55% dispersion in mineral oil) in one portion. After 1 hour stirring at r.t., MeI (0.04 ml) was added and stirring at r.t. was continued overnight. The mixture was diluted with EtOAc and washed with H2O. The aqueous phase was back extracted with EtOAc. The combined organics were washed with H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane→cyclohexane/EtOAc 65:35) to give 2-(tert-butyl-dimethyl-silanyl)-4-(1-methoxy-2-phenyl-ethyl)-imidazole-1-sulfonic acid dimethylamide (111 mg) as light yellow viscous oil. MS (ISP): 424.3 ([M+H]+)
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=[O:11].CN(C=O)C.[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>CCOC(C)=O>[Cl:23][CH2:22][CH2:21][CH2:20][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=[O:11]
Reactant: ClCCCBr
Reactant: O=c1ccc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1ccc2ccccc2n1CCCCl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 40.8 %

Procedure:
A 7 mL vial was charged with 1H-quinolin-2-one (0.62 g, 4.2 mmol), 4 mL dry DMF and NaH (60% in oil, 0.200 g, 5.1 mmol). The mixture was stirred under a N2 atmosphere at rt for 45 min, and thereafter 1-bromo-3-chloropropane (0.42 mL, 4.2 mmol) was added and the reaction was stirred at rt overnight. The reaction was diluted with EtOAc (50 mL) and washed with water (15 mL). The water phase was extracted with EtOAc (25 mL) and the combined organic phase was dried (Na2SO4), filtered, concentrated under reduced pressure and the residue was purified by flash chromatography (SiO2; CH2Cl2) to yield the title compound (0.38 g, 41%), containing 15% of 1-(3-bromopropyl)-1H-quinolin-2-one. 1H NMR (CD3OD) δ 7.90 (d, J=9.4 Hz, 1H), 7.73-7.57 (m, 3H), 7.34-7.28 (m, 1H), 6.66 (d, J=9.4 Hz), 4.46 (t, J=7.4 Hz, 2H), 3.71 (t, J=6.4 Hz, 2H), 2.21-2.02 (m, 2H); 13C NMR (CD3OD) δ 163.2, 140.7, 138.8, 131.3, 129.3, 122.8, 121.4, 120.2, 114.4, 42.18, 40.2, 30.5.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([N+:22]([O-:24])=[O:23])=[CH:11][CH:10]=2)=[O:5])C.[OH-].[K+].Cl.[CH2:29]([OH:31])[CH3:30]>O>[CH2:29]([O:31][C:7]1[C:6]([C:4]([OH:5])=[O:3])=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:22]([O-:24])=[O:23])[CH:13]=2)[N:8]=1)[CH3:30]
Reactant: CCO
Reactant: CCOC(=O)c1c(Cl)nc2ccc([N+](=O)[O-])cc2c1-c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCOc1nc2ccc([N+](=O)[O-])cc2c(-c2ccccc2)c1C(=O)O
Temperature: 80 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
A solution of 2-chloro-6-nitro-4-phenyl-quinoline-3-carboxylic acid ethyl ester (10 mg, 0.028 mmol) was suspended in ethanol and treated with 3N KOH (0.1 ml, 10.7 Eq). The mixture was warmed to 80° C. for 24 h, then further 3N KOH (0.1 ml, 10.7 Eq.) was added and stirring at 80° C. was continued for further 24 h. The mixture was diluted with water and acidified to pH 1 with HCl 1N. The slurry was extracted with dichloromethane and the extracts were evaporated to yield the title compound (7.6 mg, 82%) as a white powder. MS (ESI): 339.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]1[C:16]2[CH:25]=[C:24]([C:26](O)=[O:27])[NH:23][C:17]=2[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=1.C(Cl)(=O)C(Cl)=O.C[N:41](C)C=O.[OH-].[NH4+]>ClCCl>[F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]1[C:16]2[CH:25]=[C:24]([C:26]([NH2:41])=[O:27])[NH:23][C:17]=2[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=1
Reactant: CN(C)C=O
Reactant: Cn1cc(-c2cc(S(C)(=O)=O)ccc2Oc2ccc(F)cc2F)c2cc(C(=O)O)[nH]c2c1=O
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2Oc2ccc(F)cc2F)c2cc(C(N)=O)[nH]c2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 965.6 %

Procedure:
To a solution of Example 252g (0.10 g, 0.21 mmol) in anhydrous dichloromethane (5 mL) was added oxalyl chloride (0.037 mL, 0.42 mmol) and dimethylformamide (0.816 μl, 10.5 μmol) The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated. The residue was redissolved in dichloromethane (5 mL) and treated with ammonium hydroxide (2 mL, 92 mmol) and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was partitioned between water (15 mL) and ethyl acetate (25 mL). The aqueous layer was extracted with additional ethyl acetate (2×15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was triturated with ethyl acetate and the resulting solid was filtered, washed with dichloromethane and dried under vacuo to provide the title compound (48 mg, 47% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.33 (s, 1H), 7.98 (s, 1H), 7.98-7.88 (m, 1H), 7.82 (s, 1H), 7.56-7.40 (m, 4H), 7.19 (m, 1H), 7.00 (d, J=8.8 Hz, 1H), 6.87 (s, 1H), 3.59 (s, 3H), 3.27 (s, 3H). MS (ESI+) m/z 474.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](CC3C=C(C=CC=3)C(O)=O)[C:11]3[CH:23]=[C:24](F)[C:25](F)=[CH:26][C:10]=3[N:9]=2)=[C:4](OCC2CCCC2)[CH:3]=1.C1(N)C(N)=CC=CC=1.[Br:44]C1C=C(Cl)C=CC=1C(O)=O>>[Br:44][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[C:8]1[NH:12][C:11]2[CH:23]=[CH:24][CH:25]=[CH:26][C:10]=2[N:9]=1
Reactant: O=C(O)c1cccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)c1
Reactant: O=C(O)c1ccc(Cl)cc1Br
Agent: Nc1ccccc1N
Product: Clc1ccc(-c2nc3ccccc3[nH]2)c(Br)c1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate c, from benzene-1,2-diamine (CAS Reg. No. 76179-40-3) and 2-bromo-4-chloro-benzoic acid (CAS Reg. No. 936-08-3). Light yellow solid (92%). MS (Turbo Spray): m/z=308.8 (M+H).
Reaction SMILES: [NH2:1][C@H:2]([C:18]([O:20][CH3:21])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[NH:22]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][C:24](O)=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:31][C:30]([CH3:33])([CH3:32])[O:29][C:27](=[O:28])[NH:22][CH2:23][C:24](=[O:25])[NH:1][C@H:2]([C:18]([O:20][CH3:21])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:9])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a solution of L-Lys(Z)OMe 40 (1.05 g, 2.6 mmol) in dry DMF (40 mL) was added Boc-GlyOH (494 mg, 2.8 mmol), HATU (977 mg, 2.57 mmol), and DIEA (2.03 mL, 11.7 mmol). The mixture was stirred at rt overnight. The solvent was then removed in vacuo and the residue was dissolved in EtOAc (100 mL) and washed with saturated NaHCO3 solution water and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude compound was purified on column of silica gel (2% MeOH/DCM) to give the subject compound (960 mg, yield 90%). Intermediate 41 was characterized by the following spectroscopic data: 1H NMR (DMSO-d6, 300 MHz) δ (ppm) 8.12 (t, 1H), 7.98 (t, 1H), 7.47-7.38 (m, 5H), 6.98 (t, 1H), 5.13 (s, 2H), 4.56 (m, 1H), 4.05 (d, 2H), 3.65 (s, 3H), 3.02 (m, 2H), 1.90 (m, 2H), 1.55 (m, 2H), 1.38 (s, 9H), 1.25 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([N:15]([CH3:17])[CH3:16])=[N:11][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[H-].[Na+].IC.[C:22](O)(=O)C>O1CCCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:22])[C:10]([N:15]([CH3:17])[CH3:16])=[N:11][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: CN(C)C(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(C)C(=N[N+](=O)[O-])N(C)Cc1ccc(Cl)nc1
Reaction time: 0.5 h

Procedure:
To a mixture of 0.24 g of 1-(6-chloro-3-pyridylmethyl)-3,3-dimethyl-2-nitroguanidine (Compound No. 6) and 6 ml of dry tetrahydrofuran (THF) was added 0.045 g of 60% sodium hydride (in mineral oil) at room temperature, followed by stirring for 30 minutes. A solution of 0.16 g of iodomethane in 1 ml of THF was added to the reaction mixture and allowed to react for 3 days. After adding 0.1 ml of acetic acid, the mixture was filtered to remove insoluble materials and the filtrate was concentrated. The residue was purified by a column chromatography [developing solvent: dichloromethanemethanol (20:1)] to obtain 0.17 g of 1-(6-chloro-3-pyridylmethyl)-1,3,3-trimethyl-2-nitroguanidine (Compound No. 14) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.Cl[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1>>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[CH2:25][O:24][CH:12]1[CH:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][O:1][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)=[CH:6][CH:7]=2)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: ClCc1ccccn1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOCc3ccccn3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 53 (c)] with 2-chloromethyl-pyridine there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-{4-[2-(pyridin-2-ylmethoxy)-ethoxy]-phenyl}-piperidine-1-carboxylate as a colourless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[S:18](=[O:20])(=[O:19])[CH2:17][CH2:16][C:15]([C:21]([O:23]C)=[O:22])=[CH:14][C:13]=3[CH:25]=2)[CH:2]=1.[C:26](=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[CH3:26][CH:17]1[CH2:16][C:15]([C:21]([OH:23])=[O:22])=[CH:14][C:13]2[CH:25]=[C:9]([O:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:10]=[CH:11][C:12]=2[S:18]1(=[O:20])=[O:19]
Reactant: COC(=O)C1=Cc2cc(OCc3cccnc3)ccc2S(=O)(=O)CC1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1CC(C(=O)O)=Cc2cc(OCc3cccnc3)ccc2S1(=O)=O
Temperature: 60 °C
Reaction time: 19 h
Yield: 75.8 %

Procedure:
Into a suspension of methyl 7-(3-pyridylmethoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (650 mg) in THF/methanol (6/3 ml) was added at room temperature an aqueous solution (1.4 ml) of potassium carbonate (415 mg), and the resulting mixture was stirred at 60° C. for 19 hours. Into this reaction mixture was added further an aqueous solution (0.7 ml) of potassium carbonate (207 mg), and the resulting mixture was stirred further at 60° C. for 3 days. After cooling to room temperature, 1 N hydrochloric acid was added to the reaction mixture until the pH was adjusted to 7-8, and the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain methyl 7-(3-pyridylmethoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (493 mg) as colorless crystals.
Reaction SMILES: ClCCl.[O:4]=[C:5]1[N:9]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:8]2[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=2[NH:6]1.C(Cl)(=O)C([Cl:23])=O>CN(C)C=O>[O:4]=[C:5]1[N:9]([CH2:10][CH2:11][CH2:12][C:13]([O:15][Cl:23])=[O:14])[C:8]2[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=2[NH:6]1
Reactant: O=C(O)CCCn1c(=O)[nH]c2ccccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(CCCn1c(=O)[nH]c2ccccc21)OCl
Temperature: 10 °C

Procedure:
Dichloromethane (3772 L) and then 4-(2-oxo-2,3-dihydrobenzimidazol-1-yl)butyric acid (525 kg; 2.4 kmol) were charged to a stirred-tank reactor, followed by N,N-dimethylformamide (21 L). The resulting mixture was cooled to 10° C. Afterward, oxalyl chloride (326.8 kg)) was dosed at 10-15° C. over 2-3 hours while stirring. The resulting mixture was then stirred at 15-20° C. for an additional 1-3 hours. All the above steps were conducted under a N2 atmosphere. Conversion was checked by in-process control (“IPC”).