Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][NH2:19]>ClCCl>[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][NH:19][S:11]([C:8]1[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=1)(=[O:13])=[O:12]
Reactant: CN(C)CCN
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(S(=O)(=O)NCCN(C)C)cc1
Temperature: 25 °C

Procedure:
4-Acetylaminobenzenesulfonyl chloride is introduced into dichloromethane and treated at room temperature with two equivalents of N,N-dimethylethylenediamine and stirred at room temperature until complete conversion can be determined (LCMS). For work-up, the solvent is distilled off, the oily residue is taken up in dichloromethane or ethyl acetate and the mixture is washed with NaHCO3 solution. The phases are separated and the aqueous phase is extracted once more with dichloromethane or ethyl acetate. The organic phases are dried using Na2SO4 and concentrated. The crude product thus obtained is reacted further without further purification. (MS-CI+: 286.0; LCMS Rt=2.542 min)
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]2[O:33][C:34]([CH:37]=[O:38])=[CH:35][CH:36]=2)=[CH:4][N:3]=1.[BH4-].[Na+]>CN(C)C=O.CO>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]2[O:33][C:34]([CH2:37][OH:38])=[CH:35][CH:36]=2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(-c4ccc(C=O)o4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(-c2csc3c(-c4ccc(CO)o4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 3.3 %

Procedure:
A mixture of N-{4-[4-amino-7-(5-formyl-2-furyl)thieno[3,2-c]pyridin-3-yl]-2-methoxyphenyl}-1-methyl-1H-indole-2-carboxamide (0.060 g, 0.12 mmol) and sodium borohydride (0.013 g, 0.344 mmol) in N,N-dimethylformamide (4 mL) and methanol (4 mL) was stirred at ambient temperature for 18 hours. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (10 mL) and 0.1 N hydrochloric acid (10 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were dried over anhydrous magnesium sulfate and the solvent was removed in vacuo. The residue was purified by preparative RP-HPLC (Rainin C18, 8 mm, 300 Å, 25 cm; 40% acetonitrile-0.1M ammonium acetate isocratic for 5 minutes, then 40-100% acetonitrile-0.1M ammonium acetate over 30 min, 21 ml/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyophilized to give the title compound (2.1 mg, 0.004 mmol) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[O:13](S(C(F)(F)F)(=O)=O)[S:14]([C:17]([F:20])([F:19])[F:18])(=O)=[O:15]>N1C=CC=CC=1>[F:18][C:17]([F:20])([F:19])[S:14]([O:1][C:2]1[C:3]2[CH2:4][CH2:5][CH2:6][C:7](=[O:12])[C:8]=2[CH:9]=[CH:10][CH:11]=1)(=[O:15])=[O:13]
Reactant: O=C1CCCc2c(O)cccc21
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: O=C1CCCc2c(OS(=O)(=O)C(F)(F)F)cccc21

Procedure:
A solution of 5-hydroxy-3,4-dihydronaphthalen-1(2H)-one (5 g, 30.8 mmol) in 30 mL of dry pyridine was cooled to −5° C. and Tf2O (10.4 g, 36.96 mmol) was added dropwise. The reaction was warmed to ambient temperaure slowly and stirred over night. Pyridine was distilled off under reduce pressure, and the residue was purified with silica gel cloumn chromatography to give 5-oxo-5,6,7,8-tetrahydronaphthalen-1-yl trifluoromethanesulfonate.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][N:4]=1.O.[Na].Cl[C:15]1[N:20]=[C:19]([OH:21])[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1>C(O)C.[Ni].O>[OH:21][C:19]1[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=[C:15]([NH:9][C:6]2[CH:5]=[N:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=2)[N:20]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1O
Reactant: CSc1ccc([N+](=O)[O-])cn1
Agent: [Ni]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CSc1ccc(Nc2ncc([N+](=O)[O-])c(O)n2)cn1

Procedure:
4.5 gm (0.0264 mol) of 2-methylthio-5-nitro-pyridine were hydrogenated at 50° C. and 5 bars pressure in ethanol in the presence of Raney nickel as the catalyst. After the catalyst had been filtered off and after evaporation of the filtrate in vacuo an oil was obtained. A solution of 6.84 gm (0.032 mol) of the sodium monohydrate salt of 2-chloro-4-hydroxy-5-nitro pyrimidine in 150 ml of water was added to the solution of this oil in water. The aqueous solution was heated for 30 minutes on a steam bath, and the resulting precipitate suction-filtered off, washed with water and dried. 4-Hydroxy-2-(6'-methylmercapto-3-pyridyl)amino-5-nitro-pyrimidine was obtained.
Reaction SMILES: [OH:1][C:2]1[C:3](=O)[CH:4]=[CH:5][C:6]([N:9]=[O:10])=[CH:7][CH:8]=1.[OH-].[NH4+:13]>>[NH2:13][C:3]1[C:2](=[O:1])[CH:8]=[CH:7][C:6]([N:9]=[O:10])=[CH:5][CH:4]=1
Reactant: [NH4+]
Reactant: O=Nc1ccc(O)c(=O)cc1
Agent: [OH-]
Product: Nc1ccc(N=O)ccc1=O

Procedure:
Conc. ammonium hydroxide solution (50 ml) is added dropwise to a suspension of 2-hydroxy-5-nitroso-2,4,6-cycloheptatrien-1-one [10 g, described by T. Nozoe et al., Sci. Repts. Tohoku Univ., 35, 274- 82 (1952), (CA 47 3291a)] collected and washed with water then acetone to give 2-amino-5-nitroso-2,4,6-cycloheptatrien-1-one.
Reaction SMILES: [F:1][CH:2]([F:8])[C:3](OCC)=[O:4].C[O-].[Na+].[F:12][C:13]1[CH:14]=[C:15]([C:21](=[O:23])[CH3:22])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].Cl>C(OC)(C)(C)C>[F:1][CH:2]([F:8])[C:3](=[O:4])[CH2:22][C:21]([C:15]1[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:13]([F:12])[CH:14]=1)=[O:23]
Reactant: CCOC(=O)C(F)F
Reactant: COc1ccc(C(C)=O)cc1F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Product: COc1ccc(C(=O)CC(=O)C(F)F)cc1F
Reaction time: 16 h

Procedure:
Ethyl difluoroacetate (4.06 g, 32.7 mmol) was dissolved in methyl t-butyl ether (50 mL). To the stirred solution was added 25 weight % sodium methoxide (7.07 g, 32.7 mmol) followed by 3'-fluoro-4'-methoxyacetophenone (5.0 g, 29.7 mmol). After stirring for 16 hours, 1N HCl (50 mL) was added. The organic layer was collected and washed with water (2×50 mL), dried over anhydrous MgSO4, filtered, and added to hexanes to precipitate a tan solid (7.0 g, 96%): mp 70°-72° C.
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)[CH2:3][CH:4]([CH3:6])[CH3:5].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[C:48]([C:52]1[CH:57]=[CH:56][C:55]([C:58]2[C:63]([CH3:64])=[CH:62][C:61](O)=[CH:60][C:59]=2[CH3:66])=[CH:54][CH:53]=1)([CH3:51])([CH3:50])[CH3:49]>C1COCC1.C1(C)C=CC=CC=1>[CH3:14][O:13][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:7]([CH:2]([O:1][C:61]2[CH:62]=[C:63]([CH3:64])[C:58]([C:55]3[CH:56]=[CH:57][C:52]([C:48]([CH3:50])([CH3:49])[CH3:51])=[CH:53][CH:54]=3)=[C:59]([CH3:66])[CH:60]=2)[CH2:3][CH:4]([CH3:6])[CH3:5])=[CH:16][CH:15]=1
Reactant: Cc1cc(O)cc(C)c1-c1ccc(C(C)(C)C)cc1
Reactant: COC(=O)c1ccc(C(O)CC(C)C)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(CC(C)C)Oc2cc(C)c(-c3ccc(C(C)(C)C)cc3)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 70 %

Procedure:
Methyl 4-(1-hydroxy-3-methylbutyl)benzoate, Isomer 1 (Preparation 4) (2.00 g, 9.01 mmol) is stirred in THF/toluene and 1,1′-(azodicarbonyl)dipiperidine (ADDP) (3.41 g, 13.51 mmol) at a temperature of 0-5° C., followed by addition of tri-n-butylphosphine (3.36 mL, 13.51 mmol) and 4′-tert-butyl-2,6-dimethylbiphenyl-4-ol (Preparation 2) (2.75, 10.81 mmol). The reaction is allowed to warm to room temperature with stirring for 24 to 48 h. The reaction is loaded on silica gel, and eluted with hexanes using a gradient of 0-100% ethyl acetate to obtain 2.90 g (70%) of product. 1H NMR.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:23](S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[C:26]([F:39])[CH:25]=3)[CH:17]=2)=[C:11]([CH3:52])[CH:10]=1)(=[O:5])=[O:4])[CH3:2].SCC(O)=O.O.[OH-].[Li+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([S:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])=[C:26]([F:39])[CH:25]=3)[CH:17]=2)=[C:11]([CH3:52])[CH:10]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)CCOc1cc(C)c(-c2cccc(CN(c3ccc(CCC(=O)OC(C)(C)C)c(F)c3)S(=O)(=O)c3ccccc3[N+](=O)[O-])c2)c(C)c1
Agent: O=C(O)CS
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCS(=O)(=O)CCOc1cc(C)c(-c2cccc(CNc3ccc(CCC(=O)OC(C)(C)C)c(F)c3)c2)c(C)c1
Temperature: 25 °C
Yield: 92.9 %

Procedure:
To a solution of tert-butyl 3-(4-{({4′-[2-(ethylsulfonyl)ethoxy]-2′,6′-dimethylbiphenyl-3-yl}methyl)[(2-nitrophenyl)sulfonyl]amino}-2-fluorophenyl)propanoate (1.67 g, 2.21 mmol) and mercaptoacetic acid (0.51 mL, 6.64 mmol) in N,N-dimethylformamide (17 mL) was added lithium hydroxide monohydrate (0.56 g, 13.3 mmol) under stirring at room temperature, and the mixture was stirred at the same temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate. and saturated brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-hexane/ethyl acetate=1/1) to give the title compound (1.17 g, yield 93%) as a colorless oil.
Reaction SMILES: [O-]CC.[Na+].[Na].[H][H].[CH3:8][CH:9]([CH3:13])[CH2:10][CH2:11][SH:12].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][Cl:20]>C(O)C>[CH2:11]([S:12][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][Cl:20])[CH2:10][CH:9]([CH3:13])[CH3:8]
Reactant: ClCCCCCBr
Reactant: [H][H]
Reactant: CC(C)CCS
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CC(C)CCSCCCCCCl
Temperature: 0 °C
Yield: 86.7 %

Procedure:
Generate sodium ethoxide by carefully adding sodium metal (620 mg, 27 mmol) to absolute ethanol (25 mL) under nitrogen atmosphere and stirring until evolution of hydrogen gas ceases. Cool to 0° C. and add, by dropwise addition, a solution of 3-methyl-l-butanethiol (2.8 g, 27 mmol) in absolute ethanol (25 mL). Stir for 30 mintutes at 0° C., cool to -70° C. and transfer via cannula to another flask containing a solution of 1-bromo-5-chloropentane (5.0 g, 27 mmol) in absolute ethanol (25 mL) at -30° C. Stir at -30° C. for 30 minutes, then allow to warm to room temperature and stir overnight. Add additional sodium ethoxide and stir for 30 minutes at room temperature. Concentrate in vacuo, partition between water and ethyl ether and separate the organic phase. Extract the aqueous phase with ethyl ether (2×50 mL), combine the organic phases and dry (MgSO4). Evaporate the solvent in vacuo to yield 4.89 g of 5-chloropentyl isopentyl sulfide as a clear oil; MS (CI/CH4) m/z 209(M+1), 173(M+1-HCl).
Reaction SMILES: C(N)C1C=CC=CC=1.C(OC([N:19]1[CH2:32][CH2:31][CH2:30][C@H:20]1[C:21]([NH:23][C@H:24]([P:26](=[O:29])([OH:28])[OH:27])[CH3:25])=[O:22])=O)C1C=CC=CC=1.Br.C1OC1C>C(O)(=O)C.CO>[NH:19]1[CH2:32][CH2:31][CH2:30][C@H:20]1[C:21]([NH:23][C@H:24]([P:26](=[O:27])([OH:28])[OH:29])[CH3:25])=[O:22]
Reactant: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)P(=O)(O)O
Agent: Br
Agent: CC1CO1
Solvent: CC(=O)O
Solvent: NCc1ccccc1
Solvent: CO
Product: C[C@H](NC(=O)[C@@H]1CCCN1)P(=O)(O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2.3 of the benzylamine salt of (1R)-1-[(N-benzyloxycarbonyl-L-prolyl)amino] -ethylphosphonic acid were added to a stirred solution (45%) of hydrogen bromide in glacial acetic acid and washed in with 2.5 ml of glacial acetic acid. The mixture was stirred at room temperature for 6 hours and then 75ml of ether were added while stirring. The supernatant was decanted and the residue was again treated with 75ml of ether. The granular solid obtained was dissolved in 30ml of methanol and the solution treated with a solution of 5ml of propylene oxide in 10ml of methanol. After standing for several hours, the precipitate was filtered off, washed with methanol and ether and dried. Crystallization from water/ethanol gave 0.39 g of (1R)-1-(L-prolylamino)-ethylphosphonic acid of melting point 291°-293° C (decomposition); [α]D20 = - 92.3°(c = 0.5% in water).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:9])=[CH:10][CH:11]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C=O)cc1
Temperature: 70 °C

Procedure:
4-Formylbenzoic acid (1.50 g, 10.0 mmol), tert-butyl (2-aminophenyl)carbamate (2.08 g, 10.0 mmol), EDC (1.92 g, 10.0 nmol) and HOBt (1.35 g, 10.0 mmol) were dissolved in DMF and the solution was heated at 70° C. for 4 h. The solution was diluted with 200 mL of EtOAc and the organic solution was washed twice with 150 mL of water, then sequentially with 150 mL each of 1 N HCl, NaHCO3 (sat'd), and brine. The solution was dried over MgSO4, concentrated, then purified by flash chromatography (12-100% ethyl acetate in hexanes) to give the desired product, MS cal'd 341 (MH+), exp 341 (MH+).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH:10]([CH3:12])[CH3:11])[C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[O:4][C@@H:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[F:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32]([NH:34][C@H:35]([C:37](O)=[O:38])[CH3:36])=[O:33])[CH:27]=[C:28]([F:30])[CH:29]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[F:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32]([NH:34][C@H:35]([C:37]([NH:1][C@@H:2]2[C:8](=[O:9])[N:7]([CH:10]([CH3:12])[CH3:11])[C:6]3[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=3[O:4][C@@H:3]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:38])[CH3:36])=[O:33])[CH:27]=[C:28]([F:30])[CH:29]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CC(C)N1C(=O)[C@@H](N)[C@@H](c2ccccc2)Oc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)N1C(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)[C@@H](c2ccccc2)Oc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.7 %

Procedure:
To a stirred solution of (2R,3S)-3-amino-5-isopropyl-2-phenyl-2,3-dihydro-1,5-benzoxazepin-4(5H)-one (69b) (59 mg, 0.199 mmol) in dichloromethane (2 mL) was added N-[(3,5-difluorophenyl)acetyl]-L-alanine (1e) (59 mg, 0.242 mmol), HOBt (33 mg, 0.245 mmol), NMM (30 mg, 0.297 mmol) and EDAC-HCl (47 mg, 0.245 mmol). After stirring at ambient temperature under nitrogen for 90 min. the solvent was evaporated and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic solution was separated, washed with 1N aqueous HCl then dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 1:1 (v/v) hexane:ethyl acetate to afford the title compound (64 mg, 62%) as a white solid. TLC Rf=0.17 (1:1 hexane:ethyl acetate). 1H NMR (300 MHz, CDCl3) δ1.21 (d, 3H, J=7.0 Hz), 1.29 (d, 3H, J=7.0 Hz), 1.54 (d, 3H, J=7.0 Hz), 3.47 (s, 2H), 4.22 (m, 1H), 4.77 (m, 1H), 4.93 (t, 1H, J=7.2 Hz), 5.60 (d, 1H, J=7.4 Hz), 5.87 (br d, 1H, J=7.4 Hz), 6.25 (br d, 1H, J=7.0 Hz), 6.67-6.86 (m, 3H), 7.21-7.43 (m, 9H). MS APCI, m/z=522 (M+1). LC/MS: 2.75 min.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:9]([NH:11][N:12]([CH2:28][C@@H:29]([OH:33])[C:30]([OH:32])=[O:31])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])=[CH:16][CH:15]=2)=[O:10])[NH:7][N:8]=1)(=[O:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(Cl)Cl.O[CH2:52][C:53]1[O:54][C:55](=[O:59])[O:56][C:57]=1[CH3:58].CN1CCOCC1>>[CH3:58][C:57]1[O:56][C:55](=[O:59])[O:54][C:53]=1[CH2:52][O:31][C:30](=[O:32])[C@H:29]([OH:33])[CH2:28][N:12]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=2[F:27])=[CH:16][CH:15]=1)[NH:11][C:9]([C:6]1[NH:7][N:8]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1)=[O:10]
Reactant: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)[nH]n1
Reactant: Cc1oc(=O)oc1CO
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)OCc2oc(=O)oc2C)[nH]n1
Reaction time: 0.17 h
Yield: 1.6 %

Procedure:
(R)-3-[N′-(5-Acetyl-2H-pyrazole-3-carbonyl)-N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid (30.0 mg, 63 mmol), HOBt (26 mg, 190 μmol) and EDC (34 μL, 190 μmol) were combined in DCM (243 μL, 3.8 mmol) and stirred for 10 minutes. 4-Hydroxymethyl-5-methyl-[1,3]dioxol-2-one (66 mg, 0.5 mmol) and 4-methylmorpholine (28 μL, 250 μmol) were added and the resulting mixture was stirred at room temperature for 3 hours. The mixture was evaporated under reduced pressure, yielding a brown oil, which was purified by preparative HPLC to yield the title compound (4.6 mg, purity 97%) as a TFA salt. MS m/z [M+H]+ calc'd for C27H24ClFN4O8, 587.13. found 587.1.
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:8][N:7]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:6][CH2:5][CH:4]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:3]1.[CH3:27][Si](C)(C)[N-][Si](C)(C)C.[Li+].IC.O>C1COCC1>[F:26][C:2]1([F:1])[CH2:8][N:7]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:6][CH2:5][CH:4]([N:18]([CH3:27])[C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:3]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(NC(=O)OC(C)(C)C)CC(F)(F)C1
Agent: [Li+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2c([N+](=O)[O-])cnn2C)CC(F)(F)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
To a cooled (ice-water bath) solution of tert-butyl 6,6-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate (190 mg, 0.51 mmol) in THF (10 mL) was added lithium hexamethyldisilazide (1M in THF, 0.8 mL, 0.8 mmol) and the mixture stirred for 30 min. Iodomethane (0.06 mL, 1.02 mmol) was added and the mixture stirred at room temperature for 16 hr. Water (2 mL) was added and the mixture extracted with EtOAc (30 mL). The organic layer was separated, dried over Na2SO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-70% EtOAc/isohexane) gave tert-butyl 6,6-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl(methyl)carbamate (180 mg, 90%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.09-7.99 (m, 1H), 4.57-4.38 (m, 1H), 3.85 (s, 3H), 3.84-3.53 (m, 1H), 3.45-3.15 (m, 3H), 2.81 (s, 3H), 2.53-2.29 (m, 2H), 2.16-2.01 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[NH:11][C:10](OC)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:20]1([CH:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:27][CH2:28][NH2:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC[N:38]=C=NCCCN(C)C.Cl>ClCCl>[C:30]1([CH:26]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:27][CH2:28][NH:29][C:14]([C:13]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:9]=[C:10]([NH2:38])[NH:11][C:12]=2[CH3:17])=[O:16])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COC1=NC(c2cccc(Cl)c2)C(C(=O)O)=C(C)N1
Reactant: CCN=C=NCCCN(C)C
Reactant: NCCC(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CC1=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)N=C(N)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
158 mg (0.563 mmol) of 4-(3-chlorophenyl)-2-methoxy-6-methyl-1,4-dihydropyrimidine-5-carboxylic acid and 178 mg (0.844 mmol) of 3,3-diphenylpropylamine were dissolved in 20 ml of dichloromethane. 162 mg (0.844 mmol) of WSC hydrochloride was added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. After the concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate and then washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=2/1) to obtain the title compound.
Reaction SMILES: N1CCCC1.ClCC1C=CC([C@H](C2C=CC(Cl)=CC=2)[N:15]2[CH2:18][C:17](=[C:19]([C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=3)[S:20]([CH3:23])(=[O:22])=[O:21])[CH2:16]2)=CC=1.[I-].[Na+]>ClCCl>[F:31][C:26]1[CH:25]=[C:24]([C:19](=[C:17]2[CH2:18][NH:15][CH2:16]2)[S:20]([CH3:23])(=[O:22])=[O:21])[CH:29]=[C:28]([F:30])[CH:27]=1
Reactant: CS(=O)(=O)C(=C1CN([C@@H](c2ccc(Cl)cc2)c2ccc(CCl)cc2)C1)c1cc(F)cc(F)c1
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCNC1
Product: CS(=O)(=O)C(=C1CNC1)c1cc(F)cc(F)c1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
50 mm3 of pyrrolidine are added to a solution of 0.32 g of 1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, and 5 mg of sodium iodide in 10 cm3 of dichloromethane. After stirring for 20 hours at 20° C., 50 mm3 of pyrrolidine are added to the mixture, stirred for 8 hours and then 50 mm3 of pyrrolidine are again added and the mixture is stirred for 20 hours at 20° C. The reaction mixture is washed with water and then the organic phase is dried over magnesium sulfate and concentrated to dryness under vacuum (2.7 kPa). The residue obtained is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 1.2 cm, height 30 cm), at an argon pressure of 0.1 bar, eluting with dichloromethane and then with a dichloromethane and methanol mixture (97.5/2.5 by volume) and collecting 3 cm3 fractions. Fractions 12 to 40 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.18 g of 1-{(R*)-(4-chlorophenyl)[4-pyrrolidinylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam [a]20365 nm=−22.5 +/−0.7 (c=0.5%; dichloromethane) [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 1.78 (mt, 4H), 2.51 (mt, 4H), 2.81 (s, 3H), 3.58 (s, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.84 (tt, J=9 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:12]C(=O)OC(C)(C)C)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N+:2]=[N-:3].O1CCOCC1>C1COCC1.Cl.CCOCC>[N:1]([CH2:4][C@@H:5]([NH2:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: [N-]=[N+]=NC[C@@H](N)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of tert-butyl [(1S)-2-azido-1-phenylethyl]carbamate (210 mg, 0.8 mmol, 1.0 eq.) in THF (2 ml), 4.0M hydrogen chloride in dioxane (2.0 ml, 8.0 mmol, 10.0 eq.) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ether. The precipitate was filtered and washed with ether to yield (S)-2-Azido-1-phenyl-ethylamine 40 as a white solid in 85% yield. LC-MS [163 (M+1)]