Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27])[C:5]1[CH:14]=[C:13]([C:15]([O:17]C)=[O:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8])(=[O:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([N:4]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27])[C:5]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(=O)OC)c(N(Cc2ccc(Cl)cc2Cl)C(C)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N(Cc1ccc(Cl)cc1Cl)c1cc(C(=O)O)ccc1C(=O)O
Temperature: 60 °C
Yield: 97.9 %

Procedure:
A mixture of dimethyl 2-((N-acetyl)-(2,4-dichlorobenzyl)amino)terephthalate (2.05 g) and 10% aqueous sodium hydroxide solution (8.00 g) in methanol (20 ml) was heated at 60° C. for 1 hr. After cooling, concentrated hydrochloric acid was added to acidify the reaction mixture and the precipitated solid was collected by filtration. The solid was washed with water (60 ml) and dried to give the objective compound (1.87 g) as white crystals.
Reaction SMILES: [ClH:1].Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:33][C:34]([O:36]CC)=[O:35])[C:10]([C:12]1[CH:32]=[CH:31][C:15]2[N:16]([CH3:30])[C:17]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=3)=[N:18][C:14]=2[CH:13]=1)=[O:11].[OH-].[Na+]>>[ClH:1].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:33][C:34]([OH:36])=[O:35])[C:10]([C:12]1[CH:32]=[CH:31][C:15]2[N:16]([CH3:30])[C:17]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=3)=[N:18][C:14]=2[CH:13]=1)=[O:11]
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(COc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CC(=O)O)c3ccccn3)ccc21

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-dihydrochloride and sodium hydroxide solution.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[F:22][C:23]([F:35])([F:34])[C:24]([NH:26][C@H:27]1[C@@H:31]([CH2:32][F:33])[CH2:30][NH:29][CH2:28]1)=[O:25].C(N(C(C)C)CC)(C)C>O1CCOCC1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:29]2[CH2:30][C@H:31]([CH2:32][F:33])[C@H:27]([NH:26][C:24](=[O:25])[C:23]([F:35])([F:34])[F:22])[CH2:28]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: O=C(N[C@@H]1CNC[C@@H]1CF)C(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1c(F)c(N2C[C@H](CF)[C@H](NC(=O)C(F)(F)F)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1

Procedure:
In the same manner as described in Example 13 (1), a mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro1,4-dihydro-4-oxoquinoline-3-carboxylic acid, cis-3-trifluoroacetylamino-4-fluoromethylpyrrolidine, diisopropylethylamine, and dioxane was refluxed for 12 hours to give 5-amino-7-(cis-3-trifluoroacetylamino4-fluoromethyl-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C@@H:8]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]([NH:11][CH2:12][C:13]#[N:14])=[O:10])=[CH:4][CH:3]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:13]([CH2:12][NH:11][C:9]([C@@H:8]([NH:7][CH2:6][C:5]1[CH:19]=[CH:20][C:2]([C:37]2[CH:36]=[CH:35][C:34]([N:31]3[CH2:30][CH2:29][N:28]([C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[CH2:33][CH2:32]3)=[CH:39][CH:38]=2)=[CH:3][CH:4]=1)[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:10])#[N:14]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Reactant: CC(C)C[C@H](NCc1ccc(Br)cc1)C(=O)NCC#N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NCc1ccc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1)C(=O)NCC#N
Temperature: 95 °C

Procedure:
To (2S)-2-[(4-bromobenzyl)amino]-N-(cyanomethyl)-4-methylpentanamide (285 mg, 0.843 mmol) and 4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenylboronic acid (315 mg, 1.02 mmol) in DMF (10 mL) under dry nitrogen was added aqueous sodium carbonate (2 M, 1.3 mL, 2.53 mmol) followed by the catalyst PdCl2(dppf) (25 mg, 0.026 mmol). The reaction was heated to 95° C. for 0.5 hours and more PdCl2(dppf) (25 mg, 0.026 mmol) was added and the reaction mixture was heated overnight. Water was added and the product extracted with ether (2×), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography over silica gel (EtOAc/Hex, 4/6) to afford tert-butyl 4-(4′-{[((1S)-1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)amino]methyl}[1,1′-biphenyl]-4-yl)-1-piperazinecarboxylate.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[NH2:32][CH:33]([CH3:36])[CH2:34][OH:35].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:32][CH:33]([CH3:36])[CH2:34][OH:35])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CC(N)CO
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNC(C)CO)c4)cc23)CC1
Yield: 7.8 %

Procedure:
Following the general procedure of example 16, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.114 mmol), 2-amino-1-propanol (6.5 mg, 0.087 mmol) and NaBH(OAc)3 (58 mg, 0.261 mmol) were reacted to give the title compound (3.4 mg, 6.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:17]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:25](=[O:26])[C:24]3[CH:28]=[CH:29][C:21]([C:17]([CH3:19])([CH3:18])[CH3:20])=[CH:22][CH:23]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Product: CC(C)(C)c1ccc(C(=O)N2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc1

Procedure:
Prepare by the method of example 3.1 using 2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (2 mmol) and 4-tert-butyl-benzoyl chloride (2 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]1[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[C:20]([O:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:19][CH:18]=1.[I:34]I>C1COCC1.O>[F:16][C:17]1[C:18]([I:34])=[CH:19][C:20]([O:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=1
Reactant: II
Reactant: COCCOCOc1ccc(F)nc1C(F)(F)F
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COCCOCOc1cc(I)c(F)nc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 43.3 %

Procedure:
A dry 100 mL, 3-neck round bottom flask was fitted with an additional needle/septa, and inert atmosphere inlet, and a septa. The flask was charged with 2,2,6,6-tetramethylpiperidine (0.47 ml, 2.8 mmol), 5 mL dry THF and a stirbar. The flask was immersed in a ice-water bath and treated with a 1.6 M solution of butyllithium in hexanes (1.4 ml, 2.2 mmol) added over 15 minutes via syringe pump. The solution was stirred an additional 5 minutes and the ice-water bath was replaced with a dry ice acetone bath. To the stirring cold solution was added 6-fluoro-3-((2-methoxyethoxy)methoxy)-2-(trifluoromethyl)pyridine (0.5030 g, 1.9 mmol) dissolved in 5 mL dry THF over 2 minutes. The reaction was stirred for 1 h at −78° C. after which time a solution of iodine (0.12 ml, 2.2 mmol) dissolved in 5 mL dry THF was added via cannula over a 3 minute period. The reaction was stirred for 15 minutes, and then the cooling bath was removed. After stirring 5 minutes, the solution was poured onto sodium thiosulfate (1.8 ml, 19 mmol) dissolved in 50 mL water. The mixture was stirred for 10 minutes, and the layers were separated. The aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were washed with water (3×20 mL) and dried over MgSO4. The slurry was filtered and the filtrate was concentrated in vacuo. The sample was purified in one injection using a Waters Xterra Prep C18 MS Packed by Vydac/The Separations Group, 50 mm×300 mm (PN PA0000-050730), 10 μm particle size, spherical shape. 0→4 min@20 mL/min, 40% B; 4→5 min, 20→100 mL/min@ 40% B; 5→25 min@100 mL/min, linear gradient to 70% B; 25→35 min 100 mL/min, isocratic at 70% B; 35 min, step to 100% B @100 mL/min; 35→50 min@ 100 mL/min, 100% B; 50 min, step to 40% B @ 100 mL/min; 60 min end. A fraction that eluted from 24.4 to 26.1 minutes was isolated. The solvent was removed in vacuo to afford 2-fluoro-3-iodo-5-((2-methoxyethoxy)methoxy)-6-(trifluoromethyl)pyridine (0.3253 g, 44% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 3.39-3.42 (m, 3H) 3.60-3.65 (m, 2H) 4.00-4.06 (m, 2H) 5.26 (s, 2H) 7.65 (dd, J=4.11, 0.49 Hz, 1H). 19F NMR (376 MHz, chloroform-d) δ ppm −71.79 (d, J=3.90 Hz, 1 F)-65.02 (s, 3 F). 13C NMR (101 MHz, chloroform-d) 8 ppm 59.09 (s, 1 C) 70.25 (s, 1 C) 71.47 (s, 1 C) 100.53 (dq, J=1.73, 1.59 Hz, 1 C) 109.88 (d, J=8.67 Hz, 1 C) 119.98 (dq, J=275.70, 1.30 Hz, 1 C) 124.54 (dq, J=40.53, 1.08 Hz, 1 C) 137.97 (qd, J=35.04, 14.09 Hz, 1 C) 150.60 (d, J=5.20 Hz, 1 C) 157.42 (dq, J=245.79, 0.87 Hz, 1 C).
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[CH3:22][CH:23]1[O:28][CH:27]([CH3:29])[CH2:26][N:25]([C:30]2[CH:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=2)[CH2:24]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:36][C:33]3[CH:32]=[CH:31][C:30]([N:25]4[CH2:26][CH:27]([CH3:29])[O:28][CH:23]([CH3:22])[CH2:24]4)=[CH:35][N:34]=3)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21]
Reactant: CC1CN(c2ccc(N)nc2)CC(C)O1
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Solvent: Cc1ccccc1
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CC(C)OC(C)C4)cn3)ncc12
Temperature: 25 °C
Yield: 25.8 %

Procedure:
6-Bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 2.70 mmol) and 5-(2,6-dimethyl-morpholin-4-yl)-pyridin-2-ylamine (0.668 g, 3.73 mmol) were heated to reflux in toluene (10 mL) for 16 hours. The reaction mixture was cooled to room temperature and the precipitate that formed was collected by filtration and washed on the funnel with toluene (3×10 mL) to give 6-bromo-8-cyclopentyl-2-[5-(2,6-dimethyl-morpholin-4-yl)-pyridin-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one as a brown solid (0.358 g, 27.3%). MS (APCI) Calc'd for M+1: 513.2. Found: 513.1. Anal. Calc'd for C24H29BrN6O2: C, 56.14; H, 5.69; N, 16.37. Found; C, 55.90; H, 5.62; N, 16.10.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([NH2:23])=O)=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.B.CSC.[ClH:30]>O1CCCC1.C(O)C>[F:25][C:2]([F:1])([F:24])[O:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:23])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:8][CH:9]=1.[ClH:30]
Reactant: NC(=O)Cc1ccc(CS(=O)(=O)c2ccc(OC(F)(F)F)cc2)cc1
Agent: B
Agent: Cl
Solvent: CSC
Solvent: CCO
Solvent: C1CCOC1
Product: NCCc1ccc(CS(=O)(=O)c2ccc(OC(F)(F)F)cc2)cc1
Reaction time: 0.25 h

Procedure:
A solution of 2-[4-(4-trifluoromethoxy-benzenesulfonylmethyl)-phenyl]-acetamide (1.36 g, 3.64 mmol) in tetrahydrofuran (30 ml) was refluxed and a solution of borane-dimethylsulfid complex (2M in tetrahydrofuran, 9.11 mmol) was added. The mixture was refluxed for 2 h. The mixture was allowed to come to room temperature and was adjusted to pH=1 using a solution of HCl in ethanol (2M). After stirring the mixture for 15 min the solvents were evaporated under reduced pressure. A slurry of the resulting white powder in diethyl ether was stirred for 15 min. The remaining solid was collected, washed with diethyl ether, and dried in a vacuum oven to give white crystals of 2-[4-(4-trifluoromethoxy-benzenesulfonylmethyl)-phenyl]-ethylamine×HCl (1.22 g, 84.7%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][OH:6])[CH3:2].N1C=CC=CC=1.[F:13][CH:14]([CH2:16][C:17](Cl)=[S:18])[F:15]>ClCCl>[F:13][CH:14]([CH2:16][C:17]([O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])=[S:18])[F:15]
Reactant: CCOCCO
Reactant: FC(F)CC(=S)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOCCOC(=S)CC(F)F
Yield: 60 %

Procedure:
To a stirred and ice cooled solution of 2-ethoxyethanol (1.2 equivalents) and pyridine (1.3 equivalents) in dichloromethane (5 parts by weight) is dropwise added difluoromethylthioacetyl chloride. After stirring for 4 hours, the mixture is washed with saline, dried and concentrated. The residual liquid is distilled to give oily 2-ethoxyethyl difluoromethylthioacetate. Yield: 60%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: BrCCCCCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCCCCCOc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 66.3 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with (6-bromohexyloxy)benzene (1.5 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material from dichloromethane extraction was purified by HPLC (dichloromethane-hexane; 5:1) and crystallized from diethyl ether-hexane to provide 0.95 g of alpha-oxo-4-[[(6-phenoxy)hexyl]oxy]benzeneacetic acid methyl ester, mp 50°-52° C.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:38]=[CH:37][C:6]([O:7][C:8]2[N:12]([CH2:13][C:14]([O:16]CC)=[O:15])[N:11]=[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][O:27][CH2:26]4)[CH:20]=3)[CH:9]=2)=[CH:5][CH:4]=1.[OH-].[Na+].Cl>CCO>[F:40][C:2]([F:1])([F:39])[C:3]1[CH:38]=[CH:37][C:6]([O:7][C:8]2[N:12]([CH2:13][C:14]([OH:16])=[O:15])[N:11]=[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:31])[CH2:26][O:27][CH2:28]4)[CH:20]=3)[CH:9]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)Cn1nc(-c2cccc(C3(NC(=O)OC(C)(C)C)COC3)c2)cc1Oc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2cccc(-c3cc(Oc4ccc(C(F)(F)F)cc4)n(CC(=O)O)n3)c2)COC1
Reaction time: 0.33 h

Procedure:
Ethyl [5-(4-trifluoromethylphenoxy)-3-(3-{3-[(tert-butyloxycarbonyl)amino]oxetan-3-yl}phenyl)-1H-pyrazol-1-yl]acetate (98 mg, 0.18 mmol) was dissolved in 0.5 mL of EtOH and to the stirred solution was added 1N aqueous NaOH solution (0.35 mL, 0.35 mmol). The mixture was stirred for 20 min and then 0.35 mL of 1N aqueous HCl was added dropwise. The solvents were removed under reduced pressure and the residue was partitioned between EtOAc and 10% aqueous citric acid solution. The organic phase was washed with brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give [5-(4-trifluoromethylphenoxy)-3-(3-{3-[(tert-butyloxycarbonyl)amino]oxetan-3-yl}phenyl)-1H-pyrazol-1-yl]acetic acid as a foam. Calcd (M+1)+: 534.5. Found: 534.8
Reaction SMILES: [CH2:1]([N:8]1[CH:11]([C:12]([C:14]([OH:16])=[O:15])=[CH2:13])[CH:10]([CH:17]([OH:19])[CH3:18])[C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21]O>[Pd]>[CH2:1]([N:8]1[CH:11]([CH:12]([C:14]([O:16][CH3:21])=[O:15])[CH3:13])[CH:10]([CH:17]([OH:19])[CH3:18])[C:9]1=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: C=C(C(=O)O)C1C(C(C)O)C(=O)N1Cc1ccccc1
Agent: [Pd]
Product: COC(=O)C(C)C1C(C(C)O)C(=O)N1Cc1ccccc1
Yield: 78 %

Procedure:
To a solution of 38 mg (0.14 mmol) of 1-benzyl-4-(1-carboxyethenyl)-3-(1-hydroxyethyl)-2-azetidinone dissolved in 1 ml of methanol, 5 mg of 5% palladium charcoal was added and the mixture was stirred under hydrogen atmosphere for a night. The reaction solution was filtered with selite, the filtrate was added with an ethereal solution of diazomethane and the resultant was concentrated. The concentrate was purified with 2 g of silica-gel column (benzene:ethyl acetate 1:1) to give 30 mg of 1-benzyl-4-(1-methoxycarbonylethyl)-3-(1-hydroxyethyl)-2-azetidinone (yield: 78%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([N:24]4[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[C:25]4=[O:31])=[C:19]([CH3:32])[CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1.Br[CH2:34][CH2:35][Cl:36].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN1CCCC1=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([N:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:34][CH2:35][Cl:36])[C:25]4=[O:31])=[C:19]([CH3:32])[CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1
Reactant: Cc1cc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)cc(C)c1-n1cccc(O)c1=O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)cc(C)c1-n1cccc(OCCCl)c1=O
Temperature: 60 °C
Reaction time: 15 h

Procedure:
900 mg (1.89 mmol) of the compound from Example 72A and 1.36 g (9.49 mmol) of 1-bromo-2-chloroethane are dissolved in 30 ml of 1-methyl-2-pyrrolidone. 1.55 g (4.75 mmol) of caesium carbonate are added to the solution, and the mixture is stirred at 60° C. for 15 hours. Water is then added, and, after phase separation, the aqueous phase is extracted three times with tert-butyl methyl ether and three times with dichloromethane. The combined organic phases are washed successively with 1N aqueous sodium hydroxide solution and saturated sodium chloride solution and then dried over sodium sulphate. The drying agent is filtered off and the solvent is removed completely on a rotary evaporator. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 1:5). This gives 464 mg (45% of theory, purity according to LC-MS 74%) of the desired product.
Reaction SMILES: [F:1][CH:2]([P:13](=[O:22])([O:18]C(C)C)[O:14]C(C)C)[P:3](=[O:12])([O:8]C(C)C)[O:4]C(C)C.C[Si](Br)(C)C.C1(C)C=CC=CC=1.C(N(CCCC)CCCC)CCC>ClCCCl.CN(C=O)C>[F:1][CH:2]([P:13](=[O:14])([OH:22])[OH:18])[P:3](=[O:4])([OH:12])[OH:8]
Reactant: CC(C)OP(=O)(OC(C)C)C(F)P(=O)(OC(C)C)OC(C)C
Agent: C[Si](C)(C)Br
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCCCN(CCCC)CCCC
Product: O=P(O)(O)C(F)P(=O)(O)O
Temperature: 41 °C
Reaction time: 24 h
Yield: 269.5 %

Procedure:
To a stirred solution of tetraisopropyl fluoromethylenediphosphonate (320 mg, 0.88 mmol) in 1,2-dichloroethane (5 mL) was added dropwise trimethylsilyl bromide (0.70 mL, 5.28 mmol). The resulting solution was stirred at 40-42° C. for 24 h and 3 mL of anhydrous toluene was added. The mixture was concentrated to dryness, and coevaporated with toluene once. The residue was redissolved in DMF (3 mL)/water (2 mL) mixture and concentrated. The residue was mixed with DMF (2 mL) and tributylamine (0.42 mL, 1.76 mmol) and then concentrated to dryness. The residue was coevaporated with anhydrous DMF two times. The resulting residue was dried in a vacuum oven at 30° C. overnight to give a slightly yellow residue (460 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:30])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)[CH3:18]>>[CH2:17]([O:19][C:20](=[O:30])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:13]=2)=[O:16])[CH:24]=1)[CH3:18]
Reactant: CCOC(=O)CCc1cccc(N)c1
Reactant: O=C(O)c1cccc(-c2ccc(F)cc2)n1
Product: CCOC(=O)CCc1cccc(NC(=O)c2cccc(-c3ccc(F)cc3)n2)c1

Procedure:
Carboxylic acid (152)(50 mg, 0.23 mmol) was coupled to aniline (124)(45 mg, 0.23 mmol) using Method C. The residue was purified by column chromatography eluting with 30% EtOAc in heptane to give the title compound.
Reaction SMILES: [OH-:1].[Na+].N[C:4](=[O:28])[CH2:5][C@H:6]1[C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[O:11][CH2:10][CH2:9][N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:7]1.Cl>C(O)CCC>[C:24]([O:23][C:21]([N:8]1[CH2:7][C@@H:6]([CH2:5][C:4]([OH:28])=[O:1])[C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[O:11][CH2:10][CH2:9]1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CC(N)=O)C1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CC(=O)O)C1
Temperature: 120 °C
Reaction time: 4.5 h

Procedure:
8 N Aqueous sodium hydroxide solution (0.620 mL) was added to a solution of tert-butyl (6R,7R)-6-(2-amino-2-oxoethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (500 mg) in n-butanol (5 mL), and the mixture was stirred at 120° C. for 4.5 hr. The reaction mixture was neutralized with 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (434 mg).
Reaction SMILES: Cl.[C:2]([C:6]1[CH:7]=[C:8]([S:17][C:18]2([CH2:24][CH2:25][O:26][C:27](=[O:29])[CH3:28])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]=1[OH:12])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:37][O:38][C:39]([C:41]1[N:42]([CH3:50])[C:43]([S:46](Cl)(=[O:48])=[O:47])=[CH:44][CH:45]=1)=[O:40]>ClCCl.C(OCC)(=O)C>[CH3:37][O:38][C:39]([C:41]1[N:42]([CH3:50])[C:43]([S:46]([N:21]2[CH2:20][CH2:19][C:18]([CH2:24][CH2:25][O:26][C:27](=[O:29])[CH3:28])([S:17][C:8]3[CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]([OH:12])=[C:6]([C:2]([CH3:3])([CH3:4])[CH3:5])[CH:7]=3)[CH2:23][CH2:22]2)(=[O:48])=[O:47])=[CH:44][CH:45]=1)=[O:40]
Reactant: CC(=O)OCCC1(Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CCNCC1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)n1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(S(=O)(=O)N2CCC(CCOC(C)=O)(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)n1C
Reaction time: 0.08 h
Yield: 83.1 %

Procedure:
To acetic acid 2-[4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-piperidin-4-yl]-ethyl ester hydrochloride (Ex. 1c, 370 mg, 0.83 mmol) in 8 mL of dichloromethane was added triethylamine (293 mg, 2.9 mmol). After stirring for 5 min, 5-chlorosulfonyl-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (296 mg, 1.25 mmol) was added in 3 portions. The reaction mixture was stirred for 3 h at room temperature, and then diluted with Ethyl acetate (40 mL), washed with water (50 mL), 0.5 N HCl (2×30 mL) and water (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was chromatographed with 5-30% Ethyl acetate/hexanes to afford 5-[4-(2-acetoxy-ethyl)-4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-piperidine-1-sulfonyl]-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester as a clear oil (420 mg, 83%). ESI/CI-MS m/z 609 ([M+H]+).