Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:19]=[C:18]([CH2:20][C:21]2[C:22](=[O:45])[N:23]([C@H:33]3[CH2:38][CH2:37][C@H:36]([O:39][CH2:40][C:41]([OH:44])([CH3:43])[CH3:42])[CH2:35][CH2:34]3)[C:24]3[N:25]([N:30]=[CH:31][CH:32]=3)[C:26]=2[CH2:27][CH2:28][CH3:29])[CH:17]=[CH:16][C:15]=1[C:46]1[C:47]([C:52]#[N:53])=[CH:48][CH:49]=[CH:50][CH:51]=1>C(OCC)(=O)C>[F:13][C:14]1[CH:19]=[C:18]([CH2:20][C:21]2[C:22](=[O:45])[N:23]([C@H:33]3[CH2:38][CH2:37][C@H:36]([O:39][CH2:40][C:41]([OH:44])([CH3:42])[CH3:43])[CH2:35][CH2:34]3)[C:24]3[N:25]([N:30]=[CH:31][CH:32]=3)[C:26]=2[CH2:27][CH2:28][CH3:29])[CH:17]=[CH:16][C:15]=1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52]1[NH:3][C:4](=[O:7])[O:5][N:53]=1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(F)c2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)c(F)c2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.35 g), sodium hydrogen carbonate (0.53 g) and dimethyl sulfoxide (2 mL) was stirred at 50° C. for 30 min, 2′-fluoro-4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.23 g) was added, and the mixture was stirred at 90° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.082 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.075 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, and washed with 1 M hydrochloric acid and then with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.14 g, 56%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:2]1.Cl.[Cl:17]CCCN1CCCCC1.Cl.ClCCC[N:32]1[CH2:37][CH2:36][CH2:35][CH:34]([C:38]2C=CC(OC)=[CH:40][CH:39]=2)[CH2:33]1>>[ClH:17].[NH:32]1[CH2:37][CH2:36][CH2:35][CH:34]([CH2:38][CH2:39][CH2:40][N:13]2[CH2:14][CH2:15][CH:10]([C:3]3[C:4]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[O:1][N:2]=3)[CH2:11][CH2:12]2)[CH2:33]1
Reactant: c1ccc2c(C3CCNCC3)noc2c1
Reactant: ClCCCN1CCCCC1
Reactant: COc1ccc(C2CCCN(CCCCl)C2)cc1
Agent: Cl
Product: c1ccc2c(C3CCN(CCCC4CCCNC4)CC3)noc2c1

Procedure:
Using 4-(3-benzisoxazolyl)piperidine (191 mg, 0.80 mmol) and 1-(3-chloropropyl)piperidine hydrochloride (222 mg, 1.1 mmol) instead of 4-(3-indolyl)piperidine and 1-(3-chloropropyl)-3-(4-methoxyphenyl)piperidine hydrochloride respectively, reaction and concentration were carried out in the same procedure as Example 2. The resulting crude product was purified by column chromatography on a silica gel (silica gel NH-DM 1020 produced by Fuji Silysia Chemical Ltd., eluent; hexane:ethyl acetate=3:1) to afford a free form (236 mg) of the title compound as a pale yellow viscous oil. After adding hydrochloric acid/methanol to a solution of the free form in methanol, the mixture was concentrated and was then recrystallized from methanol/ether to afford the title compound (277 mg, yield: 86%) as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:24])=[C:6]([C@:8]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[O:22][CH3:23])([CH3:11])[CH2:9][OH:10])[CH:7]=1.N1C=CC=CC=1.[S:31](Cl)(Cl)=[O:32]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:24])=[C:6]([C:8]2([CH3:11])[CH2:9][O:10][S@@:31](=[O:32])[N:12]2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[O:22][CH3:23])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CN[C@@](C)(CO)c2cc(Br)ccc2F)c(OC)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(CN2[S@](=O)OCC2(C)c2cc(Br)ccc2F)c(OC)c1
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 99.7 %

Procedure:
To a solution of (R)-2-(5-bromo-2-fluorophenyl)-2-(2,4-dimethoxybenzylamino)propan-1-ol (14.1 g, 35.4 mmol, Eq: 1.00) and pyridine (14.0 g, 14.3 ml, 177 mmol, Eq: 5.0) in dichloromethane (258 ml) at 78° C. was dropwise added thionyl chloride (5.05 g, 3.1 ml, 42.5 mmol, Eq: 1.2), stirring was continued at 78° C. for 5 min, the cooling bath was removed and the mixture was slowly warmed up to 23° C. and stirring was continued for 20 min. Extracted with 5% citric acid and sat NaHCO3-sol., dried the organic layer over Na2SO4, filtered off and evaporated totally to give the (R)-4-(5-bromo-2-fluoro-phenyl)-3-(2,4-dimethoxy-benzyl)-4-methyl-[1,2,3]oxathiazolidine 2-oxide (15.7 g, 35.3 mmol, 99.8% yield) as a light yellow oil, which needed no further purification. MS (ISP): m/z=444.1 [M+H]+ and 446.0 [M+2+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13](O)[CH2:14][CH3:15].C(N(CC)CC)C.C(=O)([O-])[OH:25].[Na+]>C(Cl)Cl>[S:2]([O:4][CH2:15][CH2:14][CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[F:6])(=[O:25])(=[O:3])[CH3:1]
Reactant: CCC(O)c1ccccc1F
Reactant: O=C([O-])O
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCc1ccccc1F
Reaction time: 0.33 h

Procedure:
Under nitrogen gas, 0.38 ml (4.90 mM) of methanesulfonyl chloride was added to a solution of 499 mg (3.24 mM) of 2-fluorophenylpropanol and 0.90 ml (6.47 mM) of triethylamine in methylene chloride (6 ml) at 0° C. and the mixture was stirred at the prevailing temperature for 20 minutes. The reaction was stopped by adding saturated aqueous solution of sodium hydrogen carbonate. The reaction mixture was then extracted with diethyl ether. The organic layer was washed with water and saturated aqueous solution of sodium chloride and dried over MgSO4. The solvent was then distilled off under reduced pressure to provide 0.722 g (3.24 mM) of 2-fluorophenylpropyl mesylate. To a solution of 0.58 g (1.5 mM) of N-(piperidin-4-ylmethyl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.0 ml (7.2 mM) of triethylamine in ethanol was added 0.60 g (2.69 mM) of 2-fluorophenylpropyl mesylate at room temperature, and the mixture was refluxed under nitrogen for 16 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic -layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The resulting crude product was purified by column chromatography (methanol/ethyl acetate 20-50%) to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.OO.NC(N)=[O:13].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[O-]S([O-])=O.[Na+].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N+:3]=1[O-:13]
Reactant: NC(N)=O
Reactant: Brc1cccc(Br)n1
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: [O-][n+]1c(Br)cccc1Br
Temperature: 5 °C
Reaction time: 20 h
Yield: 57.4 %

Procedure:
2,6-dibromo pyridine (79 g, 334 mmol) was dissolved in 800 ml of dry dichloromethane and cooled under nitrogen to 5° C. then urea hydrogen peroxide (104 g, 1.1 mol) was added in one portion. When the mixture had cooled again to 3° C., a solution of trifluoro acetic acid anhydride (140 mL, 1 mol) in 100 ml DCM was added via dropping funnel over 45 min, whilst keeping the temperature between 5-7° C. The mixture was allowed to warm to room temperature and stirred for 20 hours. The mixture was cooled in an ice bath to 10° C. and 10% aq. Na2SO3 (˜50 g/500 ml) was added dropwise over 60 minutes until test with starch iodide paper was negative. The resulting mixture was filtered to remove a quantity of fluffy solid and the layers were separated. The aqueous layer was extracted with dichloromethane (2×200 ml) and the combined extracts were dried over MgSO4 and concentrated under reduced pressure to give a light brown solid. Recrystallisation of crude product using 600ml of boiling acetone gave 48.47 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[C:14]=3[F:22])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.O>O1CCCC1.C(OCC)(=O)C>[NH2:19][C:15]1[C:14]([F:22])=[C:13]([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[NH:8][CH:9]=2)=[O:12])[CH:18]=[CH:17][CH:16]=1
Reactant: O=C(c1cccc([N+](=O)[O-])c1F)c1c[nH]c2ncc(Br)cc12
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1cccc(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Temperature: 60 °C
Yield: 46.7 %

Procedure:
To (5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-fluoro-3-nitro-phenyl)-methanone (18, 2.27 g, 6.23 mmol) in 200 mL of tetrahydrofuran and 200 mL of ethyl acetate, stannous chloride, dehydrate (4.85 g, 2.15 mmol) is added. The reaction is heated at 60° C. for 3 days, then 300 mL of water and 200 mL of ethyl acetate are added. The mixture is treated with celite and filtered. Brine is added, the organic layer is separated, dried over magnesium sulfate, filtered and the filtrate is concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with ethyl acetate and hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (19, 972 mg).
Reaction SMILES: ClC1N=C2C(N=CN2)=C(N2CCOCC2)N=1.ICC(C)C.Cl[C:23]1[N:31]=[C:30]2[C:26]([N:27]=[CH:28][N:29]2[CH2:32][CH:33]([CH3:35])[CH3:34])=[C:25]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[N:24]=1.C(=O)([O-])[O:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46](B2OC(C)(C)C(C)(C)O2)[C:45]=1C(C)(C)C>>[CH2:32]([N:29]1[CH:28]=[N:27][C:26]2[C:30]1=[N:31][C:23]([C:46]1[CH:45]=[C:44]([OH:43])[CH:49]=[CH:48][CH:47]=1)=[N:24][C:25]=2[N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[CH:33]([CH3:35])[CH3:34]
Reactant: CC(C)(C)c1c(OC(=O)[O-])cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Cn1cnc2c(N3CCOCC3)nc(Cl)nc21
Agent: CC(C)CI
Agent: Clc1nc(N2CCOCC2)c2nc[nH]c2n1
Product: CC(C)Cn1cnc2c(N3CCOCC3)nc(-c3cccc(O)c3)nc21

Procedure:
4-(2-Chloro-9H-purin-6-yl)morpholine (75 mg) was reacted with 1-iodo-2-methylpropane via General Procedure C. 4-(2-Chloro-9-isobutyl-9H-purin-6-yl)morpholine was reacted with 150 mg tert-butyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl carbonate via General Procedure A and purified via reverse phase HPLC to give 62.6 mg of 145 as a white solid. MS (Q1) 354.2 (M)+
Reaction SMILES: [CH2:1]([PH:5](=[O:7])[OH:6])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.C[Si](Cl)(C)C.[CH2:20]([O:27][C:28]([CH:30]([CH2:43][CH2:44][C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[CH2:31]P(C)(=O)OCC1C=CC=CC=1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[CH2:1]([P:5]([CH2:31][CH:30]([C:28]([O:27][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:29])[CH2:43][CH2:44][C:45]([O:47][CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)=[O:46])(=[O:6])[OH:7])[CH2:2][CH2:3][CH3:4]
Reactant: CP(=O)(CC(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: CCCC[PH](=O)O
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCP(=O)(O)CC(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 40.6 %

Procedure:
Butylphosphinic acid (2.0 g, 16mmol) in 80 mL of dry dichloromethane was cooled to 0C under an atmosphere of nitrogen. Triethylamine (6.7 g, 66 mmol) was added followed by trimethylsilyl chloride (58 mL, 58 mmol, 1.0 M in dichloromethane). The mixture was stirred at 0° C. for 10 minutes and dibenzyl 2-methylenepentanedioate (2)(6.4 g, 20 mmol) in 20 mL of dichloromethane was added. The cold bath was removed and the reaction warmed to room temperature and stirred overnight. The mixture was then cooled to 0° C. and quenched by the slow addition of 5% hydrochloric acid. The dichloromethane layer was then removed and washed with 5% hydrochloric acid and with brine. The organic layer was dried (MgSO4) and evaporated to give a clear light golden liquid. The liquid was purified by flash chromatography and eluted with 3:1 hexane/ethyl acetate containing 5% acetic acid. The desired fractions were combined and evaporated to give butyl[2,4-di(benzyloxycarbonyl)butyl]phosphinic acid (3,R=n-butyl, R1=H) (2.9 g, 40w) as a clear and colorless oil. Rf 0.12 (3:1, Hex./EtOAc 5% AcOH).
Reaction SMILES: CN(C)[CH:3]=[C:4]1[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:5]1=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([NH:38][C:39]([NH2:41])=[NH:40])[CH:29]=[CH:30][C:31]=1[N:32]1[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]1>>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([NH:38][C:39]2[N:41]=[CH:3][C:4]3[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:5]=3[N:40]=2)[CH:29]=[CH:30][C:31]=1[N:32]1[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]1
Reactant: CCOC(=O)C1CCC(=CN(C)C)C1=O
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: CCOC(=O)C1CCc2cnc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc21

Procedure:
The title compound was prepared from crude ethyl 3-[1-dimethylamino-methylidene]-2-oxo-cyclopentanecarboxylate (70 mg, 0.3 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (83 mg, 0.22 mmol) using in analogous manner the procedure described in example 45b). Obtained as a pale-yellow solid (5 mg, 6%). MS ISP (m/e): 394.3 [(M+H)+]. mp 150-153° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[C:13]([O:17][C:18]([N:20]1[CH2:24][C@H:23]([OH:25])[CH2:22][C@H:21]1[C:26]([O:28][CH3:29])=[O:27])=[O:19])([CH3:16])([CH3:15])[CH3:14].O>O1CCCC1>[C:13]([O:17][C:18]([N:20]1[CH2:24][C@H:23]([O:25][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:22][C@H:21]1[C:26]([O:28][CH3:29])=[O:27])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Triethylamine (14.8 ml, 106.0 mM) and methanesulfonyl chloride (6.9 ml, 90.0 mM) were added to a solution of methyl (2S,4R)-N-tert-butoxycarbonyl-4-hydroxypyrrolidine-2-carboxylate (20 g, 81.5 mM) in anhydrous tetrahydrofuran (200 ml) under ice-cooling in a nitrogen gas stream, and the mixture was stirred for 30 minutes. The reaction mixture was poured into water followed by extracting with ethyl acetate, the organic layer was washed with a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium bicarbonate, water and brine in this order and dried over anhydrous magnesium sulfate and the solvent was removed to give the title compound almost quantitatively (27 g).
Reaction SMILES: CON(C)C(=O)CCC[CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:12]=[C:11]1[CH2:23][CH2:24][CH3:25].[CH3:28][Mg]Br.[CH2:31]1[CH2:35][O:34][CH2:33][CH2:32]1>C(Cl)(Cl)Cl.C(OCC)C>[CH2:23]([C:11]1[N:10]([CH2:9][CH2:8][CH2:33][CH2:32][CH2:31][C:35](=[O:34])[CH3:28])[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:12]=1)[CH2:24][CH3:25]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)N(C)OC
Reactant: C1CCOC1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CCCc1nc2cnc3ccccc3c2n1CCCCCC(C)=O
Temperature: 25 °C

Procedure:
To a solution of N-methoxy-N-methyl-6-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanamide (22.0 g, 59.7 mmol) in chloroform (20 mL) and THF (200 mL) in an ice bath was added dropwise a solution of methylmagnesium bromide (40 mL of a 3 M solution in diethyl ether, 120 mmol). After 1 hour another charge of methylmagnesium bromide (40 mL of a 3 M solution in diethyl ether, 120 mmol) was added, the reaction mixture stirred at room temperature for 1 more hour and then quenched by the addition of a 10% solution of hydrochloric acid (about 10 mL). The mixture was concentrated under reduced pressure, the residue taken up in dichloromethane (200 mL), and the solution washed successively with a saturated aqueous sodium bicarbonate solution and brine (100 mL each), dried over potassium carbonate, and filtered. The solution was concentrated under reduced pressure and chromatographed on silica gel (elution with 3% methanol in dichloromethane) to provide 7-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)heptan-2-one (12.6 g) as an oil that was used directly in the next step without further purification.
Reaction SMILES: [C:1]1(=O)[CH2:4][CH2:3][CH2:2]1.[NH:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[NH2:7]>CCCC(C)C>[C:1]1(=[N:7][NH:6][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCCC(C)C
Product: CC(C)(C)OC(=O)NN=C1CCC1
Temperature: 25 °C

Procedure:
A mixture of cyclobutanone (16.96 ml, 227 mmol) and tert-butyl hydrazinecarboxylate (30 g, 227 mmol) in isohexane (378 mL), under nitrogen was stirred at reflux for 1 hour. The reaction mixture was cooled to room temperature and stirred for 1 hour. The resulting suspension was filtered, rinsing the solid with iso-hexane (×2). The solid was dried under vacuum at 30° C. to afford the title compound;
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][C@H:4]([N:8]1[CH2:12][C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:10][C:9]1=[O:21])[C:5]([OH:7])=O.[CH3:23][C:24]1([CH3:36])[O:28][C@H:27]([CH2:29][N:30]2[CH:34]=[CH:33][C:32]([NH2:35])=[N:31]2)[CH2:26][O:25]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH3:23][C:24]1([CH3:36])[O:28][C@H:27]([CH2:29][N:30]2[CH:34]=[CH:33][C:32]([NH:35][C:5](=[O:7])[C@@H:4]([N:8]3[CH2:12][C:11]([O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[CH3:20])=[CH:10][C:9]3=[O:21])[CH2:3][CH:2]([CH3:1])[CH3:22])=[N:31]2)[CH2:26][O:25]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: Cc1ccccc1OC1=CC(=O)N([C@@H](CC(C)C)C(=O)O)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccccc1OC1=CC(=O)N([C@@H](CC(C)C)C(=O)Nc2ccn(C[C@@H]3COC(C)(C)O3)n2)C1
Temperature: 0 °C
Yield: 48.4 %

Procedure:
To a solution of (S)-4-methyl-2-(2-oxo-4-o-tolyloxy-2,5-dihydro-pyrrol-1-yl)-pentanoic acid (prepared as in Example 120, 0.228 g, 0.75 mmol) in N,N-dimethylformamide (4 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.192 g, 0.97 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.663 g, 1.50 mmol). The mixture was stirred at 0° C. and triethylamine (0.153 g, 1.51 mmol) was added. The mixture was stirred at room temperature for 4 h and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 25 g, 30% to 70% ethyl acetate/hexanes) which afforded (S)-4-methyl-2-(2-oxo-4-o-tolyloxy-2,5-dihydro-pyrrol-1-yl)-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.175 g, 48%) as a pink solid: HR-ES-MS m/z calculated for C26H34N4O5 [M+H]+ 483.2602, observed 483.2603, 1H NMR (200 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.5 Hz, 3H), 0.94 (d, J=6.5 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3H), 1.36-1.66 (m, 2H), 1.68-1.81 (m, 1H), 2.19 (s, 3H), 3.73 (dd, J=8.5, 5.7 Hz, 1H), 4.00 (dd, J=8.5, 6.3 Hz, 1H), 4.11 (t, J=5.7 Hz, 2H), 4.20 (d, J=18.4 Hz, 1H), 4.28-4.42 (m, 1H), 4.58 (d, J=18.4 Hz, 1H), 4.63 (s, 1H), 4.88 (dd, J=10.6, 4.8 Hz, 1H), 6.44 (d, J=2.4 Hz, 1H), 7.16-7.33 (m, 3H), 7.36 (d, J=7.5 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 10.80 (s, 1H).
Reaction SMILES: CS(C)=O.CCN(C(C)C)C(C)C.[F:14][C:15]([F:40])([C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([F:39])=[CH:31][CH:30]=1)[CH2:16][NH:17][C:18]1[C:19]([F:28])=[C:20]([CH2:25][CH2:26][OH:27])[C:21]([Cl:24])=[CH:22][CH:23]=1>C(Cl)Cl>[F:40][C:15]([F:14])([C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([F:39])=[CH:31][CH:30]=1)[CH2:16][NH:17][C:18]1[C:19]([F:28])=[C:20]([CH2:25][CH:26]=[O:27])[C:21]([Cl:24])=[CH:22][CH:23]=1
Reactant: OCCc1c(Cl)ccc(NCC(F)(F)c2ccc(F)c3ccccc23)c1F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=CCc1c(Cl)ccc(NCC(F)(F)c2ccc(F)c3ccccc23)c1F
Reaction time: 3.5 h
Yield: 100.2 %

Procedure:
To a solution of DMSO (470 mg, 6.0 mmol), DIEA (823 μL, 4.74 mmol) and 2-(3-{[2,2-difluoro-2-(4-fluoronaphthyl)ethyl]amino}-6-chloro-2-fluorophenyl)ethanol (723 mg, 1.82 mmol), as prepared in the preceding step, in DCM (55 mL) in an ice-bath was added sulfur trioxide pyridine complex (754 mg, 4.74 mmol). After stirring for 3.5 hours the reaction mixture was diluted with DCM (110 mL). The organic layer was separated, and the aqueous layer extracted with DCM (100 mL). The organic layers were combined, washed with 10% citric acid (3 times), H2O, and brine, dried over Na2SO4, and concentrated to give the title compound (722 mg, quantitative yield) as an orange oil. 1H-NMR (400 MHz, CDCl3) δ 9.69 (d, J=1.1 Hz, 1H), 8.22-8.18 (m, 2H), 7.67 -7.60 (m, 3H), 7.14 (t, J=9.2 Hz, 1H), 6.94 (d, J=8.8 Hz, 1H), 6.49 (t, J=8.7 Hz, 1H), 4.20 (bs, 1H), 4.00 (dt, J=13.3, 6.7 Hz, 2H), 3.83 (s, 2H).
Reaction SMILES: [C:1]([O:11][C:12]([C:15](I)([F:17])[F:16])([F:14])[F:13])([C:7]([F:10])([F:9])[F:8])([C:3]([F:6])([F:5])[F:4])[F:2]>C(O)(C)C.Cl[Hg]Cl>[C:1]([O:11][C:12]([CH:15]([F:17])[F:16])([F:13])[F:14])([C:7]([F:8])([F:10])[F:9])([C:3]([F:6])([F:5])[F:4])[F:2]
Reactant: FC(F)(F)C(F)(OC(F)(F)C(F)(F)I)C(F)(F)F
Agent: Cl[Hg]Cl
Solvent: CC(C)O
Product: FC(F)C(F)(F)OC(F)(C(F)(F)F)C(F)(F)F
Temperature: 55 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
A solution of (CF3)2CFOCF2CF2I (21.3 g) in isopropanol (8 mL) was added dropwise to a suspension of Al chips (1 g) and HgCl2 (0.4 g) in isopropanol (30 mL). After the exothermic reaction was completed, the reaction mixture was stirred for 1 hour at 55° C. The reaction mixture was then distilled and a fraction with a b.p. of less then 80° C. was collected. This fraction was washed with an aqueous HCl solution and then distilled over conc. H2SO4 to give (CF3)2CFOCF2CHF2 (11.8 g, 80% yield), b.p. 44 to 46° C. The 1H and 19F NMR were in accord with the assigned structure:
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@@H:8]([NH:10]C(=O)OC(C)(C)C)[CH3:9])=[C:4]([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=2)[CH:3]=1.[F:26][C:27]1([F:39])[O:31][C:30]2[CH:32]=[CH:33][C:34]([C:36](Cl)=[O:37])=[CH:35][C:29]=2[O:28]1>C(Cl)Cl>[NH2:10][C@@H:8]([CH3:9])[CH2:7][O:6][C:5]1[CH:18]=[CH:19][C:2]([NH:1][C:36]([C:34]2[CH:33]=[CH:32][C:30]3[O:31][C:27]([F:39])([F:26])[O:28][C:29]=3[CH:35]=2)=[O:37])=[CH:3][C:4]=1[C:20]1[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc2c(c1)OC(F)(F)O2
Reactant: C[C@@H](COc1ccc(N)cc1-c1ccnn1C)NC(=O)OC(C)(C)C
Solvent: ClCCl
Product: C[C@H](N)COc1ccc(NC(=O)c2ccc3c(c2)OC(F)(F)O3)cc1-c1ccnn1C
Temperature: 40 °C

Procedure:
To a solution of tert-butyl(S)-1-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)propan-2-ylcarbamate (40.0 mg, 115 μmol) in DCM was added 2,2-difluorobenzo[d][1,3]dioxole-5-carbonyl chloride (28.0 mg, 127 μmol) followed by TEA (32.2 μl, 231 μmol). The reaction was mixed in a rotary shaker at 25° C. for 1 hour then quenched with MeOH (100 μl). After mixing for 20 minutes TFA (400 μl) was added and the resulting mixture was heated to 40° C. and mixed for 1 hour. The organic solvent was removed under vacuum; the crude residue was dissolved in acetonitrile (0.5 mL), neutralized with saturated bicarbonate and subjected to purification by preparative LCMS. The proper fractions were pooled, frozen and lyophilized to afford the title compound as an off white solid (16.7% yield). LCMS m/z=431.3 (M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (d, J=6.82 Hz, 3 H), 3.48-3.58 (m, 1 H), 3.71 (s, 3 H), 3.99-4.08 (m, 2 H), 6.36 (d, J=1.77 Hz, 1 H), 7.25 (d, J=9.09 Hz, 1 H), 7.50 (d, J=1.77 Hz, 1 H), 7.60 (d, J=8.59 Hz, 1 H), 7.71 (d, J=2.53 Hz, 2 H), 7.82-7.91 (m, 2 H), 10.35 (s, 1 H).