Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH2:8]([O:10][C:11]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12])[CH3:9].C([N-]C(C)C)(C)C.[Li+:26].[CH2:27]=[O:28]>O1CCCC1.Cl>[CH:1]([N-:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Li+:26].[CH2:8]([O:10][C:11]([C:13]1([CH2:27][OH:28])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12])[CH3:9]
Reactant: CCOC(=O)C1CCOCC1
Reactant: C=O
Reactant: CC(C)NC(C)C
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CO)CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97 %

Procedure:
Lithium diisopropylamide was prepared by the addition of 2.5M N-butyl lithium (30.3 mL, 75.6 mmol) in hexanes to a solution of diisopropylamine (10.6 mL, 75.6 mmmol) in tetrahydrofuran (244 mL) at 0° C. and stirring for 20 minutes. Then a solution of tetrahydropyran-4-carboxylic acid ethyl ester (10 g, 63.2 mmol) in tetrahydrofuran (50 mL) was added to the solution of lithium diisopropylamide over 15 minutes at -78° C. The resulting solution was stirred an additional 50 minutes, and solid paraformaldehyde (10 g) was added in one portion. The mixture was slowly allowed to warm to room temperature over 9 hours, diluted with 2M aqueous hydrochloric acid (100 mL), and filtered over a pad of celite pad which was washed with diethyl ether (2×200 mL). The aqueous layer of the filtrate was washed with additional portions of diethyl ether (2×200 mL). The combined organic layers were washed once with 2M aqueous hydrochloric acid (100 mL), saturated aqueous sodium bicarbonate (100 mL), dried over magnesium sulfate, and concentrated in vacuo to afford a slightly impure product 4-(hydroxymethyl)tetrahydropyran-4-carboxylic acid ethyl ester (11.5 g, 97%), which was taken into the next reaction without further purification. IR (neat) 3433 (br), 1726 cm-1 ; 1HNMR (CDCl3) δ 1.30 (t, J=7.1 Hz, 3H), 1.57 (ddd, J=13.8, 10.1, 4.4 Hz, 2H), 2.07 (dm, J=13.8 Hz, 2H), 2.30-2.45 (br s, 1H), 3.56 (ddd, J=11.9, 10.3, 2.7 Hz, 2H), 3.66 (s, 2H), 3.82 (dt, J=11.9, 4.2 Hz, 2H), 4.24 (q, J=7.2 Hz, 2H); 13CNMR (CDCl3) δ 14.25 (q), 30.54 (t), 46.63 (s), 61.04 (t), 64.79 (t), 69.02 (t), 175.24 (s); HRMS Calcd for C9H16O4 : 188.1049. Found: 188.1053.
Reaction SMILES: O=[C:2]1[C:6](=[CH:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH:3]1[C:16]([O:18][CH3:19])=[O:17].P(Cl)(Cl)(Cl)(Cl)[Cl:21].CO.O>CCCCCC>[Cl:21][C:2]1[C:6](=[CH:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4][C:3]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COC(=O)C1CCC(=CCCc2ccccc2)C1=O
Solvent: CO
Solvent: CCCCCC
Solvent: O
Product: COC(=O)C1=C(Cl)C(=CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 19 %

Procedure:
To a mixture of methyl 2-oxo-3-(3-phenylpropyl-1-yl)cyclopentanecarboxylate (1 g, 3.8 mmol) in hexane (40 mL) is added phosphorus pentachloride (1.5 g, 7.6 mmol). The mixture is heated under reflux for 2.5 hours. The solution is cooled in ice and methanol (few mL) is added. The mixture is stirred at room temperature for 15 minutes. The mixture is poured into water and is extracted with hexane. The organic layer is washed with water and is dried over MgSO4. The organic layer is removed in vacuo and the residue is dissolved in dichloromethane. To this solution is added 2 M oxalyl chloride (few mL). The mixture is stirred at room temperature for 2 hours. The solvent is removed in vacuo and the residue is dissolved in dichloromethane and methanol (few mL) is added. The solution is stirred at room temperature for 15 minutes. The solvent is removed in vacuo and the residue is chromatographed on silica gel (20:1 hexane:ethyl acetate) to give methyl 2-chloro-3-(3-phenylpropyl-1-yl)-1-cyclopentenecarboxylate (0.2 g, 20%): 1H-NMR (300 MHz, CDCl3) δ (TMS) 1.50-1.70 (m, 4H), 1.78-1.92 (m, 1H), 2.07-2.19 (m, 1H), 2.53-2.71 (m, 4H), 2.78-2.92 (m, 1H), 3.78 (s, 3H), 7.17-7.32 (m, 5H); MS (EI) m/e 278 (M+).
Reaction SMILES: O.[C:2]1(C)[CH:7]=CC(S(O)(=O)=O)=C[CH:3]=1.[Br:13][CH2:14][C:15]([CH2:20][Br:21])([CH2:18][OH:19])[CH2:16][OH:17]>CC(C)=O.COC(OC)(C)C>[Br:13][CH2:14][C:15]1([CH2:20][Br:21])[CH2:18][O:19][C:2]([CH3:7])([CH3:3])[O:17][CH2:16]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCC(CO)(CBr)CBr
Solvent: CC(C)=O
Solvent: COC(C)(C)OC
Solvent: O
Product: CC1(C)OCC(CBr)(CBr)CO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Para-toluenesulfonic acid monohydrate (0.1 eq) was added at 0° C. to a 0.2M solution of 2,2-bis(bromomethyl)propane-1,3-diol in acetone/2,2-dimethoxypropane (10:1) and the solution was stirred for 2 h at RT. Filtration over a pad of neutral alumina with EtOAc afforded the title compound as a white solid after evaporation of the solvent in vacuo (quant). 1H NMR (300 MHz, CDCl3, 300 K) δ 3.80 (s, 4H), 3.58 (s, 4H), 1.42 (s, 6H).
Reaction SMILES: [Mg].II.[CH2:4](Cl)[CH:5]=[CH2:6].[CH2:8](Cl)/[CH:9]=[C:10](/[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])\[CH3:11]>C(O)(=O)C.CCOCC>[CH3:11][C:10]([CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])=[CH:9][CH2:8][CH2:6][CH:5]=[CH2:4]
Reactant: C=CCCl
Reactant: CC(C)=CCC/C(C)=C/CCl
Agent: II
Agent: [Mg]
Solvent: CC(=O)O
Solvent: CCOCC
Product: C=CCCC=C(C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Magnesium turnings (51 g., 2.1 mole) were suspended in 1700 ml. of ether and activated with a crystal of iodine. Allyl chloride (153 g., 2.0 mole) in 200 ml. of ether was added dropwise so as to maintain the mixture at reflux temperature throughout the addition. The mixture was refluxed for an additional 2 hours, then a solution of technical 82% pure geranyl chloride (210 g., 1.05 mole) in 200 ml. of ether was added dropwise at reflux temperature. The mixture was stirred for 2 hours at room temperature, then it was cooled down to 10° and slightly acidified with 20% aqueous acetic acid. The mixture was extracted with ether. The extracts were neutralised with 10% NaOH, washed with water, dried as usual and concentrated. The residue gave 217 g. of crude triene as a light yellow liquid the purity of which was 80% according to vapour phase chromatography; it was used without further purification.
Reaction SMILES: ICI.C([Zn]CC)C.[CH3:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(C1[C:18]([C:23]([O:25][CH3:26])=[O:24])=[N:19][CH:20]=CC=1)=C>C(Cl)Cl.[Cl-].[NH4+]>[CH:11]1([C:12]2[C:18]([C:23]([O:25][CH3:26])=[O:24])=[N:19][CH:20]=[CH:14][CH:13]=2)[CH2:9][CH2:10]1
Reactant: CCCCCC
Reactant: C=Cc1cccnc1C(=O)OC
Agent: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ICI
Solvent: ClCCl
Product: COC(=O)c1ncccc1C1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of diiodomethane (2.46 g, 9.20 mmol) in dry DCM (5 ml) at −10° C. was added diethyl zinc in hexane (1 M, 9.2 ml, 9.20 mmol). The reaction was stirred for 30 minutes under nitrogen. To this was then added methyl 3-ethenylpyridine-2-carboxylate (0.30 g, 1.84 mmol) as a solution in DCM (5 ml) over a 15 minute period. The reaction was then allowed to warm to room temperature and was stirred at room temperature for 15 hours. The reaction mixture was diluted with a saturated solution of ammonium chloride (25 ml) and the organics were extracted with ethyl acetate (3×30 ml). The combined organics were washed with water (25 ml), brine (25 ml), dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-15% ethyl acetate/n-hexane to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([OH:10])=[C:4]([O:11][CH3:12])[CH:3]=1.[OH-].[K+].Br[C:16](P(=O)(OCC)OCC)([F:18])[F:17]>CC#N.O>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([O:10][CH:16]([F:18])[F:17])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: CCOP(=O)(OCC)C(F)(F)Br
Reactant: COc1cc(Br)cc(OC)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: COc1cc(Br)cc(OC)c1OC(F)F
Temperature: -78 °C
Reaction time: 3.5 h
Yield: 62 %

Procedure:
5-Bromo-2-(difluoromethoxy)-1,3-dimethoxybenzene was synthesized from 4-bromo-2,6-dimethoxyphenol according to the procedure of Zafrani, Y. Tetrahedron 2009, 65, 5278 as follows. To a solution of 4-bromo-2,6-dimethoxyphenol (1.08 g, 4.6 mmol) in MeCN (27 mL) was added a solution of KOH (5.0 g, 89 mmol) in H2O (27 mL). The mixture was immediately cooled over a −78° C. bath and diethyl (bromodifluoromethyl)phosphonate (1.6 mL, 8.9 mmol) was added. The flask was sealed with a septum and the cold bath was removed. The mixture was stirred for a total of 3.5 hrs during which time the septum was ejected from the flask. The reaction was diluted with EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organics were washed with 1 M NaOH, H2O and brine then dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (0-30% EtOAc-hexanes) provided 5-bromo-2-(difluoromethoxy)-1,3-dimethoxybenzene as a white solid (0.808 g, 62% yield).
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]([F:34])([F:33])[C:8]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]([CH2:17][C:18]2[CH:19]=[C:20]([C:30](O)=[O:31])[N:21]([C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=3)[N:22]=2)[N:9]=1.N1C=CC=CC=1.[NH2:41][C:42]1[C:51]([CH3:52])=[CH:50][C:49]([Cl:53])=[CH:48][C:43]=1[C:44](NC)=[O:45]>C(#N)C>[F:34][C:7]([F:6])([F:33])[C:8]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]([CH2:17][C:18]2[CH:19]=[C:20]([C:30]3[O:31][C:44](=[O:45])[C:43]4[CH:48]=[C:49]([Cl:53])[CH:50]=[C:51]([CH3:52])[C:42]=4[N:41]=3)[N:21]([C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=3)[N:22]=2)[N:9]=1
Reactant: CNC(=O)c1cc(Cl)cc(C)c1N
Reactant: O=C(O)c1cc(Cn2nc(C(F)(F)F)cc2C(F)(F)F)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Cn4nc(C(F)(F)F)cc4C(F)(F)F)nn3-c3ncccc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under argon 0.12 ml (1.60 mmol) of methanesulphonyl chloride in 3 ml of acetonitrile are cooled to 0° C. and subsequently a solution of 540 mg (1.228 mmol) of 5-(3,5-bistrifluoromethylpyrazol-1-ylmethyl)-2-(3-chloropyridin-2-yl)-2H-pyrazole-3-carboxylic acid in 0.17 ml (2.09 mmol) of pyridine and 6 ml of acetonitrile is added dropwise. The mixture is stirred at this temperature for 15 minutes and then a solution of 228 mg (1.228 mmol) of 2-amino-5-chloro-3,N-dimethylbenzamide in 0.35 ml (4.30 mmol) of pyridine and 6 ml of acetonitrile is added. After a further 15 minutes at 0° C. the mixture is admixed with 0.12 ml (1.60 mmol) of methanesulphonyl chloride and warmed slowly to room temperature overnight. The solvent is removed in vacuo, 15 ml of water are added and the crystals formed are filtered off with suction.
Reaction SMILES: [NH2:1][O:2][CH2:3]CCC(O)=O.[C:9]1(=[O:14])[O:13][CH2:12][CH2:11][CH2:10]1.C1(=O)OC(C)CC1>>[NH2:1][O:2][CH2:3][CH2:12][CH2:11][CH2:10][C:9]([OH:13])=[O:14]
Reactant: O=C1CCCO1
Reactant: NOCCCC(=O)O
Solvent: CC1CCC(=O)O1
Product: NOCCCCC(=O)O

Procedure:
5-Aminooxyvaleric acid is prepared in the same manner using the procedure of Preparation 6 for 4-aminooxybutyric acid except that the γ-butyrolactone is replaced by γ-valerolactone.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][CH:13]([O:16][CH2:17][CH2:18][CH2:19]O)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].CCN(S(F)(F)[F:27])CC.ClCCl>C1(C)C=CC=CC=1>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][CH:13]([O:16][CH2:17][CH2:18][CH2:19][F:27])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCCC1CCC(C2CCC(OCCCO)CC2)CC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCC1CCC(C2CCC(OCCCF)CC2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.1 %

Procedure:
A mixture of 2.75 g (9.8 mmol) of 4-(4-propylcyclohexyl)-(3-hydroxypropyloxy)cyclohexane obtained in Example 4, 3.14 g (19.6 mmol) of DAST, and 25 ml of dichloromethane was stirred for 5 hours at a room temperature. The reaction product was put in 40 ml of an ice water and extracted with 40 ml of toluene. The organic layer was washed with water twice and dried over anhydrous magnesium sulfate. The magnesium sulfate was separated, the solvent was distilled off under a reduced pressure, and the residue thus obtained was subjected to a silica gel column chromatography (eluate: toluene) to obtain 1.87 g of a crude 4-(4-propylcyclohexyl)-(3-fluoropropyloxy) cyclohexane. This product was recrystallized twice from 6 ml of ethanol in a freezer to obtain 1.60 g (yield 58%) of 4-(4-propylcyclohexyl)-(3-fluoropropyloxy)cyclohexane. Several kinds of spectra well supported its structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[N:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[OH:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH3:56][N:57]1[CH:61]=[C:60]([CH2:62]O)[N:59]=[N:58]1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][C:14]([C:18]([F:19])([F:20])[F:21])=[N:13]3)=[CH:4][C:3]=1[O:22][CH2:62][C:60]1[N:59]=[N:58][N:57]([CH3:56])[CH:61]=1
Reactant: Cn1cc(CO)nn1
Reactant: Oc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1cc(COc2cc(-c3ccnc4nc(C(F)(F)F)ccc34)ccc2F)nn1

Procedure:
2-Fluoro-5-(7-trifluoromethyl[1,8]naphthyridin-4-yl)phenol (50.0 mg, 0.16 mmol), resin-bound triphenylphosphine (180 mg of 3 mmol/g resin, 5.4 mmol), diisopropylazodicarboxylate (76.8 μL, 78.8 mg, 0.40 mmol) and 1-methyl-1H-1,2,3-triazole-4-methanol (prepared as described in WO 0023449, 22.0 mg, 0.20 mmol) were stirred together in THF (3 mL) at room temperature overnight. The mixture was filtered, and the filtrate was diluted with dichloromethane (15 mL), was washed with 1 N sodium hydroxide (2×10 mL), was dried over magnesium sulfate and was concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 2.5% methanol in dichloromethane, affording 5-[4-fluoro-3-(1-methyl-1H-[1,2,3]triazol-4-ylmethoxy)phenyl]-2-trifluoromethyl[1,8]naphthyridine as a colourless solid, which was recrystallised from ethyl acetate/isohexane (26.7 mg, 41%). δH (360 MHz, CDCl3) 4.13 (3H, s), 5.35 (2H, s), 7.03-7.07 (1H, m), 7.25-7.31 (1H, m), 7.38 (1H, dd, J 2.1 and 7.7), 7.54 (1H, d, J 4.6), 7.70 (1H, s), 7.86 (1H, d, J 8.8), 8.53 (1H, d, J 8.8), 9.26 (1H, d, J 4.2). m/z (ES+) 404 [MH]+.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][CH:29]=1)[CH2:6][NH:7][C:8](=[O:26])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([O:21][CH:22]([CH3:24])[CH3:23])[CH:18]=[CH:17][C:16]=2[NH2:25])[CH:10]=1.[C:32]([O:36][C:37](=[O:51])[CH2:38][CH2:39][S:40][CH2:41][C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=1)[C:45](O)=[O:46])([CH3:35])([CH3:34])[CH3:33].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:31][C:2]([F:30])([F:1])[C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][CH:29]=1)[CH2:6][NH:7][C:8]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([O:21][CH:22]([CH3:24])[CH3:23])[CH:18]=[CH:17][C:16]=2[NH:25][C:45]([C:44]2[CH:43]=[C:42]([CH:50]=[CH:49][CH:48]=2)[CH2:41][S:40][CH2:39][CH2:38][C:37]([O:36][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:51])=[O:46])[CH:10]=1)=[O:26]
Reactant: CC(C)Oc1ccc(N)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(NC(=O)c2cccc(CSCCC(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-isopropoxyphenyl)isonicotinamide (230 mg, 0.48 mmol, 1.00 equiv, 90%) in dichloromethane (8 mL), 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid 1.1c (317 mg, 0.86 mmol, 2.00 equiv, 80%), EDC.HCl (206 mg, 1.07 mmol, 2.00 equiv), and 4-dimethylaminopyridine (131 mg, 1.07 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at 25° C. The resulting solution was diluted with 100 mL of ethyl acetate and washed with 1×20 mL of aqueous NH4Cl, 1×20 mL of 10% sodium bicarbonate, and 1×20 mL of brine. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:2). The product was obtained as 240 mg (60%) of a brown oil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].[C:13](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[F:8][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[C:3]([O:12][CH3:13])[C:2]=1[F:1]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1O
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1c([N+](=O)[O-])ccc(F)c1F
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To a solution of 2,3-difluoro-6-nitrophenol (15.01 g, 85.8 mmol) in anhydrous dimethylformamide (120 mL) was cautiously added potassium carbonate (16.6 g, 120 mmol) and methyl iodide (6.63 mL, 107 mmol). The resulting suspension was stirred overnight. The next morning the reaction was poured into water and extracted twice with diethyl ether. The organic layers were washed twice with 5% LiCl, dried over sodium sulfate. The solvents were removed under reduced pressure to afford 1,2-difluoro-3-(methyloxy)-4-nitrobenzene as a yellow oil (14.7 g, 91% yield). 1H NMR (400 MHz, CDCl3) δ ppm 4.13 (s, 3 H), 7.00 (td, J=9.07, 7.15 Hz, 1 H), 7.67 (ddd, J=9.35, 5.32, 2.20 Hz, 1 H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6]([CH3:9])([CH3:8])[N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:4]1[CH2:17][C:18]1[N:19]=[CH:20][S:21][CH:22]=1.N1C=CN=C1.[C:28]([Si:32](Cl)([CH3:34])[CH3:33])([CH3:31])([CH3:30])[CH3:29]>CN(C=O)C.C(OCC)C>[Si:32]([O:1][CH2:2][C@H:3]1[O:7][C:6]([CH3:9])([CH3:8])[N:5]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C@H:4]1[CH2:17][C:18]1[N:19]=[CH:20][S:21][CH:22]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2cscn2)[C@@H](CO)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2cscn2)[C@@H](CO[Si](C)(C)C(C)(C)C)OC1(C)C
Reaction time: 2 h

Procedure:
(4S,5S)-Tert-butyl 5-(hydroxymethyl)-2,2-dimethyl-4-(thiazol-4-ylmethyl)oxazolidine-3-carboxylate (0.096 g, 0.29 mmol) was dissolved in DMF (1 mL) with 1H-imidazole (0.026 g, 0.38 mmol) and tert-butylchlorodimethylsilane (0.053 g, 0.35 mmol). The reaction was stirred 2 hrs, diluted with diethyl ether and washed twice with water and once with brine. The organic layer was dried over magnesium sulfate and concentrated to furnish the title compound, which was used for the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH2:19])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH2:20]>>[OH2:20].[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([S:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH2:19])=[O:20])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([S:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH2:19])=[O:20])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2[nH]c(SCc3ccccc3N)nc12
Solvent: O
Product: Cc1cccc2[nH]c(S(=O)Cc3ccccc3N)nc12

Procedure:
The title compound (740 mg) was prepared by the method of Example 3 using 900 mg of the title product of Example 7 instead of the title product of Example 2. Analysis. Calc'd. for C15H15N3OS*½ H2O: C, 61.20; H,5.48; N, 14.27; S, 10.89. Found: C, 61.21; H, 5.05; N, 13.88; S, 11.12.
Reaction SMILES: C([O:3][C:4](=[O:12])[CH2:5][C:6]([CH:9]1[CH2:11][CH2:10]1)([CH3:8])[CH3:7])C.O.[OH-].[Li+]>C1COCC1.O.CO.O>[CH:9]1([C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([OH:12])=[O:3])[CH2:11][CH2:10]1
Reactant: CCOC(=O)CC(C)(C)C1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(CC(=O)O)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-cyclopropyl-3-methylbutyric acid ethyl ester (3.0 g, 17.6 mmol) and lithium hydroxide monohydrate (3.5 g, 105 mmol) in THF/H2O/MeOH (24 mL, 2:1:1 v/v) was stirred at rt overnight. The reaction mixture was diluted with water (100 mL), and washed with ethyl acetate (2×50 mL). The aqueous layer was acidified with 2M HCl and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (200 mL), dried over sodium sulfate and concentrated to give 3-cyclopropyl-3-methylbutyric acid.
Reaction SMILES: C([N:4]([CH:7]([CH3:9])C)[CH2:5]C)(C)C.CS(O[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C@H:28]3[O:32]C(C)(C)[N:30]([C:35](=[O:39])[CH:36]([Cl:38])[Cl:37])[C@@H:29]3[CH2:40][F:41])=[CH:24][CH:23]=2)=[CH:18][N:17]=1)(=O)=O.N1CCC1.Cl>CN(C)C=O>[N:4]1([CH2:15][C:16]2[N:17]=[CH:18][C:19]([C:22]3[CH:23]=[CH:24][C:25]([C@@H:28]([OH:32])[C@H:29]([NH:30][C:35](=[O:39])[CH:36]([Cl:38])[Cl:37])[CH2:40][F:41])=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[CH2:5][CH2:9][CH2:7]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC1(C)O[C@H](c2ccc(-c3ccc(COS(C)(=O)=O)nc3)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Agent: C1CNC1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(N[C@H](CF)[C@H](O)c1ccc(-c2ccc(CN3CCC3)nc2)cc1)C(Cl)Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 21.3 %

Procedure:
Diisopropylethylamine (296 μL, 1.68 mmol) is added to the product of Example 20, Step 2 (50 mg, 0.11 mmol) and azetidine.HCl salt (146 mg, 1.12 mmol) in dimethylformamide (1 mL) and the mixture heated to 60° C. for 4 hours. The solvent is removed under reduced pressure and the residue dissolved in CH2Cl2 (2 mL). The mixture is cooled to 0° C. and trifluoroacetic acid (2 mL) added. After 1 hour, the solvent is removed under reduced pressure and the crude product purified using reverse phase HPLC to give the title compound (10 mg): m/z (CI) M−H 425.1.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[Cs+].[Cs+].F[C:8]1[CH:9]=[C:10](B(O)O)[CH:11]=[C:12](F)[CH:13]=1.[O:18]1CCO[CH2:20][CH2:19]1.N#N>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[O:18]1[C:12]2[C:13](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:1](=[O:4])[CH2:20][CH2:19]1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: O=C([O-])[O-]
Reactant: C1COCCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Agent: [Cs+]
Solvent: O
Product: O=C1CCOc2ccccc21

Procedure:
To a 10 mL CEM microwave test tube was charged with Cs2CO3 (391 mg, 1.20 mmol), PdCl2(PPh3)2 (30 mg, 0.04 mmol), (S/R)-6-bromo-2-((R/S)-tetrahydro-2H-pyran-3-yl)chroman-4-one (185.7 mg, 0.60 mmol), 3,5-difluorophenylboronic acid (142 mg, 0.90 mmol), dioxane (3 mL) and H2O (0.3 mL), the system was swept with N2 and capped, and heated in a CEM microwave reactor at 100 C for 8 min. Another tube charged with the same amount of reagents and starting material was repeated the same reaction at the same temperature and reaction time. Combined the reaction mixture and evaporated. The residue was dissolved in MeOH and filtered. The filtrate was evaporated and purified by flash chromatography on silica gel and eluted with EA in hexane (0-40%) to give (S/R)-6-(3,5-difluorophenyl)-2-(R/S)-tetrahydro-2H-pyran-3-yl)chroman-4-one (281 mg). 1H NMR (400 MHz, CDCl3) δ: 8.07 (s, 1H), 7.68 (dd, J=8.4, 2.0, 1H), 7.09-7.06 (m, 3H), 6.77 (m, 1H), 4.38 (m, 1H), 3.97-3.90 (m, 2H), 3.52-3.43 (m, 2H), 2.84-2.65 (m, 2H), 2.05 (m, 2H), 1.73-1.61 (m, 4H); 19F NMR (375 Hz, CDCl3) δ: −109.82; MS ESI +ve m/z 345 (M+H)+.