Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][C@H:9]([OH:13])[CH2:8][O:7]2)([O-:3])=[O:2].[Br:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[H-].[Na+]>CN(C=O)C>[Br:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH2:21][O:13][C@@H:9]2[CH2:8][O:7][C:6]3=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][N:11]3[CH2:10]2)[CH:16]=1
Reactant: O=[N+]([O-])c1cn2c(n1)OC[C@@H](O)C2
Reactant: ClCc1cc(Br)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cn2c(n1)OC[C@@H](OCc1cc(Br)ccn1)C2
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
A solution of (S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxa-zin-6-ol (2.87 g, 15.5 mmol) and 4-bromo-2-(chloromethyl)pyridine (2.91 g, 14 mmol) in dry DMF (60 mL) was treated with NaH (0.68 g of a 60% dispersion in mineral oil, 16.9 mmol,) at 0-5° C., and the mixture was stirred at room temperature for 3 h, then quenched with water (150 mL) and extracted with EtOAc (6×150 mL). The organic layers were dried (MgSO4), evaporated, and chromatographed on silica gel, eluting with MeOH/EtOAc (1:19), to give the title compound (2.701 g, 54%) as a light yellow solid. APCI MS m/z 355.7, 357.7 (M+H). 1H NMR (400 MHz, (CD3)2SO) 68.41 (d, J=5.3 Hz, 1H), 8.01 (s, 1H), 7.59 (dd, J=5.3, 1.9 Hz, 1H), 7.55 (d, J=1.5 Hz, 1H), 4.78-4.68 (m, 3H), 4.50 (d, J=12.0 Hz, 1H), 4.35-4.22 (m, 3H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13](Cl)(=[O:29])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[C:13]([O:12][CH2:11][CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:29])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: O=C(OCCO)c1ccccc1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCCCCCC(=O)OCCOC(=O)c1ccccc1

Procedure:
2-Benzoyloxyethyl palmitate was prepared by the procedure of Example 1 from 16 grams (0.1 mole) of ethylene glycol monobenzoate and 26 gms (0.1 mole) of palmitoyl chloride. The structure of the final product was characterized on the basis of NMR and IR spectral analyses as described in Example 1.
Reaction SMILES: [NH2:1][C@H:2]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[F:23])=[CH:12][CH:11]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[P:24]([CH2:28][CH2:29][C:30](O)=[O:31])([OH:27])([OH:26])=[O:25].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]([F:23])=[C:16]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][C@@H:2]([NH:1][C:30](=[O:31])[CH2:29][CH2:28][P:24](=[O:25])([OH:27])[OH:26])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:11][CH:12]=2)[CH:21]=1
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Reactant: O=C(O)CCP(=O)(O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)CCP(=O)(O)O
Reaction time: 0.11 h
Yield: 11.8 %

Procedure:
(R)-ethyl 3-amino-4-(5′-chloro-2′-fluoro-[1,1-biphenyl]-4-yl)butanoate (114 mg, 0.306 mmol), 3-phosphonoproprionic acid (47.2 mg, 0.306 mmol), EDC (58.7 mg, 0.306 mmol) and HOBT (46.9 mg, 0.306 mmol) were mostly dissolved in DMF (1 mL), and DIPEA (0.321 mL, 1.837 mmol) was added. The reaction mixture was stirred and heated at 70° C. approximately 18 hours, then filtered and purified by HPLC: 30-80% ACN/H2O 0.1% TFA, 40 mL/min over 15 min 30×100 Sunfire C18, product elutes approximately 5.5-8 min. A mixed fraction was repurified on a 20-55% gradient over 20 min, and product eluted ˜12.5-13 min. The fractions were evaporated to dryness to afford (R)-(3-((1-(5′-chloro-2′-fluoro-[1,1-biphenyl]-4-yl)-4-ethoxy-4-oxobutan-2-yl)amino)-3-oxopropyl)phosphonic acid (17 mg) LCMS (ES+) C21H24ClFNO6P: Calc.: 471.1; Found: 472.0[M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[C:18]([N+:20]([O-])=O)[CH:19]=1)[C:7]([CH:9]1[CH2:16][CH2:15][CH2:14][CH2:13][NH:12][C:10]1=[O:11])=[O:8])([O-])=O.C(O)C.[H][H]>[Pd].C(Cl)Cl>[NH2:1][C:4]1[CH:5]=[C:6]([CH:17]=[C:18]([NH2:20])[CH:19]=1)[C:7]([CH:9]1[CH2:16][CH2:15][CH2:14][CH2:13][NH:12][C:10]1=[O:11])=[O:8]
Reactant: O=C1NCCCCC1C(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: Nc1cc(N)cc(C(=O)C2CCCCNC2=O)c1

Procedure:
A mixture of 3,5-dinitrobenzoyl caprolactam (2.00 g, 4.07 mmol), 0.08 g of 5 percent palladium on carbon and 30 ml of absolute ethanol is stirred with hydrogen under a pressure of 1 atmosphere at 10° C. When the theoretical quantity of hydrogen (0.024 mol) has been absorbed, the solution is filtered through celite. White crystals form when the filtrate is kept in a freezer, and the final product is obtained by recrystallization from CH2Cl2 to yield 65 percent of white crystals: mp 122°-124° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1I)[CH:14]=[CH:13][O:12]2.C([Mg]Cl)(C)C.I[C:24]1[CH:25]=[CH:26][C:27]2[N:28]([C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[N:31][N:32]=2)[N:29]=1.CN(C=O)C>C1COCC1.C(Cl)Cl.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:24]1[CH:25]=[CH:26][C:27]3[N:28]([C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[N:31][N:32]=3)[N:29]=1)[CH:14]=[CH:13][O:12]2
Reactant: CCOC(=O)c1nnc2ccc(I)nn12
Reactant: Fc1ccc(-c2nc3occn3c2I)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4occn34)nn12
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 58.1 %

Procedure:
A 100 mL 3-neck flask and a stir bar were dried in oven overnight and then cooled under nitrogen. The reaction was kept under a nitrogen atmosphere through its entirety. 6-(2,4-difluorophenyl)-5-iodoimidazo[2,1-b]oxazole (10.0 g, 28.9 mmol, Preparation #C.1) was added to the 3-neck flask and dissolved in THF (90 mL). The reaction mixture was cooled to about −30° C. and then a solution of i-PrMgCl (2.0 M in THF, 15.9 mL, 31.8 mmol) was added dropwise. The reaction mixture continued stirring at about −30° C. for about 15 min. In a separate flask, zinc chloride (4.73 g, 34.7 mmol) was dissolved in THF (40 mL) and cooled to about 0° C. The zinc chloride solution was added dropwise (over about 30 min) to the reaction mixture to form a dark yellow suspension. The reaction mixture was stirred at about −30° C. for about 45 min. A third flask was charged with ethyl 6-iodo-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate (9.19 g, 28.9 mmol) and DMF (80 mL). To the suspension was added Pd(PPh3)4 (2.00 g, 1.73 mmol) and the suspension was immediately poured into the reaction mixture. The reaction mixture was heated to about 80° C. for 15 min. The mixture was cooled and the DMF was removed under vacuum. The resulting solid was triturated with 1-propanol (20 mL) and filtered to afford a white solid. The material was taken up in DCM (250 mL) and washed with dilute aqueous NaHCO3 (250 mL). The organics were dried and solvent was removed in vacuo to afford the title compound (6.90 g, 16.8 mmol, 58%). LC/MS (Table 1, Method b) Rt=1.72 min; MS m/z: 411.2 (M+1)+. 1H NMR (DMSO-d6) δ 8.60 (m, 1H), 8.42 (m, 1H), 8.33 (m, 1H), 7.75 (m, 1H), 7.54-7.46 (m, 1H), 7.31 (m, 1H), 7.08 (m, 1H), 4.55 (q, 2H), 1.43 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[CH:18]=[C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:17])[C:11]2=[N:10]1.ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[CH:18]=[C:12]2[CH:13]=[N+:14]([O-:27])[CH:15]=[C:16]([F:17])[C:11]2=[N:10]1
Reactant: Fc1cccc(Cl)c1-n1cc2cncc(F)c2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1cc(F)c2nn(-c3c(F)cccc3Cl)cc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
2-(2-Chloro-6-fluorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine (9.95 g, 37.5 mmol) was suspended in DCM (150 mL) at 0° C. and meta-chloroperbenzoic acid (12.9 g, 75 mmol) was added. The reaction mixture was stirred at 0° C. for 2 hours then allowed to reach room temperature and stirred for another 3 hours. The resultant mixture was quenched with saturated aqueous sodium thiosulfate solution and the layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with diethyl ether and the solid obtained was filtered off and dried to afford the title compound as a white solid (7.22 g, 68% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.04 (d, J=2.6 Hz, 1H), 8.88 (d, J=1.4 Hz, 1H), 8.35 (dd, J=6.4, 1.5 Hz, 1H), 7.82-7.73 (m, 1H), 7.72-7.62 (m, 2H).
Reaction SMILES: [C:1]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C-:9]#[N:10].C([Al+]CC)C.Cl>C1(C)C=CC=CC=1>[O:8]=[C:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([C:9]#[N:10])[CH2:2]1
Reactant: [C-]#N
Reactant: O=C1C=CCCCC1
Agent: CC[Al+]CC
Agent: Cl
Solvent: Cc1ccccc1
Product: N#CC1CCCCC(=O)C1

Procedure:
To 100 mL of toluene add 2-cyclohepten-1-one (11.0 g, 0.1 mol) and 200 mL (1M solution in toluene, 0.2 mol) of diethylaluminum cyanide. Monitor the reaction by thin-layer chromatography. Upon completion add 1M aqueous HCl until gas evolution ceases. Extract twice with 100 mL of ether. Dry the organic phase with Na2SO4. Filter off the drying agent and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[C:24]3[C:19](=[C:20]([CH2:25][S:26][CH3:27])[CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[CH2:9][CH2:10][C:11](OCC)=[O:12])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:16]2[C:24]3[C:19](=[C:20]([CH2:25][S:26][CH3:27])[CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[CH2:9][CH2:10][CH2:11][OH:12])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCC(c1ccc(Cl)cc1)c1c[nH]c2c(CSC)cccc12
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CSCc1cccc2c(C(CCCO)c3ccc(Cl)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 420 mg (1.05 mmol) of the compound from Example 46A in 10 ml of tetrahydrofuran was added dropwise to 3.7 ml (3.7 mmol) of a 1N solution of lithium aluminum hydride in tetrahydrofuran under argon in 20 ml of tetrahydrofuran at RT. The mixture was stirred at RT for 15 min and then, while cooling in ice, 1N hydrochloric acid was added. The mixture was extracted with ethyl acetate, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid). 243 mg (65% of theory) of the target compound were obtained.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:15]=2)[N:3]=1.[NH2:25][C:26]1[CH:30]=[C:29]([CH:31]2[CH2:33][CH2:32]2)[NH:28][N:27]=1.Cl>P(Cl)(Cl)(Cl)=O.O1CCOCC1.CN1C(=O)CCC1>[CH:31]1([C:29]2[NH:28][N:27]=[C:26]([NH:25][C:2]3[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]4[CH2:13][CH2:12][CH2:11][CH:10]4[C:14]4[O:18][N:17]=[C:16]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=5)[CH:15]=4)[N:3]=3)[CH:30]=2)[CH2:33][CH2:32]1
Reactant: Cc1cc(O)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Reactant: Nc1cc(C2CC2)[nH]n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(Nc2cc(C3CC3)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Temperature: 70 °C
Yield: 37.6 %

Procedure:
A mixture of 4-hydroxy-6-methyl-2-[2-{3-(pyrid-2-yl)isoxazol-5-yl}pyrrolidin-1-yl]pyrimidine (Method 30) (200 mg, 0.62 mmol) in phosphoryl chloride (7 ml) was heated at 70° C., under nitrogen for 30 minutes. The volatiles were removed by evaporation and the residue dissolved in DCM, washed with saturated sodium hydrogen carbonate solution, dried (MgSO4) and the solvent removed by evaporation. The crude product was then treated as described in Example 12, with 3-amino-5-cyclopropyl-1H-pyrazole (Method 7 of WO-03/048133) (120 mg, 0.98 mmol), and 4M hydrogen chloride solution in dioxane (0.65 ml) in NMP (5 ml) to give the title compound (100 mg, 37%).
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[C:13]([CH3:19])=[C:12]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27])([CH3:7])[CH3:6])C.[OH-].[K+]>CO.O>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:28])=[O:3])[CH:10]=2)[N:14]([CH3:18])[C:13]=1[CH3:19]
Reactant: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccccc1OC)c(C)n2C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccccc1-c1c(C)n(C)c2ccc(OC(C)(C)C(=O)O)cc12

Procedure:
One gram (2.6 m mole) of 2-[3-(2-methoxy-phenyl)-1,2-dimethyl-1H-indole-5-yloxy]-2-methyl-propanoic acid ethylester was dissolved in 18 ml of methanol and mixed with a solution of 0.35 g of potassium hydroxide in 2 ml of water. Within three to four hours 6 ml of water were added dropwise at room temperature so slowly that no ester precipitated. After stirring of the mixture for two to three hours, the methanol was distilled off at the rotation evaporator. Subsequently 20 ml of water were added and the alkaline solution was extracted twice with ether. After the aqueous phase was acidified with hydrochloric acid, the aqueous phase was extracted with ether. The ether extracts were dried over sodium sulfate. After the ether was distilled off, the residue obtained was treated with petroleum ether, whereby the crystalline acid was obtained.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][C:11]=3[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Na].[Hg].[OH-].[Na+]>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12][C:11]=3[CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cc2cc(-c3ccccc3)ccc2o1
Agent: [Hg]
Agent: [Na+]
Agent: [Na]
Product: O=C(O)C1Cc2cc(-c3ccccc3)ccc2O1
Reaction time: 24 h

Procedure:
5.0 g of 1 was mixed with 90 ml of 10% sodium hydoxide solution. Sodium amalgam (prepared from 1.5 g of sodium and 50 l g of mercury) was added to the stirred mixture over a period of one hour. The mixture was then stirred for 24 hours and allowed to stand at room temperature for an additional 24 hours. The mercury was separated, and the solution was neutralized with dilute hydrochloric acid and extracted with ether. The extract was dried (Na2SO4) and concentrated under reduced pressure, and the residue was recrystallized from ethanol to give 2, as white crystals, mp: 186°-187° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1.FC(F)(F)C(O)=O>ClCCl>[NH:9]1[CH2:10][CH2:11][CH:6]([CH2:5][C:4]2[CH:3]=[C:2]([CH:21]=[CH:20][CH:19]=2)[NH2:1])[CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(N)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cccc(CC2CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.6 %

Procedure:
tert-Butyl 4-(3-aminobenzyl)piperidine-1-carboxylate (6.09 mmol, 1.77 g) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (5 mL) was added and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum and purified by SCX chromatography to afford the intermediate 3-(piperidin-4-ylmethyl)aniline (1.27 g).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:11]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:15](=[O:24])[CH2:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9]C.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH:11]2[N:16]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[C:15](=[O:24])[CH2:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COc1ccc(C2CCCC(=O)N2c2ccc(Cl)cc2)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1CCCC(c2ccc(O)c(O)c2)N1c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 78 %

Procedure:
To a solution of 670 mg of 6-(3,4-dimethoxyphenyl)-1-(4-chlorophenyl)-2-piperidone in 17 ml of methylene chloride was added, under ice-cooling, 1.0 ml of boron tribromide, and the mixture was stirred under ice-cooling for 1 hour and at room temperature for 45 minutes. The mixture was treated with ice-water, extracted with chloroform. The extracts were washed with water, dried, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 480 mg of 6-(3,4-dihydroxyphenyl)-1-(4-chlorophenyl)-2-piperidone as colorless prisms.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[CH3:11][S:12](C)(=[O:14])=[O:13]>>[CH3:11][S:12]([C:2]1[CH:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][N:3]=1)(=[O:14])=[O:13]
Reactant: CC(=O)c1ccnc(Br)c1
Reactant: CS(C)(=O)=O
Product: CC(=O)c1ccnc(S(C)(=O)=O)c1

Procedure:
Alternatively, (1-(2-bromo-pyridin-4-yl)-ethanone) could be converted to the corresponding methyl sulfone via the above procedure to afford 1-(2-methanesulfonyl-pyridin-4-yl)-ethanone. 1-(2-Methanesulfonyl-pyridin-4-yl)-ethanone can be converted to the title compound by methods described in example 86.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][NH:4][CH2:5][CH2:6][O:7][N:8]1C(=O)C2C(=CC=CC=2)C1=O.CNN.FC1C(O[C:32](=[O:50])[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[C:35]([F:40])[C:34]=2[NH:41][C:42]2[CH:47]=[CH:46][C:45]([I:48])=[CH:44][C:43]=2[CH3:49])=C(F)C(F)=C(F)C=1F.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.CCOCC.ClCCl>[F:40][C:35]1[C:34]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([I:48])=[CH:44][C:43]=2[CH3:49])=[C:33]([CH:38]=[CH:37][C:36]=1[F:39])[C:32]([NH:8][O:7][CH2:6][CH2:5][NH:4][CH2:3][C:2]([F:20])([F:19])[F:1])=[O:50]
Reactant: O=C1c2ccccc2C(=O)N1OCCNCC(F)(F)F
Reactant: Cc1cc(I)ccc1Nc1c(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc(F)c1F
Agent: CNN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(I)ccc1Nc1c(C(=O)NOCCNCC(F)(F)F)ccc(F)c1F
Reaction time: 8 h
Yield: 87.6 %

Procedure:
Dichloromethane (5 mL) was added to 2-[2-(2,2,2-trifluoro-ethylamino)-ethoxy]-isoindole-1,3-dione (0.46 g, 1.6 mmol) and the resultant solution was cooled to 0° C. Methylhydrazine (0.086 mL, 1.62 mmol) was added and the resultant solution was stirred at ambient temperature for 1 h. Ether (20 mL) was added and the precipitate was filtered and the filtrate was concentrated in vacuo. Dimethylformamide (5 mL) was added and the resultant solution was treated sequentially with 3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid pentafluorophenyl ester (0.847 g, 1.51 mmol) and diisopropylethylamine (0.60 mL, 3.4 mmol). The resultant reaction mixture was stirred overnight, diluted with ethyl acetate and washed with water (4×) and saturated brine, dried over magnesium sulfate and concentrated in vacuo. Purification by silica gel chromatography (hexanes-ethyl acetate, 1:1) afforded 3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-[2-(2,2,2-trifluoro-ethylamino)-ethoxy]-benzamide (0.70 g, 83% yield) as a waxy foam: 1H NMR (400 MHz, Acetone-d6) δ 10.98 (br s, 1H), 8.69 (br s, 1H), 7.52 (br s, 2H), 7.39 (dd, J=8.6 Hz, 2.0 Hz, 1H), 7.00 (m, 1H), 6.55 (dd, J=8.6 Hz, 6.4 Hz, 1H), 3.27 (q, J=10.0 Hz, 2H), 2.90 (br t, J=4.9 Hz, 2H), 2.82 (br s, 2H), 2.30 (s, 3H); 19F NMR (376 MHz, Acetone-d6) δ −73.1 (t, J=10.0 Hz, 3F), −133.8 (s, 1F), −143.2 (s, 1F); MS (APCI+)=530.0.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([C@:28]4([CH3:35])[CH2:32][O:31]C(C)(C)[O:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:36]>CCO>[ClH:36].[CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([C@:28]([OH:29])([CH3:35])[CH2:32][OH:31])[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@]2(C)COC(C)(C)O2)ns1
Agent: Cl
Solvent: CCO
Product: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@@](C)(O)CO)ns1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
(R)—N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(2,2,4-trimethyl-1,3-dioxolan-4-yl)-1,2,4-thiadiazol-5-amine (65 mg, 0.128 mmol) was dissolved in EtOH (3 mL) and 1M HCl (0.3 mL) was added. The mixture was stirred at ambient temperature for 24 hours. Additional 1M HCl (0.3 mL) was added and the mixture was stirred overnight. The mixture was partitioned between saturated aqueous sodium bicarbonate and CH2Cl2, and the organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified over silica gel (15% methanol in EtOAc) to afford (R)-2-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)propane-1,2-diol hydrochloride (42.6 mg, 0.0844 mmol, 66.0% yield) as a white solid after HCl salt formation. Mass Spectrum (apci) m/z=469.1 (M+H−HCl).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:24])[C:9]([C:15]2[CH:16]=[CH:17][C:18](=[O:23])[N:19]([CH2:21][CH3:22])[CH:20]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:25])[CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37]>>[CH2:39]([O:38][C:36]([C:28]1[CH:29]=[C:30]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:24])[C:9]([C:15]3[CH:16]=[CH:17][C:18](=[O:23])[N:19]([CH2:21][CH3:22])[CH:20]=3)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:25])[CH:3]=2)[CH:31]=[CH:32][C:27]=1[F:26])=[O:37])[CH3:40]
Reactant: CCOC(=O)c1cc(B(O)O)ccc1F
Reactant: CCn1cc(C(O)(C(C)c2ccc(Br)cc2Cl)C(F)(F)F)ccc1=O
Product: CCOC(=O)c1cc(-c2ccc(C(C)C(O)(c3ccc(=O)n(CC)c3)C(F)(F)F)c(Cl)c2)ccc1F

Procedure:
In analogy to Example 150, step 2, 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-ethyl-1H-pyridin-2-one was reacted with 4-fluoro-3-ethoxycarbonylphenylboronic acid to give the title compound as a colorless foam. MS (m/e)=526.3 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](Cl)=[N:6][OH:7])[CH3:2].[C:10]([CH:14]1[CH2:19][CH2:18][C:17](=[CH2:20])[CH2:16][CH2:15]1)([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([C:5]1[CH2:20][C:17]2([CH2:18][CH2:19][CH:14]([C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:15][CH2:16]2)[O:7][N:6]=1)=[O:9])[CH3:2]
Reactant: CCOC(=O)C(Cl)=NO
Reactant: C=C1CCC(C(C)(C)C)CC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=NOC2(CCC(C(C)(C)C)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-chloro-2-hydroxyiminoacetic acid ethyl ester (2.2 g, 14.6 mmol) in DCM (20 ml) was slowly added dropwise at 0° C. to a solution of 1-tert-butyl-4-methylenecyclohexane (740 mg, 4.86 mmol) in DCM (20 ml). Subsequently, a solution of triethylamine (1.5 ml) in DCM (10 ml) was slowly added dropwise at 0° C. and the resulting mixture was stirred overnight at RT. The reaction mixture was diluted with water. The aqueous phase was extracted several times with DMC. The combined organic phases were dried and the solvent was removed under vacuum. After purification of the residue (silica gel, hexane/ether 2:1) by column chromatography, the desired product 8-tert-butyl-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxylic acid ethyl ester was obtained as a yellowish liquid (1.21 g, 93% of the theoretical amount).