Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][CH:6]2[C:9]([OH:11])=O)[O:3]1.Cl.[CH2:13]([O:15][C:16]([C:18]1([NH2:23])[CH2:20][CH:19]1[CH:21]=[CH2:22])=[O:17])[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[CH2:13]([O:15][C:16]([C:18]1([NH:23][C:9]([CH:6]2[CH2:5][CH:4]3[CH2:8][CH:7]2[C:2](=[O:1])[O:3]3)=[O:11])[CH2:20][CH:19]1[CH:21]=[CH2:22])=[O:17])[CH3:14]
Reactant: C=CC1CC1(N)C(=O)OCC
Reactant: O=C(O)C1CC2CC1C(=O)O2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC1CC1(NC(=O)C1CC2CC1C(=O)O2)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of 13 (857 mg, 5.5 mmol), in DMF (14 mL) and DCM (25 mL) at room temperature, was added the hydrochloride of 1-amino-2-vinyl-cyclopropanecarboxylic acid ethyl ester, prepared as described in WO03/099274, (1.15 g, 6.0 mmol), HATU (2.29 g, 6.0 mmol) and DIPEA (3.82 mL, 22 mmol). The reaction was stirred under N2-atmosphere at ambient temperature for 1 h. LC/MS analysis showed complete conversion and the reaction mixture was concentrated in vacuo. The residue was redissolved in DCM (100 mL) and 0.1 M HCl (aq) and the phases were separated. The organic phase was washed with NaHCO3 (aq) and brine, dried (MgSO4) and filtered. Removal of the solvent in vacuo afforded the target compound (1.6 g, 99%). LC/MS>95%, m/z (ESI+)=294 (MH+)
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C(S)C.[N:8]1([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:28]([C:29]4[CH:34]=[CH:33][C:32]([O:35]C)=[CH:31][CH:30]=4)=[CH:27][CH:26]=[C:25]([CH3:37])[N:24]=3)=[CH:19][CH:18]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[H][H]>ClCCCl.CC(C)=O>[N:8]1([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[C:28]([C:29]4[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=4)=[CH:27][CH:26]=[C:25]([CH3:37])[N:24]=3)=[CH:21][CH:22]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: COc1ccc(-c2ccc(C)nc2-c2ccc(OCCN3CCCCC3)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCS
Solvent: CC(C)=O
Product: Cc1ccc(-c2ccc(O)cc2)c(-c2ccc(OCCN3CCCCC3)cc2)n1
Reaction time: 0.25 h
Yield: 81.5 %

Procedure:
The AlCl3 (1.2 g, 9 mmol) was stirred in 30 mL of DCE at 0° C., ethanethiol (1 mL, 14 mmol) was added, and the mixture stirred for 15 min. The 2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-3-(4-methoxyphenyl)-6-methylpyridine (0.5 g, 1.2 mmol) in 20 mL DCE was added dropwise to the reaction mixture and stirred for 2 h as it was allowed to come to rt, then quenched with 25 mL THF at 0° C., followed by 25 mL 1N HCl and worked up. The free base gave a very clean NMR, but the elemental analysis was low for carbon and hydrogen, so it was taken up in 50 mL hot acetone, citric acid H2O (0.2 g, 0.9 mmol) was added, then heated 10 min, concentrated, triturated with Et2O, filtered, and dried in vacuo to give 0.38 g (72 % yield) of product as the citrate salt: mp 90°-100° C.; 1H NMR (CDCl3) (free base) d 1.34-1.66 (comp, 6H, piperidine), 2.42-2.65 (comp, 7H, pyr-CH3 and piperidine), 2.70-2.79 (m, 2H, CH2 N), 3.95-4.10 (m, 2H, OCH2), 6.50-6.59 (m, 4H, ArH), 6.76-6.85 (d, 2H, J=8 Hz, ArH), 6.98-7.05 (d, 1H, J=8 Hz, ArH), 7.10-7.21 (m, 2H, ArH), 7.41-7.50 (d, 1H, J=8 Hz, ArH); MS(FAB) 398 [M+i]+Anal. Calcd for C25H28N2O2 ·C6H8O7 : C, 64.13; H, 6.25; N, 4.82. Found: C, 63.99; H, 6.36; N, 4.58.
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C@@H:10]([OH:21])[CH2:11][C@@H:12]([C:17]([OH:20])([CH3:19])[CH3:18])[C:13]([NH:15][CH3:16])=[O:14])=[O:7])(C)(C)C.Cl.[C:30]([O:34][C:35]([NH:37][C@H:38](C(O)=O)[CH2:39][C:40]1[N:41]=[CH:42][S:43][CH:44]=1)=[O:36])([CH3:33])([CH3:32])[CH3:31].P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>O1CCOCC1.O1CCCC1>[C:30]([O:34][C:35]([NH:37][C@H:38]([C:6]([NH:8][C@@H:9]([CH2:22][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1)[C@@H:10]([OH:21])[CH2:11][C@@H:12]([C:17]([OH:20])([CH3:18])[CH3:19])[C:13]([NH:15][CH3:16])=[O:14])=[O:7])[CH2:39][C:40]1[N:41]=[CH:42][S:43][CH:44]=1)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Reactant: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(C)(C)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)(C)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A mixture of 1.20 g (3.00 mmoles) of (2S, 4S, 5S)-5-(t-butoxycarbonylamino)-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-methylhexanamide (prepared as described in Preparation 23) in 20 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 30 minutes under an atmosphere of nitrogen. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and then diethyl ether was added to the residue. The solvent was then removed by distillation under reduced pressure from the resulting solution. The same operation was repeated in total three times, and the residue was then dried under reduced pressure for 8 hours. At the end of this time, 900 mg (3.30 mmoles) of N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine were added to a suspension of the dried material in 20 ml of anhydrous tetrahydrofuran, and then 0.50 ml (3.30 mmoles) of diethyl cyanophosphate and 0.92 ml (6.60 mmoles) of triethylamine were added to the resulting mixture, whilst ice-cooling and under an atmosphere of nitrogen. The mixture was then stirred for 5 hours, after which the solvent was removed by distillation under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (using a 20:1 by volume mixture of methylene chloride and methanol as eluent), followed by recrystallization from diisopropyl ether, to give 1.51 g (yield 91%) or the title compound as white crystals, melting at 203°-205° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Reactant: c1cncc(C2CCCCN2)c1
Solvent: ClCCl
Product: Cc1ccc(-c2oncc2C(=O)N2CCCCC2c2cccnc2)cc1
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (10 mg, 0.045 mmol) in dichloromethane (1 mL) was added 3-piperidin-2-ylpyridine (11 mg, 0.045 mmol, 1.0 eq), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C21H21N3O2: 347.1634, found 347.1644.
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7].C1(C)C(C)=CC=CC=1.[CH2:19]([CH:21]1[O:23][CH2:22]1)Cl>O>[CH2:19]([O:7][C:6](=[O:8])[C:5]([CH3:10])([CH3:9])[CH2:4][OH:3])[CH:21]1[O:23][CH2:22]1
Reactant: ClCC1CO1
Reactant: CC(C)(CO)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(C)(CO)C(=O)OCC1CO1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
96 parts by wt. 50% sodium hydroxide solution (in water) were added dropwise in 1 hour to 118 parts by wt. (1 1 mole) hydroxypivalic acid and 200 ml xylene, the temperature of the reaction mixture being kept at 110° C. The whole was kept at 110° C. for half an hour. After cooling to 50° C., 276 parts by wt. (3 mole) epichlorohydrin and 50 g Dowex were added to the reaction mixture. The temperature of the reaction mixture rose to 105° C. At this temperature the mixture was afterreacted for 1 hour. After cooling to 50° C. the water was removed azeotropically at reduced pressure (200 mbar). The salt formed and the Dowex were filtered off. The residue was washed twice with 20 ml ECH. The entire organic phase (ECH+xylene) was removed by means of rotary film evaporation. Thus 160 parts by wt. hydroxypivalic glycidyl ester were obtained in the form of a light yellow liquid with an epoxide content of 5.6 meq/g and a hydroxy content of 310 mg KOH/g.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8](Cl)[N:9]([C:12]3[CH:13]=[N:14][N:15]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH:16]=3)[C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[C:30]([O:31][CH3:32])=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:48][O:49][CH2:50][CH2:51][OH:52]>CN(C=O)C.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>[CH3:32][O:31][C:30]1[CH:29]=[C:28]([C:2]2[N:7]=[C:6]3[CH:8]([O:52][CH2:51][CH2:50][O:49][CH3:48])[N:9]([C:12]4[CH:13]=[N:14][N:15]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH:16]=4)[C:10](=[O:11])[C:5]3=[CH:4][CH:3]=2)[CH:27]=[N:26][C:25]=1[O:24][CH3:23]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cnc1OC
Reactant: O=C1c2ccc(Cl)nc2C(Cl)N1c1cnn(CC(F)(F)F)c1
Reactant: COCCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOC1c2nc(-c3cnc(OC)c(OC)c3)ccc2C(=O)N1c1cnn(CC(F)(F)F)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 21.7 %

Procedure:
As shown in step 18-ii of Scheme 18, to Compound 2060 (180 mg, 0.5127 mmol) in DMF (6 mL) was added 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Compound 2021, 163 mg, 0.62 mmol), Na2CO3 (217 mg, 2.05 mmol), Pd(PPh3)4 (30 mg, 0.026 mmol), and 2-methoxyethanol (1.5 mL, 19.0 mmol). The reaction vessel was evacuated, placed under an atmosphere of nitrogen, then warmed to 100° C. (sand bath). After 16 hours, the reaction mixture was partitioned between EtOAc and water (100 mL each). The organics were concentrated under reduced pressure and the residue dissolved in DMSO (5 mL) and purified by reversed-phase HPLC (10-90% aqueous MeCN with 0.1% TFA buffer) to give 2-(5,6-dimethoxypyridin-3-yl)-7-(2-methoxyethoxy)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 336, 55 mg) as a white lyophilizate: ESMS (M+H) 494.39; 1H NMR (CD3OD, 300 MHz) δ 8.50 (d, J=3 Hz, 1H), 8.33 (s, 1H), 8.22 (d, J=9 Hz, 1H), 8.13 (d, J=9 Hz, 1H), 8.08 (d, J=3 Hz, 1H), 8.00 (s, 1H), 6.29 (s, 1H), 4.99 (q, J=9 Hz, 2H), 4.03 (s, 3H), 3.97 (s, 3H), 3.66 (m, 1H), 3.53 (m, 3H), 3.29 (s, 3H).
Reaction SMILES: [CH2:1]([CH:4]([CH2:14][CH2:15][CH3:16])[CH2:5][CH2:6][CH2:7][CH:8]1[CH2:13][O:12][CH2:11][CH2:10][NH:9]1)[CH2:2][CH3:3].C(N(CC)CC)C.[Cl-].C[O:26][C:27](=O)[CH2:28][CH2:29][CH2:30][C:31](O)=O.Cl.C(N(CC)CC)C>CCOCC.C1C=CC=CC=1>[CH2:14]([CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH:8]1[CH2:13][O:12][CH2:11][CH2:10][N:9]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][OH:26])[CH2:15][CH3:16]
Reactant: COC(=O)CCCC(=O)O
Reactant: CCCC(CCC)CCCC1COCCN1
Agent: Cl
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCC(CCC)CCCC1COCCN1CCCCCO

Procedure:
A mixture of 8.0 grams (0.035 moles) of 3-(4-propyl-heptyl)-morpholine, 4 grams of triethylamine, 5.8 grams (0.035 moles) of glutaric acid-monomethylesterchloride and 100 ml. of benzene were refluxed for 3 hours. After cooling the triethylamine hydrochloride formed was removed by filtration and the benzene solution was directly admixed with 12 grams of lithium aluminum hydride in 500 ml of ether. The reaction mixture was refluxed for 8 hours and decomposed by slow addition of water and sodium hydroxide. The precipitate was filtered off. The ether solution was dried and evaporated to dryness and the residue was distilled at 144°-146° C./0.01 mm Hg.; yield 9.8 grams (89%). The base obtained was dissolved in ether and the hydrochloride precipitated with hydrochloric acid in ethanol. After recrystallization from ethylacetate/ether, the melting point was 59°-60° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11][CH2:12][C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15](O)=[O:16])[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:25])=O>C(Cl)Cl.CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11][CH2:12][C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([Cl:25])=[O:16])[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccccc1CSc1cccc2cccnc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccccc1CSc1cccc2cccnc12
Temperature: 25 °C

Procedure:
A solution of 1.0 eq. of 2-(quinolin-8-ylsulfanylmethyl)benzoic acid in CH2Cl2 was cooled to 0° C. To this was added 1.1 eq. of oxalyl chloride followed by one drop of DMF. The mixture was warmed to room temperature and stirred for a time sufficient for reaction completion. The mixture was concentrated to give 42 which was used directly.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[OH:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C(N=[N+]=[N-])C.[C:23](OC(=O)C)(=[O:25])[CH3:24]>C1COCC1>[C:23]([O:11][CH:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][N:2]=[CH:3]2)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:25])[CH3:24]
Reactant: OC(c1ccccc1)c1ccc2[nH]ncc2c1
Reactant: CC(=O)OC(C)=O
Agent: CCN=[N+]=[N-]
Solvent: C1CCOC1
Product: CC(=O)OC(c1ccccc1)c1ccc2[nH]ncc2c1

Procedure:
To a solution of (1H-indazol-5-yl)(phenyl)methanol (1.1 g, 5.0 mmol) in 50 mL of dry THF was added EtN3 (2.8 mL, 20 mmol) and acetic anhydride (1.9 mL, 20 mmol). The reaction was heated at reflux for 12 h. The reaction was quenched with aqueous sodium bicarbonate and extracted 2×EtOAc. The organic layers were dried over MgSO4, filtered, and concentrated. The residue was taken up in toluene and concentrated in vacuo×2 to remove any excess acetic anhydride. Obtained a quantitative yield of (1H-indazol-5-yl)(phenyl)methyl acetate. MS found: (M+H)+=309.
Reaction SMILES: [Na].[C:2]([CH2:4][C:5]([NH2:7])=[O:6])#[N:3].[Cl:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[CH2:11][N:12]=[N+:13]=[N-:14].O>C(O)C>[NH2:3][C:2]1[N:12]([CH2:11][C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[Cl:8])[N:13]=[N:14][C:4]=1[C:5]([NH2:7])=[O:6]
Reactant: [N-]=[N+]=NCc1ccccc1Cl
Reactant: N#CCC(N)=O
Agent: [Na]
Solvent: CCO
Solvent: O
Product: NC(=O)c1nnn(Cc2ccccc2Cl)c1N

Procedure:
23 g (1 mol) of sodium are dissolved in 1 litre of ethyl alcohol and 101 g (1.2 mol) of cyanoacetamide are added thereto. 167.5 g (1 mol) of o-chlorobenzyl azide are added to this suspension at 40°-45° and the whole is heated for 2 hours under reflux. After cooling to 30°, 1000 ml of water are added, the precipitated product is filtered off with suction and then washed several times with warm water. After recrystallisation from dioxan and toluene, 5-amino-1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxamide is obtained in the form of colourless crystals having a melting point of 206°-207°.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C@H:17]([CH3:31])[CH2:18][CH2:19][NH:20][C:21]([C:23]3[C:28]([CH3:29])=[N:27][CH2:26][N:25](C)[CH:24]=3)=[O:22])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.Br[CH2:35][C:36]1[CH:40]=[CH:39][S:38][CH:37]=1.[CH3:41]C#N>>[S:38]1[CH:39]=[CH:40][C:36]([CH2:35][N:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:32])([F:33])[F:1])=[CH:9][CH:8]=2)[CH:11]2[CH2:16][CH2:15][N:14]([C@H:17]([CH3:31])[CH2:18][CH2:19][NH:20][C:21]([C:23]3[C:28]([CH3:29])=[N:27][CH:26]=[N:25][C:24]=3[CH3:41])=[O:22])[CH2:13][CH2:12]2)=[CH:37]1
Reactant: BrCc1ccsc1
Reactant: CC1=NCN(C)C=C1C(=O)NCC[C@@H](C)N1CCC(Nc2ccc(OC(F)(F)F)cc2)CC1
Reactant: CC#N
Product: Cc1ncnc(C)c1C(=O)NCC[C@@H](C)N1CCC(N(Cc2ccsc2)c2ccc(OC(F)(F)F)cc2)CC1
Yield: 10 %

Procedure:
A solution of the above amide (123 mg, 0.26 mmol) and 3-(bromomethyl)thiophene (56 mg, 0.32 mmol) in CH3CN (3 mL) was stirred overnight. Standard work-up and purification afforded COMPOUND 291 as a white foam (15 mg, 10%). 1H NMR (CDCl3) δ 1.01 (d, 3H, J=9.0 Hz), 1.77 (d, 4H, J=9.0 Hz), 2.16 (t, 1H, J=12.0 Hz), 2.52 (s, 6H), 2.59 (d, 1H, J=9.0 Hz), 2.73-2.78 (m, 1H), 2.83-2.90 (m, 2H), 3.33 (td, 1H, J=9.0, 3.0 Hz), 3.55 (td, 1H, J=9.0, 3.0 Hz), 3.84 (s, 2H), 3.86-3.91 (m, 1H), 6.57 (d, 2H, J=9.0 Hz), 6.96-7.02 (m, 4H), 7.30 (dd, 1H, J=6.0, 3.0 Hz), 8.71 (d, 1H, J=3.0 Hz), 8.88 (s, 1H). ES-MS m/z 562 [M+H]+.
Reaction SMILES: [O:1](S(C(F)(F)F)(=O)=O)[S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([CH3:27])[CH2:26][O:25][CH2:24]2)=[CH:19][C:18]=1O.N1C=CC=CC=1>C(Cl)Cl>[F:6][C:5]([F:8])([F:7])[S:2]([O:1][C:18]1[CH:19]=[C:20]([C:23]2([CH3:27])[CH2:26][O:25][CH2:24]2)[CH:21]=[CH:22][C:17]=1[CH3:16])(=[O:4])=[O:3]
Reactant: Cc1ccc(C2(C)COC2)cc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(C2(C)COC2)cc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Tf2O (3.07 mL, 18.2 mmol) was added dropwise to a solution of 2-methyl-5-(3-methyloxetan-3-yl)phenol (2.70 g, 15.2 mmol) and pyridine (1.71 mL, 21.2 mmol) in DCM (25 mL) at 0° C. The red/orange mixture was stirred at 0° C. for 1.5 h, then partitioned between DCM and water. The aqueous layer was extracted with DCM (2×). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography (0-40% EtOAc/heptane) to provide 2-methyl-5-(3-methyloxetan-3-yl)phenyl trifluoromethanesulfonate. 1H NMR (400 MHz, CD2Cl2) δ ppm 7.38 (d, J=8.08 Hz, 1 H) 7.26 (dd, J=7.96, 1.89 Hz, 1 H) 7.14 (d, J=1.77 Hz, 1 H) 4.89 (d, J=5.56 Hz, 2 H) 4.66 (d, J=5.81 Hz, 2 H) 2.41 (s, 3 H) 1.75 (s, 3 H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:9]([CH3:12])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CC(N=NC(C#N)(C)C)(C#N)C.[Br:27]N1C(C)(C)C(=O)N(Br)C1=O.C(Br)C1C=CC=CC=1>ClCCCl.[W]>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:9]([CH2:12][Br:27])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(C)ccc(Br)c1OC
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: [W]
Agent: BrCc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: COC(=O)c1c(CBr)ccc(Br)c1OC
Yield: 68.9 %

Procedure:
A solution of methyl 3-bromo-2-methoxy-6-methylbenzoate (Intermediate 91, 20 g) in 1,2-dichloroethane (400 ml) was stirred and illuminated with a 500 W tungsten filament lamp and treated with a catalytic amount of AIBN. Solid 1,3-dibromo-5,5-dimethylhydantoin (20 g) was gradually added over 3 hours until NMR analysis indicated complete conversion to the desired benzyl bromide. After cooling, the mixture was evaporated to dryness and the residue was triturated with cyclohexane and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of DCM and cyclohexane with a gradient of 1-25% to give methyl 3-bromo-6-bromomethyl-2-methoxybenzoate (16.3 g) as an orange solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[C:10]([O:13]C(=O)C)(=O)[CH3:11].[N+:17]([O-])([OH:19])=[O:18]>C(O)(=O)C>[CH3:1][C:2]1[CH:8]=[C:7]([N+:17]([O-:19])=[O:18])[CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:10](=[O:13])[CH3:11]
Reactant: Cc1cccc(C)c1N
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(=O)Nc1c(C)cc([N+](=O)[O-])cc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
2,6-Dimethylaniline (30.2 g) was added slowly to acetic anhydride (200 mL) cooled to 0° C. over 10 minutes. After 30 minutes, acetic acid (40 mL) and fuming nitric acid (15 mL) were added to the reaction mixture and the cooling was removed. The reaction mixture was filtered after 1 hour and the crystals were washed with water and dried in vacuo to furnish 5.20 g (30% yield) of the title compound as a yellow solid. 1H NMR (500 MHz, DMSO-d6): 2.10 (s, 3H), 2.26 (s, 6H), 7.98 (s, 2H), 9.61 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:30]=[CH:29][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:17]=[N:18][C:19]([N:22]4[CH2:26][CH2:25][CH2:24][S:23]4(=[O:28])=[O:27])=[CH:20][CH:21]=3)=[O:15])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH3:31]B(O)O>>[O:27]=[S:23]1(=[O:28])[CH2:24][CH2:25][CH2:26][N:22]1[C:19]1[N:18]=[CH:17][C:16]([C:14]([N:11]2[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]3[CH:29]=[CH:30][C:2]([CH3:31])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)=[O:15])=[CH:21][CH:20]=1
Reactant: O=C(c1ccc(Cl)cc1)C1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)nc2)CC1
Reactant: CB(O)O
Product: Cc1ccc(C(=O)C2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)nc3)CC2)cc1
Yield: 68.1 %

Procedure:
Using [4-(4-chlorobenzoyl)piperidin-1-yl][6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)pyridin-3-yl]methanone (194 mg) described in Example 116 and methylboronic acid (110 mg) and by the reaction and treatment in the same manner as in Example 115, the title compound (126 mg) was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH2:17][CH2:18][CH2:19][O:20][Si](C(C)C)(C(C)C)C(C)C.[H-].[Na+].O>CN(C=O)C>[OH:20][CH2:19][CH2:18][CH2:17][O:15][CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: CC(C)[Si](OCCCBr)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCCOCC1CCNCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.5 g (2.3 mmol) of 1-t-butoxycarbonyl-4-hydroxymethylpiperidine and 1.4 g (4.6 mmol) of 1-bromo-3-(triisopropylsilyloxy)propane in 3 mL of DMF was added 0.12 g (4.1 mmol) of NaH (60% dispersion in mineral oil) and the reaction mixture was stirred at rt for 16 h. To the reaction mixture was added 10 mL of H2O and it was extracted with ether. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ethyl acetate=19:1) to give the title compound.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[N:18]([CH2:33][CH:34]3C[CH2:37][CH2:36][N:35]3[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=3)N=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.FC(F)(F)C(O)=O.C([O-])=O.[NH4+:56]>CO.[Pd]>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2[N:56]=[C:17]([CH:14]3[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]3)[N:18]([CH:33]3[CH2:37][CH2:36][N:35]([C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])[CH2:34]3)[CH:19]=2)=[CH:23][C:24]=1[C:29]([F:30])([F:32])[F:31]
Reactant: CC(C)(C)OC(=O)N1CCCC1Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: [NH4+]
Agent: [Pd]
Agent: O=C[O-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc(F)c(C(F)(F)F)c3)nc2C2CCNCC2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.2 %

Procedure:
To a solution of 4-[1-(1-tert-butoxycarbonyl-pyrrolidin-2-ylmethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid benzyl ester (200.00 mg; 0.32 mmol; 1.00 eq.) in methanol 5 ml added trifluoro-acetic acid (54.24 mg; 0.48 mmol; 1.50 eq.), stirred at RT for 5 min, added ammonium formate (199.96 mg; 3.17 mmol; 10.00 eq.) and 200 mg wet 10% Pd/C, stirred at RT for 1 hr, lc-ms showed clean desired. Removed off solvent, added EA 50 ml, washed with Brine and 5% NaHCO3, dried, removed off solvent, got title compound 110 mg, yield 70%.