Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][C:40]1[O:44][C:43]([C:45]2[CH:46]=[C:47]([OH:60])[CH:48]=[C:49](B3OC(C)(C)C(C)(C)O3)[CH:50]=2)=[N:42][N:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[OH:60][C:47]1[CH:48]=[C:49]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:50]=[C:45]([C:43]2[O:44][C:40]([CH3:39])=[N:41][N:42]=2)[CH:46]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: Cc1nnc(-c2cc(O)cc(B3OC(C)(C)C(C)(C)O3)c2)o1
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+]
Product: Cc1nnc(-c2cc(O)cc(-c3cn(COCC[Si](C)(C)C)c4ncnc(N[C@@H](C)c5nn6ccc(C)c6c(=O)n5-c5ccccc5)c34)c2)o1
Temperature: 100 °C
Reaction time: 48 h
Yield: 17.3 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (250 mg, 0.42 mmol) was treated with 3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (200 mg, 0.66 mmol), tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.03 mmol) and aqueous solution 2M of sodium carbonate (500 μl, 4.7 mmol) in N,N-dimethylformide (5 ml) according to the method described in Preparation 186 but stirring at 100° C. for 48 h. The crude was purified using SP1® Purification System (hexane-ethyl acetate) to obtain 50 mg (16% yield) of the title compound as a oil. Purity 95%.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[C:11]([CH3:27])=[C:12]([NH:21][C:22](=[NH:26])[S:23][CH2:24][CH3:25])[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[CH:19][CH:18]=[N:17]1)=O)(C)(C)C.[ClH:28]>>[ClH:28].[ClH:28].[NH2:8][CH2:9][C:10]1[C:11]([CH3:27])=[C:12]([NH:21][C:22](=[NH:26])[S:23][CH2:24][CH3:25])[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[CH:19][CH:18]=[N:17]1
Reactant: CCSC(=N)Nc1ccc(-n2cccn2)c(CNC(=O)OC(C)(C)C)c1C
Agent: Cl
Product: CCSC(=N)Nc1ccc(-n2cccn2)c(CN)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
A mixture of the compound (47 mg) obtained in Example 7f and 6 N HCl (6 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated at reduced pressure to give the titled compound (yield, 93%).
Reaction SMILES: [NH2:1]/[C:2](/[C:10]([F:13])([F:12])[F:11])=[C:3](/[CH3:9])\[C:4]([O:6]CC)=O.C[O-].[Na+].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=O)[O:26]CC)=[C:20]([F:30])[CH:19]=1>CN(C=O)C>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:4](=[O:6])[C:3]([CH3:9])=[C:2]([C:10]([F:11])([F:12])[F:13])[NH:1][C:25]2=[O:26])=[C:20]([F:30])[CH:19]=1
Reactant: CCOC(=O)Nc1ccc(Br)cc1F
Reactant: CCOC(=O)/C(C)=C(\N)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C(F)(F)F)[nH]c(=O)n(-c2ccc(Br)cc2F)c1=O
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 42.6 %

Procedure:
Ethyl 3-amino-4,4,4-trifluoro-2-methylcrotonate (26.0 g) was dissolved in DMF (123 ml). To this solution, a suspension of sodium methoxide in DNF (7.78 g) was added dropwise at 0° C., and the mixture was stirred at 5° C. for 30 minutes. Then, a DMF solution of ethyl N-(4-bromo-2-fluoro-phenyl)carbamate (31.44 g) was added dropwise thereto, and the mixture was stirred at 130° C. for 5 hours. After the reaction, DMF was distilled off under reduced pressure, and the residue was acidified by adding diluted hydrochloric acid thereto. This was extracted with ethyl acetate, washed with water, and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off, and the resulting residue was crystallized from ethyl acetate-n-hexane (1:3 v/v) to obtain the objective 3-(4-bromo-2-fluorophenyl)-5-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (18.78 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:40])[CH:5]=[C:6]([Cl:39])[C:7]=1[CH2:8][C@H:9]([O:25][C:26](=[O:38])[CH2:27][O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33](Cl)=[N:32][CH:31]=1)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]([F:19])[F:18])=[C:12]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)[CH:11]=1.[CH3:41][NH:42][CH3:43]>C1COCC1>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:40])[CH:5]=[C:6]([Cl:39])[C:7]=1[CH2:8][C@@H:9]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]([F:18])[F:19])=[C:12]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)[CH:11]=1)[O:25][C:26](=[O:38])[CH2:27][O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33]([N:42]([CH3:43])[CH3:41])=[N:32][CH:31]=1
Reactant: CNC
Reactant: O=C(COC(=O)c1ccc(Cl)nc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Solvent: C1CCOC1
Product: CN(C)c1ccc(C(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cn1
Yield: 88 %

Procedure:
A solution of (S)-3,5-dichloro-4-(2-(2-(6-chloronicotinoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)pyridine 1-oxide (202 mg, 0.327 mmol) and dimethylamine (327 μl, 0.654 mmol) in dry THF (5 ml) was stirred at room temperature for 2 days. The solvent was evaporated and the residue was portioned between sat. sol. NaHCO3 and ethyl acetate; the organic phase was washed with brine, dried over Na2SO4, filtered and evaporated and the residue was triturated with iPr2O, filtered and dried under vacuum to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(6-(dimethylamino)nicotinoyloxy)acetoxy)-ethyl)pyridine 1-oxide as a white solid (180 mg, 0.287 mmol, 88% yield, LC-MS purity (BPI): 98%, MS/ESI+ 626.24 [MH]+, [αD]=−37.04, c=0.50, DCM).
Reaction SMILES: [C:1]1([C:6]2([CH2:11][OH:12])[CH2:10][CH:9]=[CH:8]O2)[CH2:5][CH2:4][CH2:3][CH:2]=1.C(=O)([O-])[OH:14].[Na+]>CC(C)=O.O>[OH:14][CH:10]1[CH:9]=[CH:8][C:11](=[O:12])[CH:6]1[CH:1]1[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: OCC1(C2=CCCC2)CC=CO1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C1C=CC(O)C1C1C=CCC1
Reaction time: 24 h
Yield: 55 %

Procedure:
2-Cyclopentenyl-2-furyl methanol (131 g, 0.8 mole) was dissolved in a 2:1 mixture (1.5 liters) of acetone and water in a reactor, and polyphosphoric acid (20 g) was added thereto. Thereafter, reaction was carried out at 50° to 60° C. for about 24 hours with stirring. After completion of the reaction, the reaction solution was cooled and neutralized with addition of a saturated aqueous solution (200 ml) of sodium hydrogen carbonate, followed by extraction with a solvent. The extract was washed with water, dried and concentrated. The residue obtained was distilled under reduced pressure to obtain 72 g (yield, 55%) of pure (±)-3-hydroxy-2-(2-cyclopentenyl)-4-cyclopenten-1-one having a boiling point of 115°-120° C./3 mmHg.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:28]([OH:30])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].[F:31][C:32]1[CH:33]=[C:34]([C:38](=[N:40]O)[NH2:39])[CH:35]=[CH:36][CH:37]=1>>[F:31][C:32]1[CH:33]=[C:34]([C:38]2[N:40]=[C:28]([CH:13]3[CH2:14][CH:15]([C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:19][CH:18]=4)[CH2:16][N:11]([C:9]([N:6]4[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]4)=[O:10])[CH2:12]3)[O:30][N:39]=2)[CH:35]=[CH:36][CH:37]=1
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1
Reactant: NC(=NO)c1cccc(F)c1
Product: N#CC1CCN(C(=O)N2CC(c3ccc(OC(F)(F)F)cc3)CC(c3nc(-c4cccc(F)c4)no3)C2)CC1

Procedure:
85 mg (0.20 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethoxy)phenyl]-piperidine-3-carboxylic acid (Example 108A) and 49 mg (0.3 mmol) of 3-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 69 mg (63% of theory).
Reaction SMILES: C([Si]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)=[CH:10]\[CH3:11])(C)C)(C)(C)C.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:42]C)C=C4)N(CC2)C1.CS(N)(=O)=O>C(O)(C)(C)C.O>[N+:18]([C:14]1[CH:13]=[C:12]([C:9](=[O:8])[C@H:10]([OH:42])[CH3:11])[CH:17]=[CH:16][CH:15]=1)([O-:20])=[O:19]
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc([N+](=O)[O-])c1
Agent: CS(N)(=O)=O
Solvent: O
Solvent: CC(C)(C)O
Product: C[C@@H](O)C(=O)c1cccc([N+](=O)[O-])c1
Yield: 75.9 %

Procedure:
Compound 10g was synthesized by a procedure similar to that described for (R)-10a using (Z)-tert-butyl(1-(3-nitrophenyl)prop-1-enyloxy)dimethylsilane, (9g, 8.0 g, 0.027 mol), AD-mix-β (38 g), and CH3SO2NH2 (2.64 g, 0.0277 mol) in tert-butyl alcohol-water (110 mL:110 mL). The reaction was quenched with sodium sulfite (27.4 g). After purification by column chromatography on silica gel, 4.0 g (75%) of the desired product was isolated: [α]20D +63.8° (c 1.3, CHCl3); 1H NMR (CDCl3) δ 8.80-8.74 (m, 1H), 8.52-8.44 (m, 1H), 8.31-8.24 (m, 1H), 7.83-7.68 (m, 1H), 5.27-5.13 (m, 1H), 3.59 (d, 1H, J=6.5 Hz), 1.49 (d, 3H, J=7.08 Hz); 13C NMR (CDCl3) δ 200.4, 148.6, 134.9, 134.1, 130.2, 128.1, 121.6, 69.8, 21.9; C9H9NO4.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:28]3[CH2:33][CH2:32][C@H:31]([CH2:34][OH:35])[CH2:30][CH2:29]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([C:15]([CH3:27])=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:36]1([CH3:56])[CH:41]=[CH:40][C:39]([S:42]([O:45]S(C2C=CC(C)=CC=2)(=O)=O)(=[O:44])=[O:43])=[CH:38][CH:37]=1.[C:57](=O)(O)[O-].[Na+]>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:28]3[CH2:33][CH2:32][C@H:31]([CH2:34][OH:35])[CH2:30][CH2:29]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([C:15]([CH3:27])=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:56][C:36]1[CH:41]=[CH:40][C:39]([S:42]([O:45][CH3:57])(=[O:44])=[O:43])=[CH:38][CH:37]=1
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: O=C([O-])O
Agent: Cc1cc(-c2ccccc2)nc2cc(-c3nc([C@H]4CC[C@H](CO)CC4)n4ccnc(N)c34)ccc12
Agent: Cc1cc(-c2ccccc2)nc2cc(-c3nc([C@H]4CC[C@H](CO)CC4)n4ccnc(N)c34)ccc12
Agent: [Na+]
Solvent: c1ccncc1
Product: COS(=O)(=O)c1ccc(C)cc1
Reaction time: 24 h

Procedure:
trans-{4-[8-Amino-(4-methyl-2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]cyclohexyl}methanol (200 mg, 0.43 mmol) and toluene-4-sulfonic anhydride (150 mg, 0.47 mmol) were dissolved in anhydrous pyridine (8.7 mL) under nitrogen and allowed to sit at −10° C. for 24 h. Saturated aqueous sodium bicarbonate solution (10 mL) was added to the reaction mixture, then, stirred for 10 min. The reaction mixture was concentrated in vacuo, then, partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane. The organic extract was separated, washed once again with sodium bicarbonate (aq) and brine, dried over anhydrous sodium sulfate, then concentrated in vacuo. The crude mixture was purified by a silica gel column chromatography [Jones Flashmaster; 10 g column, dry-loaded with silica gel; eluted with 100% DCM to 1:1 EtOAc/DCM to 10% (7N ammonia/MeOH)/chloroform] to obtain the desired mono-tosylated product as a yellow solid; 1H NMR (d6-DMSO, 400 Hz) δ 8.29 (dd, J=8.4, 1.2 Hz, 2H), 8.22 (d, J=1.2 Hz, 1H), 8.19 (d, J=8.8 Hz, 1H), 8.06 (s, 1H), 7.90 (dd, J=8.4, 1.2 Hz, 1H), 7.82 (m, 2H), 7.69 (d, J=5.2 Hz, 1H), 7.563 (m, 2H), 7.50 (m, 3H), 7.08 (d, J=4.8 Hz, 1H), 6.19 (br s, 2H), 3.92 (d, J=5.6 Hz, 2H), 3.10 (m, 1H), 2.08 (s, 3H), 2.44 (s, 3H), 2.00 (m, 2H), 1.77 (m, 2H), 1.66 (m, 2H), 1.20 (m, 2H); MS (ES+): m/z 618.32 (40) [MH+], 426.21 (60) [M-191], 412.52 (100) [M-205]; tR(polar-5 min/MDPS) 3.03 min.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH3:21][O:22][CH2:23][O:24][C:25]1[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][C:26]=1[C:27]([NH:29][C:30]1[CH:42]=[C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:40]=[CH:39][C:31]=1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:28].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C1C=CC=CC=1>[Br:1][CH2:53][C:50]1[CH:51]=[CH:52][C:25]([O:24][CH2:23][O:22][CH3:21])=[C:26]([CH:49]=1)[C:27]([NH:29][C:30]1[CH:42]=[C:41]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:40]=[CH:39][C:31]=1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:28]
Reactant: COCOc1ccc(C)cc1C(=O)Nc1cc(-c2ccccc2)ccc1C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COCOc1ccc(CBr)cc1C(=O)Nc1cc(-c2ccccc2)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 69 %

Procedure:
N-Bromosuccinimide (0.25 g) and azobisisobutyronitrile (0.023 g) were sequentially added to a benzene (6.3 mL) solution of the obtained tert-butyl 2-(2-(methoxymethoxy)-5-methylbenzamido)-4-phenylbenzoate (0.63 g), followed by heating to reflux for 30 minutes. The reaction mixture was cooled to room temperature, and then a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-90% hexane/ethyl acetate] to obtain 0.51 g of tert-butyl 2-(5-(bromomethyl)-2-(methoxymethoxy)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:5].[OH2:17].[OH-].[Na+]>CO>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:7]1[CH2:8][CH:6]1[C:4]([OH:17])=[O:5]
Reactant: O
Reactant: CON(C)C(=O)C1CC1c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CC1c1ccccc1F
Temperature: 25 °C

Procedure:
A mixture of 2-(2-fluoro-phenyl)-cyclopropanecarboxylic acid methoxy-methyl-amide (8.92 g), water (20 mL), and NaOH (3.2 g) in MeOH (40 mL) was refluxed for 3 h. The reaction mixture was cooled down to room temperature and concentrated in vacuo. The residue was acidified by 6 N HCl followed by extraction with CH2Cl2. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound (7 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[N:7][OH:8])[CH2:3][CH2:2]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[F:26][C:27]([F:34])([F:33])[CH2:28][CH2:29][C:30]([OH:32])=[O:31]>>[F:26][C:27]([F:34])([F:33])[CH2:28][CH2:29][C:30]([O:32][C:4]1([N:7]=[O:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:31]
Reactant: O=C(O)CCC(F)(F)F
Reactant: ON=C1CCOCC1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: O=NC1(OC(=O)CCC(F)(F)F)CCOCC1

Procedure:
4-Nitrosotetrahydro-2H-pyran-4-yl 4,4,4-trifluorobutanoate was prepared from tetrahydro-pyran-4-one oxime, lead tetraacetate and 4,4,4,-trifluorobutyric acid using conditions of General Method 3. 1H NMR (250 MHz, chloroform-d) δ 3.91-4.19 (2H, m), 3.48-3.83 (2H, m), 2.71-2.94 (2H, m), 2.36-2.67 (2H, m), 2.15-2.34 (2H, m), 1.63-1.96 (2H, m).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[C:8]([F:15])[CH:7]=1.[NH3:16]>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:16])=[O:11])=[C:8]([F:15])[CH:7]=1
Reactant: O=C(Cl)c1ccc(OCCCCl)cc1F
Reactant: N
Product: NC(=O)c1ccc(OCCCCl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
4-(3-chloropropoxy)-2-fluorobenzoyl chloride i80 (0.73 g, 2.91 mmol, 1 eq) is treated with aqueous ammonia (35 ml) and the resulting mixture is vigorously stirred at room temperature overnight. The mixture is then filtered to give 0.41 g of 4-(3-chloropropoxy)-2-fluorobenzamide i82 as a white solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH2:11][CH2:12][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]3)O1.Br[C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:29]=1[N:38]1[C:42]([CH3:43])=[CH:41][N:40]=[CH:39]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(C)=O>[CH3:43][C:42]1[N:38]([C:29]2[CH:30]=[C:31]([C:34]([F:37])([F:35])[F:36])[CH:32]=[CH:33][C:28]=2[C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH2:11][CH2:12][N:13]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:14]3)[CH:39]=[N:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(cccc2B2OC(C)(C)C(C)(C)O2)C1
Reactant: Cc1cncn1-c1cc(C(F)(F)F)ccc1Br
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cncn1-c1cc(C(F)(F)F)ccc1-c1cccc2c1CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C

Procedure:
A solution of Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, Mo., 0.165 g, 0.233 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (ASW Medchem, Brunswick, N.J., 1.254 g, 3.49 mmol), 1-(2-bromo-5-(trifluoromethyl)phenyl)-5-methyl-1H-imidazole (derived above, 0.710 g, 2.327 mmol), and potassium phosphate (1.976 g, 9.31 mmol) in 10 mL dioxane 5 mL water was heated to 120° C. for 2 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc and the organics were concentrated. The resulting residue was purified by silica gel column chromatography (0 to 100% EtOAc/heptane) yielding tert-butyl 5-(2-(5-methyl-1H-imidazol-1-yl)-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.450 g, 0.984 mmol).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([Cl:31])=[C:12]([CH2:14][N:15]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:30])[C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[F:29])=[N:16]2)[CH:13]=1)=O)(=[O:3])[CH3:2]>C1COCC1>[Cl:31][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[O:3][C:1]([CH3:2])=[N:4][N:5]=2)=[CH:13][C:12]=1[CH2:14][N:15]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:30])[C:22]2[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=2[F:29])=[N:16]1
Reactant: CC(=O)NNC(=O)c1ccc(Cl)c(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c1
Solvent: C1CCOC1
Product: Cc1nnc(-c2ccc(Cl)c(Cn3ccc(NC(=O)c4c(F)cccc4F)n3)c2)o1
Temperature: 150 °C

Procedure:
To a solution of N-[1-({5-[(2-acetylhydrazino)carbonyl]-2-chlorophenyl}methyl)-1H-pyrazol-3-yl]-2,6-difluorobenzamide (for a preparation see Intermediate 51)(130 mg, 0.290 mmol) in THF (4 ml) was added 4A molecular sieves (513 mg) (pre-dried in an oven) and then (methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt (21 mg, 0.088 mmol, Fluka). The reaction vessel was sealed and heated in a Biotage Initiator microwave to 150° C. for 25 min. The solvent was evaporated in vacuo, the residue was dissolved in methanol (1 ml) and then filtered through a hydrophobic frit. The filtrate was dissolved in DMSO (1 ml) and the sample was purified by MDAP on Sunfire C18 column using Acetonitrile-Water with a Formic acid modifier (Method B). The solvent was evaporated in vacuo to give the title compound as a white solid (13 mg); LCMS (System 3) MH+=430/432, tRET=2.54 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:37]=[C:38]([F:41])[C:39]=1[F:40])[O:5][CH:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][NH:22][C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[CH:26][CH:25]=2)=[CH:15][CH:14]=1)[C:7]([O:9]CC)=[O:8].[OH-].[Na+]>>[F:41][C:38]1[CH:37]=[C:4]([CH:3]=[C:2]([F:1])[C:39]=1[F:40])[O:5][CH:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][NH:22][C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[CH:26][CH:25]=2)=[CH:15][CH:14]=1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)Oc1cc(F)c(F)c(F)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCOc1ccc(CC(Oc2cc(F)c(F)c(F)c2)C(=O)O)cc1)c1ccc(-c2ccccn2)cc1
Yield: 88.6 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-(3,4,5-trifluorophenoxy)-3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]propionate (380 mg), which is the product of Example 142, was reacted with aqueous sodium hydroxide solution (1N, 2.00 ml) and the reaction mixture was treated to give the title compound (320 mg) as a white powder.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=1.CI.C(=O)(O)[O-].[Na+]>O1CCCC1.CCCCCC.C(OCC)C>[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[C:19]=1[CH3:1]
Reactant: CC(C)NC(C)C
Reactant: Clc1cncc(Cl)c1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1c(Cl)cncc1Cl
Temperature: -75 °C
Reaction time: 1 h

Procedure:
A solution of diisopropylamine (10.5 mL) in dry tetrahydrofuran (150 mL) is cooled to -75° C. and treated with a solution of butyl lithium in hexane (30 mL; 2.5M) during 10 minutes. After stirring for 1 hour at -75° C. the mixture is treated with a solution of 3,5-dichloropyridine (10.8 g) in dry tetrahydrofuran (55 mL) and stirred for a further 30 minutes. It is then treated with methyl iodide (4.7 mL) in dry tetrahydrofuran (10 mL) during 10 minutes, and the solution is allowed to rise gradually to room temperature. After stirring for 2 hours, the mixture is treated with saturated aqueous sodium bicarbonate solution (50 mL), followed by diethyl ether (100 mL). The organic layer is washed with brine, dried and evaporated, and the resulting residue is subjected to flash chromatography, to give 3,5-dichloro-4-methylpyridine (10.6 g), m.p. 46°-47° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])=[O:18])=[N:16][C:12]=3[CH:11]=[C:10]([C:34]3[NH:38][C:37](=[O:39])[O:36][N:35]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:40][Mg]Br>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])([OH:18])[CH3:40])=[N:16][C:12]=3[CH:11]=[C:10]([C:34]3[NH:38][C:37](=[O:39])[O:36][N:35]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: C[C@H]1CC[C@H](Cn2c(C(=O)c3ccccc3F)nc3cc(-c4noc(=O)[nH]4)nc(-c4cncc(Cl)c4)c32)CC1
Solvent: C1CCOC1
Product: CC(O)(c1ccccc1F)c1nc2cc(-c3noc(=O)[nH]3)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: -20 °C

Procedure:
To a solution of 3-{4-(5-chloropyridin-3-yl)-2-[(2-fluorophenyl)carbonyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (Example 8.1, 44 mg, 0.08 mmol) in tetrahydrofuran (0.8 mL) at −78° C. was added dropwise methyl magnesium bromide (0.054 mL of 3.0 M in diethyl ether, 0.161 mmol). The reaction was stirred and slowly warmed to −20° C. over 3 hours. The reaction was then quenched via the addition of saturated aqueous ammonium chloride and extracted with ethyl acetate (2×). The combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified via silica gel chromatography (0-10% methanol/DCM) to afford 3-{4-(5-chloropyridin-3-yl)-2-[1-(2-fluorophenyl)-1-hydroxyethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one as a white solid. MS ESI calcd. for C29H28ClFN6O3 [M+H]+ 563. found 563.