Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][NH:8][C:7](=[O:12])[C:6]=2[CH:13]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[N+:27]([O-])([O-:29])=[O:28].[K+].[OH-].[Na+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N+:27]([O-:29])=[O:28])[C:5]2[O:11][CH2:10][CH2:9][NH:8][C:7](=[O:12])[C:6]=2[CH:13]=1
Reactant: O=C1NCCOc2ccc(F)cc21
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C1NCCOc2c1cc(F)cc2[N+](=O)[O-]

Procedure:
7-Fluoro-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (346 mg, 1.91 mmol) in Acetonitrile (10 mL) and Trifluoroacetic anhydride (0.85 mL, 6.0 mmol) was treated with Potassium nitrate (0.203 g, 2.00 mmol) at room temperature for 24 h. Aq. NaOH (15% w/w, 10 mL) was added and the mixture extracted 3×15 mL DCM. The DCM extract was washed with water (20 mL) and brine (20 mL) then dried over sodium sulfate and conc. in vacuo. 1H-, 19F-NMR and HPLC showed a 2-3:1 mixture of 7-Fluoro-9-nitro-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one and 7-Fluoro-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one, which was chromatographed (ISCO, 40 g, 0-75% EtOAc:Hex) to give 7-Fluoro-9-nitro-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one, enriched in the mixture, but still containing 7-Fluoro-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one. This mixture was dissolved in Ethanol (10 mL) and added to Palladium on Carbon 10% (0.05 g) wetted with a small amount of water. The mixture was shaken under an atmosphere of Hydrogen (40 psi) for 1.5 h, then filtered through Celite, washing with ethanol. Conc. in vacuo gave a white solid, which was taken up in Et2O with minimal MeOH to solubilize, then extracted with 15 mL 1N HCl. The aq. extract was washed once with ether (10 mL) then basified with 15% NaOH, then extracted 8×10 mL DCM. The organic layers were dried over sodium sulfate and conc. in vacuo to give 9-Amino-7-fluoro-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one as a white solid (120 mg, 35% over two steps.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[C:13]([CH3:20])=[C:14]([NH2:19])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:22])[CH3:21])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C(OCC)(=O)C.CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[C:13]([CH3:20])=[C:14]([NH:19][C:29](=[O:30])[C:28]4[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[CH:26][CH:27]=4)[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:22])[CH3:21])=[CH:4][CH:3]=1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(F)cc1)C(C)(C)O2
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(F)cc2)C(C)(C)O3)cc1
Yield: 79 %

Procedure:
By using 3-(4-fluorophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-methoxybenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 79%. Melting point: 191-194° C. (Ethyl acetate-hexane)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])/[CH:5]=[CH:6]/[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[NH:20]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][CH2:22][CH2:21]1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:6]/[C:7]([N:20]2[CH2:26][CH2:25][C:24](=[O:27])[NH:23][CH2:22][CH2:21]2)=[O:9])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: O=C1CCNCCN1
Reactant: O=C(O)/C=C/c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Temperature: 0 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
A solution of 9.77 g (43.65 mmol) of (E)-3,4-dichlorocinnamic acid in 250 ml of CH2Cl2 was treated at RT with 3 drops of DMF. 4.15 ml (48.02 mmol, 1.1 eq) of oxalyl chloride in 30 ml CH2Cl2 were added dropwise and stirring was continued for 3 h. The solution was evaporated, redissolved in 170 ml of CH2Cl2, cooled (0° C.) and treated with a solution of 4.48 g (39.29 mmol, 0.9 eq) of 2,3,6,7-tetrahydro-(1H)-1,4-diazepin-5(4H)-one and 12.17 ml (87.30 mmol, 2 eq) of triethylamine in 80 ml of CH2Cl2. The reaction was warmed up over night to RT, then partitioned between CH2Cl2/MeOH 9:1 (×3)/ aqueous 10% KHSO4, the organic phases were washed with aqueous saturated NaHCO3 and aqueous 10% NaCl, dried over Na2SO4 and evaporated. The residue was dissolved and evaporated with toluene and crystallized with CH2Cl2/Et2O to give 7.99 g (58%) of the title compound as white solid. MS: 312.8 (MH+, 2Cl).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]3[N:27]=[C:26]([C:28]#[N:29])[N:25]=[CH:24][N:23]=3)[CH:16]=2)=[CH:11][CH:10]=1)(C)(C)C>C(O)=O>[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]3[N:23]=[CH:24][N:25]=[C:26]([C:28]#[N:29])[N:27]=3)[CH:16]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(Nc3ncnc(C#N)n3)c2)cc1
Solvent: O=CO
Product: N#Cc1ncnc(Nc2cccc(-c3ccc(CN)cc3)c2)n1

Procedure:
A solution of [3′-(4-cyano-[1,3,5]triazin-2-ylamino) -biphenyl-4-ylmethyl]-carbamic acid tert-butyl ester (43 mg) in formic acid (1 ml) is stirred at 5° C. for 4.5 h. This solution is evaporated under reduced pressure. The remaining oil is treated with diethyl ether to obtain crystals of 4-(4′-aminomethyl-biphenyl-3-ylamino)-[1,3,5]triazine-2-carbonitrile, salt with formic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH2:9][C:10]1[N:11]=[CH:12][NH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:18]I>C1COCC1>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH2:9][C:10]1[N:11]=[CH:12][N:13]([CH3:18])[CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCCc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cnc(CCNC(=O)OC(C)(C)C)c1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 29.5 %

Procedure:
To a solution of [2-(1H-imidazol-4-yl)-ethyl]-carbamic acid tert-butyl ester (512 mg, 2.42 mmol) in THF (20 mL) at −10° C. was added NaH (60%, 97 mg, 2.42 mmol). After stirring at −10° C. for 30 min, MeI (0.14 mL, 2.17 mmol) was added. After stirring at −10° C. for 2.5 h, the reaction mixture was concentrated to afford a yellow oil. Purification by flash column chromatography on silica gel using 2% MeOH/CH2Cl2 afforded [2-(1-methyl-1H-imidazol-4-yl)-ethyl]-carbamic acid tert-butyl ester as a yellow oil (144 mg, 34%). Deprotection with TFA using General Procedure F gave [2-(1methyl-1H-imidazol-4-yl)-ethyl]-amine as a yellow oil (51 mg, 25%).
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][NH:10][C:11](=[O:22])[CH:12]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([NH2:21])[CH:15]=2)[CH3:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.[CH:30]([CH:32]=O)=O>O>[C:1]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][NH:10][C:11](=[O:22])[CH:12]([C:14]2[CH:15]=[C:16]3[C:17](=[CH:18][CH:19]=2)[N:20]=[CH:32][CH:30]=[N:21]3)[CH3:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C(=O)NCc1ccc(C(C)(C)C)cc1)c1ccc(N)c(N)c1
Reactant: O=CC=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C(=O)NCc1ccc(C(C)(C)C)cc1)c1ccc2nccnc2c1
Temperature: 25 °C

Procedure:
To the flask of N-(4-tert-butyl-benzyl)-2-(3,4-diamino-phenyl)-propionamide (81 mg, 0.249 mmol) was added glyoxal (4 mL, 40% in water soln.) at room temperature, and additionally added DMF (4 mL) because SM was not soluble in glyoxal sufficiently. The reaction mixture was refluxed for 2 hrs then cooled to room temperature. The mixture was diluted with H2O (25 mL) and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:1) as eluant.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CN1C(=O)CCC1>[CH:14]1([NH:20][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=2[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NC1CCCCC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: CN1CCCC1=O
Product: O=C(O)c1ccc([N+](=O)[O-])c(NC2CCCCC2)c1
Temperature: 85 °C
Reaction time: 6 h

Procedure:
A mixture of 3-fluoro-4-nitrobenzoic acid (0.35 g, 1.891 mmol) and cyclohexylamine (2.17 mL, 18.91 mmol) in NMP (10 mL) was stirred under Ar at 85° C. for 6 h. The solvent was evaporated under high vacuum. The residue was purified by chromatography using CH3Cl-MeOH (10:1) as the eluent to give the title intermediate in a quantitative yield. MS: 263.11 (M−H+).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6].[C:33]([O:37][CH2:38][CH3:39])(=[O:36])[CH:34]=[CH2:35].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.CCOCC>[ClH:1].[ClH:1].[CH2:38]([O:37][C:33](=[O:36])[CH2:34][CH2:35][N:30]1[CH2:31][CH2:32][CH:27]([O:26][C:10]2[N:9]=[N:8][C:7]([CH2:3][CH2:4][CH2:5][CH3:6])=[C:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:17][CH:18]=3)[CH:11]=2)[CH2:28][CH2:29]1)[CH3:39]
Reactant: C=CC(=O)OCC
Reactant: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCc1nnc(OC2CCN(CCC(=O)OCC)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 135.9 %

Procedure:
To a solution of 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (Example 14, 2.0 mmol, 965 mg) in DCM (5 mL) was added ethyl acrylate (6.0 mmol, 0.66 mL), and DIEA (6.0 mmol, 1.05 mL). The mixture was stirred at room temperature over night then condensed. The residue was purified by silica gel chromatography (DCM to DCM+10% 2N NH3 in MeOH) to give a colorless sticky solid, which was dissolved in DCM (2.0 mL), 2N HCl in ether (2.0 mL) was added, kept at room temperature for 10 min, condensed, triturated with hexanes to provide the title compound (792 mg). LCMS: m/z 512 [M+2]. 1H NMR (400 MHz, CD3OD): δ 7.30-7.34 (2H, m), 7.01-7.07 (3H, m), 5.47-5.53 (1H, m), 4.37-4.43 (1H, m), 4.20 (2H, q), 3.35-3.70 (5H, m), 2.87-2.95 (5H, m), 2.20-2.35 (4H, m), 1.96-2.03 (2H, m), 1.78-1.84 (2H, m), 1.35-1.64 (7H, m), 1.28 (3H, t), 1.20-1.26 (3H, m), 0.80 (3H, t).
Reaction SMILES: [C:1]([N:6]1[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:10][O:9][CH2:8][C@@H:7]1/[CH:19]=[CH:20]/[C:21](OC)=O)(=[O:5])CC=C.C(N1[C@H](C2C=CC(Cl)=CC=2)COC[C@@H]1/C=C\C(OC)=O)(=O)CC=C.C(N(CC)CC)C.[H][H]>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.ClCCl.CO.[Pt]=O>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C@@H:11]2[CH2:10][O:9][CH2:8][C@@H:7]3[CH2:19][CH2:20][CH2:21][C:1](=[O:5])[N:6]23)=[CH:17][CH:16]=1
Reactant: C=CCC(=O)N1[C@@H](/C=C/C(=O)OC)COC[C@H]1c1ccc(Cl)cc1
Reactant: [H][H]
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Agent: O=[Pt]
Agent: C=CCC(=O)N1[C@@H](/C=C\C(=O)OC)COC[C@H]1c1ccc(Cl)cc1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC[C@H]2COC[C@@H](c3ccc(Cl)cc3)N12
Reaction time: 0.17 h

Procedure:
Grubbs catalyst 2nd generation (21.3 mg) was added to a solution of methyl 3-[(3S,5R)-4-but-3-enoyl-5-(4-chlorophenyl)morpholin-3-yl]-(E)-acrylate and methyl 3-[(3S,5R)-4-but-3-enoyl-5-(4-chlorophenyl)morpholin-3-yl]-(Z)-acrylate (87.9 mg) in dichloromethane (10 mL), and the reaction solution was heated under reflux in a nitrogen atmosphere for 1.5 hours. The reaction solution was returned to room temperature. Triethylamine (500 μL) was added to the reaction solution, which was then stirred for 10 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain a crude product. Platinum oxide (6.02 mg) was added to a solution of the crude product in methanol (3 mL), and the reaction solution was stirred in a hydrogen atmosphere at room temperature for one hour. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: heptane-ethyl acetate system) to obtain 48.7 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:13])[CH:11]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].[F:14][C:15]([F:20])([F:19])[C:16](O)=O>>[F:14][C:15]([F:20])([F:19])[C:16]1[N:4]2[CH:5]=[CH:6][C:7]3[C:12]([C:3]2=[N:1][N:2]=1)=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=3
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ccc2ccnc(NN)c2c1
Product: Cc1ccc2ccn3c(C(F)(F)F)nnc3c2c1
Yield: 20 %

Procedure:
A solution of 1-hydrazino-7-methylisoquinoline in excess trifluoroacetic acid was allowed to reflux for two hours. Removal of the excess acid in vacuo, treatment of the residue with sodium bicarbonate solution and filtration provided the crude product which was recrystallized from cyclohexane to give the product in a yield of 20%; m.p. 205°-206°C.
Reaction SMILES: Br[CH:2]1[C:6](=[O:7])[N:5]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[Cl:16])[N:4]=[C:3]1[NH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:19].[CH3:39][C:40]1[C:44]([N+:45]([O-:47])=[O:46])=[CH:43][NH:42][N:41]=1>C(OCC)(=O)C>[Cl:16][C:9]1[CH:10]=[C:11]([Cl:15])[CH:12]=[C:13]([Cl:14])[C:8]=1[N:5]1[C:6](=[O:7])[CH:2]([N:42]2[CH:43]=[C:44]([N+:45]([O-:47])=[O:46])[C:40]([CH3:39])=[N:41]2)[C:3]([NH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:19])=[N:4]1
Reactant: Cc1n[nH]cc1[N+](=O)[O-]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1Br
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCNC(=O)NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1n1cc([N+](=O)[O-])c(C)n1

Procedure:
13 g of 4-bromo-1-(2,4,6-trichlorophenyl)-3-(3-octadecylureido)-2-pyrazolin-5-one and 10 g of 3-methyl-4-nitropyrazole were mixed at 90° C. for 2 hours. To the reaction mixture, 200 ml of ethyl acetate was added and the mixture was washed several times with water. The ethyl acetate layer was dried with anhydrous sodium sulfate and concentrated. The residual oil was dissolved in 50 ml of chloroform and purified with column chromatography using 500 g of silica gel (art 7734 manufactured by MERCK & Co.) wetted with chloroform as a bulking agent. Upon elution with a solvent mixture of chloroform and ethyl acetate (10:1), 10.9 g of an oily comprising the desired coupler was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[C:9]2[SH:16])=[CH:4][CH:3]=1.[CH3:17][NH:18][O:19][CH3:20].C(N=C=NCCCN(C)C)C.O>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([N:18]([O:19][CH3:20])[CH3:17])=[O:15])=[CH:11][N:10]=[C:9]2[SH:16])=[CH:6][CH:7]=1
Reactant: CNOC
Reactant: O=C(O)c1cnc(S)n1-c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: CON(C)C(=O)c1cnc(S)n1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A solution of 1-(4-fluorophenyl)-2-mercapto-1H-imidazole-5-carboxylic acid (4) (2.2 g, 9.23 mmol), N,O-dimethylhydroxylamine (0.9 g, 9.23 mmol), and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) (1.77 g, 9.23 mmol) in pyridine was heated at 40° C. overnight. The reaction was cooled to room temperature, water was added and the solution was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield 1-(4-fluorophenyl)-2-mercapto-N-methoxy-N-methyl-1H-imidazole-5-carboxamide (5) as a light yellow solid.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:48])[CH2:9][C@H:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)[C@@H:7]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:6]([C@@H:25]([CH2:45][CH3:46])[CH2:26][O:27][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[C:5]1=[O:47])[CH:2]=[CH2:3].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O.CCOC(C)=O>[CH2:1]([C@@:4]1([CH3:48])[CH2:9][C@H:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)[C@@H:7]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[N:6]([C@@H:25]([CH2:45][CH3:46])[CH2:26][OH:27])[C:5]1=[O:47])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cc(F)cc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cc(F)cc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (2.15 g, 3.06 mmol; Example 393, Step A) in THF (30.6 ml) at rt was added TBAF (1.0 M in THF) (6.12 ml, 6.12 mmol). The light yellow mixture was stirred at rt overnight. The mixture was diluted with water and EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (40 g column; eluent: 0 to 50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:22]2[CH:26]=[C:25]([C:27]3[C:28]4[CH:35]=[CH:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:29]=4[N:30]=[CH:31][N:32]=3)[CH:24]=[N:23]2)[CH2:7][N:6]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH:10]([CH3:21])[CH2:9]2)[CH2:5]1)#[N:2].Cl.O1CCOCC1>CO>[CH3:21][CH:10]1[CH2:9][CH:8]([N:6]2[CH2:7][C:4]([CH2:3][C:1]#[N:2])([N:22]3[CH:26]=[C:25]([C:27]4[C:28]5[CH:35]=[CH:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:42])([CH3:41])[CH3:43])[C:29]=5[N:30]=[CH:31][N:32]=4)[CH:24]=[N:23]3)[CH2:5]2)[CH2:13][CH2:12][NH:11]1
Reactant: CC1CC(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC1CC(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)CCN1
Temperature: 25 °C
Yield: 119.8 %

Procedure:
To a solution of tert-butyl 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2-methylpiperidine-1-carboxylate (0.5 g) in methanol (2 mL) was added 10 mL of a 4.0 N solution of hydrogen chloride in 1,4-dioxane (40 mmol). The resulting solution was stirred at room temperature for an hour. The solvents were removed under reduced pressure to give 0.5 g (99%) of {1-(2-methylpiperidin-4-yl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile as a white solid. LC-MS: 507.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)=[CH:5][NH:4][N:3]=1.[CH2:20]([O:22][C:23](=[O:34])[C:24](=[CH:30]OCC)[C:25](OCC)=[O:26])[CH3:21].[O-]CC.[Na+].C(O)C.Cl>O.C(O)C>[CH2:13]([C:10]1[CH:9]=[CH:8][C:7]([C:6]2[CH:5]=[N:4][N:3]3[C:25]([OH:26])=[C:24]([C:23]([O:22][CH2:20][CH3:21])=[O:34])[CH:30]=[N:1][C:2]=23)=[CH:12][CH:11]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1n[nH]cc1-c1ccc(Cc2ccccc2)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cnc2c(-c3ccc(Cc4ccccc4)cc3)cnn2c1O
Yield: 99.7 %

Procedure:
A mixture of 3-amino-4-(4-benzylphenyl)pyrazole (0.75 g), ethoxymethylenemalonic diethylester (1.30 g) and ethanol (30 ml) was stirred under heating reflux for 48 hours. After cooling, sodium ethoxide -ethanol was added, and was stirred at room temperature for 12 hours. Then, at 0° C., 10% hydrochloric acid was added to adjust to acid, and water (50 ml) was added and stirred for 30 minutes. The precipitate was separated by filtration, washed with water, and dried to give the title compound (1.12 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]([C:21]1[S:25][N:24]=[CH:23][N:22]=1)[S:7]([C:10]1[C:19]([F:20])=[CH:18][C:13]2[NH:14][C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:51]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][C:59]=2[CH2:61]O)[CH2:54][CH2:53][C:52]21[O:66][CH2:65][CH2:64][O:63]2.C1COCC1>C(Cl)Cl.CCOC(C)=O>[CH2:51]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][C:59]=2[CH2:61][N:14]2[C:13]3[CH:18]=[C:19]([F:20])[C:10]([S:7]([N:6]([CH2:5][C:4]4[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:3]=4[O:2][CH3:1])[C:21]4[S:25][N:24]=[CH:23][N:22]=4)(=[O:8])=[O:9])=[CH:11][C:12]=3[O:16][C:15]2=[O:17])[CH2:54][CH2:53][C:52]21[O:63][CH2:64][CH2:65][O:66]2
Reactant: OCc1cccc2c1CC1(CC2)OCCO1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)[nH]c3cc2F)c(OC)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)n(Cc4cccc5c4CC4(CC5)OCCO4)c3cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a flask containing N-(2,4-Dimethoxybenzyl)-5-fluoro-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydro-1,3-benzoxazole-6-sulfonamide (11-3) (2.13 g, 4.57 mmol), resin bound (PS) TRIPHENYLPHOSPHINE (5.27 g, 9.70 mmol) & DTBAD (2.187 g, 9.50 mmol) & (3′,4′-dihydro-1′H-spiro[[1,3]dioxolane-2,2′-naphthalen]-8′-yl)methanol (19-3) (1.162 g, 5.28 mmol) was added anhydrous THF (40 ml). The reaction mixture was then capped (not under N2) & stirred at room temperature for ˜16 hours (overnight). Followed by LC/MS. The reaction mixture was diluted with DCM/EtOAc, filtered (to remove the resin), it was noticed that the filtrate was cloudy white so it was filtered to yield 3-((3′,4′-dihydro-1′H-spiro[[1,3]dioxolane-2,2′-naphthalen]-8′-yl)methyl)-N-(2,4-dimethoxybenzyl)-5-fluoro-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide (19-4).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:15]1[C:20]([CH:21]([CH2:26][CH2:27][CH3:28])[C:22]([O:24][CH3:25])=[O:23])=[C:19]([CH3:29])[N:18]=[C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:16]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[CH3:29][C:19]1[C:20]([CH:21]([CH2:26][CH2:27][CH3:28])[C:22]([O:24][CH3:25])=[O:23])=[C:15]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:16]=[C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:18]=1
Reactant: Oc1ccccc1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Oc1ccccc1
Temperature: 100 °C
Yield: 68.5 %

Procedure:
Phenol (0.141 g; 1.5 mmol) and cesium carbonate (0.489 g; 1.5 mmol) were added to a solution of methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.159 g; 0.5 mmol) in tetrahydrofuran (1.5 mL) and heated in a seal tube to 100° C. for 18 h. The mixture was diluted with a saturated solution of sodium hydrogen carbonate and was extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.129 g (58%) of the title compound.