Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B2OCCCO2)=[C:23]([F:33])[C:22]=1[O:34][CH3:35].[F-].[Cs+].C(#N)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([O:34][CH3:35])[C:23]=2[F:33])[N:5]=[C:4]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:3]=1
Reactant: COc1c(Cl)ccc(B2OCCCO2)c1F
Reactant: O=C(OCc1ccccc1)c1cc(Cl)c(Cl)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: O
Product: COc1c(Cl)ccc(-c2nc(C(=O)OCc3ccccc3)cc(Cl)c2Cl)c1F
Temperature: 25 °C

Procedure:
A 250 mL three-neck flask equipped with a reflux condenser and nitrogen inlet was charged with benzyl 4,5,6-trichloropicolinate (17.77 g, 56.10 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (19.20 g, 79.0 mmol) and CsF (17.04 g, 112.0 mmol). Acetonitrile (100 mL) and water (30 mL) were added. The reaction mixture was evacuated/backfilled with nitrogen (5×). Solid Pd(PPh3)2Cl2 (1.724 g, 2.456 mmol) was added. The solution was evacuated/backfilled with nitrogen (5×) and then stirred at reflux for 90 min. A white solid precipitated upon cooling to room temperature. The solid was filtered, washed with water and dried in air (18.66 g, 75%): 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H, pyridine H), 7.52-7.32 (m, 5H, phenyl), 7.27 (dd, JH-H=8.4 Hz, JF-H=1.7 Hz, 1H, aromatic), 7.10 (dd, JH-H=8.4 Hz, JF-H=6.8 Hz, 1H, aromatic), 5.44 (s, 2H, CH2Ph), 3.98 (d, J JF-H=1.3 Hz, 3H, OMe); 13C{1H} NMR (101 MHz, CDCl3) δ 163.0, 153.7, 153.5 (d, JF-C=253 Hz, C2′), 146.0, 144.5 (d, JF-C=13 Hz), 144.1, 135.0, 134.2, 129.9 (d, JF-C=3 Hz), 128.5, 126.1, 125.8 (d, JF-C=14 Hz), 125.3 (d, JF-C=3 Hz), 124.9 (d, JF-C=2 Hz), 67.9 (CH2), 61.5 (d, JF-C=4 Hz, OMe). Anal. Calcd for C20H13Cl3FNO3: C, 54.51; H, 2.97; N, 3.18. Found: C, 54.60; H, 3.08; N, 3.16.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.Cl.[CH3:17][O:18][NH2:19].[OH-].[Na+]>O1CCOCC1.O>[CH2:13]([NH:12][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:7]=[C:2]([NH:19][O:18][CH3:17])[N:3]=1)[CH2:14][CH3:15]
Reactant: CON
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCNc1nc(NCCC)nc(NOC)n1
Temperature: 60 °C
Yield: 90.2 %

Procedure:
A mixture of 6-chloro-N,N′-dipropyl-[1,3,5]triazine-2,4-diamine (XXXIV) (2.30 g, 10.01 mmol), O-methyl-hydroxylamine hydrochloride (1.67 g, 20.02 mmol) and NaOH (0.72 g, 18.00 mmol) in 1,4-dioxane (30 mL) and water (6 mL) was heated at 60° C. for 3 h. After this time, NaOH (0.72 g, 18.00 mmol) was added and the reaction mixture was heated for another 3 h. The volatiles were removed under reduced pressure. Saturated NaHCO3 solution (100 mL) was added to the residue, the mixture was extracted with EtOAc (3×25 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography using gradient elution from CH2Cl2/EtOH (99:1) to CH2Cl2/EtOH (95:5) to yield 2.17 g (90%) of N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-methyl-hydroxylamine (XLI). ESI-MS (m/z): 241 [M+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C([Sn](CCCC)(CCCC)[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)CCC>>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: O=C1Cc2cc(-c3cccs3)ccc2N1

Procedure:
The title compound was prepared as described for Example 37 using 5-bromooxindole and tri-n-butyl(2-thienyl)tin: MS (ES) n/z 216 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.CO.[C:21]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>C1COCC1>[CH3:21][O:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=C1COc2c1ccc(O)c2CN1CCOCC1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1CN1CCOCC1)OCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
A solution of 6-hydroxy-7-(morpholinomethyl)benzofuran-3(2H)-one (0.586 g, 2.35 mmol), methanol (0.0904 g, 2.82 mmol) and triphenylphosphine (0.923 g, 3.52 mmol) in THF (12 mL) was added with a solution of a 40% solution of diethyl azodicarboxylate in toluene (1.84 g, 4.23 mmol) in THF (6 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 6-methoxy-7-(morpholinomethyl)benzofuran-3(2H)-one (0.509 g, 82%).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]([C:16]1[S:17][C:18]([Sn](CCCC)(CCCC)CCCC)=[CH:19][N:20]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])[CH3:3].Cl[C:35]1[N:40]=[C:39]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][C@@H:42]2[CH3:47])[CH:38]=[C:37]([CH2:48][S:49]([CH3:52])(=[O:51])=[O:50])[N:36]=1>C1(C)C=CC=CC=1.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>[CH3:47][C@H:42]1[CH2:43][O:44][CH2:45][CH2:46][N:41]1[C:39]1[CH:38]=[C:37]([CH2:48][S:49]([CH3:52])(=[O:51])=[O:50])[N:36]=[C:35]([C:18]2[S:17][C:16]([N:8]([C:9]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:15])[C:6](=[O:7])[O:5][C:2]([CH3:4])([CH3:1])[CH3:3])=[N:20][CH:19]=2)[N:40]=1
Reactant: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(Cl)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s2)n1
Yield: 93.3 %

Procedure:
A mixture of tert-butyl N-[(2-methylpropan-2-yl)oxycarbonyl]-N-(5-tributylstannyl-1,3-thiazol-2-yl)carbamate (3 g, 5.1 mmol), 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidine (1 g, 3.2 mmol) and palladium tetrakis (triphenylphosphine) (50 mg), in toluene (10 mL) was heated at 105° C. for 2 hours under nitrogen. The mixture was chromatographed on silica to give the desired material (1.7 g).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([OH:8])=O)(=[O:3])[CH3:2].CCN=C=[N:13][CH2:14][CH2:15][CH2:16]N(C)C.Cl.C(N)C#C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([NH:4][CH2:5][C:6]([NH:13][CH2:14][C:15]#[CH:16])=[O:8])(=[O:3])[CH3:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(=O)NCC(=O)O
Agent: C#CCN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C#CCNC(=O)CNC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
To a solution of N-acetylglycine (200 mg, 1.71 mmol), DMAP (11 mg, 0.09 mmol) and EDC hydrochloride (360 mg, 1.88 mmol) in DCM (10 mL) was added propargylamine (109 μL, 1.71 mmol). The reaction mixture was stirred at RT overnight and then evaporated in vacuo. The residue was purified by flash column chromatography, eluting with 0 to 5% methanol in DCM, to afford the title compound (12) (218 mg, 83%) as a white solid: 1H NMR (500 MHz, CDCl3) δ: 2.07 (3H, s), 2.25 (1H, t), 3.95 (2H, d), 4.07 (2H, dd), 6.34 (1H, br s), 6.49 (1H, b s).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[NH:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[N:11]=1.[OH-].[Na+].[CH3:21]OS(OC)(=O)=O>CN(C)C=O>[CH3:21][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[NH:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: c1ccc2[nH]c(-c3nc4ccccc4[nH]3)nc2c1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cn1c(-c2nc3ccccc3[nH]2)nc2ccccc21
Reaction time: 24 h
Yield: 39.3 %

Procedure:
To a flask were added 1.2 g 1H,1′H-2,2′-bibenzimidazole, 0.45 g sodium hydroxide, 100 ml N,N-dimethylformamide and 1.4 g dimethylsulfate. The mixture was heated to 45 C under nitrogen for 16 hours and another 0.45 g sodium hydroxide and 2.8 g dimethylsulfate were added and the mixture was stirred at 45 C for 24 hours. Another 4.2 g of dimethylsulfate were added and the mixture was stirred at 45 C for 24 hours, then cooled to 22 C and quenched with 350 ml water. The off-white solid was filtered and washed with water. After dissolving the product in 125 ml hot ethanol, 44 ml water were added and the solution was cooled to 5 C, filtered, washed with 50% ethanol and dried leaving 0.5 g white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[S:20])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Br[CH2:22][CH2:23][CH2:24]Br.CCO[CH2:29][CH3:30]>O1CCOCC1>[CH2:22]([S:20][C:10]1[NH:11][C:12]([C:30]2[CH:29]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=1)[CH2:23][CH2:24][S:20][C:10]1[NH:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=1
Reactant: CCOCC
Reactant: Fc1ccc(-c2[nH]c(=S)[nH]c2-c2ccc(F)cc2)cc1
Reactant: BrCCCBr
Solvent: C1COCCO1
Product: Fc1ccc(-c2nc(SCCCSc3nc(-c4ccc(F)cc4)c(-c4ccc(F)cc4)[nH]3)[nH]c2-c2ccc(F)cc2)cc1

Procedure:
A mixture of 4,5-bis(4-fluorophenyl)-1H-imidazole-2-thione (8 g, 0.028 mol) and 1,3-dibromopropane (2.8 g, 0.014 mol) in dioxane (175 ml) was refluxed for 2.5 hours. After cooling, ether (300 ml) was added and the resulting white solid was collected by filtration, washed with ether and recrystallized from dioxane-ether to give the title compound as its dihydrobromide salt (hydrate), m.p. 176°-178°.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][C:9]2[CH:21]=[CH:20][C:12]3[C:13]([CH3:19])([CH3:18])[CH:14]=[C:15]([CH3:17])[O:16][C:11]=3[CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[OH-:25].[Na+]>C(OCC)(=O)C.O.CC(C)=O>[OH:25][C:15]1([CH3:17])[CH2:14][C:13]([CH3:19])([CH3:18])[C:12]2[CH:20]=[CH:21][C:9]([O:8][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:23][CH:22]=3)=[CH:10][C:11]=2[O:16]1
Reactant: [OH-]
Reactant: CC1=CC(C)(C)c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2O1
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(O)CC(C)(C)c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2O1
Yield: 70 %

Procedure:
A mixture of 6.5 g of the 7-(4-nitrophenoxy)-2,4,4-trimethyl-4H-1-benzopyran, 26 ml of water, 13 ml of conc. hydrochloric acid and 65 ml of acetone was refluxed for 2 hours. An 10% aqueous solution of sodium hydroxide was added to the reaction mixture to neutralize it, and then 100 ml of water and 200 ml of ethyl acetate were added, and the mixture was subjected to oil-water separation. The oil layer was washed with 50 ml of brine, dried over magnesium sulfate and concentrated. Toluene (5 ml) and 45 ml of hexane was added to the residue, and the precipitated crystals were collected by filtration, washed with 50 ml of hexane and dried to give 5.1 g (yield 70%) of a pale brown powder (mp. 159°-160° C., recrystallized from ethanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:19](=[CH:20][CH:21]=1)[C:9]1[O:10][C:11]3([CH2:17][S:18][C:8]=1[C:7](=[O:22])[C:6]2=[O:23])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3.[CH2:24]([C@H:31]1[CH2:33][O:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[OH:32][C@@H:31]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:33][N:14]1[CH2:15][CH2:16][C:11]2([O:10][C:9]3[C:19]4[C:5]([C:6](=[O:23])[C:7](=[O:22])[C:8]=3[S:18][CH2:17]2)=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=4)[CH2:12][CH2:13]1
Reactant: c1ccc(C[C@H]2CO2)cc1
Reactant: COc1ccc2c(c1)C(=O)C(=O)C1=C2OC2(CCNCC2)CS1
Product: COc1ccc2c(c1)C(=O)C(=O)C1=C2OC2(CCN(C[C@@H](O)Cc3ccccc3)CC2)CS1

Procedure:
Compound 203 was synthesized using 8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-benzyloxirane and conditions outlined in procedure Y. M.p.=146-147° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.73 (d, J=8.6 Hz, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.31 (d, J=3.0 Hz, 1H), 7.28-7.12 (m, 4H), 4.43 (d, J=4.7 Hz, 1H), 3.84 (s, 3H), 3.03 (s, 2H), 2.80-2.68 (m, 2H), 2.58 (dd, J=7.4, 14.0 Hz, 1H), 2.47-2.26 (m, 3H), 1.99-1.90 (m, 2H), 1.87-1.72 (m, 2H). LCMS: 466 [M+H].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:27])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=3)[CH:12]=[CH:13][CH:14]=2)[C:5]([Cl:28])=[CH:4][N:3]=1>O.CO.C(O)(=O)C.[Fe]>[NH2:24][C:20]1[CH:19]=[C:18]([CH2:17][C:16]([NH:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][C:6]3[C:5]([Cl:28])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:10]=2)=[O:27])[CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cc1cccc([N+](=O)[O-])c1)Nc1cccc(Nc2nc(Cl)ncc2Cl)c1
Agent: [Fe]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: Nc1cccc(CC(=O)Nc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
To a solution N-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}-2-(3-nitrophenyl)acetamide (0.055 g, 0.13 mmol) in water (0.1 mL), methanol (0.5 mL) and acetic acid (0.20 mL) was added iron (0.030 g, 0.53 mmol) powder in one batch. The mixture was stirred at 0° C. for 0.5 h. The reaction was mixed with celite, filtered, and the cake was washed with EtOAc. The brown filtrate was concentrated and EtOAc and NaHCO3/water added. The aqueous phase was extracted with EtOAc. The organics were combined, died over Na2SO4 and concentrated to give the desired product as a yellow powder (30 mg, 58%). LCMS for C18H15Cl2N5O (M+H)+: m/z=388.0, 390.0.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[C:9]([O:15][CH:16]([CH3:18])[CH3:17])[CH:8]=1.CN(C)[CH:21]=[O:22].B(F)(F)F.CCOCC>O1CCCC1.O>[CH3:14][S:13][C:10]1[CH:11]=[CH:12][C:7]([CH:21]=[O:22])=[CH:8][C:9]=1[O:15][CH:16]([CH3:18])[CH3:17]
Reactant: CN(C)C=O
Reactant: CSc1ccc(Br)cc1OC(C)C
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc(C=O)cc1OC(C)C
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A solution of n-butyllithium in hexanes (14.82 mL; 2.5M) is added to a solution of 4-bromo-2-prop-2-yloxythioanisole (8.8 g) in dry tetrahydrofuran (70 mL), whilst cooling the mixture to -70° C. under nitrogen. The mixture is stirred for 1 hour at -70° C. Dry dimethylformamide (5.22 mL) and boron trifluoride diethyl etherate (8.29 mL) are added sequentially and the mixture is allowed to warm to room temperature. The mixture is poured into water and the product is extracted with dichloromethane. The extract is dried over magnesium sulfate and concentrated in vacuo, and the residue is subjected to flash chromatography on silica gel, eluting with a mixture of pentane and ethyl acetate (9:1 v/v) to give 4-methylthio-3-prop-2-yloxybenzaldehyde, in the form of a soft yellow solid, m.p. 50°-54° C.
Reaction SMILES: C([O:8][C:9]1[C:17]([Cl:18])=[C:16]([CH3:19])[C:15]([CH3:20])=[C:11]([C:12]([OH:14])=[O:13])[C:10]=1[NH2:21])C1C=CC=CC=1>CCO.[Pd]>[Cl:18][C:17]1[C:9]([OH:8])=[C:10]([NH2:21])[C:11](=[C:15]([CH3:20])[C:16]=1[CH3:19])[C:12]([OH:14])=[O:13]
Reactant: Cc1c(C)c(C(=O)O)c(N)c(OCc2ccccc2)c1Cl
Agent: [Pd]
Solvent: CCO
Product: Cc1c(C)c(C(=O)O)c(N)c(O)c1Cl
Reaction time: 5 h
Yield: 46.4 %

Procedure:
3-Benzyloxy-4-chloro-5,6-dimethylanthranilic acid (10 mg, 0.03 mmol) was dissolved in EtOH (1.5 mL) and 10% Pd/C (2 mg) was added. Hydrogenation at room temperature and atmospheric pressure for 5 h, filtration, evaporation yielded 7 mg of crude product. Purification by preparative HPLC (Lichrosorb-C18, MeOH-Phosphate buffer (pH3) 50:50) adjusting the pH to 5 with NaHCO3 (aq), concentrating by a stream of N2, extracting with EtOAc (3×5 mL), washing the organic phase with brine, drying (MgSO4) and evaporating afforded the title compound (3 mg). 1H NMR (DMSO-d6): δ 3.3 (br, OH), 3.16 (s, 2 H), 2.16 (s, 3 H), 2.15 (s, 3 H); 13C NMR (DMSO-d6): δ 169.92, 137.87, 135.16, 126.38, 123.51, 121.39, 117.31, 17.72, 15.95; MS (EI, 70 eV): m/z (rel.int.) 217/215 (M+, 21/63),199/197 (20/59), 171/169 (37/100).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]=1[C:15]([F:18])([F:17])[F:16].[CH3:20][C:21]1([CH3:42])[O:25][CH:24]([C:26]2[CH:35]=[C:34]3[C:29]([C:30]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[CH:31][CH2:32][O:33]3)=[CH:28][CH:27]=2)[CH2:23][O:22]1.C(N(CC)CC)C>ClCCl>[CH3:20][C:21]1([CH3:42])[O:25][CH:24]([C:26]2[CH:27]=[CH:28][C:29]3[C:30]4([N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)[CH:31]([C:3]([C:4]5[O:8][N:7]=[C:6]([C:9]6[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=6)[C:5]=5[C:15]([F:18])([F:17])[F:16])=[N:2][O:1]4)[CH2:32][O:33][C:34]=3[CH:35]=2)[CH2:23][O:22]1
Reactant: CC1(C)OCC(c2ccc3c(c2)OCC=C3N2CCOCC2)O1
Reactant: ON=C(Cl)c1onc(-c2ccccc2)c1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)OCC(c2ccc3c(c2)OCC2C(c4onc(-c5ccccc5)c4C(F)(F)F)=NOC32N2CCOCC2)O1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 12 %

Procedure:
To a solution of the N-hydroxy-3-phenyl-4-(trifluoromethyl)isoxazole-5-carbimidoyl chloride (Intermediate 1-12, 0.340 g, 1.170 mmol) in dichloromethane (3.5 mL) was added 4-(7-(2,2-dimethyl-1,3-dioxolan-4-yl)-2H-chromen-4-yl)morpholine (Preparation 60C, 0.473 M in dichloromethane) (2.47 mL, 1.17 mmol). The reaction mixture was cooled to 0° C., and triethylamine (0.324 mL, 2.34 mmol) was added dropwise over 10 min. The ice-bath was removed, and the resulting cloudy solution was stirred at room temperature for 1.5 h. The reaction mixture was diluted with dichloromethane (50 mL), washed with water (25 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford the crude product as an orange oil. The compound was purified by flash silica gel chromatography using a mixture of ethyl acetate and hexane (5%-12%-20%) to give 7-(2,2-dimethyl-1,3-dioxolan-4-yl)-9b-morpholino-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,9b-dihydro-3aH-chromeno[3,4-d]isoxazole (0.080 g, 0.140 mmol, 12% yield) as a yellow solid. The product had an HPLC ret. time=3.25 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=572.1.
Reaction SMILES: N[C@@](C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)CO.[C:38]([C@H:42]1[CH2:47][CH2:46][C@H:45]([O:48][C:49]2[C:50]([Cl:68])=[C:51]3[C:56](=[C:57]([Cl:60])[C:58]=2[Cl:59])[CH:55]=[C:54]([C@:61]2([CH3:67])[CH2:65][O:64]C(=O)[NH:62]2)[CH:53]=[CH:52]3)[CH2:44][CH2:43]1)([CH3:41])([CH3:40])[CH3:39]>>[NH2:62][C@@:61]([C:54]1[CH:53]=[CH:52][C:51]2[C:56](=[C:57]([Cl:60])[C:58]([Cl:59])=[C:49]([O:48][C@H:45]3[CH2:46][CH2:47][C@H:42]([C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:43][CH2:44]3)[C:50]=2[Cl:68])[CH:55]=1)([CH3:67])[CH2:65][OH:64]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2c(Cl)c(Cl)c3cc([C@]4(C)COC(=O)N4)ccc3c2Cl)CC1
Agent: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2c(Cl)c(Cl)c3cc([C@@](C)(N)CO)ccc3c2Cl)CC1

Procedure:
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5,7,8-trichloronaphthalen-2-yl)propan-1-ol was synthesized as per (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(trifluoromethoxy)phenyl)naphthalen-2-yl)propan-1-ol (Example 221) in 37% yield using (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5,7,8-trichloronaphthalen-2-yl)-4-methyloxazolidin-2-one as starting material. MS: m/z=441.25 [M−NH2]+. 1H NMR (MeOD) δ: 8.42 (d, J=1.5 Hz, 1H), 8.28 (d, J=9.5 Hz, 1H), 7.89 (dd, J=9.0, 2.0 Hz, 1H), 4.31-4.42 (m, 1H), 3.78 (d, J=11.0 Hz, 1H), 3.72 (d, J=11.0 Hz, 1H), 2.14-2.22 (m, 2H), 1.85-1.93 (m, 2H), 1.63-1.76 (m, 2H), 1.56 (s, 3H), 1.04-1.15 (m, 3H), 0.90 (s, 9H)
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: NC(=NO)c1cccc(F)c1
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1
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: [CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13](C(O)=O)[N:14]2[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=C2C(=CC=1)[N:32]([C:36](N)=[O:37])C=C2N=C=O)C=C>>[CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]([N:32]=[C:36]=[O:37])[N:14]2[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)c1cc(C(=O)O)n2ccccc12
Reactant: C=CCOc1ccc2c(c1)c(N=C=O)cn2C(N)=O
Product: O=C=Nc1cc(C(=O)OCc2ccccc2)c2ccccn12

Procedure:
The title compound was prepared from indolizine-1,3-dicarboxylic acid 1-benzyl ester using the protocol described in step E scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]([CH3:19])([CH3:18])[CH2:10]2)[C:5]([F:20])=[CH:4][N:3]=1.[O:21]1[CH2:24][CH:23]([N:25]2[CH2:30][CH2:29][CH:28]([O:31][C:32]3[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][C:33]=3[C:39]([F:42])([F:41])[F:40])[CH2:27][CH2:26]2)[CH2:22]1.CC1C=CC(S(O)(=O)=O)=CC=1>CC(O)C.CCOC(C)=O>[CH3:18][C:11]1([CH3:19])[CH2:10][C@H:9]([NH:8][C:6]2[C:5]([F:20])=[CH:4][N:3]=[C:2]([NH:36][C:35]3[CH:37]=[CH:38][C:32]([O:31][CH:28]4[CH2:27][CH2:26][N:25]([CH:23]5[CH2:24][O:21][CH2:22]5)[CH2:30][CH2:29]4)=[C:33]([C:39]([F:42])([F:41])[F:40])[CH:34]=3)[N:7]=2)[CH2:17][C@H:16]2[N:12]1[CH2:13][CH2:14][CH2:15]2
Reactant: Nc1ccc(OC2CCN(C3COC3)CC2)c(C(F)(F)F)c1
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2F)C[C@@H]2CCCN21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC1(C)C[C@H](Nc2nc(Nc3ccc(OC4CCN(C5COC5)CC4)c(C(F)(F)F)c3)ncc2F)C[C@@H]2CCCN21
Temperature: 100 °C
Yield: 70 %

Procedure:
A mixture of (7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-5,5-dimethyloctahydroindolizin-7-amine (0.25 g, 1.0 eq, 0.8 mmol), 4-((1-(oxetan-3-yl)piperidin-4-yl)oxy)-3-(trifluoromethyl)aniline (0.3 g, 1.2 eq, 1.0 mmol), PTSA (0.14 g, 0.9 eq, 0.8 mmol) was taken in iPrOH (20 mL) and heated at 100° C. overnight. The volatiles were removed under vacuum to leave a crude solid. The crude mixture was dissolved in EtOAc (50 mL) and partitioned with 1N aqueous NaOH solution (25 mL). Organic layers were separated and the aqueous layer was washed with EtOAc (2×20 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to leave a crude solid. The solid was purified by column chromatography on silica gel (ISCO System) using 2M NH3 in MeOH/CH2Cl2 (gradient system from 0:1 to 2:8) as eluent to give the product in 70% yield.