Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]([O:27][CH2:28][C:29]3([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:20]=[N:21][C:22]=2[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[C:19]([O:27][CH2:28][C:29]3([OH:35])[CH2:34][CH2:33][N:32]([CH3:36])[CH2:31][CH2:30]3)[N:20]=[N:21][C:22]=2[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCCc1nnc(OCC2(O)CCNCC2)cc1-c1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCCCc1nnc(OCC2(O)CCN(C)CC2)cc1-c1ccc(OCc2ccccc2)cc1
Reaction time: 0.33 h

Procedure:
A suspension of 4-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-piperidin-4-ol dihydrochloride (0.1 mmol) aqueous formaldehyde (37%, 0.3 mmol) and molecular sieves in anhydrous DCM may be stirred for 20 minutes. To this suspension at room temperature may be added sodium triacetoxyborohydride (0.3 mmol). The reaction mixture may be monitored by LCMS until the reaction is complete. The reaction may be quenched with saturated NaHCO3 and the layers may be separated. The organic layer may be dried and the solvent may be removed under reduced pressure. The crude product may be purified by flash chromatography using with 1-5% (2N ammonia in MeOH) in DCM to give 4-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-1-methyl-piperidin-4-ol. The neutral amine may be treated with 2N HCl in diethyl ether and DCM. The volatiles may be removed under reduced pressure and the salt triturated with diethyl ether and filtered to provide the title compound. LCMS: m/z 463 [M+1]. 1H NMR (400 MHz, CDCl3) δ 7.32-7.49 (5H, m), 7.19-7.25 (2H, m), 7.02-7.09 (2H, m), 6.78 (1H, bs), 5.12 (2H, s), 4.58-4.83 (1H, m), 4.32 (2H, s), 2.54-2.69 (3H, m), 2.40-2.51 (2H, m), 2.27-2.36 (3H, m), 1.71-1.83 (2H, m), 1.59-1.70 (2H, m), 1.18-1.51 (5H, m), 0.81 (3H, t).
Reaction SMILES: [C:1]1([CH:7]([NH2:30])[CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]4)=[O:18])[CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:32]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[O:33]>C(Cl)(Cl)Cl>[C:1]1([CH:7]([NH:30][C:32]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[O:33])[CH2:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][N:14]([C:17]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]4)=[O:18])[CH2:15][CH2:16]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(CCCN1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1)c1ccccc1
Reactant: CC(C)COC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)COC(=O)NC(CCCN1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1)c1ccccc1
Reaction time: 3 h

Procedure:
2 Grams of 6-[4-(4-phenyl-4-aminobutyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril was dissolved in 30 ml of chloroform, then to this solution was added 0.76 ml of isobutyl chloroformate at 0° C.-5° C. The reaction mixture was stirred at the same temperature for 3 hours, then concentrated. The residue thus obtained was purified by means of a silica gel column chromatography (eluent: dichloromethane:methanol=40:1), then converted into an oxalate by stirring with oxalic acid in acetone, and the oxalate was recrystallized from ethanol-water to yield 1.9 g of 6-[4-(4-phenyl-4-isobutoxycarbonylaminobutyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril.oxalate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.C(O)(=O)C(O)=O.[OH:26][C@H:27]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29]>C(Cl)Cl>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])[N:3]=[C:2]2[N:33]1[CH2:32][CH2:31][N:30]([C:28](=[O:29])[C@H:27]([OH:26])[CH2:36][CH:37]([CH3:38])[CH3:39])[CH2:35][CH2:34]1
Reactant: Oc1ccccc1-c1nc(Cl)c2cc(F)ccc2n1
Reactant: CC(C)C[C@@H](O)C(=O)N1CCNCC1
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Product: CC(C)C[C@@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)CC1
Reaction time: 2 h
Yield: 91.5 %

Procedure:
To a mixture of 2-(4-chloro-6-fluoroquinazolin-2-yl)phenol (200 mg, 0.72 mmol) and CH2Cl2 (7 mL) was added (R)-2-hydroxy-4-methyl-1-(piperazin-1-yl)pentan-1-one oxalate (275 mg, 0.95 mmol). The reaction was complete after two hours. Purification via silica gel chromatography using 0-10% EtOAc in 50:50 mixture of CH2Cl2:hexanes gave (R)-1-(4-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one (289 mg, 91%). LC/MS: m/z 439.30 (M+H)+ at 3.00 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.46 (m, 1H), 8.02 (m, 1H), 7.84 (m, 2H), 7.40 (m, 1H), 6.97 (m, 2H), 4.92 (d, J=7.2 Hz, 1H), 4.38 (m, 1H), 3.98 (m, 4H), 3.76 (m, 4H), 1.80 (m, 1H), 1.42 (m, 2H), 0.92 (q, J=3.8 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[N:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[N:11]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:10]2[CH:14]=[CH:13][N:12]=[N:11]2)[N:3]=1.[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:11]2[N:12]=[CH:13][CH:14]=[N:10]2)[N:3]=1
Reactant: c1c[nH]nn1
Reactant: BrCc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cccc(Cn2ccnn2)n1
Product: Brc1cccc(Cn2nccn2)n1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
2-Bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (1.50 g, 5.98 mmol), 1H-1,2,3-triazole (520 mL, 8.97 mmol), and K2CO3 (1.652 g, 11.96 mmol) were combined in DMF (5.0 mL) and stirred at 50° C. overnight. The mixture was diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. Flash chromatography (0-100% EtOAc/hexanes) separated the two regioisomeric products to provide 2-bromo-6-(1H-1,2,3-triazol-1-ylmethyl)pyridine (lower Rf) and 2-bromo-6-(2H-1,2,3-triazol-2-ylmethyl)pyridine (higher Rf) as colorless solids.
Reaction SMILES: CC(C)([O-:4])C.[K+].O[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH3:17][O:18][C:19]1[C:20]([N+:28]([O-:30])=[O:29])=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23].Cl>C1COCC1.C(Cl)Cl>[OH:4][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9](=[O:10])[CH2:8][C:22]([C:21]1[CH:25]=[CH:26][CH:27]=[C:19]([O:18][CH3:17])[C:20]=1[N+:28]([O-:30])=[O:29])=[O:23]
Reactant: CC(C)(C)[O-]
Reactant: O=C(CO)c1ccccc1
Reactant: COc1cccc(C(=O)Cl)c1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cccc(C(=O)CC(=O)c2ccccc2O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 94.1 %

Procedure:
To a 300-mL, three-neck, round-bottom flask with a mechanical stirrer is added potassium tert.-butoxide (2.5 g, 22 mmol). The flask is cooled to 0° C. and dry THF (10 mL) is added. To this solution, 2-hydroxy-acetophenone (3.5 mL, 18.6 mmol) in THF (10 mL) is added slowly over 30 minutes keeping the temperature below 5° C. The resulting yellow paste is warmed to 25° C. and stirred for 35 minutes. The mixture is cooled to 0° C. and 3-methoxy-2-nitrobenzoyl chloride (4.3 g, 20 mmol) in THF (15 mL) is added slowly over 15 minutes, keeping the temperature below 5° C. The mixture is warmed to 25° C. and stirred for 1 hour. The mixture is cooled to 5° C. and solid potassium tert.-butoxide (2.5 g, 22 mmol) is added forming a dark brown paste. THF (30 mL) is added and the mixture is heated at reflux for 3 hours. The mixture is cooled to 25° C. and 3N HCl is added until the pH falls to 2. The mixture is concentrated under reduced pressure to leave a brown solid. The brown solid is dissolved in CH2Cl2 (200 mL) and H2O (50 mL), washed with saturated NaHCO3 solution (200 mL), saturated brine (200 mL), and H2O (200 mL). The organic layer is dried (Na2SO4) and concentrated under reduced pressure to yield 1-(2-hydroxyphenyl)-3-(3-methoxy-2-nitrophenyl)propane-1,3-dione (5.52 g, 79%) as a tautomeric mixture.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH:11][C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=2)=[O:22])=[O:10])[CH2:5][CH2:4]1.[CH3:32][I:33]>>[I-:33].[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:21]([C:13]2[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:12]=2[NH:11][C:9]([CH:6]2[CH2:5][CH2:4][CH:3]([N+:2]([CH3:32])([CH3:31])[CH3:1])[CH2:8][CH2:7]2)=[O:10])=[O:22])=[N:25][CH:26]=1
Reactant: CI
Reactant: CN(C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Product: C[N+](C)(C)C1CCC(C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Product: [I-]

Procedure:
Trans-3-[4-(dimethylamino)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (150 mg) obtained in Example 306 and methyl iodide (21 μl) are treated in a similar manner to Example 367 to give the title compound (137 mg).
Reaction SMILES: [CH2:1]([C:5]1[NH:9][CH:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>O1CCCC1>[CH2:1]([C:5]1[N:9]([S:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:25])=[O:24])[CH:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(C(=O)OCC)c[nH]1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1cc(C(=O)OCC)cn1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
Under an argon atmosphere, ethyl 5-butyl-1H-pyrrole-3-carboxylate (976 mg) was dissolved in tetrahydrofuran (50 mL), sodium hydride (60% in oil, 240 mg) was added and the mixture was stirred at room temperature for 30 min. Benzenesulfonyl chloride (0.77 mL) was added, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→8:2), and the obtained solid was washed with hexane to give the title compound as a colorless solid (yield 780 mg, 47%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH3:15][C:16]1[S:20][C:19]([C:21]2[S:22][CH:23]=[CH:24][C:25]=2[NH2:26])=[N:18][CH:17]=1>>[CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([NH:26][C:25]3[CH:24]=[CH:23][S:22][C:21]=3[C:19]3[S:20][C:16]([CH3:15])=[CH:17][N:18]=3)=[O:14])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Cc1cnc(-c2sccc2N)s1
Reactant: O=C(O)Cc1cccc2cnccc12
Product: Cc1cnc(-c2sccc2NC(=O)Cc2cccc3cnccc23)s1

Procedure:
The title compound was prepared from 2-(isoquinolin-5-yl)acetic acid and 2-(5-methylthiazol-2-yl)thiophen-3-amine using Protocol A. Method[7], MS (ESI) 366.0 [M+H], Retention time=3.157 min; 1H-NMR (300 MHz, CDCl3) δ 11.24 (s, 1H), 9.67 (s, 1H), 8.57 (d, J=6.6 Hz, 1H), 8.30 (d, J=6.6 Hz, 1H), 8.26 (d, J=8.24 Hz, 1H), 8.08-8.04 (m, 2H), 7.96-7.91 (m, 1H), 7.20 (d, J=5.5 Hz, 1H), 6.97 (d, J=1.1 Hz, 1H), 4.31 (s, 2H), 2.43 (d, J=1.1 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]2[CH:12]=1.O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[N:5]1[C:4]([CH2:3][CH2:2][O:1][C:14]2[CH:46]=[CH:45][C:17]([CH2:18][CH:19]3[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]3=[O:44])=[CH:16][CH:15]=2)=[CH:12][N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=12
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCc1cn2ccccc2n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: O=C1SC(Cc2ccc(OCCc3cn4ccccc4n3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 0.80 g of 2-(2-hydroxyethyl)imidazo[1,2-a]pyridine (prepared as described in Preparation 26), 2.79 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 1.7 ml of tributylphosphine, 1.51 g of 1,1'-(azodicarbonyl)dipiperidine and 30 ml of benzene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 1:4 to 0:1 by volume as the eluent, to give 0.97 g of the title compound, melting at 135.5-142.4° C. (with decomposition).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[O:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[CH2:44][NH2:45].NN>CCO.O>[NH2:3][CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:45][CH2:44][CH:40]2[CH2:41][CH2:42][CH2:43][O:39]2)=[O:34])[C:15]1=[O:38]
Reactant: NCC1CCCO1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCn1c(=O)c(C(=O)NCC2CCCO2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.252 g, 0.49 mmol) in EtOH (15 mL) under nitrogen was treated with 1-(tetrahydro-2-furanyl)methanamine (0.252 mL, 2.44 mmol) for 15 min.@150° C. in a microwave vessel. The reaction was transferred to a test tube, diluted with EtOH (30 mL), and treated with hydrazine (0.4 mL, 13 mmol)@50° C. overnight. After the reaction was cooled to ambient temperature the resulting suspension was diluted with water (120 mL) and refrigerated overnight. The resulting suspension was filtered, washed with 2:1 water:EtOH and thoroughly dried under high vacuum to provide the title compound as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.49-1.61 (m, 1H), 1.80-2.00 (m, 3H), 2.78 (t, J=6.46 Hz, 2H), 3.25-3.41 (m, 1H), 3.49-3.59 (m, 1H), 3.68 (t, J=6.81 Hz, 1H), 3.75-3.86 (m, 1H), 3.95-4.05 (m, 1H), 4.16 (s, 2H), 4.18-4.26 (m, 2H), 7.14 (ddd, J=8.95, 6.91, 1.82 Hz, 2H), 7.35-7.43 (m, 2H), 8.15 (d, J=1.40 Hz, 1H), 8.51 (s, 1H), 10.44-10.53 (m, 1H); ES+ MS: 441 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].COC(C)(C)C.S([O:19][CH2:20][CH3:21])(OCC)(=O)=O.[Cl:22][C:23]1[CH:39]=[CH:38][C:26]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH2:34][C:35](O)=[O:36])=[CH:25][CH:24]=1>O.CN(C)C=O>[Cl:22][C:23]1[CH:39]=[CH:38][C:26]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH2:34][C:35]([O:19][CH2:20][CH3:21])=[O:36])=[CH:25][CH:24]=1
Reactant: CCOS(=O)(=O)OCC
Reactant: O=C(O)Cc1ccccc1Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccccc1Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.8 %

Procedure:
After mixing 259.1 g of potassium carbonate (1.88 mol, granular reagent), 985 mL of tert-butyl methyl ether, 493 mL of N,N-dimethylformamide and 202.4 g (1.31 mol) of diethyl sulfate, a mixture of 328.4 g (1.25 mol) of 2-(2-(4-chlorophenoxy)phenyl)acetic acid and 164 mL of N,N-dimethylformamide was added dropwise to the obtained mixture over a period of one hour. The internal temperature of the mixture during the dropwise addition was 25-40° C. Upon completion of the dropwise addition, the obtained mixture was stirred at 25° C. for 12 hours, and completion of the reaction was confirmed by high-performance liquid chromatography. A 1642 mL portion of water was slowly added dropwise to suspend the reaction. The internal temperature of the mixture during the dropwise addition was 25-35° C. The obtained mixture was subjected to liquid separation, and after washing the organic layer with 656 mL of water and 495 mL of brine in that order, the obtained organic layer was subjected to dehydration treatment with anhydrous magnesium sulfate and the treated organic layer was concentrated to obtain 366.4 g of crude ethyl 2-(2-(4-chlorophenoxy)phenyl)acetate as an oil.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][C:38]=1[Cl:46])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40]([N:24]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:23][C:8]3[C:9]([C:19]([NH:21][CH3:22])=[O:20])=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:39][C:38]=1[Cl:46])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Reactant: OB(O)c1ccc(OCc2ccccc2)c(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(OCc4ccccc4)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Yield: 53.8 %

Procedure:
A mixture of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (1.00 g, 2.49 mmol), (4-(benzyloxy)-3-chlorophenyl)boronic acid (1.31 g, 4.97 mmol), copper(II) acetate (0.903 g, 4.97 mmol), and triethylamine (2.00 mL, 14.4 mmol) in anhydrous DCM (25 mL) was treated with powdered 3 angstrom molecular sieves (2.00 g). The resulting mixture was stirred at RT under air using a drying tube to exclude moisture. After 18 hours the mixture was treated with an additional 1.00 g portion of (4-(benzyloxy)-3-chlorophenyl)boronic acid. After another 18 hours the mixture was diluted with 15 mL of DCM and treated with 1.30 g of (4-(benzyloxy)-3-chlorophenyl)boronic acid, 0.900 g of copper(II) acetate, 2.00 g of 3 angstrom molecular sieves and 2 mL of triethylamine. After 16 more hours the mixture was filtered through Celite to remove solids and the filtrate concentrated to dryness at reduced pressure. The residue was suspended in EtOAc and the undissolved solids removed by filtration through Celite. The filtrate was washed with water (2×), brine (1×), dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude material was purified by flash chromatography (silica gel, gradient from DCM to 7:3 DCM/EtOAc) followed by recrystallization from hexane/EtOAc to afford the title compound (0.83 g, 54%) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.40-8.47 (m, 1H) 8.20 (s, 1H) 7.93-8.00 (m, 2H) 7.69 (d, J=2.6 Hz, 1H) 7.52 (dd, J=8.9, 2.7 Hz, 1H) 7.30-7.48 (m, 7H) 7.25 (d, J=9.1 Hz, 1H) 7.14 (s, 1H) 5.21 (s, 2H) 3.33 (s, 3H) 2.82 (d, J=4.6 Hz, 3H) 2.17-2.33 (m, 1H) 0.75-1.09 (m, 3H) 0.42 (br. s., 1H). LCMS (m/z, ES+)=619, 621 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.C(N(CC)CC)C.[C:30]12([NH2:40])[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]3)[CH2:31]1)[CH2:37]2>C(O)C>[CH3:21][P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:40][C:30]34[CH2:31][CH:32]5[CH2:38][CH:36]([CH2:35][CH:34]([CH2:33]5)[CH2:39]3)[CH2:37]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH3:22])=[O:20]
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(NC34CC5CC(CC(C5)C3)C4)n2)cc1
Yield: 8 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (prepared as in Example 1: 27 mg, 0.078 mmol) in 1.5 mL of ethanol was added 10 μL of triethylamine and 1-Adamantanamine (12 mg, 0.078 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (3 mg, 8% yield.) MS/ES+: m/z=465.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:4][CH2:5][O:6][CH2:7][CH:8]=1.ClC1C=CC=C([C:16](OO)=[O:17])C=1.C[OH:21]>>[CH3:1][O:2][C:3]1([O:17][CH3:16])[CH2:4][CH2:5][O:6][CH2:7][CH:8]1[OH:21]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CO
Reactant: COC1=CCOCC1
Product: COC1(OC)CCOCC1O
Reaction time: 5 h

Procedure:
To a solution of 4-methoxy-3,6-dihydro-2H-pyran (5.00 g, 43.8 mmol) in methanol (100 mL) at 0° C. was dropwise added a solution of m-chloroperbenzoic acid (15.1 g, 87.6 mmol) in methanol (15 mL). After being stirred for 5 h, methanol was removed in vacuo and the white residue was dissolved in methylene chloride (300 mL). To the solution was added K2CO3. The resulting solution was stirred for 1 h and filtered through celite. The filtrate was evaporated in vacuo to provide the desired product which was used directly for the next reaction without purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5](=[O:8])[CH2:6]Cl.[N:13]1([C:18]2[S:22][S:21][C:20](=[S:23])[CH:19]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1.[I-:24].[Na+]>CC(C)=O>[OH2:1].[I-:24].[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5](=[O:8])[CH2:6][S:23][C:20]1[S:21][S:22][C:18](=[N+:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)[CH:19]=1
Reactant: O=C(CCl)c1ccc(O)c(O)c1
Reactant: S=c1cc(N2CCCC2)ss1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O
Product: O=C(CSc1cc(=[N+]2CCCC2)ss1)c1ccc(O)c(O)c1
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
3,4-Dihydroxyphenacyl chloride (7 g) is added to a suspension of 5-(pyrrolidin-1-yl)-1,2-dithiol-3-thione (5.1 g) and sodium iodide (6.2 g) in acetone (90 cc), and the reaction mixture is kept under reflux for 1 hour. After cooling, the insoluble product is filtered off and washed successively with acetone (3×20 cc), with water (3×20 cc) and then with diethyl ether (3×20 cc). By recrystallisation of the resulting product from a dimethylformamide/methanol mixture (20/80 by volume; 600 cc) and then desolvation by stirring for 30 minutes in water (100 cc), N-[5-(3,4-dihydroxyphenacylthio)-1,2-dithiol-3-ylidene]-pyrrolidinium iodide hydrate (6.9 g), melting at about 130° C., is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([NH:18][C@H:19]([C:23]([OH:25])=O)[C@@H:20]([CH3:22])[OH:21])=[O:17])[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH2:27]([O:29][C:30](=[O:36])[C@H:31]([CH:33]([CH3:35])[CH3:34])[NH2:32])[CH3:28]>C(Cl)(Cl)Cl.CO>[CH2:27]([O:29][C:30](=[O:36])[C@H:31]([CH:33]([CH3:35])[CH3:34])[NH:32][C:23](=[O:25])[C@H:19]([C@@H:20]([CH3:22])[OH:21])[NH:18][C:16](=[O:17])[C@H:14]([CH3:15])[NH:13][C:11](=[O:12])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:28]
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)N[C@H](C(=O)O)[C@@H](C)O
Reactant: CCOC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1)[C@@H](C)O)C(C)C

Procedure:
Following General Procedure C and using N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-threonine (prepared from N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-threonine methyl ester (from Example 144 above) using General Procedure AF) and L-valine ethyl ester hydrochloride (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.1 in 96:4 CHCl3/MeOH) and the product was purified by silica gel chromatography using 96:4 CHCl3/MeOH as the eluent.