Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].COC1C=CC(C(C2C=CC(OC)=CC=2)[O:12][CH:13](C2C=CC=CC=2)[CH:14]2[O:18][CH:17]([N:19]3[CH:24]=[CH:23][C:22](=[O:25])[NH:21][C:20]3=[O:26])[CH:16]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:15]2[O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])=CC=1.[CH3:57][O:58][C:59]1[CH:66]=[CH:65][C:62]([CH2:63]Cl)=[CH:61][CH:60]=1.C1(S(O)(=O)=O)C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C>[Si:28]([O:27][C@@H:16]1[C@H:15]([O:35][Si:36]([C:39]([CH3:41])([CH3:42])[CH3:40])([CH3:37])[CH3:38])[C@@H:14]([CH2:13][OH:12])[O:18][C@H:17]1[N:19]1[CH:24]=[CH:23][C:22](=[O:25])[N:21]([CH2:63][C:62]2[CH:65]=[CH:66][C:59]([O:58][CH3:57])=[CH:60][CH:61]=2)[C:20]1=[O:26])([C:31]([CH3:33])([CH3:34])[CH3:32])([CH3:30])[CH3:29]
Reactant: COc1ccc(C(OC(c2ccccc2)C2OC(n3ccc(=O)[nH]c3=O)C(O[Si](C)(C)C(C)(C)C)C2O[Si](C)(C)C(C)(C)C)c2ccc(OC)cc2)cc1
Reactant: COc1ccc(CCl)cc1
Agent: O=S(=O)(O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3O[C@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 58.8 %

Procedure:
Following the procedure (Myers, A. G.; Gin, D. Y.; Rogers, D. H., J. Amer. Chem. Soc., 1994, 116, 4697-4718), a suspension of sodium hydride (1.55 g, 38.75 mmole, 60% oil dispersion) in anhydrous dimethylformamide (40 ml) was cooled at 0° C. under argon, and to this mixture was added a solution of 1-[5-[bis-(4-methoxy-phenyl)-phenyl-methoxymethyl]-3,4-bis-(tert-butyl-dimethyl-silanyloxy)-tetrahydro-furan-2-yl]-1H-pyrimidine-2,4-dione (20 g, 25.8 mmole, obtained from Reference Example 1) in anhydrous dimethylformamide (35 ml) over a period of 15 min. Neat p-methoxybenzyl chloride (7 ml, 51 mmole) was added to this solution. The resulting mixture was stirred at 0° C. for 15 h under argon, and diluted with ethyl acetate (700 ml). The organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness in vacuo. The oily residue was dissolved in chloroform (200 ml) and cooled at 0° C. under nitrogen. Benzenesulfonic acid (6 g, 37.93 mmole) was added portionwise, and the resulting red solution was stirred at 0° C. under nitrogen for 2 h. The mixture was diluted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness in vacuo. The residue was chromatographed (flash column, silica gel, methylene chloride:diethyl ether:methanol=95:3:2) to give 1-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(hydroxymethyl)tetrahydro-2-furanyl]-3-(4-methoxybenzyl)-2,4(1H,3H)-pyrimidinedione as white solid (9 g, 59%).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:13]([O:17][C:18]([NH:20][CH:21]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:22](O)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].CCN=C=NCCCN(C)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:13]([O:17][C:18]([NH:20][CH:21]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:22]([O:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:23])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CCOC(=O)c1ccccc1O
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1OC(=O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.7 %

Procedure:
To a solution of ethyl 2-hydroxybenzoate (0.5 g, 3.0 mmol) in CH2Cl2 (8 mL) was added 2-(tert-butoxycarbonylamino)-3-phenylpropanoic acid (0.8 g, 3.0 mmol), EDCI (0.63 g, 3.3 mmol) and dimethylaminopyridine (0.037 g, 0.3 mmol). The reaction was stirred (RT, 3 h) and then partitioned between CH2Cl2 and brine. The aqueous layer was extracted with CH2Cl2 and the combined organic extracts were dried over MgSO4. The crude material was purified by silica gel chromatography (0-10% MeOH/CH2Cl2) to afford ethyl 2-(2-(tert-butoxycarbonylamino)-3-phenylpropanoyloxy)benzoate (1.2 g). Mass calculated for C235H27NO6=413.46; found: [M+Na]+=437.1.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[O:14][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:12][N:11]=1)=O)(C)(C)C.Cl.C(Cl)Cl.C(OCC)(=O)C>O1CCOCC1>[NH2:8][CH2:9][C:10]1[O:14][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:12][N:11]=1
Reactant: CCOC(=O)c1nnc(CNC(=O)OC(C)(C)C)o1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nnc(CN)o1
Reaction time: 12 h
Yield: 8.4 %

Procedure:
Crude, unpurified compound 8 (5 g) is added portionwise to a 0° C. commercially available solution of hydrogen chloride in 1,4-dioxan (Aldrich, 4 M, 35 ml.) Compound 8a slowly dissolves to afford a clear yellow solution. After stirring for approximately 12 hours, the reaction mixture turns cloudy. TLC on silica using methylene chloride:ethyl acetate (9:1) as the eluent shows the starting material has been consumed. The reaction mixture is filtered and a white solid is obtained. The solid is washed exhaustively with ether (50 mL) to afford 266 mg of compound 9.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[C:13]([O:17][C:18]([N:20]1[CH2:24][C@H:23]([OH:25])[CH2:22][C@H:21]1[C:26]([O:28][CH3:29])=[O:27])=[O:19])([CH3:16])([CH3:15])[CH3:14].O>O1CCCC1>[C:13]([O:17][C:18]([N:20]1[CH2:24][C@H:23]([O:25][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:22][C@H:21]1[C:26]([O:28][CH3:29])=[O:27])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Triethylamine (14.8 ml, 106.0 mM) and methanesulfonyl chloride (6.9 ml, 90.0 mM) were added to a solution of methyl (2S,4R)-N-tert-butoxycarbonyl-4-hydroxypyrrolidine-2-carboxylate (20 g, 81.5 mM) in anhydrous tetrahydrofuran (200 ml) under ice-cooling in a nitrogen gas stream, and the mixture was stirred for 30 minutes. The reaction mixture was poured into water followed by extracting with ethyl acetate, the organic layer was washed with a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium bicarbonate, water and brine in this order and dried over anhydrous magnesium sulfate and the solvent was removed to give the title compound almost quantitatively (27 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@@H:7]([O:9][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a solution of (2S,4R)-N-tert-butoxycarbonyl-4-hydroxyproline methyl ester (30.2 g, 123 mmol) in methylene chloride (300 ml) were dropwise added successively triethylamine (41.2 ml, 0.295 mmol) and methanesulfonyl chloride (17.1 ml, 0.221 mol) at 0° C. in a nitrogen atmosphere. The mixture was stirred at 0° C. for 2 h, and saturated aqueous sodium hydrogencarbonate was added. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo. The residue was subjected to silica gel flash column chromatography (heptane-ethyl acetate=5:5) to give (2S,4R)-N-tert-butoxycarbonyl-4-methanesulfonyloxyproline methyl ester (39.5 g, yield: 99.1%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH2:16]([N:18]1[C:26]2[C:21](=[N:22][CH:23]=[C:24]([CH3:27])[CH:25]=2)[N:20]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:19]1=[O:35])[CH3:17].[H-].[Na+]>COCCOC>[CH2:16]([N:18]1[C:26]2[C:21](=[N:22][CH:23]=[C:24]([CH3:27])[CH:25]=2)[N:20]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:2]3[N:3]=[C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][N:5]4[C:10]=3[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:30][CH:29]=2)[C:19]1=[O:35])[CH3:17]
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(C)cc21
Reactant: CCOC(=O)c1c(Cl)nc2ccccn12
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1c(Oc2ccc(-n3c(=O)n(CC)c4cc(C)cnc43)cc2)nc2ccccn12
Temperature: 50 °C
Yield: 12.1 %

Procedure:
The mixture of ethyl 2-chloroimidazo[1,2-a]pyridine-3-carboxylate (504 mg), 1-ethyl-3-(4-hydroxyphenyl)-6-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (302 mg) and NaH (67.3 mg) in DME (4 mL) was heated at 50° C. for 1 h. The mixture was heated at 200° C. for 3 h under microwave irradiation. The mixture was poured into sat. NaHCO2, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc/hexane) to give the title compound (62.0 mg) as a white solid.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].C(O)(=O)C.C(O)(=O)C.[C:65]1([Bi](C2C=CC=CC=2)C2C=CC=CC=2)[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1.C(O)(=O)C.C(=O)(O)O.C1([Bi](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.C([O-])(O)=O.[Na+].CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: c1ccc([Bi](c2ccccc2)c2ccccc2)cc1
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C(O)O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reaction time: 120 h

Procedure:
To a stirred solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.126 mmol, 1 eq) and Cu(OAc)2 (2.8 mg, 0.014 mmol. 0.11 eq) in CH2Cl2 (1 ml) in a 16 mL screw-cap vial equipped with a magnetic stir-bar was added triphenyl bismuth diacetate [prepared immediately prior to use by addition of acetic acid (0.030 mL, 0.504 mmol, 4 eq) to a suspension of triphenyl bismuth carbonate (127 mg, 0.253 mmol. 2 eq) in CH2Cl2 (1 ml)]. The reaction vessel was capped and the mixture stirred for five days. The reaction mixture was diluted with several milliliters of saturated aqueous NaHCO3 and extracted 4 times with CH2Cl2. The organic extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The product was isolated by preparative TLC on silica gel (eluted with 3:4 EtOAc/hexanes to afford 46 mg of 17-ethyl-1,14-dihydroxy 12-[2'-(4"-phenyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone. (1H NMR, 13C NMR and mass spectral analysis were consistent with the desired structure.)
Reaction SMILES: Cl.Cl.C[O:4][C:5](=[O:13])[C@H:6]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[NH2:7].[OH-].[Na+]>CO>[NH2:7][C@H:6]([C:5]([OH:13])=[O:4])[CH2:8][CH2:9][CH2:10][CH2:11][NH2:12]
Reactant: COC(=O)[C@@H](N)CCCCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NCCCC[C@H](N)C(=O)O
Temperature: 110 °C

Procedure:
20.88 Grams (90 mmol) of L-lysine methyl ester dihydrochloride was dissolved in 18 ml of methanol, and 45 ml of 2 N aqueous sodium hydroxide solution was added thereto to prepare a treating agent solution. An untreated cotton cloth (480 mm×510 mm, 45 g) was allowed to uniformly absorb the total amount of the above treating agent solution and then air-dried for 2 hours at room temperature. The dried cloth was heat-treated for 20 minutes at 140° C. in a batch type hot air oven (“IPHH-2000”, an inert oven manufactured by Tabaiesbeck Co., Ltd.) and washed with water. It was further washed with 5% aqueous sodium bicarbonate solution and rinsed three times with water and subsequently was washed with 10% aqueous citric acid solution and rinsed three times with water, and finally washed with household washing detergent solution, rinsed with water and air-dried. A part of the cloth was cut and a solution of ninhydrin in butanol was sprayed on it. Thereafter, it was heated for 10 minutes in an oven of 110° C. to cause coloring thereby the presence of the amino acid was confirmed. Also, a part of the cloth was cut and subjected to an infrared spectroscopic analysis whereby there was confirmed a peak based on ester bond at 1742 cm−1. As a result of determination for the amount of the L-lysine bonded, it was 0.10 mmol based on 1 g of the cloth. The degree of esterfication was 0.0 16.
Reaction SMILES: CN(OC)[C:3](=[O:17])[C@H:4]([CH2:13][CH:14]([CH3:16])[CH3:15])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[C:6]([NH:5][C@H:4]([CH:3]=[O:17])[CH2:13][CH:14]([CH3:15])[CH3:16])([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:7]
Reactant: CON(C)C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C

Procedure:
Boc-L-Leucine-N-methyl-N-methoxy amide (1.0 g, 3.64 mmol) was dissolved in Et2O (36 mL) and cooled in a brine-ice bath. LiAlH4 (0.138 g, 3.64 mmol) was added and the reaction was stirred cold. The reaction was quenched by dropwise addition of a solution of sodium thiosulfate (0.5 g) in H2O (16 mL). Water (100 mL) was added and the aqueous layer was extracted with Et2O (3×100 mL). The organic layer was washed with 1N HCl, saturated bicarbonate solution, and brine, dried over Na2SO4, and concentrated. The crude material was carried on immediately without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[Cl:23])[C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+]>O1CCCC1.CO>[Cl:18][C:17]1[CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=[C:13]([Cl:23])[C:12]=1[N:9]1[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1
Reactant: CCOC(=O)c1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Yield: 90.8 %

Procedure:
To a solution of 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (5.83 g) in tetrahydrofuran (20 ml) and methanol (20 ml) was added 4 N aqueous solution of sodium hydroxide (30 ml), and stirred at room temperature. After completion of the reaction, the solvent was evaporated, to the aqueous layer was added concentrated hydrochloric acid under ice-cooling to adjust the layer to pH 5, the precipitated solid was collected by filtration, and dried at 60° C. under air blow to give the titled compound (4.89 g) as a white solid. MS (ESI) m/z: 339, 341 (M+H)+.
Reaction SMILES: [C:1]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([F:24])[CH:13]=1)([O:3][CH2:4][C:5]1C=CC=CC=1)=[O:2].CC(C)([O-])C.[Li+].ClC[C@@H](O)[CH2:34][N:35]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[Cl-].[NH4+]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:43]([N:35]([CH2:34][C@@H:4]1[O:3][C:1](=[O:2])[N:11]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[C:14]([F:24])[CH:13]=2)[CH2:5]1)[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O[C@H](CCl)CN(Cc1ccccc1)Cc1ccccc1
Reactant: O=C(Nc1ccc(N2CCOCC2)c(F)c1)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1O[C@@H](CN(Cc2ccccc2)Cc2ccccc2)CN1c1ccc(N2CCOCC2)c(F)c1
Temperature: -30 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
N-carbobenzoxy-3-fluoro-4-morpholinylaniline (0.33 g, 1 mmol) was added to 8 mL of toluene. The solution was cooled to −30° C. under the protection of nitrogen flow and then 50 mmol of lithium tert-butoxide was added. The mixture was stirred at −30° C.˜20° C. for 2 hours. (S)-1-chloro-3-(dibenzylamino)propan-2-ol (1.45 g, 5 mmol) was added and then the solution was heated slowly to 60° C. and stirred for 2 hours. After the solution was cooled down, saturated ammonium chloride solution and ethyl acetate were added to separate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to provide 285 mg of white solid in 60% yield. HPLC: 99.2%.
Reaction SMILES: [CH:1]([P:3](=[O:9])([CH:7]=[CH2:8])[CH:4]([CH3:6])[CH3:5])=[CH2:2].C1COCC1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH2:15]([N:22]1[CH2:8][CH2:7][P:3](=[O:9])([CH:4]([CH3:6])[CH3:5])[CH2:1][CH2:2]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: C=CP(=O)(C=C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)P1(=O)CCN(Cc2ccccc2)CC1
Temperature: 85 °C
Yield: 62.6 %

Procedure:
A 20 L four-necked round bottom flask fitted with an overhead stirrer and reflux condenser, flame dried and cooled in a stream of nitrogen, was charged with the product of Step 1 (250 g, 1734 mmol), THF (2500 mL), water (2500 mL) and benzyl amine (297.3 g, 2774 mmol). The reaction mixture was heated at 85° C. for 16 h. After completion, THF was removed under reduced pressure. The aqueous layer was extracted with ether to remove the excess of benzyl amine and later with dichloromethane (2×2500 mL). The combined dichloromethane layers were washed with brine (2×1000 mL), dried over sodium sulfate and concentrated to give 1-benzyl-4-(propan-2-yl)-1,4-azaphosphinane 4-oxide (273 g, 63%) as brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.O.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:24](#[N:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>[Cu]Br.[I-].[Zn+2].[I-]>[Br:8][C:6]1[CH:5]=[CH:4][N:3]2[N:31]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:1]=[C:2]2[CH:7]=1
Reactant: Nc1cc(Br)ccn1
Reactant: N#Cc1ccccc1
Agent: [Cu]Br
Agent: [I-]
Agent: [Zn+2]
Solvent: O
Product: Brc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 130 °C
Yield: 51 %

Procedure:
A mixture of 2-amino-4-bromopyridine (5.00 g, 28.9 mmol), copper (I) bromide (207 mg, 1.44 mmol), 1,10-phenanthroline monohydrate (289 mg, 1.44 mmol), zinc iodide (923 mg, 2.89 mmol) and benzonitrile (125 mL) was heated in a 250-mL 3-necked flask to 130° C. During 23 h a gentle flow of air was bubbled through the reaction mixture (93% conversion, HPLC method cf. example 1.3). The dark brown suspension was then cooled to 0-5° C. and filtered. The filter cake was washed with TBME (50 mL) and dried to yield crude 7-bromo-2-phenyl-[1,2,4]triazolo[1,5-a]pyrdine (5.36 g, 51%) as a green solid with 76.0% purity (HPLC area-%, HPLC method cf. example 1.3). Major by-product: 7-Iodo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (13.0%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH:6]1[CH:7]=[C:8]2[CH2:22][C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([OH:21])[C:15]=3[C:13](=[O:14])[C:9]2=[C:10]([OH:12])[CH:11]=1>C1C=CC=CC=1.N1C=CC=CC=1>[OH:21][C:20]1[C:15]2[C:13](=[O:14])[C:9]3[C:8](=[CH:7][CH:6]=[CH:11][C:10]=3[OH:12])[CH:22]([C:1](=[O:4])[CH2:2][CH3:3])[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: CCC(=O)Cl
Reactant: O=C1c2c(O)cccc2Cc2cccc(O)c21
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCC(=O)C1c2cccc(O)c2C(=O)c2c(O)cccc21

Procedure:
24.9 g (0,269 moles) propionyl chloride is added, while stirring, to a mixture containing 50.9 g (0,225 moles) anthralin in 1575 ml of benzene and 27.5 ml of pyridine. The reaction mixture is cooked using a return condenser for 20 hours while stirring. The solution is filtered and the filtrate is evaporated dry under a lowered pressure. The residue is crystallized out from acetic acid. Yield 27.6 g (43.5% of the theoretical). M.p.=149°-154° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[S:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>ClCCl>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[S:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(O)=S)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(C(=S)Cl)cc1

Procedure:
A solution of 50 g. of 4-methylthiobenzoic acid in dichloromethane is treated with excess thionyl chloride at its reflux temperature until no acid remains (according to infrared spectral analysis). Distillation at reduced pressure (b.p. 140° C./0.2 mm. Hg) provides a clear liquid which gradually solidifies to provide 4-methylthiobenzoyl chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[S:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>CN(C)C=O>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[S:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(O)=S)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccc(C(=S)Cl)cc1

Procedure:
4-Methylthiobenzoic acid, 16.8 g (0.1 mole) is refluxed for 30 minutes in 50 ml of thionyl chloride (SOCl2) and 1 drop of dimethylformamide (DMF). The thionyl chloride is removed under vacuum and azeotroped with 50 ml of benzene to give 4-methylthiobenzoyl chloride as an oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:7]=[C:6](C(O)=O)[N:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:4]=1>CN(C=O)C.[OH-].[NH4+].O.[Cu]=O>[Cl:2][C:3]1[CH:7]=[CH:6][N:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:4]=1
Reactant: O=C(O)c1cc(Cl)nn1-c1cccnc1
Agent: O=[Cu]
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccn(-c2cccnc2)n1
Temperature: 120 °C
Reaction time: 5 h
Yield: 73.4 %

Procedure:
3-Chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid hydrochloride (1.00 g, 3.65 mmol) was stirred in N,N′-dimethylformamide (10 mL). Copper (II) oxide (0.0580 mg, 0.730 mmol) was added and the reaction was heated at 120° C. for 16 hours, at which point the reaction was ˜20% complete. Additional copper (II) oxide (0.112 g, 1.46 mmol) was added and the reaction was stirred for 5 hours. The mixture was diluted with ammonium hydroxide and water and extracted with ethyl acetate. The organic layer was washed with lithium chloride (15%) and concentrated to provide an orange solid. The residue was purified by flash column chromatography using ethyl acetate as eluent and the pure fractions were concentrated to afford the desired product as a white solid (0.481 g, 69.7%): mp: 66-68° C.; 1H NMR (400 MHz, CDCl3) δ 8.93 (d, J=27 Hz, 1H), 8.57 (dd, J=4.8, 1.4 Hz, 1H), 8.02 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.91 (d, J=2.6 Hz, 1H), 7.47-7.34 (m, 1H), 6.45 (d, J=2.6 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 148.01, 142.72, 140.12, 135.99, 128.64, 126.41, 124.01, 108.0.