Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([OH:40])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2].[CH3:43][O:44][C:45]([C:47]1[CH:52]=[CH:51][C:50](B(O)O)=[CH:49][CH:48]=1)=[O:46].C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:38])([F:39])[F:37])[CH:27]=3)[C:22]([O:40][C:50]3[CH:51]=[CH:52][C:47]([C:45]([O:44][CH3:43])=[O:46])=[CH:48][CH:49]=3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(Oc3ccc(C(=O)OC)cc3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
(2R,4S)-4-{[3, 5-Bis(trifluoromethyl)benzyl]-(5-hydroxypyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (170 mg) is dissolved in methylene chloride (3 ml), and thereto are added 4-methoxycarbonylphenylboronic acid (51 mg), copper (II) acetate (52 mg), triethylamine (79 μl) and molecular sieves 4A (170 mg). The mixture is stirred overnight at room temperature. The insoluble materials are removed by filtration and the filtrate is partitioned by adding ethyl acetate and saturated brine. The organic layer is washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=9:1→3:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-methoxycarbonylphenoxy)-pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (132 mg). MS (m/z): 734 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].Br[CH2:11][C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:15][O:14][C:12](=[O:13])[CH2:11][O:9][C:8]1[C:3]([C:1]#[N:2])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ncccc1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1cccnc1C#N
Temperature: 0 °C
Yield: 98.9 %

Procedure:
2-Cyano-3-hydroxypyridine (5.00 g) is dissolved in acetone (50 ml), and thereto are added methyl bromoacetate (7.0 g) and potassium carbonate (6.3 g). The mixture is heated under reflux for 1.5 hours. After allowing to cool, ice-water is poured to the reaction solution and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is suspended in diethyl ether/n-hexane and the solid is collected by filtration to give the title compound (7.91 g).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.[CH3:10][C:11]([CH3:16])([CH3:15])[C:12](N)=[O:13].N>S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O>[CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][C:12](=[O:13])[C:11]([CH3:16])([CH3:15])[CH3:10]
Reactant: CC(C)(C)C(N)=O
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: N
Agent: O=C1NS(=O)(=O)c2ccccc21
Product: CC(C)(C)C(=O)N[Si](C)(C)C
Yield: 125.4 %

Procedure:
7.7 ml (37 mmoles) of hexamethyldisilazane were added to 5.0 g (49.5 mmoles) of α,α-dimethylpropionamide and 10 mg (0.05 mmole) of saccharin in 15 ml of refluxing tolune over 15 minutes and after refluxing for 45 minutes, the evolution of ammonia had stopped completely. Evaporation and drying in vacuo yielded 8.04 g (98%) of N-trimethylsilyl-α,α-dimethylpropionamide melting at 101°-105.5° C. According to NMR analysis, the purity of the product was 92%.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13](Cl)=[O:14])=[CH:9][CH:8]=2)[N:3]=1.[H][H].NC(N)=S>C1(C)C(C)=CC=CC=1.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH3:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][CH:8]=2)[N:3]=1
Reactant: [H][H]
Reactant: Cc1ccn(-c2ccc(C(=O)Cl)cc2)n1
Agent: [Pd]
Agent: NC(N)=S
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1C
Product: Cc1ccn(-c2ccc(C=O)cc2)n1
Temperature: 80 °C
Yield: 92 %

Procedure:
Using the method of Rosenmund, 88 g of the above 3-methyl-1-(4-chloroformylphenyl)pyrazole are hydrogenated with hydrogen at 140° C. in 900 ml of xylene with the addition of 0.23 g of thiourea and 9 g of Pd/BaSO4 (5%). After cooling to 80° C. and removing the catalyst by filtration, the xylene solution is evaporated to dryness and the precipitated product is recrystallised from a mixture of hexane and toluene, affording 68.3 g of 3-methyl-1-(4-formylphenyl)pyrazole in the form of pale yellow crystals with a melting point of 96°-98° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[CH:5]=[C:4]([NH:10][C:11](=[O:32])[CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH2:25][CH3:26])([CH3:24])[CH3:23])=[CH:18][C:17]=2[C:27]([CH2:30][CH3:31])([CH3:29])[CH3:28])[CH2:13][CH3:14])[C:3]=1[OH:33].[C:34]([O-])(=[O:36])[CH3:35].[Na+].C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)(=O)C.S(=O)(=O)(O)O.CN(C)C=O.O.CO>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][C:34](=[O:36])[CH3:35])[CH:5]=[C:4]([NH:10][C:11](=[O:32])[CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH2:25][CH3:26])([CH3:24])[CH3:23])=[CH:18][C:17]=2[C:27]([CH2:30][CH3:31])([CH3:29])[CH3:28])[CH2:13][CH3:14])[C:3]=1[OH:33]
Reactant: CC(=O)[O-]
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(O)c(C)c(Cl)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(OC(C)=O)c(C)c(Cl)c1O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 671.4 %

Procedure:
263 g of 2-chloro-3-methyl-4-hydroxy-6-[α-(2,4-di-tert-amylphenoxy)butyramido]phenol and 5 g of sodium acetate were dissolved in 500 ml of glacial acetic acid and heated for 30 minutes at 80° C. After cooling the reaction solution, 1.5 l of water and 2 - 3 drops of concentrated sulfuric acid were added thereto and the system stirred at room temperature for 30 minutes and the diacetyl compound was deposited in the form of an oil. The oil was dissolved in 2 l of dimethylformamide and a solution of 1 l of water, 250 g of sodium carbonate and 1 l of methanol was added thereto and the system stirred at room temperature for 1 hour. 150 ml of concentrated hydrochloric acid was then added to the mixture and the mixture was poured into water and the precipitated crystals were recrystallized from methanol to obtain 212 g of the desired compound having a melting point of 188° to 190° C.
Reaction SMILES: [CH2:1]([NH:7][S:8]([C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([N+:18]([O-:20])=[O:19])[C:12]=1Cl)(=[O:10])=[O:9])[C@@H:2]1[O:6][CH2:5][CH2:4][CH2:3]1.[H-].[Na+].[OH2:24]>>[CH2:1]([NH:7][S:8]([C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([N+:18]([O-:20])=[O:19])[C:12]=1[OH:24])(=[O:10])=[O:9])[C@@H:2]1[O:6][CH2:5][CH2:4][CH2:3]1
Reactant: O
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NC[C@H]2CCCO2)c1Cl
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NC[C@H]2CCCO2)c1O
Yield: 62.3 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, N-((2R)-tetrahydrofurfuryl)-2,6dichloro-3-nitrobenzenesulfonamide (1.17 g, 3.29 mmol), 80% NaH (303 mg, 10.1 mmol) and water (0.063 mL, 3.49 mmol) were reacted to form the desired product (690 mg, 63%). EI-MS m/z 335(M-H)−.
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH2:16]([NH:18][C:19]1[N:20]=[N+:21]([O-:34])[C:22]2[C:31]([N:32]=1)=[CH:30][C:29]1[CH2:28][N:27]([CH3:33])[CH2:26][CH2:25][C:24]=1[CH:23]=2)[CH3:17].C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[CH2:16]([NH:18][C:19]1[N:20]=[N+:21]([O-:34])[C:22]2[C:31]([N+:32]=1[O-:4])=[CH:30][C:29]1[CH2:28][N:27]([CH3:33])[CH2:26][CH2:25][C:24]=1[CH:23]=2)[CH3:17]
Reactant: CCNc1nc2cc3c(cc2[n+]([O-])n1)CCN(C)C3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CN(C)CC3
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 7.5 %

Procedure:
H2O2 (70%, 1.7 mL, ca. 17 mmol) was added dropwise to a stirred solution of TFAA (2.4 mL, 17 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C., added to a solution of 1-oxide 258 (440 mg, 1.7 mmol) and TFA (0.66 mL, 8.5 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 20° C. for 4 h, diluted with dilute aqueous NH3 solution (80 mL) and extracted with DCM (4×125 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (1-10%) of MeOH/DCM, to give 1,4-dioxide 259 (35 mg, 8%) as a red solid: mp 120-124° C.; 1H NMR δ 8.10 (s, 1H, H-10), 7.96 (s, 1H, H-5), 6.95 (br s, 1H, NH), 3.78 (s, 2H, H-6), 3.63 (dq, J=7.2, 6.0 Hz, 2H, CH2N), 3.10 (t, J=6.0 Hz, 2H, H-8), 2.75 (t, J=6.0 Hz, 2H, H-9), 2.50 (s, 3H, NCH3), 1.36 (t, J=7.2 Hz, 3H, CH3); 13C NMR δ 149.3, 145.5, 136.5, 135.3, 129.3, 120.5, 113.9, 58.1, 52.1, 45.8, 36.5, 29.1, 14.8; MS (APCI) m/z 276. (MH+, 100%); HRMS (FAB+) calcd for C13H18N5O2 (MH+) m/z 276.1461, found 276.1456.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[NH2:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20][CH2:19]1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20][CH2:19]2)[N:3]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: O[C@H]1CC[C@H](Nc2nc(Cl)nc3c2ncn3C2CCCC2)CC1

Procedure:
Trans-2-chloro-6-[(4-hydroxy)cyclohexylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, trans-4-(amino)cyclohexanol, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:17][CH:16]=[CH:15][C:10]=1[CH2:11][CH:12]1[CH2:14][O:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:30])[CH2:27][CH2:28][SH:29].C(N(CC)CC)C>CO>[CH2:1]([O:8][C:9]1[C:18]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:17][CH:16]=[CH:15][C:10]=1[CH2:11][CH:12]([OH:13])[CH2:14][S:29][CH2:28][CH2:27][C:26]([O:25][CH3:24])=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCS
Reactant: c1ccc(COc2c(CC3CO3)cccc2C2CCCC2)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CCSCC(O)Cc1cccc(C2CCCC2)c1OCc1ccccc1

Procedure:
20 g (59 mmol) of (2-benzyloxy-3-cyclopentylbenzyl)-oxirane, 24.5 g (0.204 mol) of methyl-3-mercaptopropionate and 26.1 g (0.257 mol) of triethylamine are stirred in 150 ml of dry methanol at room temperature and under protective gas (argon or nitrogen) overnight. The solvent is removed by distillation in vacuo, and the residue is chromatographed on a silica gel column (gradient dichloromethane→ethyl acetate). 19.0 g (65% of theory) or methyl 7-(2-benzyloxy-3-cyclopentylphenyl)-6-hydroxy-4-thiaheptanoate are obtained.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[N:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=[CH:8][CH:7]=1.[CH3:15]O>C(Cl)(Cl)Cl>[Cl:5][C:6]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)c1cccc(Cl)n1
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccc(Cl)n1
Yield: 100 %

Procedure:
Add thionyl chloride (3.7 mL, 50.8 mmol) to a solution of 6-chloropicolinic acid (4.0 g, 25.4 mmol) in methanol (85 mL) at 0° C. Stir the resultant solution for 15 minutes at 0° C., 0.5 hours at room temperature, and 6 hours at 50° C. Concentrate the reaction in vacuo and dilute with CHCl3 (150 mL). Wash the organic solution with saturated aqueous sodium bicarbonate (3×100 mL), and brine (1×100 mL) and dry with sodium sulfate. Filtration and concentration afford methyl 6-chloropicolinate 4.38 g (100%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[O:33].CCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:32]([NH:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][CH3:23])=[O:33])=[CH:18][CH:17]=1
Reactant: COc1ccccc1N=C=O
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccccc1NC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Yield: 75 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinazoline (100 mg) was dissolved in toluene (10 ml) with heat, 2-methoxyphenyl isocyanate (0.36 ml) was added, and the admixture was refluxed with heat for 40 minutes. After removing the solvent by distillation, the resulting residue was purified by column chromatography on silica gel eluting with chloroform/methanol (100/1) and then with chloroform/acetone (5/1) to obtain 112 mg of the title compound (yield: 75%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH:13]=[C:14]1[NH:18][C:17](=[O:19])[CH2:16][S:15]1>>[NH:13]=[C:14]1[NH:18][C:17](=[O:19])[C:16](=[CH:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)[S:15]1
Reactant: O=Cc1ccc2ncccc2c1
Reactant: N=C1NC(=O)CS1
Product: N=C1NC(=O)C(=Cc2ccc3ncccc3c2)S1

Procedure:
Following the general method as outlined in Example 1, starting from quinoline-6-carbaldehyde (intermediate 5) and 2-imino-1,3-thiazolidin-4-one, the title compound was obtained.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:13])[CH:9]=[C:10]([O:11][CH3:12])[C:5]=2[CH:4]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1>CN(C=O)C>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][CH:4]1[O:3][B:2]([OH:1])[C:6]2[CH:7]=[C:8]([O:13][C:27]3[CH:32]=[N:31][CH:30]=[CH:29][N:28]=3)[CH:9]=[C:10]([O:11][CH3:12])[C:5]1=2)[CH3:19]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(OC)c21
Reactant: Clc1cnccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(OC)c21
Temperature: 90 °C
Yield: 81 %

Procedure:
A mixture of ethyl 2-(1,6-dihydroxy-4-methoxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (0.15 g, 0.56 mmol), cesium carbonate (0.37 g, 1.12 mmol) and 2-chloropyrazine (96 mg, 0.84 mmol) in DMF (2 mL) was heated to 90° C. for 3 hr. The reaction mixture was quenched by saturated aqueous NaHCO3 (20 mL) and extracted with EtOAc (15 mL×2). The combined extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/PE=1/2) on silica gel to give the title compound as a light yellow solid (156 mg, Y: 81.2%). MS (ESI) m/z=345 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:5]([OH:25])[CH2:6][N:7]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:8]([CH3:17])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[CH2:37]([O:44][CH2:45][C:46](Cl)=[O:47])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[OH-].[Na+].Cl.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C.C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH2:37]([O:44][CH2:45][C:46]([NH:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH:5]([OH:25])[CH2:6][N:7]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:8]([CH3:17])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)=[O:47])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(Cc1ccc(O)cc1)N(Cc1ccccc1)CC(O)c1ccc(OCc2ccccc2)c(N)c1
Reactant: O=C(Cl)COCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(Cc1ccc(O)cc1)N(Cc1ccccc1)CC(O)c1ccc(OCc2ccccc2)c(NC(=O)COCc2ccccc2)c1

Procedure:
In 20 ml. of anhydrous pyridine there was dissolved 2 g. of 3-amino-4-benzyloxy-α-[N-benzyl-N-(1-methyl-2-p-hydroxyphenylethyl)-aminomethyl]benzyl alcohol (prepared in the aforesaid Reference Example 7-a) and the solution was cooled to temperatures from -20° to -30° C. A solution of 2.28 g. of benzyloxyacetyl chloride in 5 ml. of toluene was added dropwise to the solution thus cooled and while stirring the mixture, the temperature of the mixture was elevated slowly to room temperature. After stirring the mixture overnight, the solvent was distilled off under reduced pressure and the residue was mixed with 50 ml. of water. After washing the benzene solution thus obtained with water, benzene was distilled off from the reaction mixture under reduced pressure to provide a red oily material. The product was dissolved in 50 ml. of ethanol and after adding to the solution 5 ml. of water and 10 ml. of 4N sodium hydroxide solution, the resultant mixture was stirred for two hours. After adjusting the pH of the reaction mixture to 3 by adding 1N hydrochloric acid, an excessive amount of sodium carbonate was added thereto. Then, ethanol was distilled off under reduced pressure and the residue was extracted with benzene. The extract was washed three times with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide a yellow oily material. The product was then subjected to a silica gel column chromatography (65 ml.). The product was eluted using 9 : 1 benzene-acetone mixture and the effluent was concentrated under reduced pressure to provide 3-benzyloxyacetylamino-4-benzyloxy-α-[N-benzyl-N-(1-methyl-2-p-hydroxyphenylethyl)aminomethyl]benzyl alcohol.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(C)([O-])C.[Na+].O1CCOCC1>C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Ic1ccc(OCc2ccccc2)cc1
Reactant: C1CC2(CCN1)OCCO2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: c1ccc(COc2ccc(N3CCC4(CC3)OCCO4)cc2)cc1
Yield: 73.6 %

Procedure:
1,4-Dioxa-8-azaspiro[4,5]decane (653 g, 4.56 mol), 1-(benzyloxy)-4-iodobenzene (1 kg, 3.8 mol), sodium tert-butoxide (511 g, 5.32 mol), Pd(OAc)2 (17 g, 76 mmol) and biphenyl-2-yl(dicyclohexyl) phosphine (54 g, 152 mmol) were mixed, and 1,4-dioxane, this was stirred overnight at 80° C. in a nitrogen atmosphere. The reaction solution was cooled with ice, diluted with ethyl acetate, washed with water and saturated saline in that order, and the organic layer was dried with sodium sulfate. The solvent was evaporated off under reduced pressure, and the resulting residue was purified through silica gel column chromatography (eluate: chloroform/ethyl acetate=10/1), and the resulting crude product was suspended in a mixed solvent of chloroform/hexane and filtered under suction to obtain the entitled compound (910 g, 73%) as a brown solid.
Reaction SMILES: C(N)(=O)C=C.COC.C1(C=CC(O)=CC=1)O.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.C([O:41][CH:42]([NH:50][C:51](=[O:54])[CH:52]=[CH2:53])[C:43]([O:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:44])CCC>C(O)CCC>[C:51]([NH:50][CH:42]([OH:41])[C:43]([O:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:44])(=[O:54])[CH:52]=[CH2:53]
Reactant: C=CC(=O)NC(OCCCC)C(=O)OCCCC
Agent: C=CC(N)=O
Agent: COC
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Solvent: CCCCO
Product: C=CC(=O)NC(O)C(=O)OCCCC
Reaction time: 3 h

Procedure:
The procedure of Example I is again followed using the following charge: butyl glyoxylate hemiacetal 315 parts (1.5 moles), acrylamide 110 parts (1.5 moles), methyl ether of hydroquinone 400 parts per million and ethylenediamine tetraacetic acid 200 parts per million. The reaction is run for 3 hours at 60°-65° C. and then by-product butanol is stripped under vacuum. The material is not isolated, instead it is used directly to make butyl acrylamidoglycolate butyl ether.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]([OH:19])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][CH2:27][C:28]2[N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:31][C:32]=2[CH3:33])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]([O:19][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:31][C:32]=3[CH3:33])=[CH:40][CH:41]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)Cc1cn(Cc2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 67.9 %

Procedure:
A mixture of ethyl (1-benzyl-3-hydroxy-1H-pyrazol-4-yl)acetate (521 mg), 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (628 mg), potassium carbonate (553 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 5 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl [1-benzyl-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazol-4-yl]acetate (731 mg, yield 68%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][O:20][CH3:21])[CH2:15][C@H:14]1[C@@H:13]([CH3:22])[S:12][C:11]([NH:23]C(=O)C1C=CC=CC=1)=[N:10]2.FC1C=C(F)C=CC=1[C@]12CO[C@@H](CF)C[C@H]1[C@@H](C)SC(NC(=O)C1C=CC=CC=1)=N2.FC1C=C(F)C=CC=1[C@]12CO[C@@H](CF)C[C@H]1[C@@H](C)SC(N)=N2.CO>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][O:20][CH3:21])[CH2:15][C@H:14]1[C@@H:13]([CH3:22])[S:12][C:11]([NH2:23])=[N:10]2
Reactant: COC[C@H]1C[C@H]2[C@@H](C)SC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Agent: C[C@H]1SC(N)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CF)C[C@@H]12
Agent: C[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CF)C[C@@H]12
Solvent: ClCCl
Solvent: CO
Product: COC[C@H]1C[C@H]2[C@@H](C)SC(N)=N[C@@]2(c2ccc(F)cc2F)CO1

Procedure:
N-[(4R,4aR,6R,8aS)-8a-(2,4-Difluorophenyl)-6-(methoxymethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C20) was deprotected using the method described for conversion of N-[(4R,4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(fluoromethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C19) to (4R,4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(fluoromethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine (1) in Example 1. In this case, the chromatography was carried out using a gradient of 0% to 10% methanol in dichloromethane; the product was isolated as a white solid. Yield: 69.3 mg, 0.202 mmol, 83%. LCMS m/z 343.2 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 7.32 (ddd, J=9.6, 9.0, 6.6 Hz, 1H), 6.92-7.00 (m, 2H), 4.10 (dd, J=11.1, 2.2 Hz, 1H), 3.75-3.82 (m, 1H), 3.72 (d, J=11.1 Hz, 1H), 3.47 (dd, half of ABX pattern, J=10.3, 6.4 Hz, 1H), 3.41 (dd, half of ABX pattern, J=10.3, 3.9 Hz, 1H), 3.38 (s, 3H), 3.05-3.13 (m, 1H), 2.71-2.78 (m, 1H), 1.55-1.62 (m, 1H), 1.36-1.47 (m, 1H), 1.17 (d, J=6.8 Hz, 3H).