Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][C:9]#[N:10])=[CH:5][CH:4]=1.[CH3:13][O:14][P:15]([O:18][CH3:19])[O:16]C>>[CH3:13][O:14][P:15]([CH2:6][C:5]1[CH:4]=[CH:3][CH:12]=[CH:11][C:2]=1[C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][C:9]#[N:10])=[CH:5][CH:4]=1)([O:18][CH3:19])=[O:16]
Reactant: N#CC=Cc1ccc(CBr)cc1
Reactant: COP(OC)OC
Product: COP(=O)(Cc1ccccc1-c1ccc(C=CC#N)cc1)OC
Temperature: 0 °C

Procedure:
390 g of 4-bromomethylcinnamonitrile are suspended in 600 ml of trimethylphosphite and the suspension is added in portions to 250 ml of well stirred trimethylphosphite of 90° C., such that the strongly exothermic reaction can be kept under control. Excess trimethylphosphite is then distilled off under a water jet vacuum and 330 ml of toluene and 660 ml of hexane are added to the residue, which is cooled to 0° C. The crystallised product is filtered with suction and vacuum dried at 50° C., affording 427 g of 4-(dimethoxyphosphorylmethylphenyl)cinnamonitrile with a melting point of 98°-101° C.
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[N-:14]=[N+:15]=[N-:16].[Na+].CS(C)=O>O>[N:14]([CH2:2][C@@H:3]([OH:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[N+:15]=[N-:16]
Reactant: O[C@H](CCl)COc1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NC[C@@H](O)COc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of (S)-1-Chloro-3-(4-fluoro-phenoxy)-propan-2-ol (5.0 g, 24.5 mmol), sodium azide (3.19 g, 49.0 mmol) and DMSO (25 mL) was stirred at 80° C. for 6 h. Then the reaction mixture was poured into water (100 mL), extracted with hexane-Et2O (1:1) mixture (2×100 mL). Extracts were washed with brine (100 mL), dried over Na2SO4 and evaporated. The residue was dried under vacuum at RT. Colorless oil, 4.83 g (22.9 mmol, 93%).
Reaction SMILES: CO/N=C(/C1OCCON=1)\C1C=CC=CC=1O.[C:18]([O:27][CH3:28])(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[OH:21].Cl[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+]>>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][O:21][C:20]1[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=1[C:18]([O:27][CH3:28])=[O:26])[CH3:35]
Reactant: CCOC(=O)CCl
Reactant: COC(=O)c1ccccc1O
Agent: CO/N=C(/C1=NOCCO1)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)COc1ccccc1C(=O)OC

Procedure:
Another synthesis of (E)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O-methyl oxime (13) is illustrated in Scheme 2B. According to the synthesis, methyl salicylate reacts with ethyl chloroacetate in the presence of potassium carbonate to give methyl 2-(2-ethoxy-2-oxoethoxy)benzoate (6). Hydrolysis of methyl 2-(2-ethoxy-2-oxoethoxy)benzoate (6) followed by a consecutive cyclization of 2-(carboxymethoxy)benzoic acid (7) with acetic anhydride in the presence of sodium acetate gives benzofuran-3-yl acetate (8) which is converted to benzofuran-3(2H)-one (9) by methanolysis. Treatment of benzofuran-3(2H)-one (9) with O-methylhydroxylamine and sodium acetate affords benzofuran-3(2H)-one O-methyl oxime (10) which is oxidized with tert-butyl nitrate in hydrochloric acid to yield exclusively or predominantly (3E)-benzofuran-2,3-dione O3-methyl dioxime (11A). In the presence of potassium hydroxide and 2-haloethanol, the (3E)-benzofuran-2,3-dione O3-methyl dioxime (11A) may form (3E)-benzofuran-2,3-dione O2-(2-hydroxyethyl) O3-methyl dioxime (12A), which may undergo potassium hydroxide-catalyzed cyclization to provide (E)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O-methyl oxime (13).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[C:19]([Cl:32])[CH:18]=2)=[C:6]([NH:8][C:9](=[O:15])[CH2:10][CH2:11][C:12](O)=[O:13])[CH:7]=1.[NH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][OH:40]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[C:19]([Cl:32])[CH:18]=2)=[C:6]([NH:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][OH:40])=[O:13])[CH:7]=1
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2NC(=O)CCC(=O)O)cc1Cl
Reactant: NCCCCCCO
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2NC(=O)CCC(=O)NCCCCCCO)cc1Cl

Procedure:
The reaction and work up was conducted as described in the preparation of compound 205. Starting compounds were N-(5-bromo-2-{[3-chloro-4-(2-methylbenzoyl)phenyl]amino}phenyl)-succinamic acid (600 mg, 1.16 mmol) (prepared by a similar method as described in WO 01/05746) and 6-aminohexanol (151 mg, 1.28 mmol). The crude product was purified by flash chromatography using EtOAc as the eluent to afford the title compound as a yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[N:3]=[CH:2]1.OS(O)(=O)=O.[CH3:16]O>>[CH3:16][O:9][C:8](=[O:10])[CH2:7][CH2:6][C:4]1[N:3]=[CH:2][NH:1][CH:5]=1
Reactant: CO
Reactant: O=C(O)CCc1c[nH]cn1
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1c[nH]cn1
Yield: 90 %

Procedure:
A solution of 3-(1H-imidazol-4-yl)-propionic acid (1.95 g, 13.9 mmol) and H2SO4 (catalytic) in MeOH (30 mL) was heated at reflux for 15 h, then concentrated in vacuo. The residue was dissolved in CH2Cl2 (40 mL) and washed with saturated NaHCO3(aq) (30 mL). The aqueous phase was saturated with sodium chloride and extracted with EtOAc (4×25 mL). The combined organic phases were dried (MgSO4) and concentrated in vacuo to give a yellow oil (1.93 g, 90%). 1H NMR (CDCl3) δ 2.68 (t, 2H, J=7.2 Hz), 2.93 (t, 2H, J=7.2 Hz), 3.69 (s, 3H), 6.81 (s, 1H), 7.55 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:13]([OH:14])=[CH:12][C:11]2[C:10]([CH3:16])([CH3:15])[CH2:9][CH2:8][C:7]([CH3:18])([CH3:17])[C:6]=2[CH:5]=1)=O.C1(C)C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O>[OH:14][C:13]1[C:4]([C:2](=[S:35])[CH3:1])=[CH:5][C:6]2[C:7]([CH3:18])([CH3:17])[CH2:8][CH2:9][C:10]([CH3:16])([CH3:15])[C:11]=2[CH:12]=1
Reactant: CC(=O)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=S)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Temperature: 120 °C
Reaction time: 24 h

Procedure:
To 5,6,7,8-tetrahydro-3-hydroxy-5,5,8,8-tetramethyl-2-naphthyl methyl ketone (13.3 mg, 53.9 μmol) were added anhydrous toluene (1 mL) and Lawesson's reagent (32.0 mg, 80.9 mmol) followed by stirring at 120° C. for 24 hours. The reaction solution was poured into cold water and extracted by dichloromethane, and the combined organic layers were concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using hexane/ethyl acetate (12/1) as an elution solvent. The yield was 4.2 mg (30%).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:31])[NH:12][C@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:14]3)[N:10]=2)[CH2:3]1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>C(Cl)Cl>[CH3:32][S:33]([O:1][CH:2]1[CH2:3][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:31])[NH:12][C@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:14]3)[N:10]=2)[CH2:5]1)(=[O:35])=[O:34]
Reactant: O=C(N[C@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1csc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N[C@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)cs2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.8 %

Procedure:
To a solution of 3-hydroxy-1-{4-[(3S)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (350 mg, 0.782 mmol) (obtained as described in Reference Example 52(6)) in methylene chloride (18 ml) were added methanesulfonyl chloride (182 μl, 2.35 mmol) and triethylamine (329 μl, 2.35 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 1.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (98:2) as the eluant to afford 3-methanesulfonyloxy-1-{4-[(3S)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (410 mg, yield 99%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][C:12]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=1)=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.P(Br)(Br)(Br)=O.BrC1C2C(N=C3C=1C(C1C=C(C)C=C(C)C=1)=CC=C3)=CC=CC=2.[CH3:52][Sn:53](Cl)([CH3:55])[CH3:54]>>[CH3:23][C:18]1[CH:17]=[C:16]([C:12]2[CH:13]=[CH:14][C:15]3[C:10]([CH:11]=2)=[N:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:2]=3[Sn:53]([CH3:55])([CH3:54])[CH3:52])[CH:21]=[C:20]([CH3:22])[CH:19]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Cc1cc(C)cc(-c2ccc3c(Br)c4ccccc4nc3c2)c1
Agent: Cc1cc(C)cc(-c2cccc3nc4ccccc4c(Br)c23)c1
Agent: O=P(Br)(Br)Br
Product: Cc1cc(C)cc(-c2ccc3c([Sn](C)(C)C)c4ccccc4nc3c2)c1

Procedure:
Suzuki coupling of commercially available 3-bromoaniline, 25, and 3,5-dimethylboronic acid afforded 3-(3,5-dimethylphenyl)aniline, 26, in high yields. Treatment of 26 with 2-chlorobenzoic acid, 27, gave N-3-(3,5-dimethylphenyl)anthranilic acid, 28, which was converted to 9-bromo-3-(3,5-dimethylphenyl)acridine, 29, using phosphorous oxybromide. As expected, we observed that 9-bromo-1-(3,5-dimethylphenyl)acridine was formed as a major by-product during ring construction. Lithiation of 29 at −78° C. followed by stannylation with trimethylstannyl chloride resulted in the formation of 3-(3,5-dimethylphenyl)-9-trimethylstannylacridine, 30, in high yields. Employing stannane 30 and 1,8-dibromonaphthalene, 31, in a CuO-promoted Stille coupling previously developed in our laboratories yielded 1,8-bis(3,3′-(3,5-dimethylphenyl)-9,9′-diacridyl)naphthalene, 32. Oxidation of 32 using m-chloroperoxybenzoic acid gave 1,8-bis(3,3′-(3,5-dimethylphenyl)-9,9′-diacridyl)naphthalene N,N′-dioxide, 33.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:16]([CH2:17][CH2:18][CH3:19])=[CH:15][C:12]([CH2:13]O)=[CH:11][C:10]=1[CH2:20][CH2:21][CH3:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:23][C:24]1[N:29]=[C:28]2[N:30]=[C:31]([CH2:33][CH3:34])[NH:32][C:27]2=[C:26]([CH3:35])[CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:23][C:24]1[N:29]=[C:28]2[N:30]([CH2:13][C:12]3[CH:15]=[C:16]([CH2:17][CH2:18][CH3:19])[C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[C:10]([CH2:20][CH2:21][CH3:22])[CH:11]=3)[C:31]([CH2:33][CH3:34])=[N:32][C:27]2=[C:26]([CH3:35])[CH:25]=1
Reactant: CCCc1cc(CO)cc(CCC)c1O[Si](C)(C)C(C)(C)C
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)cc(CCC)c1O[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a solution of 4.2 g (13.0 mmol) of the product of Step E, 2.5 g (14.0 mmol) of 5,7-dimethyl-2-ethylimidazo[4,5-b]pyridine (Example 24, Step C), and 5.62 (20.0 mmol) of triphenylphosphine dissolved in 40 mL of THF, was added 3.396 g (20.0 mmol) of diethyl azodicarboxylate and the mixture was stirred for 1 hour. The reaction mixture was then concentrated in vacuo and the residual oil was purified on a silica gel flash chromatography column eluted with 25-40% ethyl acetate/hexane to afford 5 g (80%) of the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:27]=[C:28]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:29]=[CH:30][C:31]=1[Cl:32].[Cl:39][C:40]1[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=1[CH3:45]>>[Cl:39][C:40]1[C:41]([C:50]([F:52])([F:51])[F:53])=[N:42][N:43]([CH2:46][C:47]([N:36]2[CH2:37][CH2:38][N:33]([C:28]3[CH:29]=[CH:30][C:31]([Cl:32])=[C:26]([Cl:25])[CH:27]=3)[CH2:34][CH2:35]2)=[O:48])[C:44]=1[CH3:45]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(Cl)c(Cl)c2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(3,4-Dichlorophenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.40 (d, 1H), 7.16 (s, 1H), 6.95 (d, 1H), 5.37 (s, 2H), 3.59 (m, 4H), 3.31 (m, 2H), 3.21 (m, 2H), 2.18 (s, 3H) ppm; MS (ES) M+H expected=455.0, found=455.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][O:17][CH3:18])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li]CCCC.ClCC[I:35]>C1COCC1.O.[Au]>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][O:17][CH3:18])[C:10]=1[I:35])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCOc1cccc(NC(=O)OC(C)(C)C)c1
Reactant: ClCCI
Agent: [Au]
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COCOc1cccc(NC(=O)OC(C)(C)C)c1I
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 13 (124 mg, 0.49 mmol) in 2.0 mL anhydrous THF was cooled to −20° C. and treated with TMEDA (0.26 mL, 1.71 mmol) followed by n-BuLi (0.69 mL of a 2.5 M solution in hexanes, 1.71 mmol) in a slow dropwise manner. The resulting gold solution stirred for 4 h at −20° C. The reaction mixture was treated with 1-chloro-2-iodoethane (0.126 mL, 1.71 mmol) and stirred for 15 min at 25° C. The reaction was diluted with H2O (30 mL), extracted with Et2O (3×20 mL), and the combined organic extracts were washed with saturated aqueous NaCl, dried Na2SO4) and concentrated under reduced pressure. Flash chromatography (SiO2, 2.5×10 cm, 0-10% EtOAc/hexane gradient) yielded recovered 13 (51.8 mg, 41%) and 14 (85.5 mg, 46%) as a white solid: mp 82-84° C.; 1H NMR (CDCl3, 400 MHz) δ7.72 (d, J=8.2 Hz, 1H), 7.21 (t, J=6.0 Hz, 1H), 7.01 (br s, 1H), 6.72 (dd, J=1.2, 8.2 Hz, 1H), 5.21 (s, 2H), 3.47 (s, 3H), 1.49 (s, 9H);13C NMR (CDCl3, 100 MHz) δ156.0, 152.5, 140.1, 129.5, 113.4, 108.9, 94.8, 82.4, 80.9, 54.4, 28.3; IR (film) νmax 3388, 2977, 1736, 1592, 1515, 1465, 1406, 1252, 1226, 1153, 1005 cm−1; FABHRMS (NBA/CsI) m/z 511.9351 (C13H18INO4+Cs+ requires 511.9335).
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[Si:8]([O:25][C@H:26]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@@H:27]1[C:38](OC)=[O:39])([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CO>CCCCCC>[Si:8]([O:25][C@H:26]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@@H:27]1[CH2:38][OH:39])([C:21]([CH3:23])([CH3:24])[CH3:22])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)[C@@H]1[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CC[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@H]1CO
Yield: 207.7 %

Procedure:
2.0 M of a solution of (trimethylsilyl)diazomethane in hexane (40 mL) was added dropwise to 1-tert-butyl 2-methyl (2S,3S)-3-{[tert-butyl(diphenyl)silyl]oxy}pyrrolidine-1,2-dicarboxylate (11.6 g) and methanol (50 mL) with stirring. The reaction solution was concentrated and the residue was added dimethylformamide (100 mL), tert-butyldiphenylchlorosilane (13.7 mL) and imidazole (6.37 g) and stirred at room temperature for overnight. The reaction solution was added water and extracted with a mixture solution of hexane/ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was added tetrahydrofuran (100 mL), methanol (3 mL) and lithium borohydride (2.51 g) at 0° C. and stirred at room temperature for 1 hour. The reaction solution was added water and aqueous 5% potassium sulfate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→75:25) to obtain the title compound (22.7 g) having the following physical properties.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC.Cl[C:23]1[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][N:24]=1>[Cu](I)I.O.CN(C=O)C>[N:1]1([C:23]2[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][N:24]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Nc1ccnc(Cl)c1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccnc(-n2cncn2)c1
Temperature: 150 °C
Reaction time: 14.5 h
Yield: 4.1 %

Procedure:
1H-1,2,4-triazole (540 mg), cesium carbonate (1.9 g), trans-N,N′-dimethylcyclohexane-1,2-diamine (74 mg), and copper iodide (50 mg) were added to a tube containing a DMF (5 ml) solution containing 2-chloropyridin-4-amine (500 mg) and the tube was sealed, followed by stirring at 150° C. for 14.5 hours. The reaction solution was adjusted to room temperature, and water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (chloroform:methanol=1:0 to 10:1), and a brown solid of 2-(1H-1,2,4-triazol-1-yl)pyridin-4-amine (25.8 mg) was thus obtained.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:8]([O:9][CH3:10])[CH2:7][CH2:6][CH:5]([CH2:11][CH2:12][N:13]=[C:14]=[O:15])[CH2:4]1.[F:16][C:17]1[C:18](=[O:24])[NH:19][C:20](=[O:23])[NH:21][CH:22]=1>N1C=CC=CC=1>[CH3:1][O:2][CH:3]1[CH:8]([O:9][CH3:10])[CH2:7][CH2:6][CH:5]([CH2:11][CH2:12][NH:13][C:14]([N:21]2[CH:22]=[C:17]([F:16])[C:18](=[O:24])[NH:19][C:20]2=[O:23])=[O:15])[CH2:4]1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: COC1CCC(CCN=C=O)CC1OC
Solvent: c1ccncc1
Product: COC1CCC(CCNC(=O)n2cc(F)c(=O)[nH]c2=O)CC1OC
Temperature: 90 °C
Yield: 48.3 %

Procedure:
A mixture of 2.12 g of 2-(3, 4-dimethoxycyclohexyl) ethylisocyanate, 1.5 g of 5-fluorouracil and 50 ml of pyridine was heated at 90° C. for 2 hr. The solution was cooled to 50° C. and pyridine was evaporated under reduced pressure. The residue was shaked in a mixture of 80 ml of dichloromethane and 100 ml of hydrochloric acid water, and the lower layer of the solution was dried and evaporated. The residue was chromatographed on silica gel and 1.65 g of 1-(3, 4-dimethoxycyclohexylethylcarbamoyl)-5-fluorouracil (melting point: 129° C.) was obtained (Compound No. 8). NMR: 0.73-2.27 (9H b CH2) 2.77-3.40 (2H b CH2 --NH) 3.30-3.57 (H b CHOCH3) 3.35 (6H s OCH3) 3.50-3.77 (H b CHOCH3) 8.42 (H d C6 --H) 9.20 (H b NH CO).
Reaction SMILES: C([O:3][C:4]([C:6]1(C(OCC)=O)[CH:10]([CH3:11])[CH2:9][CH2:8][NH:7]1)=[O:5])C.CC1(C)CCNC1C(O)=O.C(C1(C(OCC)=O)C(C)(C)CCN1)(OCC)=O>>[CH3:11][C@@H:10]1[CH2:9][CH2:8][NH:7][C@H:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1(C(=O)OCC)NCCC1C
Agent: CC1(C)CCNC1C(=O)O
Agent: CCOC(=O)C1(C(=O)OCC)NCCC1(C)C
Product: C[C@@H]1CCN[C@H]1C(=O)O

Procedure:
The title compound was prepared by acidic hydrolysis of diethyl-3-methylpyrrolidine-2,2-dicarboxylate according to the procedure described in Morgan, B. A.; Schafer, D. J. U.S. Pat. No. 4,060,603 for the preparation of 3,3-dimethyl-dl-proline from 2,2-dicarboethoxy-3,3-dimethylpyrrolidine.
Reaction SMILES: [CH3:1][O:2]/[CH:3]=[C:4]1\[CH2:5][C@@H:6]([C:16]([O:18][CH3:19])=[O:17])[N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8]\1.[O-2].[Mg+2].[H][H]>[Pd].CO>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:5]1
Reactant: [H][H]
Reactant: CO/C=C1\C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Agent: [Mg+2]
Agent: [O-2]
Solvent: CO
Product: COC[C@H]1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Yield: 99.2 %

Procedure:
A solution of (5,E)-1-tert-butyl 2-methyl 4-(methoxymethylene)pyrrolidine-1,2-dicarboxylate (9 g, 33.21 mmol), magnesium oxide (12 g, 33.21 mmol) and palladium on carbon (3 g) in methanol (100 mL) was held under a steady flow of hydrogen at RT for 2 h, and filtered. The organic phase was concentrated to provide the title intermediate (9 g, 100% yield) as a colorless oil. 1H NMR (400 MHz, (CD3)2S═O): δ(ppm) 1.367 (s, 9H), 1.620-1.670 (m, 1H), 1.904-1.953 (m, 1H), 3.110-3.140 (s, 3H, J=12 Hz), 3.255-3.360 (m, 2H), 3.523-3.561 (m, 1H), 3.653 (s, 3H), 4.241-4.283 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[C:22]3[CH2:21][CH2:20][CH2:19][C:18]=3[C:17]([OH:23])=[CH:16][C:15]=2[CH3:24])=[CH:11][C:10]=1[CH:27]([CH3:29])[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[C:15]([CH3:24])=[CH:16][C:17]([O:23][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:18]3[C:22]=2[CH2:21][CH2:20][CH2:19]3)=[CH:11][C:10]=1[CH:27]([CH3:29])[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(O)c2c(c1Oc1ccc(OCc3ccccc3)c(C(C)C)c1)CCC2
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1cc(C)c(Oc2ccc(OCc3ccccc3)c(C(C)C)c2)c2c1CCC2

Procedure:
The title compound was prepared in a similar manner to those described in Reference Example 11 using 7-(4-benzyloxy-3-isopropylphenoxy)-6-methylindan-4-ol instead of 2-hydroxy-5-(5-methyl-7-nitroindan-4-yloxy)benzaldehyde and using ethyl bromoacetate instead of benzyl bromide.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[C:21]([O:33][CH2:34][CH2:35][OH:36])[C:22]=3[O:23][C:24]3[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=3[Cl:32])[C:17](O)=[O:18])(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[C:21]([O:33][CH2:34][CH2:35][OH:36])[C:22]=3[O:23][C:24]3[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=3[Cl:32])[C:17]([NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:18])(=[O:11])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Nc1ccccc1
Reactant: COc1ccc(Cl)c(Oc2c(NS(=O)(=O)c3ccc4c(c3)OCO4)cc(C(=O)O)cc2OCCO)c1
Product: COc1ccc(Cl)c(Oc2c(NS(=O)(=O)c3ccc4c(c3)OCO4)cc(C(=O)Nc3ccccc3)cc2OCCO)c1

Procedure:
Analogously to Example 74, by condensing 3-(benzo[1,3]-dioxol-5-sulphonylamino)-4-(2-chloro-5-methoxy-phenoxy)-5-(2-hydroxy-ethoxy)-benzoic acid with aniline there was obtained 3-(benzo[1,3]dioxol-5-sulphonylamino)-4-(2-chloro-5-methoxy-phenoxy)-5-(2-hydroxy-ethoxy)-N-phenyl-benzamide.