Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH:17][CH2:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][C:28]=2[O:29][CH3:30])[N:25]=[CH:24][N:23]=[C:22]3[NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[C:42](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([N:17]([CH2:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][C:28]=2[O:29][CH3:30])[N:25]=[CH:24][N:23]=[C:22]3[NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])[CH3:42])([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNC1(C(=O)O)CCCN(C(=O)OC(C)(C)C)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(=O)O)CCCN(C(=O)OC(C)(C)C)C1
Yield: 89.3 %

Procedure:
1-(tert-Butoxycarbonyl)-3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]piperidine-3-carboxylic acid (Isomer 1) (400 mg, 0.71 mmol) was dissolved in 5% acetic acid in dichloromethane (25 ml) and 37% aqueous formaldehyde (5 ml) added. The mixture was stirred rapidly and sodium triacetoxyborohydride (151 mg, 0.71 mmol) added. Over a period of 5 hours a further 3 equivalents of sodium triacetoxyborohydride were added. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate, the layers separated and the organic phased dried (MgSO4) and concentrated under reduced pressure. Column chromatography on silica, eluting with 10% ammonia in methanol/dichloromethane gave 1-(tert-butoxycarbonyl)-3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidine-3-carboxylic acid (Isomer 1) (364 mg, 85%) as a white solid; 1H NMR Spectrum: (DMSO d6 100° C.) 1.27 (s, 9H); 1.47 (m, 1H); 1.86 (m, 1H); 2.01 (m, 2H); 2.30 (s, 3H); 3.30 (m, 1H); 3.44 (m, 1H); 3.63 (d, 1H); 3.74 (d, 1H); 3.81 (d, 1H); 3.88 (d, 1H); 3.96 (s, 3H); 7.19 (s, 1H); 7.25 (t, 1H); 7.40 (t, 1H); 7.65 (m, 1H); 8.22 (s, 1H); 8.41 (s, 1H); Mass Spectrum: (M+H)+ 574.5.
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[CH2:19]([C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.C>O1CCOCC1.C(#N)C>[CH2:19]([C:26]1[CH:27]=[C:28]([NH:29][C:3]([C:5]2[CH:6]=[CH:7][N:8]3[C:12]=2[CH2:11][S:10][CH:9]3[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:4])[CH:30]=[CH:31][CH:32]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Nc1cccc(Cc2ccccc2)c1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(Cc2ccccc2)c1)c1ccn2c1CSC2c1cccnc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 30.8 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (5.7 g) is added, at a temperature between 60° and 65° C., to a solution of 3-benzylaniline (3.5 g) and triethylamine (3.9 g) in dioxane (100 cc) which is heated to a temperature in the vicinity of 60° C., in the course of 25 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 6 hours and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue is dissolved in methylene chloride (250 cc). The solution obtained is washed twice with distilled water (160 cc in total), twice with an aqueous 1N sodium hydroxide solution (200 cc in total) and 5 times with distilled water (500 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. A crude product (5 g) is thereby obtained, which is dissolved in boiling acetonitrile (50 cc). Decolourizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 4° C. for 1 hour. The crystals formed are separated by filtration, washed with acetonitrile cooled to a temperature in the vicinity of 4° C. (10 cc) and twice with diethyl ether (20 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-(3-benzylphenyl)-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (2.4 g) in the form of white crystals, m.p. 139.5° C., is thereby obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](O)=[O:25])=[CH:15][C:13]=2[N:14]=1.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:63][C:64]1[CH:69]=[CH:68][C:67]([C:70]([F:73])([F:72])[F:71])=[CH:66][N+:65]=1[O-]>[Fe].C(O)(=O)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:22])([CH3:23])[O:21][C:17]=3[C:16]([C:24]([NH:63][C:64]3[CH:69]=[CH:68][C:67]([C:70]([F:72])([F:71])[F:73])=[CH:66][N:65]=3)=[O:25])=[CH:15][C:13]=2[N:14]=1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Reactant: Nc1ccc(C(F)(F)F)c[n+]1[O-]
Agent: [Fe]
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(C(F)(F)F)cn3)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 8.7 %

Procedure:
The title compound was prepared by following the procedure described for Example-121 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.100 g, 0.266 mmol), COMU (0.284 g, 0.663 mmol), DIPEA (0.085 g, 0.658 mmol), 2-amino-5-(trifluoromethyl)pyridine 1-oxide (Intermediate-41, 0.052 g, 0.292 mmol), DMF (5 mL), iron powder (0.100 g) and acetic acid (5.0 mL) to afford 0.012 g of the desired product. 1HNMR (DMSO-d6): δ 1.57 (s, 6H), 3.12 (s, 2H), 7.33 (m, 3H), 7.54 (s, 1H), 8.23 (d, J=8.7 Hz, 1H), 8.48 (d, J=8.70 Hz, 1H), 8.57 (s, 1H), 10.47 (s, 1H), 11.00-12.00 (s, 2H); MS [M]+: 520.18.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:12])[CH3:11])=[N:2]1.C(N(CC)CC)C.[C:20](Cl)(=[O:23])[O:21][CH3:22]>C(Cl)(Cl)Cl>[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([C:20]([O:21][CH3:22])=[O:23])[N:2]=1)(=[O:12])[CH3:11]
Reactant: COC(=O)Cl
Reactant: CC(=O)c1n[nH]c2ccccc12
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)n1nc(C(C)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 1-(1H-indazol-3-yl)ethanone (5.0 g) and triethylamine (6.53 mL) in chloroform (80 mL) was added dropwise a solution of methyl chlorocarbonate (3.24 g) in chloroform (20 mL) under ice-cooling over 1 hour, and the mixture was stirred at room temperature for 14 hours. The reaction solution was washed with aqueous saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated tinder reduced pressure. The resulting residue was triturated with n-hexane to give methyl 3-acetyl-1H-indazole-1-carboxylate) [REx(101-1)] (6.67 g) as a colorless powder.
Reaction SMILES: S(Cl)(Cl)=O.N1C=CC=CC=1.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:34])[CH2:19][C:20]([C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=2)(O)[C:21]([F:24])([F:23])[F:22])=[CH:14][C:13]=1[CH3:35]>C1(C)C=CC=CC=1>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:34])[CH:19]=[C:20]([C:26]2[CH:27]=[C:28]([Cl:33])[CH:29]=[C:30]([Cl:32])[CH:31]=2)[C:21]([F:23])([F:24])[F:22])=[CH:14][C:13]=1[CH3:35]
Reactant: Cc1cc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Temperature: 80 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
0.391 g of thionyl chloride and 0.104 g of pyridine were added to toluene (3 g) solution of 0.3 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-3-hydroxy-4,4,4-trifluorobutan-1-one synthesized in Step 3 at room temperature and stirred for 1 hour at 80° C. After completion of the reaction, the reaction solution was cooled to room temperature, and separated by adding toluene and 2N hydrochloric acid. The organic phase was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Although the obtained residue includes a mixture of geometric isomers, this residue was purified by silica gel column chromatography which eluted the residue with ethyl acetate-hexane (1:10) to obtain 0.244 g of the target product as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])=[CH:22][CH:21]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)=[O:32])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccc(Cl)cc1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3ccc(Cl)cc3)n2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(4-chloro-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 01b: tR=1.01 min; [M+H]+=411.11.
Reaction SMILES: [CH3:1][N:2]([CH2:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[S:3]([N:6]1[C:11]2([CH2:13][CH2:12]2)[CH2:10][N:9]([C:14]2[C:15]3[CH:22]=[CH:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4].CCN(C(C)C)C(C)C.[OH:38][CH2:39][CH2:40][C:41](O)=[O:42].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CS(C)=O>[OH:42][CH2:41][CH2:40][C:39]([N:26]1[CH2:27][CH2:28][CH:24]([CH2:23][N:2]([CH3:1])[S:3]([N:6]2[C:11]3([CH2:13][CH2:12]3)[CH2:10][N:9]([C:14]3[C:15]4[CH:22]=[CH:21][NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH2:8][CH2:7]2)(=[O:4])=[O:5])[CH2:25]1)=[O:38]
Reactant: CN(CC1CCNC1)S(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Reactant: O=C(O)CCO
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CN(CC1CCN(C(=O)CCO)C1)S(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 40 °C
Reaction time: 1 h

Procedure:
N-methyl-N-(pyrrolidin-3-ylmethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,8-diazaspiro[2.5]octane-8-sulfonamide (intermediate 25) (0.042 mmol) was dissolved in dry DMSO (0.5 mL), added DIPEA (0.25 mL), 3-hydroxypropanoic acid (0.050 mmol) and Pybrop (0.050 mmol) then stirred at 40° C. for 1 h. The pure compound was obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [C:1]1([C:7]([NH2:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[CH2:22][CH3:23]>C(#N)C>[C:1]1([C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:20][CH2:22][CH3:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCI
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 72 h
Yield: 27.9 %

Procedure:
Triphenylmethylamine (1.00 g, 3.86 mmol) (Wako Pure Chemical Industries, Ltd.) and iodoethane (1.50 g, 9.62 mmol) (Wako Pure Chemical Industries, Ltd.) were dissolved in acetonitrile (5 mL) (Wako Pure Chemical Industries, Ltd.), and the mixture was left to stand still at room temperature for 3 days. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform (Wako Pure Chemical Industries, Ltd.) as an eluent), to thereby obtain the title compound (0.31 g, 28% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH2:19])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH:19][C:30](=[O:31])[O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1Cc2cccc(-c3ccc(Cl)cc3Cl)c2O1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(-c3ccc(Cl)cc3Cl)c2O1)OCc1ccccc1
Yield: 86.9 %

Procedure:
Treatment of (±)-1-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.9 g, 5.75 mmol) with diisopropylethylamine (1.11 g, 8.62 mmol) followed by benzyl chloroformate (1.18 g, 6.89 mmol) generally according to the procedure described for Intermediate 12 gave 2.14 g (87%) of (±)-benzyl {[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a white solid. mp 87-89° C.; Anal. calcd. for C23H19Cl2NO3: C, 64.5; H, 4.47; N, 3.27. Found: C, 64.65; H, 4.78; N, 3.08. Chiral HPLC separation of (±)-benzyl {[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (Chiralcel AD, methanol:water 95:5) provided two fractions. Fraction 1 (Rt=8.094 min, Chiralcel AD, methanol:water 95:5); Fraction 2 (Rt=9.152 min, Chiralcel AD methanol:water 95:5).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]([CH2:23][C@H:24]3[CH2:29][CH2:28][C@H:27]([CH3:30])[CH2:26][CH2:25]3)[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@H:12]3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][C:6]=2[CH:5]=[C:4]([Cl:31])[N:3]=1.[Cl:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[N:37][CH:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:31][C:4]1[N:3]=[C:2]([C:35]2[CH:36]=[N:37][CH:38]=[C:33]([Cl:32])[CH:34]=2)[C:7]2[N:8]([CH2:23][C@H:24]3[CH2:25][CH2:26][C@H:27]([CH3:30])[CH2:28][CH2:29]3)[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@H:12]3[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[N:10][C:6]=2[CH:5]=1
Reactant: OB(O)c1cncc(Cl)c1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(Cl)nc(Cl)c32)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(Cl)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 90 °C

Procedure:
4,6-dichloro-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine (3.44 g, 7.49 mmol), 5-chloropyridine-3-boronic acid (1.32 g, 08.39 mmol), cesium carbonate (12.2 g, 37.4 mmol), and 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride (1.1 g, 1.49 mmol) were combined in a vial that had been oven-dried and flushed with nitrogen. Dioxane (75 mL) was added, and the vial was sealed and heated to 90° C. for 4 hours. The reaction mixture was cooled to room temperature, filtered over celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford 6-chloro-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine. MS ESI calc'd. for C29H31Cl2N5O [M+H]+ 536. found 536.
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.C([C@:20]([C@:24](CC1C=CC=CC=1)([C@@:26](CC1C=CC=CC=1)([C@@H:28]([CH:30](CC1C=CC=CC=1)[OH:31])[OH:29])[OH:27])[OH:25])([OH:23])[CH:21]=[O:22])C1C=CC=CC=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH2:1]([C:21]([C@@H:20]([C@H:24]([C@@H:26]([C@@H:28]([CH2:30][OH:31])[OH:29])[OH:27])[OH:25])[OH:23])=[O:22])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1
Reactant: O=C[C@@](O)(Cc1ccccc1)[C@](O)(Cc1ccccc1)[C@@](O)(Cc1ccccc1)[C@H](O)C(O)Cc1ccccc1
Reactant: COc1cc(C(=O)O)ccc1O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(CC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)ccc1O

Procedure:
Vanillic acid having a benzyl-protected hydroxyl group at the 4 position and 2,3,4,6-tetrabenzyl glucose having benzyl-protected hydroxyl groups at positions other than the 1 position (Sigma-Aldrich) were condensed in a DMF solvent (at a reaction temperature of 60° C.) using the following condensing agents: 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI, Kokusaikagaku Co., Ltd.), 4-dimethylaminopyridine (DMAP, Tokyo Kasei Kogyo), and triethylamine (Et3N, Wako Pure Chemical Industries, Ltd.). The obtained condensate was a mixture comprising a anomer and β anomer at a ratio of 1:2. The condensate was purified using an open column (at different concentration ratios of hexane:ethyl acetate=6:1 and 5:1). A unreacted starting material was removed. The yield was found to be 84%: Molecular MS [M+Na]+ m/z 803.14, 1H NMR (300 MHz, CDCl3): δ7.60 (1H, dd, H-6), 7.59 (1H, d, H-2), 7.45-7.26 (60H, m, H-benzylic CH2), 6.90 (1H, d, H-5), 6.55 (1H, d, H-Glc1α, J=3.21), 5.84 (1H, d, H-Glc1β, J=7.65), 5.25 (10H, s, H-benzylic CH2), 4.96-3.56 (94H, m, CH3, H-Glc).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([N:11]([CH3:13])[CH3:12])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])(=O)C.[Na+].[Br:26]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.C(O)(=O)C>[NH2:1][C:2]1[N:10]=[C:9]([N:11]([CH3:12])[CH3:13])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:26])[N:6]2[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrBr
Reactant: CN(C)c1nc(N)c2ncn(Cc3ccccc3)c2n1
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(C)c1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
6-Amino-9-benzyl-2-dimethylaminopurine (66 mg, 0.25 mmol) was dissolved in a mixture of methylene chloride (50 ml) and acetic acid (10 ml). To the solution were added sodium acetate (202 mg, 2.46 mmol) and bromine (0.5 ml), and the mixture was stirred at room temperature for 1 hour. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, washed with aqueous saturated sodium hydrogen carbonate, dried on sodium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (68 mg, yield 80%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[CH3:21].C1CCC(N=NC2(C#N)CCCCC2)(C#N)CC1>C(Cl)(Cl)(Cl)Cl>[CH3:9][O:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[CH2:21][Br:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc([N+](=O)[O-])cc1CBr
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.1 %

Procedure:
N-Bromosuccinimide (2.18 g, 12.30 mmol) was added to a stirred solution of 2-methyl-4-nitro-benzoic acid methyl ester (2 g, 10.25 mmol) and ABCN (626 mg, 2.56 mmol) in carbon tetra-chloride (80 ml) at room temperature. The reaction was heated at reflux for 2 hrs and then allowed to cool to room temperature and stirred for 15 hrs. The solvent was evaporated in vacuo and the resulting residue filtered through a pad of silica (eluting with dichloromethane). The solvent was evaporated in vacuo to afford the title compound as a yellow solid (2.70 g, 96%). HPLC retention time 4.49 min. Mass spectrum (ES+) m/z 256 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([N:14]2[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]2)=[O:13])=[CH:4][N:3]=1.O1CCCC1.O1CCCC1.Cl[Zn][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=1>Cl[Ni](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:41][C:37]1[CH:36]=[C:35]([CH:40]=[CH:39][CH:38]=1)[CH2:34][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([N:14]2[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]2)=[O:13])=[CH:4][N:3]=1
Reactant: Cl[Zn]Cc1cccc(Cl)c1
Reactant: O=C(c1cnc(Cl)nc1C(F)(F)F)N1CCS(=O)(=O)CC1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1cnc(Cc2cccc(Cl)c2)nc1C(F)(F)F)N1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of 4-{[2-chloro-4-(trifluoromethyl)pyrimidin-5-yl]carbonyl}thiomorpholine 1,1-dioxide (500 mg), dichlorobis(triphenylphosphine)nickel (II) (190 mg), tetrahydrofuran (10 mL) was added a 0.5 M chloro(3-chlorobenzyl)zinc tetrahydrofuran solution (3.2 mL), followed by stirring at room temperature for 6 hours. To the reaction mixture was added water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, then dried over anhydrous magnesium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate). To the obtained pale yellow solid were added 1,4-dioxane (10 mL) and 1-methylpiperazine (0.16 mL), followed by stirring at room temperature for 6 hours. To the reaction mixture was added water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, then dried over anhydrous magnesium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate). The obtained white solid was washed with ethanol to obtain 4-{[2-(3-chlorobenzyl)-4-(trifluoromethyl)pyrimidin-5-yl]carbonyl}thiomorpholine 1,1-dioxide (212 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][C@H:5]1[O:7][C@@H:6]1[CH2:8][OH:9].O(O)O.[N:15]([Si](C)(C)C)=[N+:16]=[N-:17].[F-].C([Al+]CC)C>ClCCl>[N:15]([C@@H:5]([CH2:4][CH:3]([O:10][CH3:11])[O:2][CH3:1])[C@H:6]([OH:7])[CH2:8][OH:9])=[N+:16]=[N-:17]
Reactant: COC(C[C@H]1O[C@@H]1CO)OC
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC[Al+]CC
Agent: OOO
Agent: [F-]
Solvent: ClCCl
Product: COC(C[C@H](N=[N+]=[N-])[C@H](O)CO)OC

Procedure:
A mixture of the epoxy alcohol (2R,3R) 3-(2,2-dimethoxyethyl)oxirane-methanol and azidotrimethylsilane in dichloromethane is reacted with diethylaluminum fluoride to obtain (2S,3S) 3-azido-5,5-dimethoxypentane1,2-diol: ##STR6##
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([O:10]C)=O.[N:12]1([C:18]#[N:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.Cl.C1(OC)CCCC1>>[Br:7][C:5]1[S:4][C:3]2[C:8](=[O:10])[NH:19][C:18]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:1][C:2]=2[CH:6]=1
Reactant: N#CN1CCOCC1
Reactant: COC(=O)c1sc(Br)cc1N
Agent: Cl
Solvent: COC1CCCC1
Product: O=c1[nH]c(N2CCOCC2)nc2cc(Br)sc12
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A mixture of methyl 3-amino-5-bromothiophene-2-carboxylate (200 mg) produced in Example 1, step C, morpholine-4-carbonitrile (0.17 mL) and 4M hydrochloric acid/cyclopentylmethylether solution (3.0 mL) was stirred at 110° C. for 4 hr. The reaction system was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate was added to the residue. The precipitate was collected by filtration and washed with water. The obtained pale-brown solid was washed with a mixed solvent of ethyl acetate/hexane (1:1) to give the title compound (144 mg) as a pale-yellow solid.