Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][C:12]1[CH:13]=[C:14]([O:18][CH3:19])[CH:15]=[CH:16][CH:17]=1.[Al+3].[Cl-].[Cl-].[Cl-]>O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:17]2[CH:16]=[CH:15][C:14]([O:18][CH3:19])=[CH:13][C:12]=2[CH3:11])=[O:7])=[CH:4][CH:3]=1
Reactant: COc1cccc(C)c1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: COc1ccc(C(=O)c2ccc(Br)cc2)c(C)c1
Temperature: 25 °C
Yield: 73 %

Procedure:
To a mixture of 4-bromobenzoyl chloride (1.12 g, 5.12 mmol) and 3-methyl anisole (1.95 mL, 15.47 mmol) at 0° C. was added AlCl3 (0.83 g, 6.20 mmol). The mixture was allowed to warm to RT over 12 h with stirring. Water was added slowly, and the mixture was extracted with CH2Cl2. The organics were dried with MgSO4 and concentrated. The crude material was purified by chromatography on silica gel (EtOAc:hexanes) to yield 1.14 g (73%) of compound 27. 1H NMR (400 MHz, CDCl3): δ 2.41 (s, 3H), 3.86 (s, 3H), 6.74 (dd, J=2.5 Hz, 8.6 Hz, 1H), 6.82 (d, J=2.6 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.58 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H).
Reaction SMILES: N1C=CC=CC=1NC1C=CC=CC=1N.CC1C=C(C=CC=1)/C=C/[C:21](Cl)=[S:22].[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1/[CH:42]=[CH:43]/[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1/[CH:42]=[CH:43]/[C:44]1[CH:45]=[CH:46][C:47]([S:22][CH3:21])=[CH:48][CH:49]=1
Reactant: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Reactant: Cc1cccc(/C=C/C(=S)Cl)c1
Agent: Nc1ccccc1Nc1ccccn1
Product: CSc1ccc(/C=C/c2nc3ccccc3n2-c2ccccn2)cc1

Procedure:
The titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and (E)-3-methylthiocinnamoyl chloride (Miller, R. D.; Reiser, O. J. Heterocycl. Chem. 1993, 30, 755) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). MW: 343.46; mp: 139.6-140.6° C.; 1H-NMR (CDCl3) δ: 8.78 (1H, dd, J=5.1, 2.2 Hz), 8.00 (1H, ddd, J=7.7, 7.7, 2.2 Hz), 7.96 (1H, d, J=16.1 Hz), 7.83 (1H, d, J=7.3 Hz), 7.54-7.39 (5H, m), 7.38-7.18 (4H, m), 7.10 (1H, d, J=16.1 Hz), 2.49 (3H, s).
Reaction SMILES: [C:1]([O:5][CH2:6][C@@H:7]([OH:16])[CH2:8][C:9](=[O:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12])([CH3:4])([CH3:3])[CH3:2].C(OC)(=O)C.CCN(CC)CC>CO>[C:1]([O:5][CH2:6][C@@H:7]([OH:16])[CH2:8][C@@H:9]([OH:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)CC(=O)C[C@H](O)COC(C)(C)C
Solvent: CO
Solvent: CCN(CC)CC
Solvent: COC(C)=O
Product: COC(=O)C[C@H](O)C[C@H](O)COC(C)(C)C
Temperature: 30 °C
Reaction time: 21 h
Yield: 65 %

Procedure:
Methyl (5S)-6-t-butoxy-5-hydroxy-3-oxohexanoate synthesized in the same manner as in Example 5, except for replacing t-butyl acetate with methyl acetate was used. That is, 16.9 mg (0.01 mmole) of Ru2Cl4 ((R)-BINAP)2 (NEt3) was weighed, and 500 mg (2.15 mmole) of methyl (5S)-6-t-butoxy-5-hydroxy-3-oxohexanoate and 50 ml of methanol were added thereto to form a solution. The solution was transferred to a 100 ml-volume autoclave whose atmosphere had been displaced with nitrogen, and the solution was stirred at 30° C. for 21 hours under a hydrogen pressure of 50 kg/cm2 to conduct hydrogenation. The solvent was removed by distillation, and the residue was purified by silica gel column chromatography (diethyl ether/hexane: 5/1 by volume) to obtain 323 mg (yield: 65%) of methyl (3R,5S)-6-t-butoxy-3,5-dihydroxyhexanoate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH3:12])[CH:3]=1.Br[CH2:14][CH2:15][CH2:16][Cl:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: ClCCCBr
Reactant: COc1cc(O)ccc1C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(OCCCCl)ccc1C(C)=O
Yield: 47.4 %

Procedure:
A mixture of 10.6 g (0.637 mole) of 1-(4-hydroxy-2-methoxyphenyl)ethanone, 20 g (0.127 mole) of 1-bromo-3-chloropropane and 26.4 g (0.19 mole) of anhydrous potassium carbonate in 250 ml of acetone was heated at reflux for 20 hr. The mixture was cooled, filtered and the filtrate concentrated under vacuum pump pressure at 90° C. to give an oil which gradually crystallized. The solid was triturated with petroleum ether (30°-60° C.), collected by filtration and dried to yield 14.6 g (94%) of white solid, m.p. 47°-49° C. on recrystallizing from isopropyl ether.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][NH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:10][C:11]1[C:12]([CH:17]=O)=[N:13][CH:14]=[CH:15][CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:8][NH:9][CH2:17][C:12]2[C:11]([CH3:10])=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1CN
Reactant: Cc1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CNCc1ncccc1C

Procedure:
Using General Procedure B: Reaction of 3-methyl-2-aminomethylpyridine and 3-methyl-2-pyridinecarboxaldehyde in CH2Cl2 with NaBH(OAc)3 gave bis-(3-methyl-pyridin-2-ylmethyl)-amine as a yellow oil. 1H NMR (CDCl3) δ 2.33 s, 6H), 4.06 (s, 4H), 7.08 (dd, 2H, J=9, 6 Hz), 7.42 (dd, 2H, J=9, 3 Hz), 8.41 (d, 2H, J=3 Hz).
Reaction SMILES: [O:1]([C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[NH:10][C:11]([NH:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[CH:17][N:18]2[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]2[N:30](C(OC(C)(C)C)=O)[CH:31]=[CH:32][C:25]=12)=[O:12])[CH3:2].Cl>CO>[ClH:9].[O:1]([C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[NH:10][C:11]([NH:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[CH:17][N:18]2[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]2[NH:30][CH:31]=[CH:32][C:25]=12)=[O:12])[CH3:2]
Reactant: COc1ccc(Cl)cc1NC(=O)Nc1cccc2c1ccn2Cc1ccnc2c1ccn2C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: COc1ccc(Cl)cc1NC(=O)Nc1cccc2c1ccn2Cc1ccnc2[nH]ccc12
Reaction time: 8 h
Yield: 180.3 %

Procedure:
1-(2-Methoxyl-5-chlorophenyl)-3-{1-[1-(t-butyloxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]-1H-indol-4-yl}urea (500 mg, 0.92 mmol) was added to 25% HCl in methanol solution. The mixture was stirred overnight, then concentrated to afford the product 1-(2-Methoxyl-5-chlorophenyl)-3-[1-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-1H-indol-4-yl]urea hydrochloride (400 mg, 90%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23](O)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N2CCN(C([C:39]3[CH:40]=[C:41]4[C:45](=[CH:46][CH:47]=3)[NH:44][C:43](C(N3CCS(=O)(=O)CC3)=O)=[CH:42]4)=O)CC2)CCCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.N1C2C(=CC=CC=2)CC1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:44]3[C:45]5[C:41](=[CH:40][CH:39]=[CH:47][CH:46]=5)[CH2:42][CH2:43]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: c1ccc2c(c1)CCN2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc2[nH]c(C(=O)N3CCc4ccccc43)cc2c1)N1CCN(C2CCCC2)CC1
Yield: 49 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride (example 34, intermediate b), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), indoline (commercially available) and N,N-diisopropyl-ethylamine in N,N-dimethylformamide, to give the desired product as a light yellow solid (49%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[S:14][C:13](=[C:15]3[S:19][C:18](=[N:20][C:21]4[CH:22]=[C:23]([NH:30][C:31](=[O:36])[CH2:32][N:33]([CH3:35])[CH3:34])[CH:24]=[CH:25][C:26]=4[NH:27][CH2:28][CH3:29])[N:17]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:16]3=[O:44])[N:12]([CH3:45])[C:11]=2[CH:46]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[S:14][C:13](=[C:15]3[S:19][C:18](=[N:20][C:21]4[CH:22]=[C:23]([NH:30][C:31](=[O:36])[CH2:32][N:33]([CH3:35])[CH3:34])[CH:24]=[CH:25][C:26]=4[NH:27][CH2:28][CH3:29])[N:17]([CH2:37][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:16]3=[O:44])[N:12]([CH3:45])[C:11]=2[CH:46]=1
Reactant: CCNc1ccc(NC(=O)CN(C)C)cc1N=C1SC(=C2Sc3ccc(OCCN=[N+]=[N-])cc3N2C)C(=O)N1Cc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCNc1ccc(NC(=O)CN(C)C)cc1N=C1SC(=C2Sc3ccc(OCCN)cc3N2C)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.1 %

Procedure:
To a solution of the above N-(3-{5-[5-(2-azidoethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-3-benzyl-4-oxothiazolidin-2-ylideneamino}-4-ethylamino-phenyl)-2-dimethylaminoacetamide (0.34 mmol) in THF (13 mL) was added triphenylphosphine (100 mg, 380 mmol) and H2O (20 mL). The solution was stirred 48 h at room temperature. The solvent was removed under reduced pressure, and the crude material was chromatographed (silica gel, 0–5% MeOH/DCM) to afford the title compound (157 mg, 72% overall).
Reaction SMILES: [H-].[Na+].C(S)C.C[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]=[CH:16][CH:15]=[C:14]([C@@H:18]([OH:29])[C@H:19]3[N:24]4[CH2:25][C@H:26]([CH:27]=[CH2:28])[C@@H:21]([CH2:22][CH2:23]4)[CH2:20]3)[C:12]=2[CH:13]=1.Cl>CCCCCC.CN(C=O)C>[CH2:28]=[CH:27][C@@H:26]1[CH:21]2[CH2:20][C@@H:19]([C@H:18]([OH:29])[C:14]3[CH:15]=[CH:16][N:17]=[C:11]4[C:12]=3[CH:13]=[C:8]([OH:7])[CH:9]=[CH:10]4)[N:24]([CH2:23][CH2:22]2)[CH2:25]1
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Solvent: CCCCCC
Product: C=C[C@H]1CN2CCC1C[C@H]2[C@H](O)c1ccnc2ccc(O)cc12
Temperature: 100 °C
Reaction time: 13 h
Yield: 93.4 %

Procedure:
NaH (60% in mineral oil, 800 mg, 20.0 mmol, 10.0 equiv) was washed with hexane, dried, and suspended in DMF (20 mL). To this suspension at 0° C. was added ethanethiol (2.96 mL, 40.0 mmol, 20.0 equiv) dropwise over 5 min. The reaction mixture was stirred at 23° C. for 10 min before the addition of quinine (649 mg, 2.00 mmol, 1.00 equiv) in DMF (10 mL) and further stirred for 13 hr at 100° C. The reaction mixture was cooled to 23° C. and neutralized with aqueous 1N HCl. The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×30 mL). The combined organic phases were washed with brine (50 mL) and dried (K2CO3). The filtrate was concentrated in vacuo and the residue was triturated with Et2O to afford 580 mg of the title compound as a colorless solid (93% yield).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]C.[C:9]([O:13][CH3:14])(=[O:12])[CH:10]=[CH2:11].C(OOC(C)(C)C)(C)(C)C>[Br-].[Zn+2].[Br-]>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:14]1[O:13][C:9](=[O:12])[CH2:10][CH2:11]1
Reactant: CCCCCCCO
Reactant: C=CC(=O)OC
Agent: CC(C)(C)OOC(C)(C)C
Agent: [Br-]
Agent: [Zn+2]
Product: CCCCCCC1CCC(=O)O1
Temperature: 165 °C

Procedure:
To an autoclave (a volume of 1 L) was charged 349 g (3.0 mol) of n-heptanol and 0.06 g (0.27 mmol) of zinc bromide. The mixture was heated and stirred at 165° C. Into the mixture in this state was injected a mixed liquor of 57 g (0.66 mol) of methyl acrylate and 9.9 g (0.068 mol) of di-t-butylperoxide over 6 hours. The resulting mixture was stirred at the temperature for further 1 hour. Subsequently, unreacted n-heptanol was distilled off followed by vacuum distillation, yielding γ-decalactone. Gas chromatographic analysis showed that the yield of γ-decalactone was 69%. The resulting γ-decalactone was plastic-like in odor and acidulous, which indicated an inferior aroma.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:46][C:47]1[CH:48]=[C:49]([NH:53][C:54]([C:56]2[C:57]([NH:71][CH2:72][CH2:73][CH3:74])=[N:58][C:59]([NH:62][CH2:63][CH2:64][C:65]3[CH:70]=[CH:69][N:68]=[CH:67][CH:66]=3)=[N:60][CH:61]=2)=[O:55])[CH:50]=[CH:51][CH:52]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.CN(C)C=O>[O:13]=[C:11]([NH:46][C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([NH:53][C:54]([C:56]2[C:57]([NH:71][CH2:72][CH2:73][CH3:74])=[N:58][C:59]([NH:62][CH2:63][CH2:64][C:65]3[CH:66]=[CH:67][N:68]=[CH:69][CH:70]=3)=[N:60][CH:61]=2)=[O:55])[CH:48]=1)[C@@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH3:10]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)Nc1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)Nc1cccc(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1
Reaction time: 2 h
Yield: 97.3 %

Procedure:
To N-Boc-L-alanine (57 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg) and 1-hydroxybenzotriazole monohydrate (81 mg), N,N-dimethylformamide (2 mL) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture, N,N-diisopropylethylamine (153 μL) and N-(3-aminophenyl)-4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)pyrimidine-5-carboxamide (A4, 98 mg) were added at room temperature, and the mixture was stirred at the same temperature for 5 hours. To the reaction mixture, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent, 98 to 90% ethyl acetate in methanol) to obtain oily (S)-tert-butyl (1-oxo-1-((3-(4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)pyrimidine-5-carboxamido)phenyl)amino)propan-2-yl)carbamate (A5, 137 mg).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:53]1([S:59]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=2[C:68]2[CH:73]=[CH:72][CH:71]=[C:70]([NH2:74])[CH:69]=2)(=[O:61])=[O:60])[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>CN(C=O)C>[N:53]1([S:59]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=2[C:68]2[CH:73]=[CH:72][CH:71]=[C:70]([NH:74][C:24]([C:19]3[C:20](=[O:23])[O:21][C:22]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:69]=2)(=[O:61])=[O:60])[CH2:54][CH2:55][O:56][CH2:57][CH2:58]1
Reactant: Nc1cccc(-c2ccccc2S(=O)(=O)N2CCOCC2)c1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccccc2S(=O)(=O)N2CCOCC2)c1)c1cc2cccc(OC(F)(F)F)c2oc1=O
Temperature: 25 °C
Yield: 51.8 %

Procedure:
DIEA (0.009 mL, 0.052 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.013 g, 0.047 mmol) and HATU (0.020 g, 0.052 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′-(Morpholine-4-sulfonyl)-biphenyl-3-ylamine (0.015 g, 0.047 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected were collected and the solvent removed under vacuum to give 0.014 g of product in 50% yield: LCMS (ESI) m/z 591 (MH+).
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:28][C@H:26]([OH:27])[CH2:25][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([N:16]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:17])=[O:15])[CH2:7][C:8]1[CH:13]=[N:12][CH:11]=[CH:10][CH:9]=1)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:1]1[CH2:28][C@H:26]([OH:27])[CH2:25][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([N:16]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:17])=[O:15])[CH2:7][C:8]1[CH:13]=[N:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CN(Cc1ccccc1)C(=O)[C@H](Cc1cccnc1)NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(Cc1ccccc1)C(=O)[C@H](Cc1cccnc1)NC(=O)[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The resultant Boc-Hyp-Pal-N(Me)Bzl is dissolved in 40 ml of CH2Cl2 and mixed with 20 ml of TFA whilst cooling with ice. The mixture is stirred for 15 minutes at ambient temperature, concentrated on the rotary evaporator, the residue is taken up in ethyl acetate and extracted twice with saturated NaHCO3 solution. The aqueous phase is extracted successively with ethyl acetate and CH2Cl2. All the organic phases are united, dried with MgSO4, concentrated and the residue is chromatographed over silica gel by means of acetonitrile/water/MeOH (4:1:1). 0.39 g of H-Hyp-Pal-N(Me)Bzl is obtained as a highly viscous, colourless oil. [α]D20 (MeOH)=-38.1°.
Reaction SMILES: [Na+].[C:2]1([C:8]2[CH:24]=[CH:23][C:11]([C:12]([O:14][CH2:15][C:16]([F:22])([F:21])[S:17]([O-:20])(=[O:19])=[O:18])=[O:13])=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].FC(F)(F)S([O-])(=O)=O.[C:34]1([CH:40]([SH+:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:41]1([CH:40]([SH+:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1.[F:22][C:16]([F:21])([S:17]([OH:20])(=[O:19])=[O:18])[CH2:15][O:14][C:12](=[O:13])[C:11]1[CH:10]=[CH:9][C:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:24][CH:23]=1
Reactant: O=C(OCC(F)(F)S(=O)(=O)[O-])c1ccc(-c2ccccc2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Agent: [Na]
Product: O=C(OCC(F)(F)S(=O)(=O)O)c1ccc(-c2ccccc2)cc1
Yield: 85.7 %

Procedure:
<2> The reaction described in <3> of Synthesis Example 1 was performed under the same conditions, except that the 4-phenylbenzoyloxymethyl difluoromethanesulfonic acid sodium salt (2.81 g) produced in <1> of Synthesis Example 8 above was used instead of the benzoyloxymethyldifluorosulfonic acid sodium salt in the reaction with diphenylmethylphenylsulfonium trifluoromethanesulfonic acid sodium salt, and thus 3.71 g (yield 85.7%) of 4-phenylbenzoic acid 2,2-difluoro-2-sulfoethyl ester diphenylmethylphenylsulfonium salt as shown in the following reaction scheme 17 was obtained. The structure of the product was confirmed by 1H-NMR (see FIG. 16).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N=C=NC(C)C)(C)C.[C:29]([N:36]1[CH2:41][CH2:40][CH2:39][CH:38](O)[CH2:37]1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].[Cl:43][C:44]1[N:49]=[CH:48][N:47]=[C:46]2[NH:50][N:51]=[CH:52][C:45]=12>O1CCCC1>[C:32]([O:31][C:29]([N:36]1[CH2:41][CH2:40][CH2:39][CH:38]([N:50]2[C:46]3=[N:47][CH:48]=[N:49][C:44]([Cl:43])=[C:45]3[CH:52]=[N:51]2)[CH2:37]1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Reactant: Clc1ncnc2[nH]ncc12
Agent: CC(C)N=C=NC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(n2ncc3c(Cl)ncnc32)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 11.1 %

Procedure:
A solution of triphenylphosphine (1.41 g, 5.4 mmol) in tetrahydrofuran (50 mL) under argon was cooled to 0° C. Diisopropylcarbodiimide (1.06 mL, 5.4 mmol) was added dropwise, followed by 1-Boc-3-hydroxypiperidine (Alfa Aesar, Ward Hill, Mass., USA; 0.92 g, 4.6 mmol) and then 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 30; 0.55 g, 3.6 mmol). The mixture was stirred at room 0° C. for 4 h and the volatiles were then evaporated. The crude product was purified by silica gel chromatography, eluting with 16-20% ethyl acetate/hexanes to give 3-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (135 mg, 11%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=O)[CH:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH3:12])=[N:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.ClC(Cl)(Cl)C(Cl)(Cl)Cl.N>C1COCC1.CO.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH3:12])=[N:9][N:8]=2)[CH:7]=1
Reactant: CC(C(=O)NNc1ccc(F)cn1)N1CCOCC1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(c1nnc2ccc(F)cn12)N1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.1 %

Procedure:
To a solution of Intermediate 46a (3.43 g, 12.8 mmol), Ph3P (6.71 g, 25.6 mmol) and Et3N (7.14 mL, 51.2 mmol) in THF (75 mL) at 0° C. was added hexachloroethane (6.06 g, 25.6 mmol) and the solution stirred at RT for 4 h. The brown suspension was filtered and the solid washed with THF (10 mL). The combined organics were applied to an SCX-2 cartridge, which was washed with DCM-MeOH (1:1, 100 mL) and MeOH (100 mL). The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave an off-white solid. FCC, using 1-5% [2M NH3 in MeOH] in DCM, gave the title compound as an off-white solid (1.70 g, 53%). 1H NMR (300 MHz, CDCl3): 1.66 (3H, d, J 6.8), 2.45-2.60 (4H, m), 3.63-3.76 (4H, m), 4.28 (1H, q, J 6.8), 7.21 (1H, ddd, J 10.0, 7.5, 2.3), 7.76 (1H, ddd, J 10.0, 4.9, 0.9), 8.50 (1H, ddd, J 3.9, 2.3, 0.9).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:12].N[C:14]1C(Cl)=NC(CC)=NC=1NC>>[Cl:1][C:2]1[N:10]=[C:9]([CH2:11][CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:12]
Reactant: Cc1nc(Cl)c2ncn(C)c2n1
Reactant: CCc1nc(Cl)c(N)c(NC)n1
Product: CCc1nc(Cl)c2ncn(C)c2n1
Yield: 65 %

Procedure:
This was prepared in a manner similar to that described in Example 27 for 6-chloro-2,9-dimethylpurine, except that 5-amino-4-chloro-2-ethyl-6-methylaminopyrimidine was used as the starting material, and the final product was purified by chromatography. The title compound was obtained in 65% yield. NMR (CDCl3, δ from TMS): 1.4 (t, CH2CH3), 3.06 (q, CH2CH3), 3.88 (s, NCH3), 8.00 (s, H8).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][CH:9]2[C:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=1)=[O:15])([O-])=O>C(OCC)(=O)C.[C].[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][CH:9]2[C:14]([O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:22]=1)=[O:15]
Reactant: CCOC(=O)c1ccc(OC(=O)C2CCCc3c2cccc3[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(OC(=O)C2CCCc3c(N)cccc32)cc1

Procedure:
A 5.2-g portion of the p-ethoxycarbonylphenyl 5-nitro-1,2,3,4-tetrahydro-1-naphthoate obtained above was catalytically reduced with 5% palladium-carbon in ethyl acetate. After removal of the catalyst by filtration, the ethyl acetate was removed by distillation to obtain p-ethoxycarbonylphenyl 5-amino-1,2,3,4-tetrahydro-1-naphthoate which was dissolved in diethyl ether and dry gaseous hydrogen chloride was introduced thereinto to obtain 4.5 g of p-ethoxycarbonylphenyl 5-amino-1,2,3,4-tetrahydro-1-naphthoate hydrochloride, m.p. 218°-219° C.