Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([Si](C)(C)[O:6][C@@H:7]1[C@@H:11]([CH2:12][OH:13])[O:10][C@@H:9]([N:14]2[CH:22]=[C:20]([CH3:21])[C:18](=[O:19])[NH:17][C:15]2=[O:16])[CH2:8]1)(C)C.[H-].[Na+].[CH2:27]([O:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][C:42]=1[O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:38]Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[I-].[Na+]>O1CCCC1.CO.C(Cl)Cl>[CH2:27]([O:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][C:42]=1[O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:38][O:13][CH2:12][C@H:11]1[O:10][C@@H:9]([N:14]2[CH:22]=[C:20]([CH3:21])[C:18](=[O:19])[NH:17][C:15]2=[O:16])[CH2:8][C@@H:7]1[OH:6])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: ClCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](COCc3ccc(OCc4ccccc4)c(OCc4ccccc4)c3)O2)c(=O)[nH]c1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 31.7 %

Procedure:
713 mg (2 mmol) of 3'-O-[(1,1-dimethylethyl)dimethylsilyl]thymidine [Can. J. Chem., 56, 2768 (1978)] were dissolved in 5 ml of tetrahydrofuran, and 175 mg (4 mmol) of sodium hydride (as a 55% w/w dispersion in mineral oil) were added to the resulting solution under an argon atmosphere. The mixture was then stirred at 60° C. for 2 hours. At the end of this time, the temperature of the mixture was reduced to room temperature, and then 678 mg (2 mmol) of 3,4-dibenzyloxybenzyl chloride was added, followed by 149.9 mg (1 mmol) of sodium iodide, and the resulting mixture was stirred at room temperature for 19 hours, and then at 60° C. for 5 hours. At the end of this time, the solvent was distilled off under reduced pressure, and the residue was dissolved in 50 ml of ethyl acetate. The resulting solution was washed twice, each time with 50 ml of 0.01N aqueous hydrochloric acid; it was then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was dissolved in 4 ml of tetrahydrofuran, and 4 ml of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran was added to the solution. The mixture was then stirred at room temperature for 2 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was dissolved in 50 ml of ethyl acetate. The resulting solution was washed twice, each time with 50 ml of a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was applied to a chromatography column [LiChroprep (trade mark) Si60, 40-63 μm, Groβe C, Merck] and eluted using a gradient elution method, with methylene chloride containing from 1 to 4% by volume of methanol, to give 345.4 mg (yield 31.7%) of the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:31]=[CH:32][CH:33]=1)[CH2:16][O:17][C:18]1[CH:30]=[CH:29][C:21]2[S:22][C:23]([C:26]([NH2:28])=O)=[C:24]([CH3:25])[C:20]=2[CH:19]=1.CS(Cl)(=O)=O.O.C(OCC)(=O)C>N1C=CC=CC=1>[C:26]([C:23]1[S:22][C:21]2[CH:29]=[CH:30][C:18]([O:17][CH2:16][C:15]3[CH:31]=[CH:32][CH:33]=[C:13]([O:12][CH2:11][C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=4)[CH:14]=3)=[CH:19][C:20]=2[C:24]=1[CH3:25])#[N:28]
Reactant: Cc1c(C(N)=O)sc2ccc(OCc3cccc(OCc4ccc5ccccc5n4)c3)cc12
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: Cc1c(C#N)sc2ccc(OCc3cccc(OCc4ccc5ccccc5n4)c3)cc12
Reaction time: 16 h

Procedure:
To a stirred solution of 5-[3-(2-quinolinylmethyloxy)benzyloxy]-3-methylbenzo(b)thiophene-2-carboxamide (454.5 mg, 1 mmol) in pyridine (10 ml) at room temperature is added methanesulfonyl chloride (387 μL, 5 mmol). The solution is stirred for 16 hours and water (50 ml) and ethyl acetate (100 ml) are added. Extraction with ethyl acetate, washing with water and brine, drying (MgSO4) and concentration affords a crude product which is chromatographed over silica gel. Elution with 25% ethyl acetate in hexane provides 2-cyano-5-[3-(2-quinolinylmethyloxy)benzyloxy]-3-methylbenzo(b)thiophene.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:3]=1.[F:22][C:23]([F:37])([F:36])[C:24]1[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:26][CH:27]=[CH:28][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.O>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([N:33]3[CH2:34][CH2:35][N:30]([C:25]4[C:24]([C:23]([F:37])([F:22])[F:36])=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:31][CH2:32]3)[N:3]=[C:4]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[N:5]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: Fc1ccc(-c2cc(Cl)nc(-c3ccncc3)n2)cc1Cl
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Fc1ccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(-c3ccncc3)n2)cc1Cl

Procedure:
Dissolve 4-chloro-6-(3-chloro-4-fluorophenyl)-2-(pyridin-4-yl)pyrimidine (64 mg, 0.2 mmoles) and 1-(3-(trifluoromethyl)-pyridin-2-yl)piperazine (46 mg, 0.2 mmoles) in DMA (2.0 mL) under nitrogen atmosphere. Add anhydrous powdered K2CO3 (55 mg, 0.4 mmoles) to this mixture and heat at 140° C. for 20 hours. Cool, dilute with water (5 mL), extract with EtOAc (3×2 mL) and dry over MgSO4. Filter, and concentrate under vacuum to afford crude product. Wash the crude product with Et2O (2.0 mL) to afford the title product as cream colored solid. NMR (CDCl3) δ 3.34 (4H, s), 3.99 (4H, s), 7.20 (1H, m), 7.47 (1H, s), 7.43 (1H, t), 8.09 (1H, d, J=2.0), 8.30 (2H, m), 8.35 (1H, m), 8.55 (2H, m), 8.70 (2H, m). Mass spec m/z=515.24.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:30])[C:17]([CH3:29])([CH3:28])[O:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].CO>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16](=[O:30])[C:17]([CH3:28])([CH3:29])[O:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: COc1ccc(C2=C(c3ccc(OCc4ccccc4)cc3)C(=O)C(C)(C)O2)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(C2=C(c3ccc(O)cc3)C(=O)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 107.2 %

Procedure:
5% Palladium on carbon (7.0 g) was added to a solution 4-(4-(benzyloxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (19 g, 42.1 mmol) in methanol (25 ml) at RT under an atmosphere of nitrogen. The nitrogen atmosphere was changed to an atmosphere of hydrogen. The reaction mixture was stirred under an atmosphere of hydrogen at RT for 4 h (the reaction was monitored by TLC). The reaction mixtures was filtered over through a pad of Celite®, washed with methanol, concentrated in vacuo and the resultant residue was slurried with heptane. The solid was filtered & dried under vacuum to afford 4-(4-hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (14.0 g, 95%,) as light yellow solid. 1H NMR, 500 MHz, DMSO-d6: δ 9.5 (bs, 1H), 7.55 (d, 2H), 7.05 (d, 2H), 7.0 (d, 2H), 6.75 (d, 2H), 3.8 (s, 3H), 1.4 (s, 6H). MS: [M+H]: m/z=311.2. HPLC: (98.8%, Eclipse XDB-C18, 150×4.6 mm, 5 um. Mobile Phase: 0.1% TFA in Water. (A). ACN (B), Flow rate: 1.5 ml/min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([OH:17])[CH:10]=2.[I-].[N:24]1([C:34](N2C=C[N+](C)=C2)=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([O:17][C:34]([N:24]1[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26][CH2:25]1)=[O:35])[CH:10]=2
Reactant: Cc1c(Cc2ccc(Cl)c(Cl)c2)c(=O)oc2cc(O)ccc12
Reactant: C[n+]1ccn(C(=O)N2CCCc3ccccc32)c1
Agent: [I-]
Product: Cc1c(Cc2ccc(Cl)c(Cl)c2)c(=O)oc2cc(OC(=O)N3CCCc4ccccc43)ccc12

Procedure:
The title compound was prepared from 3-(3,4-dichloro-benzyl)-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. HPLC-MS m/z=494 (M+1), Rt: 5.86 min.
Reaction SMILES: [OH:1][CH:2]([CH2:16][Cl:17])[CH2:3][O:4][C:5]1[CH:15]=[CH:14][C:8]2[C:9](=[O:13])[CH:10]=[CH:11][O:12][C:7]=2[CH:6]=1.[CH3:18][C:19]([NH2:22])([CH3:21])[CH3:20]>C(O)C>[ClH:17].[O:12]1[C:7]2[CH:6]=[C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:16][NH:22][C:19]([CH3:21])([CH3:20])[CH3:18])[CH:15]=[CH:14][C:8]=2[C:9](=[O:13])[CH:10]=[CH:11]1
Reactant: O=c1ccoc2cc(OCC(O)CCl)ccc12
Reactant: CC(C)(C)N
Solvent: CCO
Product: CC(C)(C)NCC(O)COc1ccc2c(=O)ccoc2c1
Product: Cl
Reaction time: 0.17 h

Procedure:
A solution of 10.0 g 7-(2-hydroxy-3-chloro-1-propyloxy)-4H-1-benzopyrane-4-one with 100 cm3 ethanol was boiled with 20 cm3 1,1-dimethylethylamine for 2.5 hours. The solution was evaporated under reduced pressure, the residue was dissolved in 200 ml ethanol, to the obtained solution 40 ml 10% aqueous hydrochloric acid was added and the mixture was boiled for 10 minutes. The solvent was removed under reduced pressure and the residue was crystallized from aceton; 1-(4H-1-benzopyrane-4-one-7-yloxy)-3-(1,1-dimethylethylamino)-2-propanol hydrochloride salt (m.p. 176°-178° C.) was obtained.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][C@H:6]([CH3:10])[CH2:5]1.[CH3:11][C:12]([O:15][C:16]([N:18]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[N:19]([C:27]1[C:32]([F:33])=[C:31](Cl)[N:30]=[C:29]([Cl:35])[N:28]=1)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])([CH3:14])[CH3:13].C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOCC>[CH3:14][C:12]([O:15][C:16]([N:18]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[N:19]([C:27]1[C:32]([F:33])=[C:31]([N:7]2[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5][C@H:6]2[CH3:10])[N:30]=[C:29]([Cl:35])[N:28]=1)[C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[O:17])([CH3:11])[CH3:13]
Reactant: C[C@@H]1CN(C)CCN1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Agent: Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1CN(C)CCN1c1nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1F
Temperature: 0 °C
Yield: 81.9 %

Procedure:
To (3R)-1,3-dimethylpiperazine dihydrochloride (102.22 g, 546.3 mmol) was added a solution of tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (271.71 g, 546.3 mmol) in DMF (900 mL). The mixture was cooled to 0° C., and N,N-diisopropylethylamine (295 mL, 1694 mmol) was added. The solution was stirred and warmed to room temperature overnight. The solution was then diluted with Et2O (1000 mL) and washed with water (1000 mL). The aqueous phase was extracted with a fresh portion of Et2O (1000 mL), and the combined organic phase was washed with water (2×500 mL). The organic phase was then diluted with DCM (1000 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was filtered through a silica gel plug (30% EtOAc in hexanes; 1% Et3N). The solution was then concentrated in vacuo, and the residue was azeotroped with MeOH. The residue was diluted with MeOH (1000 mL), and crystallized by addition of water. The resulting solid was collected by vacuum filtration and washed with 10% MeOH in water. The resulting yellow solid was dried at 50° C. under high vacuum to give tris(1,1-dimethylethyl)2-{2-chloro-6-[(2R)-2,4-dimethyl-1-piperazinyl]-5-fluoro-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (257.34 g, 82% yield) as a light yellow solid. LCMS: (M+H)+: 575.2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH:25]1[CH2:29][CH2:28][CH:27]([NH:30]C(=O)OC(C)(C)C)[CH2:26]1>>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([N:13]1[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:24])[CH2:15][CH2:14]1)[CH:3]=[C:2]2[N:25]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26]1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)cc(N3CCC(N)C3)c2c1

Procedure:
The title compound was prepared in analogy to Example 19-1 in Scheme 7 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to the one in Example 18-1) and tert-butyl pyrrolidin-3-ylcarbamate. MS obsd. (ESI+) [(M+H)+] 407, 1H NMR (400 MHz, CD3OD) δ ppm 7.81 (s, 1 H), 7.71 (t, J=8.21 Hz, 2 H), 7.57-7.36 (m, 3 H), 7.27 (dd, J=8.59, 1.77 Hz, 1 H), 6.11 (s, 1 H), 5.21 (d, J=16.17 Hz, 1 H), 4.76 (d, J=15.92 Hz, 2 H), 4.50 (brs, 1 H), 3.88-3.71 (m, 2 H), 3.71-3.53 (m, 2 H), 3.53-3.36 (m, 3 H), 2.40 (s, 3 H), 2.26 (dq, J=12.63, 6.23 Hz, 1 H), 1.98-1.78 (m, 1 H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[C:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:7]([C:12]2[CH:13]=[CH:14][C:15](=[O:21])[N:16]([CH:18]([CH3:20])[CH3:19])[CH:17]=2)=[N:8][C:9]=1[CH2:10][OH:11].CI.[CH3:30]COC(C)=O>CN(C=O)C.O>[NH2:3][C:4]1[N:5]=[C:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:7]([C:12]2[CH:13]=[CH:14][C:15](=[O:21])[N:16]([CH:18]([CH3:20])[CH3:19])[CH:17]=2)=[N:8][C:9]=1[CH2:10][O:11][CH3:30]
Reactant: CC(C)n1cc(-c2nc(CO)c(N)nc2-c2ccccc2)ccc1=O
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COCc1nc(-c2ccc(=O)n(C(C)C)c2)c(-c2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under ice-bath cooling, NaH (60% pure, 18 mg) was added to a suspension of 5-[5-amino-6-(hydroxymethyl)-3-phenyl-2-pyrazinyl]-1-isopropyl-2(1H)-pyridone (100 mg) in DMF (1.0 ml). After 10 minute stirring, MeI (127 mg) was added to the mixture. After 10 minutes stirring at the same temperature, the mixture was allowed to warm to 25° C. After 3.5 hours stirring, EtOAc and water were poured into the mixture, and the organic layer was separated, washed with water and brine, and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography, triturated with IPE, and dried in vacuo to give 5-[5-amino-6-(methoxymethyl)-3-phenyl-2-pyrazinyl]-1-isopropyl-2(1H)-pyridone (40 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[Cl:27])=[CH:12][C:5]=1[O:6][CH:7]([CH3:11])[C:8](O)=[O:9])([O-:3])=[O:2].S(Cl)([Cl:30])=O>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[Cl:27])=[CH:12][C:5]=1[O:6][CH:7]([CH3:11])[C:8]([Cl:30])=[O:9])([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)O
Solvent: Cc1ccccc1
Product: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)Cl
Temperature: 67 °C

Procedure:
2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]propionic acid (100 grams) and toluene (40 ml) were charged into a glass reaction vessel equipped with a magnetic stirrer. The mixture was heated on a steam bath until a solution was obtained. The solution was allowed to cool and thionyl chloride (100 ml) was added dropwise with stirring. After the addition was completed, the mixture was warmed to 67° C. with continued stirring for a period of about 21/2 hours. After this time the mixture was stripped of solvent in a rotary evaporator under reduced pressure leaving as the residue 105 grams of the desired product, 2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]propionyl chloride as a burgundy colored viscous oil.
Reaction SMILES: O[CH:2]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[N+:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([O-:18])=[O:17].[OH-].[K+].C(O)C>O>[N+:16]([CH:19]([CH:2]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])([O-:18])=[O:17]
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: OC1c2ccccc2Oc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C1c2ccccc2Oc2ccccc21)[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
9-Hydroxyxanthene (9.9 g, 50 mmol) and ethyl nitroacetate (6.1 mL, 55 mol) are mixed and heated at 100° C. (oil bath) for 1.5 hours. After cooling, a waxy mixture is suspended in 40 mL of absolute alcohol and 40 mL of 1.25 M of ethanolic potassium hydroxide solution is added. The solution is stirred for 45 minutes at room temperature and ethanol is stripped off. The remaining solid is suspended in water and extracted with diethyl ether. The aqueous portion is acidified with 85% phosphoric acid to pH 2 to 3 to give a white suspension which is cooled overnight. The precipitate is collected by filtration and dried in a vacuum oven at 50° C. This gives 9.18 g of the title compound as a white solid; mp 89°-91° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17](OC)=[O:18])[N:12]3[C:21]=2[CH:22]=O)=[CH:5][CH:4]=1)#[N:2].[CH3:24][O:25][C:26]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:27]=1[CH2:28][NH2:29].[BH3-]C#N.[Na+].C([O-])(O)=O.[Na+]>CO.C(Cl)Cl>[CH3:24][O:25][C:26]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:27]=1[CH2:28][N:29]1[C:17](=[O:18])[C:13]2[N:12]3[C:21](=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=2)[CH2:22]1
Reactant: COC(=O)c1cccc2nc(-c3ccc(C#N)cc3)c(C=O)n12
Reactant: COc1ccc(CN)c(OC)c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CN2Cc3c(-c4ccc(C#N)cc4)nc4cccc(n34)C2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a solution of (B1) in MeOH (0.2 M), 2,4-dimethoxybenzylamine (1.2 eq.) and Ti(iPrO)4 (2.0 eq.) were added and the reaction mixture was stirred at RT for 2 h. Then, NaBH3CN (1.5 eq.) was added and stirring was continued for 24 h. The solvent was reduced in vacuo and the residue pardoned between sat. aq. NaHCO3 and DCM. The aqueous phase was separated and extracted several times with DCM. The combined organic extracts were washed with brine and dried (Na2SO4). Evaporation of the solvent gave a residue which was purified by flash column on silica using a gradient of EtOAc/Petroleum ether from 50:50 to 70:30 to yield (55%) the title compound as a yellow powder. 1H NMR (600 MHz, DMSO-d6, 330K) δ 7.94 (2H, d, J=8.6 Hz), 7.90 (2H, d, J=8.6 Hz), 7.72 (1H, d, J=9.0 Hz), 7.47 (1H, d, J=7.0 Hz), 7.35 (1H, dd, J=8.4, 7.0 Hz), 7.23 (1H, d, J=8.3 Hz), 6.61 (1H, d, J=2.0 Hz), 6.48 (1H, dd, J=8.3, 2.0 Hz), 5.38 (2H, s), 4.72 (2H, s), 3.86 (3H, s), 3.74 (3H, s). MS (ES+) C25H20N4O3 requires: 424, found: 425 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]([Br:14])[O:9][C:10]2=[O:13])=[CH:6][CH:5]=1)([O-])=O.[C:15]1([P:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)(=O)CC>[Br-:14].[NH2:1][C:4]1[CH:12]=[C:11]2[C:7](=[CH:6][CH:5]=1)[CH:8]([P+:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[O:9][C:10]2=[O:13]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1OC(Br)c2ccc([N+](=O)[O-])cc21
Solvent: CCOC(=O)CC
Product: Nc1ccc2c(c1)C(=O)OC2[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
A solution of 6-nitro-3-bromo-3H-isobenzofuran-1-one (8.7 g, 0.034 mol) in ethyl propionate (464 ml) was heated to 70-75° C., and stirred while 313 ml of an ethyl propionate solution of triphenyl phosphine (36 g, 0.137 mol, 4 eq) were added dropwise over a time of 7 hours. Heating and stirring were continued overnight, and then the mixture was cooled down to room temperature. The precipitate was collected, dried up under vacuum and purified by flash chromatography over silica gel. A gradient of dichloromethane-methanol-acetic acid, from 97-3-0 to 93-5-2 was used as the eluant, to yield 6.2 g of the title compound. [M]+=410; HPLC r.t. 4.72; 1H-NMR (DMSO-d6), diagnostic signals (ppm): 6.01 (br. s, 2H exchangeable with deuterated water), 6.49 (dd, 1H), 6.80 (d, 1H), 6.87 (d, 1H), 7.62-8.00 (m, 15H), 8.17 (s, 1H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[C:6]([C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[C:13](Cl)=[O:14])([CH3:9])([CH3:8])[CH3:7].O.Cl>C1C=CC=CC=1>[CH2:1]([N:3]([CH2:4][CH3:5])[C:13](=[O:14])[C:12]1[CH:11]=[C:10]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:18]([OH:19])=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:16]=1)[CH3:2]
Reactant: CCNCC
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Product: CCN(CC)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
To a solution of 25 milliliters of diethylamine in 50 milliliters of dry benzene was added a solution of 2.0 grams of 3,5-di-t-butyl-4-hydroxybenzoyl chloride in benzene. The resulting mixture was refluxed for 1 hour, cooled, and poured into 100 milliliters of cold water. The excess amine was neutralized with dilute hydrochloric acid; the benzene layer was removed, washed with water, dried, and evaporated, leaving an oil. Addition of a small amount of petroleum ether gave crystals, which were filtered, and recrystallized from heptane, yielding 1.3 grams of N,N-diethyl-3,5-di-t-butyl-4-hydroxybenzamide; melting point 136°-137.5°C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[CH:24](=O)[C:25]1[C:26]([O:31][CH3:32])=[CH:27][CH:28]=[CH:29][CH:30]=1.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])=[N:15][C:14]=2[CH:16]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Reactant: COc1ccccc1C=O
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1-c1nc2cc(-c3nc4ccccc4o3)ccc2n1C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (150 mg, 0.485 mmol) in dimethylformamide (3 mL) was added o-anisaldehyde (79.2 mg, 0.582 mmol) and oxone (179 mg, 0.291 mmol), and this was stirred at room temperature for 2 hours. After the reaction was complete, aqueous potassium carbonate solution was added, and after this was filtered and washed with water, drying yielded the title compound (170 mg, 82% yield) as pale yellow crystals.
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH2:7][OH:8])=[CH:4][N:3]=[CH:2]1.[CH3:9][S:10](Cl)(=[O:12])=[O:11].CCN(CC)CC.O>C(Cl)Cl>[S:1]1[C:5]([CH2:6][CH2:7][O:8][S:10]([CH3:9])(=[O:12])=[O:11])=[CH:4][N:3]=[CH:2]1
Reactant: OCCc1cncs1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCCc1cncs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
At 0° C., to a solution of 2-thiazol-5-yl-ethanol (0.154 g, 1.19 mmol) in CH2Cl2 (10 mL) was added MsCl (0.150 g, 1.31 mmol) and Et3N (0.180 g, 1.79 mmol). The mixture was stirred at room temperature for 1 h. Water (20 mL) was added, and the mixture was extracted with CH2Cl2 (3×30 mL). The extracts were combined and dried over Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (EtOAc), affording methanesulfonic acid 2-thiazol-5-yl-ethyl ester as a pale yellow liquid (0.246 g, 100%). 1H NMR (CDCl3) δ 2.99 (s, 3H), 3.33 (t, 2H, J=6.3 Hz), 4.42 (t, 2H, J=6.3 Hz), 7.73 (s, 1H), 8.74 (s, 1H).