Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:14]([CH2:15][O:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][N:12]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:11][CH:10]2[O:43][CH2:44][C:45]2[CH:54]=[CH:53][C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[CH:46]=2)=[CH:5][CH:4]=1.[CH2:55]([N:62]=[C:63]=[O:64])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>>[CH2:55]([NH:62][C:63]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:14]([CH2:15][O:16][C:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:13][N:12]([C:36]([O:38][C:39]([CH3:42])([CH3:40])[CH3:41])=[O:37])[CH2:11][CH:10]2[O:43][CH2:44][C:45]2[CH:54]=[CH:53][C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[CH:46]=2)=[CH:5][CH:4]=1)=[O:64])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: O=C=NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)C(c2ccc(CO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)C(c2ccc(COC(=O)NCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 24(m), reaction of tert-butyl (3RS,4RS,5SR)-4-(4-hydroxymethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-5-trityloxymethyl-piperidine-1-carboxylate with benzyl isocyanate gave tert-butyl (3RS,4RS,5SR)-4-(4-benzylcarbamoyloxymethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-5-trityloxymethyl-piperidine-1-carboxylate, from which by cleavage of the trityl group by means of a mixture of trifluoroacetic acid and trifluoroacetic anhydride in methylene chloride analogously to Example 86(u) there was obtained tert-butyl (3SR,4RS,5RS)-4-(4-benzylcarbamoyloxymethyl-phenyl)-3-hydroxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate. Subsequent alkylation with methyl iodide analogously to Example 1(g) yielded tert-butyl (3SR,4RS,5RS)-4-[4-[(benzyl-methyl-carbamoyloxy)-methyl]-phenyl]-3-methoxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 656 (M+NH4)+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[CH2:10][N:11]=[C:12]=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][N:18]([CH3:20])[NH2:19].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:17][N:18]([CH3:20])[NH:19][C:12]([NH:11][CH2:10][C:9]1[CH:14]=[CH:15][CH:16]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=1)=[O:13]
Reactant: O=C=NCc1cccc(-c2ccccc2)c1
Reactant: CN(C)N
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN(C)NC(=O)NCc1cccc(-c2ccccc2)c1
Reaction time: 1.5 h
Yield: 42.5 %

Procedure:
To a solution of 2.56 g of this crude 3-phenylbenzylisocyanate in 8 ml of toluene was added dropwise 0.78 g (13 mmol) of N,N-dimethylhydrazine with ice-cooling. The mixture was removed from an ice bath and stirred for 1.5 hours. The reaction mixture was concentrated and the residue was subjected to silica gel column chromatography (eluted with n-hexane:ethyl acetate=1:1 and then 1:2) to obtain 1.40 g (5.20 mmol) of 1,1-dimethyl-4-(3-phenylbenzyl)semicarbazide.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[CH2:3][CH2:4][CH2:5][S:6]([O-:9])(=[O:8])=[O:7].[Na+].C[Si](C)(C)CCCS([O-])(=O)=O>O>[CH3:10][Si:2]([CH3:1])([CH3:11])[CH2:3][CH2:4][CH2:5][S:6]([OH:9])(=[O:8])=[O:7]
Reactant: C[Si](C)(C)CCCS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: C[Si](C)(C)CCCS(=O)(=O)O

Procedure:
A solution of sodium 3-(trimethylsilyl)-1-propanesulfonate (9 grams, 41.2 mmol) dissolved in demineralized water (75 ml) was added drop wise into a short column packed with an excess (15-20 times the molar amount of 3-(trimethylsilyl)-1-propanesulfonate) of Tulsion T-42 MP(H+) acidic ion exchange resin. Then the resin bed was washed with water until the pH of the solution eluting from the column was about 5 to 6. The water solution of the free 3-(trimethylsilyl)-1-propanesulfonic acid thus obtained was neutralized with tetra-n-butylammonium hydroxide until the pH of the solution was about 5 to 5.5. The resulting mixture was extracted with chloroform (three times) and the combined chloroform washes was washed with water (three times). The chloroform layer was separated, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to remove solvent and other volatiles. The residual material was finally dried at 40° C. and 0.1 mm Hg to afford tetra-n-butylammonium 3-(trimethylsilyl)-1-propanesulfonate as a hygroscopic white solid. The yield of the product was 17.4 grams, or 97% of the theoretical amount. Proton NMR spectrum of the compound indicated that it was the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16]S(C(C)(C)C)=O)[C:11]([O:13][CH2:14][CH3:15])=C)=[CH:4][CH:3]=1.[O:30]1CCOCC1>>[NH2:16][C:8]1([C:11]([O:13][CH2:14][CH3:15])=[O:30])[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)[CH2:6][C:7]21[CH2:23][CH2:24][CH:25]([O:28][CH3:29])[CH2:26][CH2:27]2
Reactant: C=C(OCC)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Reactant: C1COCCO1
Product: CCOC(=O)C1(N)c2cc(Br)ccc2CC12CCC(OC)CC2
Yield: 38 %

Procedure:
To solution of compound 5 (100 mg, 0.26 mmol) and Lawesson'reagent (104 mg, 0.26 mmol) in dioxane (3 mL) was heated at 150° C. for 30 min in a microwave reactor. The mixture was cooled, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexanes:EtOAc=20:1) to give compound 7 (30 mg, 38%) as a light orange solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:28][CH2:29][CH:30]([OH:41])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1>>[OH:41][CH:30]([CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[CH2:29][NH:28][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: COc1ccc(OCC(O)CN)cc1
Product: COc1ccc(OCC(O)CNC2CCN(c3ccc(NS(=O)(=O)c4ccc(NC(C)=O)cc4)cc3)CC2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and 1-amino-3-(4-methoxy-phenoxy)-propan-2-ol according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.55–1.75 (m, 2 H), 1.95–2.15 (m, 2 H), 2.06 (s, 3 H), 2.50–3.20 (m, 5 H), 3.85–3.95 (m, 2 H), 4.10–4.20 (m, 1 H), 5.70 (brs, 1 H), 6.80 (d, J=9.0 Hz, 2 H), 6.80–6.95 (m, 6 H), 7.59 (d, J=9.0 Hz, 2 H), 7.69 (d, J=9.0 Hz, 2 H), 10.38 (s, 1 H); MS (ES) m/z: 569.6 (MH+); HRMS Calcd. for C29H37N4O6S (MH+): 569.2434. Found: 569.2418.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[N:22]([CH:24]=[CH:25][CH:26]=3)[CH:23]=2)=[CH:8]1)(C)(C)C.Cl.[Cl:28][CH2:29][CH2:30][N:31]1[CH:35]=[CH:34][N:33]=[CH:32]1>>[ClH:28].[N:31]1([CH2:30][CH2:29][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]4[N:22]([CH:24]=[CH:25][CH:26]=4)[CH:23]=2)=[CH:8][C:7]3=[N:6][OH:5])[CH:35]=[CH:34][N:33]=[CH:32]1
Reactant: CC(C)(C)ON=c1cc(-c2cn3cccc3cn2)oc2ccc(O)cc12
Reactant: ClCCn1ccnc1
Agent: Cl
Product: ON=c1cc(-c2cn3cccc3cn2)oc2ccc(OCCn3ccnc3)cc12

Procedure:
6-(2-Imidazol-1-yl-ethoxy)-2-pyrrolo[1,2-a]pyrazin-3-yl-chromen-4-one oxime, hydrochloride was prepared in 13% overall yield using the method described in example 123, starting from 6-Hydroxy-2-pyrrolo[1,2-a]pyrazin-3-yl-chromen-4-one O-tert-butyl-oxime (example 123B) and 1-(2-Chloro-ethyl)-1H-imidazole hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])OC)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:15]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)([O-:17])=[O:16]>CO>[N+:15]([C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[O:14])=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: COC(=O)Nc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: CO
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)Nc1ccc([N+](=O)[O-])cc1

Procedure:
One proceeds as described in Example 6 with the difference that a distillating column is attached to the flask, the mixture is maintained in gentle boiling and methanol is removed continuously from the mixture. After 2 hours of reaction the end-product is filtered off, 50 mmoles of methyl N-(4-nitrophenyl)-carbamate and 50 mmoles of 4-nitroaniline are added to the filtrate, and the reaction is repeated. The results of four subsequent cycles are summarized in Table 2.
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[CH:9][N:4]2[N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1>ClCCl>[F:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:2]2[S:6][C:5]3=[N:7][CH:8]=[CH:9][N:4]3[N:3]=2)=[CH:13][CH:12]=1
Reactant: Oc1ccc(F)cc1
Reactant: Brc1nn2ccnc2s1
Solvent: ClCCl
Product: Fc1ccc(Oc2nn3ccnc3s2)cc1
Temperature: 135 °C
Yield: 52.9 %

Procedure:
A mixture of 2-bromo-imidazo[2,1-b][1,3,4]thiadiazole (1.0 g, 4.90 mmol) and 4-fluorophenol (2.2 g, 19.60 mmol) was heated under microwave irradiation at 135° C. for 3.5 hours. On cooling, the mixture was diluted with dichloromethane (7 mL), adsorbed in silica and purified by column chromatography (Biotage™/Flash, silica, methanol:dichloromethane 0.2:9.8 to 2:8) to give 2-(4-fluoro-phenoxy)-imidazo[2,1-b][1,3,4]thiadiazole as a white solid (610 mg, 53% yield).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([CH2:17][CH2:18][CH3:19])[C:3]=1[C:20]([NH2:22])=[O:21].[Cl:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32](OC)=O)[CH:27]=[CH:28][C:29]=1[Cl:30].[O-]CC.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Cl:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:31][C:32]1[NH:22][C:20](=[O:21])[C:3]2[C:4]([CH2:17][CH2:18][CH3:19])=[N:5][N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[C:2]=2[N:1]=1
Reactant: CCCCCCC(CCC)n1nc(CCC)c(C(N)=O)c1N
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCC(CCC)n1nc(CCC)c2c(=O)[nH]c(Cc3ccc(Cl)c(Cl)c3)nc21
Yield: 55.1 %

Procedure:
10 mg (0.019 mmol) of 5-amino-3-propyl-1-(4-decyl)-1H-pyrazole-4-carboxamide and 20 mg (0.091 mmol) of methyl 3,4-dichlorophenylacetate are refluxed for 6 hours in 0.3 ml of a 0.5M ethanolic sodium ethoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 5 mg (48%) of a solid, Rf=0.70 (dichloromethane/methanol=15:1).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([NH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)(=[O:36])[CH3:35]
Reactant: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c13)OCO2
Reactant: CC(=O)Cl
Product: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(C)=O)CC4)c[nH]c13)OCO2

Procedure:
Starting from cis-4-[5-(2-methoxy-ethoxy)-benzo[1,3]dioxol-4-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A186) and acetyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][CH2:12][O:13][C:14]1[C:18](=O)[C:16](=[O:17])[C:15]=1[O:20]CC>C(O)C>[CH2:12]([O:13][C:14]1[C:15](=[O:20])[C:16](=[O:17])[C:18]=1[NH:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[CH:8][C:9]=1[OH:10])[CH3:11]
Reactant: N#Cc1cccc(O)c1N
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(Nc2c(O)cccc2C#N)c(=O)c1=O

Procedure:
A solution of 2-amino-3-hydroxybenzonitrile (1.00 g, 0.0075 mol) and diethyl squarate (1.10 ml, 0.0075 mol) in dry ethanol (20 ml) was heated at 85° C. for three days. During the course of the reaction, a tan precipitate forms. The solid is filtered through a Buchner funnel, washed with cold ethanol, adsorbed on silica gel, and flash chromatographed using hexane/ethyl acetate (2:1) as the eluant to give 3-ethoxy-4-(2-hydroxy-6-cyanophenyl)amino-3-cyclobutene-1,2-dione, 0.50 g (0.0019 mol, 26%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH2:28][O:29][CH3:30])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25](=[O:26])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:28][O:29][CH3:30])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(F)cc1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.8 %

Procedure:
A mixture of 4-fluoro-N2-phenylbenzene-1,2-diamine (450 mg, 2.2 mmol), (S)-2-tertbutoxycarbonylamino-3-methoxypropionic acid (525 mg, 2.4 mmol), HOAt (330 mg, 2.4 mmol), 4-methylmorpholine (0.53 mL, 4.8 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (460 mg, 2.4 mmol) in DCM (10 mL) was stirred at RT for 18 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic phase was washed with brine, dried (MgSO4) concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cyclohexane) to afford [(S)-1-(4-fluoro-2-phenylaminophenylcarbamoyl)-2-methoxyethyl]carbamic acid tert-butyl ester (0.655 g, 74%). A solution of the compound thus obtained (0.655 g) in AcOH (10 mL) was heated at 70° C. for 56 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cyclohexane) to afford the title compound (227 mg, 28%). LCMS (Method J): RT 3.59 and 3.70 min [M+H]+ 386.2
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[C:25]([N+:26]([O-])=O)=[C:24]([CH3:29])[CH:23]=[CH:22][N:21]=2)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1COCC1.[Zn]>[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[C:25]([NH2:26])=[C:24]([CH3:29])[CH:23]=[CH:22][N:21]=2)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1ccnc(Nc2ccc(OCc3ccccc3)cc2)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1ccnc(Nc2ccc(OCc3ccccc3)cc2)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a mixture of zinc (40.2 g), THF (50 ml) and acetic acid (100 ml) was added slowly a solution of N-[4-(benzyloxy)phenyl]-4-methyl-3-nitropyridin-2-amine (13.75 g) in THF (150 ml), and the obtained mixture was stirred at room temperature for 30 min. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with 1 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate) and recrystallized from hexane/ethyl acetate to give the title compound (8.77 g).
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].C(N(CC)CC)C.Cl.[CH3:14][NH:15][C:16]1[CH:58]=[CH:57][C:19]([O:20][CH2:21][C:22]([NH:24][C@H:25]([C:30]([NH:32][C@@H:33]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C@H:34]([OH:49])[C:35]([N:37]2[CH2:48][CH2:47][CH2:46][C@H:38]2[C:39]([NH:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:36])=[O:31])[CH2:26][C:27](=[O:29])[NH2:28])=[O:23])=[CH:18][CH:17]=1.Cl>CN(C)C=O>[Br:1][CH2:2][C:3]([N:15]([C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]([NH:24][C@H:25]([C:30]([NH:32][C@@H:33]([CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[C@H:34]([OH:49])[C:35]([N:37]2[CH2:48][CH2:47][CH2:46][C@H:38]2[C:39]([NH:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:36])=[O:31])[CH2:26][C:27](=[O:29])[NH2:28])=[O:23])=[CH:57][CH:58]=1)[CH3:14])=[O:4]
Reactant: CNc1ccc(OCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc2ccccc2)[C@H](O)C(=O)N2CCC[C@H]2C(=O)NC(C)(C)C)cc1
Reactant: O=C(Cl)CBr
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C(=O)CBr)c1ccc(OCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc2ccccc2)[C@H](O)C(=O)N2CCC[C@H]2C(=O)NC(C)(C)C)cc1
Reaction time: 24 h
Yield: 68.5 %

Procedure:
0.59 ml (7.2 mmol) of bromoacetyl chloride and 1.6 ml (11.7 mmol) of triethylamine were added, whilst ice-cooling, to a solution of 3.0 g (4.5 mmol) of 1-[(2S,3S)-3-{N2 -[4-(methylamino)phenoxyacetyl]-L-asparaginyl}amino-2-hydroxy-4-phenylbutyryl]-N-t-butyl-L-prolinamide hydrochloride (prepared as described in Example 20) in 10 ml of dimethylformamide, and the resulting mixture was stirred for 1 day. At the end of this time, the reaction mixture was neutralized by the addition of 1N aqueous hydrochloric acid. It was then concentrated by evaporation under reduced pressure, and the concentrate was diluted with ethyl acetate. The resulting diluted solution was washed with 1N aqueous hydrochloric acid, with a 5% w/v aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. It was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography, using a 1:15 by volume mixture of methanol and methylene chloride as the eluent, to give 2.3 g of the title compound as a colorless powder, melting at 116°-122° C.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[N:18]=[C:17]2[C:13]([NH:14][C:15](=[O:40])[N:16]2[C:19]2[CH:24]=[C:23]([O:25][CH2:26][C:27]3[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[C:29]([F:35])[C:28]=3[F:36])[C:22]([O:37][CH3:38])=[CH:21][C:20]=2[Cl:39])=[C:12]([O:41][CH3:42])[N:11]=1)=O)(C)(C)C.Cl.C(OCC)C>O1CCCC1>[ClH:39].[NH2:8][CH2:9][C:10]1[N:18]=[C:17]2[C:13]([NH:14][C:15](=[O:40])[N:16]2[C:19]2[CH:24]=[C:23]([O:25][CH2:26][C:27]3[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[C:29]([F:35])[C:28]=3[F:36])[C:22]([O:37][CH3:38])=[CH:21][C:20]=2[Cl:39])=[C:12]([O:41][CH3:42])[N:11]=1
Reactant: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(CNC(=O)OC(C)(C)C)nc32)cc1OCc1c(OC)ccc(F)c1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(CN)nc32)cc1OCc1c(OC)ccc(F)c1F
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a solution of 2-(tert-butoxycarbonylaminomethyl)-9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-6-methoxy-7,9-dihydro-8H-purin-8-one (36 mg) in tetrahydrofuran (1 mL) was added hydrochloric acid (4 mol/L ethyl acetate solution, 2 mL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour, and then stirred at room temperature for 3 hours. To the reaction mixture was added diethyl ether, and the insoluble material was collected by filtration. The collected material was washed with diethyl ether, and dried under reduced pressure to give the title compound (14 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:11][OH:12])(C)[CH2:7][C:6]=2[CH:13]=1.C(N(CC)CC)C.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:21]([O:12][CH2:11][CH:8]1[CH2:7][C:6]2[CH:13]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:9]1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(CO)Cc2cc(F)ccc2O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC1Cc2cc(F)ccc2O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 105.1 %

Procedure:
To an ice cold solution of (5-fluoro-2-methyl-2,3-dihydrobenzofuran-2-yl)methanol (854) (0.530 g, 3.15 mmol) in DCM (3.2 mL) was added triethylamine (0.878 mL, 6.3 mmol), DMAP (0.077 g, 0.63 mmol) and acetic anhydride (0.222 mL, 2.4 mmol). The solution was stirred at 0° C. for 2 h. The layers were separated and washed with water (2×5 mL), 1N HCl (5 mL), brine (100 mL) and dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (0-10% EtOAc in hexanes) to provide the desired (5-fluoro-2,3-dihydrobenzofuran-2-yl)methyl acetate (866) (0.530 g, 80.0%) as a colorless oil.
Reaction SMILES: [CH:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][C:10]([NH:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([O-:18])=[O:17])=[S:11])=[CH:6][C:5]=1[CH3:24])([CH3:3])[CH3:2].[I-].[Li+]>N1C=CC=CC=1>[CH:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][C:10]([NH:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=[O:17])=[S:11])=[CH:6][C:5]=1[CH3:24])([CH3:3])[CH3:2]
Reactant: Cc1cc(OCC(=S)Nc2cccc(C(=O)[O-])c2)ccc1C(C)C
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: Cc1cc(OCC(=S)Nc2cccc(C(=O)O)c2)ccc1C(C)C
Yield: 45.7 %

Procedure:
A solution of 3-[2-(4-isopropyl-3-methyl-phenoxy)thioacetylamino]benzoate (0.50 g, 1.4 mmol) in pyridine (15 mL) was treated with anhydrous lithium iodide (1.87 g), and the resulting mixture was heated to reflux for 10 h. The solution was cooled and evaporated, and the residue was partitioned between 1 N aqueous HCl and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The residual solid was purified by column chromatography to afford the title product (0.22 g, 0.64 mmol, 46%). m.p. 174–176° C. 1H NMR (CDCl3, 300 MHz): δ 9.84 (1H, br s), 8.39 (1H, t, J=2 Hz), 8.28 (1H, ddd, J=8, 2, 1 Hz), 8.00 (1H, dt, J=8, 2 Hz), 7.55 (1H, t, J=8 Hz), 7.19 (1H, d, J=8 Hz), 6.83–6.77 (2H, m), 4.97 (2H, s), 3.03 (1H, m, J=7 Hz), 2.32 (3H, s), 1.20 (6H, d, J=7 Hz). Mass spectrum (ES−): m/z 342. Elemental analysis: calculated for C19H21NO3S C, 66.45; H, 6.16; N, 4.08. observed C, 66.71; H, 6.65; N, 4.02.
Reaction SMILES: [CH3:1][C:2]([C@@:4]1([OH:29])[CH2:27][C@H:26]([OH:28])[C:7]2=[C:8]([OH:25])[C:9]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]=4[O:23]C)[C:13](=[O:14])[C:10]=3[C:11]([OH:12])=[C:6]2[CH2:5]1)=[O:3].[Cl-].[Cl-].[Cl-].[Al+3].C(O)(=O)C(O)=O>ClCCl>[CH3:1][C:2]([C@:4]1([OH:29])[CH2:5][C:6]2[C:7](=[C:8]([OH:25])[C:9]3[C:21](=[O:22])[C:20]4[C:19]([OH:23])=[CH:18][CH:17]=[CH:16][C:15]=4[C:13](=[O:14])[C:10]=3[C:11]=2[OH:12])[C@@H:26]([OH:28])[CH2:27]1)=[O:3]
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(C)=O)C[C@@H]3O
Agent: O=C(O)C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)[C@]1(O)Cc2c(O)c3c(c(O)c2[C@@H](O)C1)C(=O)c1c(O)cccc1C3=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a refluxed solution of 10 g. of daunomycinone (II) in 1 liter of dichloromethane, 30 g. of aluminum trichloride were added over a two hour period with stirring. After an additional 4 hour period, the reaction mixture was cooled and poured into ice water containing 150 g. of oxalic acid. The organic layer was separated, washed with water and concentrated in vacuo to yield 6 g. of crystalline 4-demethoxy-4-hydroxy-daunomycinone (III), which were collected by filtration.