Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[N:19]4[N:20]=[C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[C:25](Br)[CH:24]=5)[CH:22]=[C:18]4[N:17]=[C:16]([CH3:30])[C:15]=3[C@H:31]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:32]([O:34][CH3:35])=[O:33])[CH:12]=2)[O:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].[OH:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[N:19]4[N:20]=[C:21]([C:23]5[CH:24]=[C:25]([C:43]6[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=6[OH:41])[CH:26]=[CH:27][CH:28]=5)[CH:22]=[C:18]4[N:17]=[C:16]([CH3:30])[C:15]=3[C@H:31]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:32]([O:34][CH3:35])=[O:33])[CH:12]=2)[O:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1CCOc2ccc(-c3c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc4cc(-c5cccc(Br)c5)nn34)cc21
Reactant: OB(O)c1ccccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC1CCOc2ccc(-c3c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc4cc(-c5cccc(-c6ccccc6O)c5)nn34)cc21
Reaction time: 1.5 h
Yield: 80.5 %

Procedure:
A solution of ((2S)-methyl 2-(7-(4-allylchroman-6-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.430 g, 0.711 mmol), (2-hydroxyphenyl)boronic acid (0.196 g, 1.423 mmol) and 2.0 M aq. Na2CO3 (1.1 ml, 2.1 mmol) in DMF (7 ml) was sparged with nitrogen for 10 min, treated with Pd(Ph3P)4 (0.058 g, 0.050 mmol), then sparged for 5 min. The reaction was stirred for 90 min, then cooled, diluted with water (20 mL) and extracted into Et2O (2×50 mL). The combined extracts were dried (MgSO4), filtered, and concentrated and the residue was purified by biotage (24 g SiO2, 0% (3 CV), 0-60% (15 CV), 60% (2 CV), EtOAc in hexanes) to afford the desired product (0.360 g, 0.572 mmol, 80% yield) as a pale yellow glassy solid. 1H NMR (500 MHz, CDCl3) δ: 8.07-7.89 (m, 2H), 7.70 (s, 1H), 7.60-7.49 (m, 2H), 7.49-7.36 (m, 2H), 7.34-7.29 (m, 2H), 7.07-6.97 (m, 3H), 6.95-6.90 (m, 1H), 5.96-5.71 (m, 1H), 5.37-5.19 (m, 2H), 5.16-4.97 (m, 2H), 4.39-4.25 (m, 2H), 3.88-3.79 (m, 3H), 3.12-2.88 (m, 1H), 2.72-2.63 (m, 3H), 2.61-2.32 (m, 1H), 2.22-2.08 (m, 1H), 2.02-1.88 (m, 1H), 1.06-0.92 (m, 9H). LCMS (M+H)=618.5.
Reaction SMILES: O[C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:64]=[N+:65]=[N-:66])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[N:64]([C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:3]1)=[N+:65]=[N-:66]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 76.7 %

Procedure:
To a stirred mixture of tert-butyl (2S,4R)-4-hydroxy-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate (3.00 g, 11.6 mmol, step 2 of Example 9) in tetrahydrofuran (50 mL) were added triphenylphosphine (4.55 g, 17.4 mmol) and diethyl azodicarboxylate solution (50% in toluene, 7.56 mL, 17.36 mmol) at room temperature. After stirring for 15 min, diphenyl phosphoryl azide (3.74 mL, 17.36 mmol) was added to the mixture. The resulting mixture was stirred at room temperature for 40 h and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (4:1) to give 2.53 g (77%) of the title compound as a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:8][CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:9]1[N:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cnc1C(=O)OCC
Product: CCOC(=O)c1cc([N+](=O)[O-])c(Cl)nc1C(=O)OCC
Temperature: 60 °C

Procedure:
100 g (0.352 mol) of diethyl 5-nitropyridine-2,3-dicarboxylate were added to 500 ml of phosphoryl chloride in the course of 15 minutes with stirring at 60° C., heated to reflux and stirred for 1 1/2 hours. After cooling, the reaction mixture was concentrated under reduced pressure and the residue dissolved again in methylene chloride. After stirring with ice-water, the aqueous phase was washed again with methylene chloride and the organic extracts were then washed in succession with water, saturated sodium hydrogencarbonate and sodium chloride solution and dried over magnesium sulfate. After filtering off with suction through neutral alumina and concentrating, 68.8 g (64.6% of theory) of the title compound of m.p. 70°-72° C. were obtained. (Not claimed according to the invention)
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[N:12][CH:13]=2)[CH2:3]1.[C:16]([C:19]1[CH:20]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1)(=[O:18])[CH3:17].C(N(C(C)C)CC)(C)C>ClCCl>[C:16]([C:19]1[CH:20]=[C:21]([S:25]([N:7]2[CH2:6][CH2:5][N:4]([C:8]3[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[N:12][CH:13]=3)[CH2:3][C@H:2]2[CH3:1])(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1)(=[O:18])[CH3:17]
Reactant: C[C@@H]1CN(c2ccc(C#N)nc2)CCN1
Reactant: CC(=O)c1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1cccc(S(=O)(=O)N2CCN(c3ccc(C#N)nc3)C[C@H]2C)c1
Temperature: 25 °C
Yield: 80.3 %

Procedure:
To a stirred solution of 5-[(3R)-3-methylpiperazin-1-yl]pyridine-2-carbonitrile (250 mg, 1.24 mmol) and 3-acetylbenzenesulfonyl chloride (270.3 mg, 1.24 mmol) in anhydrous dichloromethane (4 mL) was added diisopropylethylamine (0.43 mL, 2.48 mmol). The mixture was stirred at room temperature for over night. Reaction was complete as determined by TLC. The reaction mixture was purified via flash column chromatography to yield 5-{(3R)-4-[(3-acetylphenyl)sulfonyl]-3-methylpiperazin-1-yl}pyridine-2-carbonitrile in 80.3% yield (383 mg) as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(O[C@@H:29]1[O:46][CH2:45][C@@H:40]([O:41][C:42](=[O:44])[CH3:43])[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:30]1[O:31][C:32](=[O:34])[CH3:33])(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[Br:1][C:2]1[N:3]([C@@H:45]2[O:46][CH2:29][C@@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:40]2[O:41][C:42](=[O:44])[CH3:43])[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: CC(=O)O[C@@H]1OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: Clc1cc2nc(Br)[nH]c2cc1Cl
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1c(Br)nc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Yield: 56 %

Procedure:
2-Bromo-5,6-dichlorobenzimidazole (4.0 g, 15 mmol), N,O-bis(trimethylsiyl)acetamide (Aldrich, 3.7 mL, 15 mmol), and 1,2-dichloroethane (Aldrich Sure Seal, 75 mL) were combined and refluxed under nitrogen for 0.5 h. The solution was cooled to room temperature and trimethylsilyl triflate (Aldrich, 3.2 ml, 16 mmol) was added. Immediately, 4.8 g (15 mmol) solid 1,2,3,4-tetra-O-acetyl-b-D-ribopyranose (beta-D-ribopyranose 1,2,3,4-tetraacetate, Aldrich, Milwaukee) was added. The solution was stirred under nitrogen at reflux for 0.5 h, then poured into 7% aqueous sodium bicarbonate and extracted with dichloromethane. The organic layers was dried with magnesium sulfate (anhyd.), filtered, and evaporated. The crude residue was purified on a silica gel column (5×20 cm, 230-400 mesh) with CH2Cl2 to give 2-bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl-β-D-ribopyranosyl)-1H-benzimidazole which was fractionated in two parts based on elution. The faster product fraction was impure (1.9 g) and purified by a second column to give 1.4 g (2.7 mmol); the slower product fraction was (3.0 g, 5.7 mmol) for a total yield of 56%; m.p. 100-110° C.; 1H NMR (DMSO-d6) δ 8.39 (s, 1H), 7.91 (s, 1H), 5.95-5.92 (d, 1H, J=9.6 Hz), 5.73-5.70 (d, 1H, J=9.6 Hz), 5.67 (bs, 2H), 4.13-4.09 (dd, 1H, J=6.3 Hz and J=5.8 Hz), 4.00-3.95 (overlapping dd, 1H), 2.19 (s, 3H), 1.98 (s, 3H), 1.74 (s, 3H).
Reaction SMILES: [N+](C(C)C)([O-])=[O:2].C[O-].[Na+].[C:10]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][C:15]=1[O:22][CH3:23])([O:12][CH3:13])=[O:11]>CO>[C:10]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:2])=[CH:16][C:15]=1[O:22][CH3:23])([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1ccc(CBr)cc1OC
Reactant: CC(C)[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(C=O)cc1OC
Yield: 83 %

Procedure:
2-Nitropropane (1.0 g) was added to sodium methoxide (from 0.24 g sodium) in methanol (30 ml) and the solution refluxed for 1/2 hour. 4-Carbomethoxy-3-methoxybenzyl bromide (2.67 g) in methanol was added and the solution refluxed for 1 hour. The methanol was evaporated, the residue partitioned between 2N sodium hydroxide and chloroform. The chloroform layer was shaken with further sodium hydroxide until no more yellow colour was extracted, dried and evaporated to yield the title compound (1.66 g). τ(CDCl3) 6.1 (3H, s), 6.05 (3H, s), 2.4-2.6 (2H, m), 2.07 (1H, d, J=8 Hz), -0.05 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=[O:15])[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][C:19](F)=[CH:18][C:17]=2[F:24])=[CH:4][CH:3]=1.[CH3:25][O-:26].[Na+].CO>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=[O:15])[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][C:19]([O:26][CH3:25])=[CH:18][C:17]=2[F:24])=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Cc1n[nH]c(=O)c(-c2c(F)cc(F)cc2F)c1-c1ccc(Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(F)c(-c2c(-c3ccc(Cl)cc3)c(C)n[nH]c2=O)c(F)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 69.1 %

Procedure:
0.35 g of 5-(4-chlorophenyl)-6-methyl-4-(2,4,6-trifluorophenyl)-2H-pyridazin-3-one, 0.96 g of sodium methoxide (28% methanol solution) and 6 ml of methanol were mixed and stirred for 14 hours under reflux with heating. Next, to the reaction mixture was added 0.96 g of sodium methoxide (28% methanol solution), and stirred for 9 hours under reflux with heating. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with water, and dried over anhydrous magnesium sulfate, then; concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent: hexane+tert-butyl methyl ether), to obtain 0.25 g of 5-(4-chlorophenyl)-4-(2,6-difluoro-4-methoxyphenyl)-6-methyl-2H-pyridazin-3-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([OH:16])=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:16]
Reactant: C1COCCN1
Reactant: COc1ccc2[nH]c(C)c(CC(=O)O)c2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(C)c(CC(=O)N3CCOCC3)c2c1
Reaction time: 2 h
Yield: 67 %

Procedure:
To 5-methoxy-2-methyl-3-indoleacetic acid (0.665g; 3.03 mmol) in 6 mL of THF was added DCC (0.661 g; 3.2 mmol). After 2 h of stirring, morpholine (1 mL; 11.4 mmol) was added and stirred for another 1 h. The reaction mixture was filtered and the solvent removed. Chromatography on silica gel (eluted with EtOAc) yielded 0.585 g (64%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1Br.[C:21]([NH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)(=[O:23])[CH3:22]>CN(C)P(=O)(N(C)C)N(C)C>[F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[N:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:21](=[O:23])[CH3:22])[CH2:26][CH2:27]1
Reactant: CC1CCc2c(Br)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: CC(=O)NC1CCNCC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(=O)NC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2CCC4C)CC1
Temperature: 150 °C
Yield: 19.9 %

Procedure:
A mixture of 3.5 g of 9-fluoro-8-bromo-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 6 g of 4-acetylaminopiperidine and 30 ml of hexamethylphosphoric triamide was heated at 150° C. for 4 hours. After completion of reaction, hexamethylphosphoric triamide was distilled off under reduced pressure, and the residue was recrystallized from dimethylformamide-water. Crystals which formed were again recrystallized from dimethylformamide to give 0.82 g of 9-fluoro-8-(4-acetylamino-1-piperidyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. m.p. 274°-277° C., white rhombic crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)=[O:5])[CH3:2].[Cl:16][C:17]1[CH:18]=[C:19]([CH:29]=[CH:30][C:31]=1[Cl:32])[O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClC(Cl)C>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:10]=[CH:11][C:12]([NH:15][CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[C:21]([O:20][C:19]3[CH:29]=[CH:30][C:31]([Cl:32])=[C:17]([Cl:16])[CH:18]=3)[CH:22]=2)=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: O=Cc1cccc(Oc2ccc(Cl)c(Cl)c2)c1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(NCc2cccc(Oc3ccc(Cl)c(Cl)c3)c2)cc1
Reaction time: 12 h
Yield: 85.8 %

Procedure:
To a mixture of (+)-(trans)-ethyl-2-(4-aminophenyl)cyclopropanecarboxylate (III-1b) (0.099 g, 0.482 mmol) in dichloroethane (3.0 mL) was added 3-(3,4-dichlorophenoxy)benzaldehyde (0.116 g, 0.434 mmol). The mixture was stirred for 12 h followed by addition of sodium triacetoxyborohydride (0.140 g, 0.660 mmol). The mixture was stirred for 6 h at RT. Water was added (10 mL), and the layers were separated. The aqueous phase was extracted with CH2Cl2 (2×10 mL). The combined organics were dried with MgSO4 and concentrated. The crude material was purified by chromatography (EtOAc/hexanes) to give the title compound (0.17 g, 85%, mixture of ethyl and methyl ester). 1H NMR (400 MHz, CDCl3) δ 7.35-7.31 (m, 2H), 7.14 (d, J=7.5 Hz, 1H), 7.05-7.00 (m, 2H), 6.92-6.87 (m, 3H), 6.81 (dd, J=8.8 Hz, 2.7 Hz, 1H), 6.52 (d, J=8.4 Hz, 2H), 4.31 (s, 2H), 4.14 (q, J=7.1 Hz, 2H), 2.42 (m, 1H), 1.77 (m, 1H), 1.51 (m, 1H), 1.28-1.20 (t+m, 4H).
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH2:10][CH2:11][C@@H:12]2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=2)[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:32][CH2:33][O:34]C)[CH:4]=[CH:5]2.O.[C:37](O)(=O)C>>[C:33]([O:32][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:18]([CH3:19])[CH2:17][CH2:16][C@:14]45[C:15]=2[C:2]=1[O:1][C@H:13]4[C@@H:12]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=1)[CH2:11][CH2:10][C@@H:9]35)(=[O:34])[CH3:37]
Reactant: CC(=O)O
Reactant: COCOc1ccc2c3c1O[C@H]1[C@@H](OCc4ccc(C(=O)OC)cc4)CC[C@H]4[C@@H](C2)N(C)CC[C@@]341
Solvent: O
Product: COC(=O)c1ccc(CO[C@H]2CC[C@H]3[C@H]4Cc5ccc(OC(C)=O)c6c5[C@@]3(CCN4C)[C@H]2O6)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
4,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-((4-(methyloxycarbonyl)-phenyl)-methoxy)-morphinane (1.40 g, 2.92 mmol) is dissolved with water (35 ml) and glacial acetic acid (35 ml) and then stirred for 4 hours at 100° C. The volatile components are eliminated using the Rotavapor. The residue thus obtained is purified by flash chromatography (100 g of silica gel; mobile phase: methylene chloride/methanol= 4:1). The product is dissolved in a mixture of water and glacial acetic acid and lyophilised. Yield: 1.225 g 4,5α-epoxy-17-methyl-6α-((4-(methyloxycarbonyl)-phenyl)-methoxy)-morphinan-3-ol acetate (84.7%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][CH2:26][CH3:27])[C@@H:17]([O:18]C(=O)C)[C@H:12]2[O:13]C(=O)C)=[C:4](Cl)[N:3]=1.[I:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][NH2:34].Cl>>[I:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][NH:34][C:4]1[C:5]2[N:6]=[CH:7][N:8]([C:9]=2[N:10]=[C:2]([Cl:1])[N:3]=1)[C@@H:11]1[O:23][C@H:22]([CH2:24][O:25][CH2:26][CH3:27])[C@@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: NCc1cccc(I)c1
Reactant: CCOC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Product: CCOC[C@H]1O[C@@H](n2cnc3c(NCc4cccc(I)c4)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
Method B. The reaction was carried out with 2,6-dichloro-9-(2,3-di-O-acetyl-5-O-ethyl-β-D-ribofuranosyl)-purine (63, 375 mg, 0.87 mmol) and 3-iodobenzylamine.HCl (1.31 mmol, 352 mg). The mixture was purified by column chromatography (eluens 5% MeOH in CH2Cl2). Yield 366 mg (0.67 mmol, 77%), mp 80–82° C.; Rf 0.53 (10% MeOH in CH2Cl2); 1H NMR (DMSO-d6) δ 8.97 (bs, 1H, NH), 8.40 (s, 1H, H-8), 7.74 (s, 1H, CCHCI), 7.60 (d, 1H, J=6.87 Hz, CCHCHCH), 7.35 (d, 1H, J=8.24 Hz, CCHCH), 7.12 (t, 1H, J=7.21 Hz, CCHCH), 5.84 (d, 1H, =4.46 Hz, H-1′), 5.56 (d, 1H, J=5.49 Hz, OH-2′), 5.30 (d, 1H, J=5.15 Hz, OH-3′), 4.60 (d, 2H, J=4.46 Hz, NHCH2), 4.51 (d, 1H, J=5.15 Hz, H-2′), 4.14–4.11 (m, 1H, H-3′), 4.02 (q, 1H, J=3.43 Hz, H-4′), 3.63–3.58 (m, 2H, H-5′), 3.49 (q, 2H, J=6.52 Hz, CH2CH3), 1.13 (t, 3H, J=6.52 Hz, CH3); MS m/z 546 (+H)+; Anal. (C19H21ClIN5O4.0.8 HCON(CH3)2) C, H, N.
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=O)C.Cl.[CH2:16](O)[CH3:17]>>[NH2:4][C:5]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH2:16][CH3:17])=[O:8]
Reactant: CCO
Reactant: CC(=O)Nc1cc(Br)ccc1C(=O)O
Agent: Cl
Product: CCOC(=O)c1ccc(Br)cc1N
Temperature: 25 °C
Yield: 21 %

Procedure:
A solution of 119 g (0.461 mol) of 2-acetylamino-4-bromobenzoic acid and 3 liters of absolute ethanol was cooled to 0° C. and was then saturated with a stream of dry hydrogen chloride gas. The solution was then heated under reflux for 24 hours. Upon cooling to room temperature, the solution was evaporated to about 750 ml and then poured into 2 liters of aqueous saturated sodium bicarbonate. The aqueous phase was extracted three times with 300 ml portions of chloroform. The combined extracts were dried over anhydrous sodium sulfate, filtered, and evaporated to afford 23.8 g (21%) of ethyl 2-amino-4-bromobenzoate as an oil: ir(CHCl3) 3504 cm, 3390, 1685, 1610, 1580 among others; 1H-NMR(CDCl3) 1.3 ppm (triplet, 3H, CH2CH3), 4.3 (quartet, 2H, CH2CH3), 5.8 (broad singlet, 2H, NH2), 6.6 [doublet (part of AB pattern), 1 H, aromatic H], 6.8 (singlet, 1H, aromatic H), 7.7 [doublet (part of AB pattern), 1H, aromatic H].
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]([NH:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:14]C)=[O:5].[CH2:16]([O:19]C1C=C(C)C(=C(C)C=1)N)[CH2:17][CH3:18].C(O)(=O)C.O.O.O.C([O-])(=O)C.[Na+]>O>[Br:1][CH2:2][CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:14])=[CH:9][C:10]([O:19][CH2:16][CH2:17][CH3:18])=[CH:11][C:12]=1[CH3:13])=[O:5]
Reactant: CCc1cccc(C)c1NC(=O)CCBr
Reactant: CCCOc1cc(C)c(N)c(C)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCOc1cc(C)c(NC(=O)CCBr)c(C)c1
Yield: 93 %

Procedure:
This compound was prepared analogously to 3-bromo-2'-ethyl-6'-methylpropionanilide of Example 11A from 20 g 4-propoxy-2, 6-xylidine, 95 ml glacial acetic acid, 37 g sodium acetate trihydrate, 150 ml water 21.2 g 3-bromopropionyl bromide. The yield was 93% of recrystallized (methanol:water) material melting at 121.5°-122.5° C.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:19]([O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)([CH3:21])[CH3:20]>>[CH:19]([O:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)=[CH:25][CH:24]=1)([CH3:21])[CH3:20]
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: CC(C)Oc1ccc(N)cc1
Product: CC(C)Oc1ccc(NC(=O)c2cccc(S(=O)(=O)N3CCCCC3)c2)cc1

Procedure:
The entitled compound was produced according to the method of Example 73 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 4-isopropoxyaniline as the starting materials.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[C:19]1(B(O)O)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:27]2[C:28]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:24]=[CH:25][CH:26]=2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Reactant: OB(O)c1cccc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(CC1CCCC1)c1ccc(-c2cccc3ccccc23)cc1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (3.87 g, 10.81 mmol), 1-naphthaleneboronic acid (2.79 g, 16.22 mmol), triethylamine (4.5 mL, 32.44 mmol), palladium (II) acetate (72.8 mg, 0.324 mmol), and tri-o-tolylphosphine (204.1 mg, 0.670 mmol) in dry N,N-dimethylformamide (43 mL) was heated at 100° C. under nitrogen for 1 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove N,N-dimethylformamide. The residue was diluted with ethyl acetate (200 mL). The organic phase was washed with a saturated aqueous sodium bicarbonate solution (1×100 mL) and water (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 19/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propionic acid methyl ester (3.51 g, 90%) as a yellow oil: EI-HRMS m/e calcd for C25H26O2 (M+) 358.1933, found 358.1930.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:14]=O)=[N:4][CH:5]=[C:6]([N:8]([CH3:13])[CH:9]([CH3:12])[CH2:10][CH3:11])[N:7]=1.[CH2:16]([NH:23][CH2:24][C@@H:25]([OH:29])[CH2:26][O:27][CH3:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:16]([N:23]([CH2:14][C:3]1[C:2]([Cl:1])=[N:7][C:6]([N:8]([CH3:13])[CH:9]([CH3:12])[CH2:10][CH3:11])=[CH:5][N:4]=1)[CH2:24][C@@H:25]([OH:29])[CH2:26][O:27][CH3:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCC(C)N(C)c1cnc(C=O)c(Cl)n1
Reactant: COC[C@H](O)CNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCC(C)N(C)c1cnc(CN(Cc2ccccc2)C[C@@H](O)COC)c(Cl)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
To a solution of 3-chloro-5-[methyl(1-methylpropyl)amino]pyrazine-2-carbaldehyde (342 mg), (2R)-1-(benzylamino)-3-methoxypropan-2-ol (351 mg) and acetic acid (258 μL) in acetonitrile (5 mL) was added sodium triacetoxyborohydride (477 mg), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added dropwise saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 10→50% ethyl acetate/hexane) to give the title compound (389 mg, 64%).