Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH2:10].[C:11](N1C=CN=C1)([N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)=[S:12]>C(#N)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)=[S:12]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc2ccccc2[nH]1
Solvent: CC#N
Product: S=C(Nc1nc2ccccc2[nH]1)n1ccnc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
To 1H-benzo[d]imidazol-2-amine (1.28 g, 9.61 mmol) in acetonitrile (30 mL) was added 1,1′-thiocarbonyldiimidazole (2.227 g, 12.5 mmol). The reaction mixture was stirred at 50° C. for 18 hours. The reaction was cooled to room temperature and the precipitate was filtered and washed with acetonitrile (2×50 mL). The yellow powder was dried in a vacuum oven (40° C.) for 1 hour to yield N—(1H-benzo[d]imidazol-2-yl)-1H-imidazole-1-carbothioamide (1.8 g, 7.4 mmol, 77% yield) and then used in the next step without any further purification or characterization.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C@H:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16]([C@:18]34[CH2:44][CH2:43][C@@H:42]([C:45]([CH3:47])=[CH2:46])[C@@H:19]3[C@@H:20]3[C@@:33]([CH3:36])([CH2:34][CH2:35]4)[C@@:32]4([CH3:37])[C@@H:23]([C@:24]5([CH3:41])[C@@H:29]([CH2:30][CH2:31]4)[C:28]([CH3:39])([CH3:38])[C@@H:27]([OH:40])[CH2:26][CH2:25]5)[CH2:22][CH2:21]3)=[O:17])[CH2:11]2)[CH2:5][CH2:4]1)[CH3:2].N1C=CC=CC=1.[CH3:54][C:55]1([CH3:62])[CH2:59][C:58](=[O:60])[O:57][C:56]1=[O:61]>C(OCC)(=O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C@H:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16]([C@:18]34[CH2:44][CH2:43][C@@H:42]([C:45]([CH3:47])=[CH2:46])[C@@H:19]3[C@@H:20]3[C@@:33]([CH3:36])([CH2:34][CH2:35]4)[C@@:32]4([CH3:37])[C@@H:23]([C@:24]5([CH3:41])[C@@H:29]([CH2:30][CH2:31]4)[C:28]([CH3:38])([CH3:39])[C@@H:27]([O:40][C:58](=[O:60])[CH2:59][C:55]([CH3:62])([CH3:54])[C:56]([OH:61])=[O:57])[CH2:26][CH2:25]5)[CH2:22][CH2:21]3)=[O:17])[CH2:11]2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCN(CC)CC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC1(C)CC(=O)OC1=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCN(CC)CC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-N-((1R,3S)-3-((4-ethylpiperazin-1-yl)methyl)cyclopentyl)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxamide (Example 35, 0.24 mmol) in pyridine (5 ml) dimethyl amino pyridine (0.32 g, 0.48 mmol) and 3,3-dimethyldihydrofuran-2,5-dione (1.3 ml) were added and the contents were refluxed for about 16 hours and completion of the reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate (30 ml). The organic layer was washed with 5% aqueous HCl, washed with water followed by brine solution, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.1 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.80-0.95 (m, 16H) 1.23-1.90 (m, 41H); 2.03-3.08 (m, 16H), 4.13-4.18 (m, 1H), 4.46 (s, 1H), 4.58 (s, 1H), 4.72 (s, 1H); 5.61-5.63 (m, 1H); ES Mass: [M+1] 778 (100%); HPLC: 78.4%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)=[O:20].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:18][C:19]([N:21]2[CH2:22][CH2:23][N:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:25][CH2:26]2)=[O:20])[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: CCOC(=O)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(CC(=O)N2CCN(c3ccc(F)cc3)CC2)c1

Procedure:
Protocol T was followed using 1H-Pyrazole-4-carboxylic acid ethyl ester, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 8.2 (s, 1H), 7.92 (s, 1H), 6.94–7.0 (m, 2H), 6.82–6.88 (m, 2H), 5.0 (s, 2H), 4.1–4.2 (q, 2H), 3.74–3.82 (t, 2H), 3.62–3.72 (t, 2H), 3.0–3.12 (m, 4H), 1.28–1.42 (t, 3H). MS (ES) M+H expected 360.39, found 361.1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:24][C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[CH:30][NH:31]2)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[NH:31]1[C:32]2[C:28](=[CH:27][CH:26]=[C:25]([O:24][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)[CH:33]=2)[CH:29]=[CH:30]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Reactant: Oc1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4cc[nH]c4c3)ncnc2cc1OCCCN1CCCCC1
Temperature: 90 °C
Yield: 94 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (200 mg, 0.59 mmol), (prepared as described for the starting material in Example 67), 6-hydroxyindole (96 mg, 0.715 mmol) in DMF (3 ml) containing cesium carbonate (291 mg, 0.894 mmol) was heated at 90° C. for 4 hours. After cooling, the mixture was diluted with water, the precipitate was filtered, washed with water and dried under vacuum. The solid was purified by column chromatography eluting with methylene chloride/methanol (90/10 increasing to 50/50) to give 4-(indol-6-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline (240 mg, 93%).
Reaction SMILES: C([Mg]Cl)(C)C.[CH2:6]([N:13]1[C:17]([C:18]2[CH:19]=[CH:20][C:21]3[O:26][CH2:25][CH2:24][CH2:23][C:22]=3[CH:27]=2)=[C:16](Br)[C:15]([C:29]([F:32])([F:31])[F:30])=[N:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:34](=[O:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36]>O1CCCC1.O>[CH2:6]([N:13]1[C:17]([C:18]2[CH:19]=[CH:20][C:21]3[O:26][CH2:25][CH2:24][CH2:23][C:22]=3[CH:27]=2)=[C:16]([C:34](=[O:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:15]([C:29]([F:32])([F:31])[F:30])=[N:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: FC(F)(F)c1nn(Cc2ccccc2)c(-c2ccc3c(c2)CCCO3)c1Br
Reactant: CCOC(=O)C(=O)Cl
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(=O)c1c(C(F)(F)F)nn(Cc2ccccc2)c1-c1ccc2c(c1)CCCO2
Temperature: -20 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
Under nitrogen, isopropyl magnesium chloride 2M in tetrahydrofuran (0.30 mL, 0.59 mmol) was added dropwise to a solution of 1-benzyl-4-bromo-5-(3,4-dihydro-2H-1-benzopyran-6-yl)-3-(trifluoromethyl)-1H-pyrazole (49d) (200 mg, 0.46 mmol) in anhydrous tetrahydrofuran (1.0 mL), previously cooled to −20° C. After 2 hour stirring at the same temperature, ethyl chlorooxoacetate (87 μL, 0.78 mmol) was dropwise added. The mixture was stirred at −20° C. for 60 minutes before being poured in water (2 mL). The mixture was extracted with ethyl acetate (2×3 mL) and the organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (cyclohexane/ethyl acetate 75/25) to provide the desired keto-ester (49e) (80 mg, 0.17 mmol, 38%)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:11])=[CH:8][C:9]=1[OH:10])([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+].C([CH2:20][C:21](Br)([CH3:25])[C:22](O)=[O:23])C>C(#N)C.C(O)C.C(O)(=O)C.[Fe]>[CH3:20][C:21]1([CH3:25])[C:22](=[O:23])[NH:1][C:4]2[CH:5]=[CH:6][C:7]([CH3:11])=[CH:8][C:9]=2[O:10]1
Reactant: Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: CCCC(C)(Br)C(=O)O
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CC#N
Product: Cc1ccc2c(c1)OC(C)(C)C(=O)N2
Temperature: 80 °C
Reaction time: 6 h

Procedure:
6-Nitro-m-cresol (30.6 g) was dissolved in acetonitrile (400 ml), and thereto was added cesium carbonate (163.3 g), and the mixture was warmed to 80° C. To the mixture was added dropwise ethyl 2-bromoisobutyric acid (60 ml), and the mixture was stirred at 80° C. for 6 hours. To the mixture was added dropwise again ethyl 2-bromoisobutyric acid (60 ml), and the mixture was further stirred at 80° C. for 8 hours. The reaction solution was cooled to room temperature, and filtered through celite. The filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water (twice) and saturated aqueous sodium chloride solution (once), and dried over sodium sulfate. The mixture was filtered, and concentrated under reduced pressure to give a crude product. The obtained crude product was dissolved in ethanol (100 ml), and added dropwise in to a solution of iron (90 g) in acetic acid (300 ml), wherein the suspension was previously and separately warmed to 75° C. After the addition was completed, the mixture was stirred at 80° C. for 5 hours, and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed successively with water and saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The obtained crude product was washed with hexane, and collected by filtration to give the title compound (32 g) as whited crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33])=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl.[N:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47]Cl)[CH:42]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:47][C:43]4[CH:42]=[N:41][CH:46]=[CH:45][CH:44]=4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33])=[O:24]
Reactant: ClCc1cccnc1
Reactant: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ccnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ccnc2cc1OCc1cccnc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)-oxy]phenyl}-N′-(2,4-difluorophenyl)urea (55 mg), potassium carbonate (31 mg), and 3-picolyl chloride hydrochloride (22 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at 80° C. for one hr. The solvent was removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 30 mg (yield 48%) of the title compound.
Reaction SMILES: Cl[CH2:2][CH:3]1[O:8][CH2:7][C@@H:6]2[CH2:9][S:10][CH2:11][N:5]2[CH2:4]1.[F:12][C:13]([F:18])([F:17])[C:14]([OH:16])=[O:15].[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][C:34]([OH:40])=[C:35]([O:38][CH3:39])[CH:36]=3)[N:31]=[CH:30][N:29]=2)[CH:23]=[CH:24][C:25]=1[Cl:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[F:12][C:13]([F:18])([F:17])[C:14]([OH:16])=[O:15].[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][C:34]([O:40][CH2:2][CH:3]4[O:8][CH2:7][C@@H:6]5[CH2:9][S:10][CH2:11][N:5]5[CH2:4]4)=[C:35]([O:38][CH3:39])[CH:36]=3)[N:31]=[CH:30][N:29]=2)[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: ClCC1CN2CSC[C@H]2CO1
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCC1CN2CSC[C@H]2CO1
Yield: 9.6 %

Procedure:
A solution of (8aR)-6-(chloromethyl)tetrahydro-1H-[1,3]thiazolo[4,3-c][1,4]oxazine (11.6 mg, 0.0599 mmol), 4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol trifluoroacetate (salt) (30.0 mg, 0.0644 mmol), and potassium carbonate (45.0 mg, 0.326 mmol) in N,N-dimethylacetamide (1.0 mL) was heated in a sealed tube to 150° C. for 12 h. The crude reaction mixture was directly purified via reverse-phase preparative HPLC (acetonitrile/water/0.1% TFA). Lyophillization of the pure fractions yielded 3.5 mg (8.9%) of N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(8aR)-tetrahydro-1H-[1,3]thiazolo[4,3-c][1,4]oxazin-6-ylmethyl]oxy}quinazolin-4-amine trifluoroacetate. 1H NMR (400 MHz, d6-DMSO): 8.80 (s, 1H), 8.11 (s, 1H), 7.99 (s, 1H), 7.74 (s, 2H), 7.29 (s, 1H), 4.29 (d, 2H), 4.11 (m, 2H), 4.00 (s, 3H), 3.96 (m, 1H), 2.99 (m, 2H), 2.56 (t, 1H), 2.367 (m, 1H); MS (EI) for C22H22N4O3SCl2: 492 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[NH:4][C:3]=1[C:14]([O:16]C)=O.[NH2:18][C:19]1[CH:24]=[N:23][CH:22]=[C:21]([Cl:25])[N:20]=1.C1(C)C(C)=CC=CC=1>CO>[Cl:25][C:21]1[N:20]=[C:19]([NH:18][C:14]([C:3]2[NH:4][S:5](=[O:12])(=[O:13])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2]=2[OH:1])=[O:16])[CH:24]=[N:23][CH:22]=1
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1
Reactant: Nc1cncc(Cl)n1
Solvent: Cc1ccccc1C
Solvent: CO
Product: O=C(Nc1cncc(Cl)n1)C1=C(O)c2ccccc2S(=O)(=O)N1
Yield: 32.6 %

Procedure:
A mixture of 5.1 g (20 mmols) of methyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide, 3.0 g (23 mmols) of 2-amino-6-chloropyrazine and 400 ml of xylene was refluxed for 12 hours in a nitrogen atmosphere. The methanol formed by the reaction was removed with the aid of a 4 Å molecular sieve arranged in a Soxhlet attachment. After cooling, the reaction mixture was concentrated by evaporation, and the residue was purified by chromatography on a silicagel column, yielding 2.3 g (33% of theory) of N-(6-chloro-pyrazin-2-yl)-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][C:31]1[S:35][CH:34]=[N:33][C:32]=1[C:36](O)=[O:37]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36]([C:32]4[N:33]=[CH:34][S:35][C:31]=4[CH3:30])=[O:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1scnc1C(=O)O
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2ncsc2C)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 5-methylthiazole-4-carboxylic acid (21 mg, 0.15 mmol).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[O:9][CH:6]1OC)(=[O:3])[CH3:2].C(OC(C)C)(C)C.C(OC(=O)C)(=O)C.S(=O)(=O)(O)O.[C:40]([O-:43])(=[O:42])[CH3:41].[Na+].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[C:40]([O:43][CH:6]1[O:9][C@@H:10]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:5]1[O:4][C:1](=[O:3])[CH3:2])(=[O:42])[CH3:41]
Reactant: COC1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(=O)[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC[C@@H]1OC(OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 0 °C
Yield: 126.5 %

Procedure:
A 100-ml four-necked flask was subjected to nitrogen substitution. 11.32 g (corresponding to 40 mmol of L-ribose) of the 2,3,5-tri-O-acetyl-1-O-methyl-L-ribofuranose obtained in Example B1(1) and 20 ml of diisopropyl ether were added to the flask. The flask was maintained at a temperature of 0±5° C. in an ice bath, and 8.17 g (2.0 equivalents) of acetic anhydride was added thereto. While stirring in an ice bath, 3.2 g (0.8 equivalents) of concentrated sulfuric acid was added dropwise thereto at an internal temperature of 0±5° C. The mixture was stirred in an ice bath for 3.5 hours, and the reaction product was then maintained at 5° C. or lower in a refrigerator overnight. While stirring in an ice bath, 7.87 g of sodium acetate was added to the reaction product, and the obtained mixture was then stirred in an ice bath for 30 minutes. 120 ml of ethyl acetate and a saturated sodium bicarbonate aqueous solution were added to the reaction solution at room temperature until the aqueous layer was neutralized, followed by liquid separation. The aqueous layer was extracted with 120 ml of ethyl acetate, and organic layers were gathered. The gathered layers were washed with 120 ml of a saturated sodium bicarbonate aqueous solution and then with 120 ml of a saturated sodium chloride aqueous solution 2 times. The organic layer was dried over anhydrous sodium sulfate, and the drying agent was then removed by filtration, concentrated under reduced pressure. Thus, 16.10 g of crude 1,2,3,5-tetra-O-acetyl-L-ribofuranose was obtained in the form of yellow oil. The obtained compound was analyzed by HPLC. As a result, it was found that the crude product contained 9.76 g of 1,2,3,5-tetra-O-acetyl-L-ribofuranose, that the ratio of α-/β-anomers was 7/93, and that the total reaction yield of the β-anomer from L-ribose was 72%.
Reaction SMILES: CS(Cl)(=O)=O.[C:6]1([CH3:16])[CH:11]=[CH:10][C:9](S(Cl)(=O)=O)=[CH:8]C=1.[CH2:17]([N:19]([CH2:22][CH3:23])CC)C.[N:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1C>N1C=CC=CC=1>[N:19]12[CH2:22][CH2:23][CH2:25][N:24]=[C:16]1[CH2:6][CH2:11][CH2:10][CH2:9][CH2:8]2.[N:24]12[CH2:28][CH2:27][CH2:26][C:25]1=[N:19][CH2:17][CH2:30][CH2:29]2
Reactant: CCN(CC)CC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cccc(C)n1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: C1CCC2=NCCCN2CC1
Product: C1CN=C2CCCN2C1

Procedure:
This compound is converted into sulfonate by allowing it to react with methanesulfonyl chloride or p-toluenesulfonyl chloride using triethylamine, pyridine or the like base as an acid-removing agent, and the resulting compound is then allowed to react with pyridine, 2,6-lutidine or the like aromatic heterocyclic compound or 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene or the like organic base to give ethyl 1-tert-butoxycarbonylaminocyclobutanepropenoate.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].C(O[C:13](=[O:22])[CH2:14][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=O)C.CC#N.O>CO>[CH2:20]([O:19][C:17](=[O:18])[CH:15]=[C:14]1[C:13](=[O:22])[N:2]([CH3:1])[C:3]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:9]1)[CH3:21]
Reactant: CNc1ccccc1N
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Solvent: CC#N
Solvent: CO
Solvent: O
Product: CCOC(=O)C=C1Nc2ccccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-methyl-1,2-phenylenediamine (6.1 g, 4.99 mmol) in MeOH (50 mL) was added in portion of oxalacetic acid diethyl ester (9.9 g, 5.26 mmol). The mixture was then stirred at rt for 1 h. The precipitate was collected via filtration and was washed with small amount of methanol to yield a pale brownish solid as the pure product: 1H NMR (DMSO-d6) δ=11.1 (bs, 1H), 7.45–7.42 (m, 1H), 7.32–7.29 (m, 1H), 7.15–7.10 (m, 2H), 5.53 (s, 1H), 4.14 (q, J=9.0 Hz, 2H), 3.51 (s, 3H), 1.23 (t, J=9.0 Hz, 3H); HPLC (CH3CN—H2O-0.1% TFA) (short column): Rt=3.91 min.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:5][C@H:6]([CH3:12])[C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:4].[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([O-:15])=[O:14].CN1CCOCC1.O>C1(C)C=CC=CC=1>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([S:22]([O:1][C:2]2[C:3]([O:5][C@H:6]([CH3:12])[C:7]=2[C:8]([O:10][CH3:11])=[O:9])=[O:4])(=[O:24])=[O:23])=[CH:20][CH:21]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C1=C(O)C(=O)O[C@@H]1C
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN1CCOCC1
Product: COC(=O)C1=C(OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C(=O)O[C@@H]1C
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
34.44 g of (R)-2-hydroxy-3-methoxycarbonyl-2-penten-4-olide are dissolved in 170 ml of toluene at 40° C., 49.4 g of p-nitrobenzenesulphonyl chloride in 160 ml of toluene are added and the whole is cooled to 5° C. Within a period of 30 minutes, 20.3 g of N-methylmorpholine are metered in at from 0°to 5° C. 350 ml of water are added, the toluene product phase is removed, and the aqueous phase is re-extracted twice with 100 ml of toluene. The toluene phases are washed with sodium chloride solution and with water, filtered over a small amount of silica gel and concentrated by evaporation. The residue is crystallised from ethyl acetate/cyclohexane. [α]D20 =+12.4° (3% in CHCl3), m.p. 123°-124° C.
Reaction SMILES: [C:1]1(OC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl[CH2:14][CH2:15][CH2:16][C:17]([Cl:19])=[O:18].[OH2:20]>ClC1C=CC=CC=1>[Cl:19][CH:17]([OH:18])[CH2:16][CH2:15][C:14]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:20]
Reactant: O
Reactant: O=C(Cl)CCCCl
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: O=C(CCC(O)Cl)c1ccccc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
32.4 g of anisole are dissolved in 30 ml of chlorobenzene. 53.6 g of AlCl3 are introduced in portions, at not more than 35° C., with ice-cooling. 42.3 g of γ-chlorobutyric acid chloride are added dropwise at a temperature of 15°-35° C. and the mixture is then slowly warmed to 100° C. After stirring for three hours at 100° C., the mixture is cooled to room temperature and discharged into water and the mixture is then extracted with ether. Evaporation of the ether phase, after this has been washed until neutral and dried, yields a reddish solid. This is recrystallised from hexane/ethanol using active charcoal. 45 g of γ-chloro-4-hydroxybutyrophenone of the formula: ##STR42## are then obtained in the form of colourless crystals with a melting point of 108°-111° C.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:10](=[O:17])[N:11]([CH2:15][CH3:16])[CH:12]=[CH:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].S([O-])(O[O-])(=O)=[O:20].[K+].[K+].[OH2:27]>O1CCCC1>[CH2:1]([S:8]([C:9]1[C:10](=[O:17])[N:11]([CH2:15][CH3:16])[CH:12]=[CH:13][N:14]=1)(=[O:20])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)([O-])O[O-]
Reactant: CCn1ccnc(SCc2ccccc2)c1=O
Reactant: O
Agent: [K+]
Agent: [Na]
Solvent: C1CCOC1
Product: CCn1ccnc(S(=O)(=O)Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
To 177 mg (0.72 mM) of 3-(benzylthio)-1-ethylpyrazin-2(1H)-one and 66.4 mg (0.79 mM) of sodium hydrogenocarbonate in 4 ml of tetrahydrofurane were added 1.67 g (2.87 mM) of potassium peroxymonosulfate (oxone) in 4 ml of water. The reaction mixture was then stirred at room temperature for 16 h. Water was added and the organic phase was extracted twice with ethyle acetate. The combined organic layer was washed with water, dried on anhydrous sodium sulfate and the solvent was removed under vacuum, to give a solid, which was triturated in diisopropyle oxide, filtrated and dried under vacuum, to give 103 mg of 3-benzylsulfonyl-1-ethylpyrazin-2(1H)-one. Yield: 52%.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]2[N:22]=[C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]3=[N:19]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C1(C)C=CC=CC=1>[N:19]1[N:18]([CH2:17][CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[N:22]=[C:21]2[CH2:23][CH2:24][CH2:25][CH2:26][C:20]=12
Reactant: [H][H]
Reactant: c1ccc(COc2ccc(OCCn3nc4ccccc4n3)cc2)cc1
Solvent: Cc1ccccc1
Product: Oc1ccc(OCCn2nc3c(n2)CCCC3)cc1
Yield: 67.8 %

Procedure:
5.5 g of 1-benzyloxy-4-[2-(2H-benzotriazol-2-yl)ethoxy]benzene[prepared as described in Example 15(a)] were hydrogenated in a manner analogous to that described in Example 1(b) until no more hydrogen was taken up, whereby 2.8 g (69%) of 4-[2-(4,5,6,7-tetrahydro-2H-benzotriazol-2-yl)ethoxy]phenol having a melting point of 93° C. (from toluene) were obtained.