Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][O:2][C@@H:3]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=[O:5].[C:24]([O:28][C:29]([NH:31][C:32]1[S:33][C:34]([Cl:42])=[C:35]([C:37](=O)[C:38]([OH:40])=[O:39])[N:36]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>CO>[C:20]([O:19][C:17](=[O:18])[CH2:16][C@H:3]([O:2]/[N:1]=[C:37](/[C:35]1[N:36]=[C:32]([NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[S:33][C:34]=1[Cl:42])\[C:38]([OH:40])=[O:39])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=[O:5])([CH3:23])([CH3:22])[CH3:21]
Reactant: COc1ccc(COC(=O)[C@H](CC(=O)OC(C)(C)C)ON)cc1
Reactant: CC(C)(C)OC(=O)Nc1nc(C(=O)C(=O)O)c(Cl)s1
Solvent: CO
Product: COc1ccc(COC(=O)[C@H](CC(=O)OC(C)(C)C)O/N=C(\C(=O)O)c2nc(NC(=O)OC(C)(C)C)sc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
To a solution of (S)-4-tert-butyl 1-(4-methoxybenzyl) 2-(aminooxy)succinate (39.7 g, 122 mmol) in Methanol (300 mL) was added a solution of 2-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)-2-oxoacetic acid (Example 21b) (34 g, 111 mmol) at 0° C. Then the mixture was allowed to warm up to rt and stirred for 2 h. LCMS indicated completion of the reaction and the product as a mixture of Z/E isomer (19:1). The reaction mixture was concentrated and the residue was purified by reverse phase automatic C18 column chromatography (Combinflash RF, 150 g column, six runs), eluting with Acetonitrile/Water (0-90%) to afford (S,Z)-2-(((4-(tert-butoxy)-1-((4-methoxybenzyl)oxy)-1,4-dioxobutan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)acetic acid (46 g, 74.9 mmol, 67.6% yield) as pale yellow solid. LCMS: (M+H)+: 614.4. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.44 (s, 9 H) 1.55 (s, 9 H) 2.74-2.96 (m, 2 H) 3.78 (s, 3 H) 5.06-5.13 (m, 1 H) 5.17 (s, 2 H) 6.86 (d, J=8.84 Hz, 2 H) 7.32 (d. J=8.59 Hz, 2 H)
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]([CH3:23])[CH3:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1(C)C(C)(C)OB([C:43]2[CH:44]=[C:45]([N:49]3[CH:53]=[CH:52][CH:51]=[N:50]3)[CH:46]=[CH:47][CH:48]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:49]1([C:45]2[CH:44]=[C:43]([C:19]([C:11]3[N:10]([S:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)(=[O:9])=[O:8])[C:14]4=[N:15][CH:16]=[CH:17][CH:18]=[C:13]4[CH:12]=3)=[CH:20][CH:21]([CH3:23])[CH3:22])[CH:48]=[CH:47][CH:46]=2)[CH:53]=[CH:52][CH:51]=[N:50]1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CC1(C)OB(c2cccc(-n3cccn3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)C=C(c1cccc(-n2cccn2)c1)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 120.1 %

Procedure:
A suspension of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl ester (prepared as in Example 130, 3.0 g, 6.04 mmol), 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (4.08 g, 15.1 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.5 g, 0.71 mmol) in dioxane (30 mL) and an aqueous sodium carbonate solution (2N, 15 mL) was heated at 100° C. in a microwave for 2 h. At this time, the reaction mixture was cooled to 25° C., diluted with ethyl acetate (350 mL) and washed with a saturated aqueous sodium carbonate solution (2×75 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (300-400 mesh, 50% ethyl acetate/petroleum ether) afforded 2-(1-(3-(1H-pyrazol-1-yl)phenyl)-3-methylbut-1-enyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (3.4 g, 60.1%) as a gray solid: 1H NMR (300 MHz, CDCl3) δ ppm 8.49 (d, 1H, J=2.1 Hz), 8.40 (dd, 1H, J1=4.8 Hz, J2=1.8 Hz), 8.10 (dd, 2H, J1=7.8 Hz, J2=1.8 Hz), 7.44 (dd, 1H, J1=7.8 Hz, J2=1.2 Hz), 7.68-7.61 (m, 4H), 7.55 (t, 1H, J=8.1 Hz), 7.42-7.33 (m, 4H), 7.06 (d, 1H, J=7.8 Hz), 6.89 (s, 1H), 6.52 (t, 1H, J=1.8 Hz), 6.35 (d, 1H, J=9.6 Hz), 1.14 (d, 3H, J=5.1 Hz), 1.12 (d, 3H, J=4.8 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>O>[C:15]1([CH:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:12][CH:9]2[CH2:8][CH2:7][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)N1CCC(O)CC1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)N1CCC(OC(c2ccccc2)c2ccccc2)CC1
Temperature: 140 °C

Procedure:
A mixture of 17.3 parts of 1-(ethoxycarbonyl)-4-hydroxypiperidine, 24.7 parts of bromodiphenylmethane and 7 parts of potassium carbonate is stirred and heated in an oil-bath for 3 hours at 140° C. The reaction mixture is cooled, water is added and the product is extracted with methylbenzene. The extract is washed a few times with water, dried, filtered and evaporated. The oily residue is distilled, yielding ethyl 4-(diphenylmethoxy)-1-piperidinecarboxylate; bp. 150° C. at 0.4 mm. pressure.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:16][C:17]#[N:18]>>[N:9]1([CH2:8][CH2:7][N:1]2[CH2:2][CH2:3][N:4]([CH2:16][C:17]#[N:18])[CH2:5][CH2:6]2)[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1
Reactant: C1CN(CCN2CCOCC2)CCN1
Reactant: N#CCBr
Product: N#CCN1CCN(CCN2CCOCC2)CC1

Procedure:
The title compound is synthesized by coupling of 4-(2-piperazin-1-yl-ethyl)-morpholine (commercially available from ABCR GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+H=239.3; 1HNMR(DMSO-d6) 3.70 (s, 2H), 3.30 (bs, 4H), 2.60-2.30 (m, 16H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:28].Br[CH2:37][CH2:38][OH:39].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[OH:39][CH2:38][CH2:37][N:33]1[CH2:32][CH2:31][CH:30]([NH:29][C:27]([C:4]2[N:5]([CH3:26])[C:6]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]([CH2:16][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:8](=[O:25])[C:7]=3[C:3]=2[O:2][CH3:1])=[O:28])[CH2:35][CH2:34]1
Reactant: COc1c(C(=O)NC2CCNCC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C(=O)NC2CCN(CCO)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Temperature: 100 °C
Reaction time: 15 h
Yield: 33 %

Procedure:
A mixture of the compound of Example 77 (200 mg, 0.399 mmol), 2-bromoethanol (42.5 μL, 0.599 mmol), potassium carbonate (248 mg, 1.80 mmol) and DMF (5 mL) was stirred at 100° C. for 15 hr. The reaction mixture was diluted with water, and extracted twice with ethyl acetate. The extract was combined, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate), and the obtained solid was recrystallized from ethyl acetate-ethanol to give the title compound (68.0 mg, 33%) as white crystals.
Reaction SMILES: CN(C=[C:5]1[C:9](=[O:10])[N:8]([C:11](OC(C)(C)C)=[O:12])[CH:7]2[C:18]3[C:23]([CH2:24][CH:6]12)=[CH:22][CH:21]=[C:20]([C:25]([O:27][CH3:28])=[O:26])[CH:19]=3)C.Cl>O1CCOCC1.C(OCC)(=O)C>[OH:10][CH:9]=[C:5]1[C:11](=[O:12])[NH:8][CH:7]2[C:18]3[C:23]([CH2:24][CH:6]12)=[CH:22][CH:21]=[C:20]([C:25]([O:27][CH3:28])=[O:26])[CH:19]=3
Reactant: COC(=O)c1ccc2c(c1)C1C(C2)C(=CN(C)C)C(=O)N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(c1)C1NC(=O)C(=CO)C1C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
To a solution of tert-butyl 7-methyl 3-(dimethylaminomethylene)-2-oxo-4,8b-dihydro-3aH-indeno[1,2-b]pyrrole-1,7-dicarboxylate (610 mg, 1.6 mmol) in dioxane (20 mL) was added HCl (36%, 2.9 mL, 32 mmol). The solution was stirred overnight at room temperature. The solution was diluted with ethyl acetate and washed twice with water, brine, dried over magnesium sulphate and concentrated to give title compound (0.300 g, 73%). This compound was used without extra purification. LC/MS (method B) RT: 0.65 min; ES−: 258, M−H+.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[CH:23]=[N:24][N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:29](OCC)=[O:30].[O-]CC.[Na+].Cl>C(O)C>[OH:30][CH:29]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[CH:23]=[N:24][N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCOC=O
Reactant: Cc1c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)cnn1C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)cnn1C
Temperature: 78 °C
Yield: 74 %

Procedure:
1,5-Dimethyl-1H-pyrazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.172 g, 0.4594 mmol) and ethyl formate (0.11 mL, 1.37 mmol) were dissolved in anhydrous ethanol (5 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (0.86 mL, 2.3 mmol). This reaction mixture was heated at 78° C. for 0.5 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a brown precipitate. The suspension was filtered and the solids were washed with 0° C. EtOH to afford the pure 1,5-Dimethyl-1H-pyrazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.136 g, 0.34 mmol, 74%).
Reaction SMILES: CO.[Cl-].[NH4+].[Br:5][C:6]1[CH:7]=[CH:8][N:9]2[C:14]=1[C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:17]=1[F:25])=[CH:12][CH:11]=[N:10]2>O1CCCC1.[Zn]>[Br:5][C:6]1[CH:7]=[CH:8][N:9]2[C:14]=1[C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[F:25])=[CH:12][CH:11]=[N:10]2
Reactant: O=[N+]([O-])c1ccc(Oc2ccnn3ccc(Br)c23)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2ccnn3ccc(Br)c23)c(F)c1
Temperature: 70 °C
Yield: 93.7 %

Procedure:
Methanol (1.2 mL), zinc powder (300 mg, 4.57=1) and ammonium chloride (130 mg, 2.47 mmol) were sequentially added to a solution of 5-bromo-4-(2-fluoro-4-nitrophenoxy)pyrrolo[1,2-b]pyridazine (67 mg, 0.19 mmol) in tetrahydrofuran (4.7 mL) and heated at 70° C. for 1.5 hours. Upon completion of the reaction, the resulting reaction mixture was cooled to room temperature and filtered by passing through a celite pad. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (1-6% ethyl acetate in dichloromethane) to give the target compound (57 mg, 0.178 mmol, 93% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[C:5](=[CH:7][CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)[OH:6].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[CH:8]=[CH:7][C:5]=1[O:6][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1cc(C(C)=O)ccc1OCc1ccccc1
Yield: 71.4 %

Procedure:
A mixture of 5-acetylsalicylic acid methyl ester (13.59 g, 70 mmol), benzyl bromide (17.96 g, 105 mmol), potassium carbonate (19.35 g, 140 mmol) and methyl ethyl ketone (350 mL) was refluxed for 8 hours. After cooling, the solvent was evaporated under reduced pressure. 2N Hydrochloric acid was added to the residue, and it was extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated, the residue was recrystallized from isopropyl ether to give the title compound (14.20 g, 71.4%) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:40])[NH:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]2[C:20]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[CH:19][N:18]=[C:17]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-])=O)[CH:32]=3)[N:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N.O>C(O)C>[C:1]1([CH2:7][O:8][C:9](=[O:40])[NH:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]2[C:20]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[CH:19][N:18]=[C:17]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([NH2:37])[CH:32]=3)[N:16]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cnc(Nc2cccc([N+](=O)[O-])c2)nc1NCCCNC(=O)OCc1ccccc1
Agent: N
Solvent: O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCc1cnc(Nc2cccc(N)c2)nc1NCCCNC(=O)OCc1ccccc1
Yield: 99.5 %

Procedure:
Phenylmethyl[3-[[5-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]methyl]-2-[(3-nitrophenyl)amino]pyrimidin-4-yl]amino]propyl]carbamate (244 mg), dissolved in ethanol (30 ml), was slowly added to a mixture of FeSO4 heptahydrate (1.25 g), concentrated ammonia solution (25%; 1.25 ml) and water (5 ml). After refluxing for 3 h the mixture was filtered and the filter cake washed with ethyl acetate. The filtrate was washed with water and brine, dried (Na2SO4), filtered and evaporated to yield the crude title compound (230 mg), which was used in the next step without further purification.
Reaction SMILES: [SH:1][C:2]1[C:3](=[O:11])[N:4]([CH2:8][CH2:9][CH3:10])[CH:5]=[CH:6][N:7]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][S:1][C:2]2[C:3](=[O:11])[N:4]([CH2:8][CH2:9][CH3:10])[CH:5]=[CH:6][N:7]=2)=[CH:15][CH:14]=1
Reactant: CCCn1ccnc(S)c1=O
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCCn1ccnc(SCc2ccc(Cl)cc2)c1=O
Yield: 88 %

Procedure:
500 mg (2.30 mM) of 3-mercapto-1-propylpyrazin-2(1H)-one, 319.2 μl (1.21 mM) of 4-chlorobenzylbromide and 637 mg (4.6 mM) of potassium carbonate in 4 ml of tetrahydrofurane were stirred overnight at room temperature. Water was added and the aqueous layer was extracted with ethyle acetate. The organic layer was separated and washed with water, dried on anhydrous sodium sulfate and evaporated under vacuum, to give an oil which was purified by silica gel column chromatography, using dichloromethane/dimethylketone (98/2) as eluant, to give 600 mg of 3-[(4-chlorobenzyl)thio]-1-propylpyrazin-2(1H)-one. Yield: 88%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:17][C:11]3([CH2:16][CH2:15][S:14][CH2:13][CH2:12]3)[CH:10]=[C:9]([C:18](O)=[O:19])[C:8]=2[CH:21]=1)([O-:3])=[O:2].[C:22](N1C=CN=C1)([N:24]1C=CN=C1)=O.CN.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:22][NH:24][C:18]([C:9]1[C:8]2[CH:21]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[O:17][C:11]2([CH2:16][CH2:15][S:14][CH2:13][CH2:12]2)[CH:10]=1)=[O:19]
Reactant: O=C(O)C1=CC2(CCSCC2)Oc2ccc([N+](=O)[O-])cc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)C1=CC2(CCSCC2)Oc2ccc([N+](=O)[O-])cc21
Reaction time: 20 h
Yield: 33.6 %

Procedure:
To a mixture of 80 mg of 6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydrothiopyran]-4-carboxylic acid and 7 ml of tetrahydrofuran was added 80 mg of 1,1'-carbonyldiimidazole with stirring under ice-cooling and the mixture was stirred for 1 hour. 0.7 ml of 40% methylamine (methanol solution) was added therein and the mixture was stirred under ice-cooling for 1 hour and then at room temperature for 20 hours. An aqueous potassium carbonate solution was added therein and the reaction mixture was extracted with methylene chloride. An organic layer was washed with water and dried, and the solvent was distilled. The residue was purified according to silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) and further recrystallized by a mixed solvent of ethyl acetate and hexane to obtain 28 mg of N-methyl-6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydrothiopyran]-4-carboxamide with a melting point of 208°-209° C.
Reaction SMILES: [OH-].[Na+].[C:3]([C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[N:18]1[C:22]([CH2:23][N:24]([CH3:26])[CH3:25])=[N:21][C:20]([CH2:27][O:28]C(=O)C)=[N:19]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.O>[C:3]([C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[N:18]1[C:22]([CH2:23][N:24]([CH3:25])[CH3:26])=[N:21][C:20]([CH2:27][OH:28])=[N:19]1)(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)OCc1nc(CN(C)C)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)Cc1nc(CO)nn1-c1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
60 ml of 1N sodium hydroxide solution (0.060 mole) is added at room temperature, with stirring, to a solution of 8.26 g (about 0.020 mole) of crude [[1-(2-benzoyl-4-chlorophenyl)-5-[(dimethylamino)-methyl]-1H-1,2,4-triazol-3-yl]-methyl]-acetate (see Example 20) in 250 ml of methanol and 115 ml of water. The temperature of the reaction solution rises to 33°. The reaction mixture is stirred for one hour at room temperature, and is subsequently concentrated in vacuo. Water is added to the residue, and extraction is performed twice with ethyl acetate. The combined organic phases are extracted three times with 2 N hydrochloric acid. There are added to the aqueous acidified extracts ice and sufficient sodium carbonate to bring the pH-value to 10. The precipitated base is taken up in ethyl acetate. The organic phase is washed twice with water and once with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated in vacuo. There is obtained crude 1-(2-benzoyl-4-chlorophenyl)-5-[(dimethylamino)-methyl]-1H-1,2,4-triazole-3-methanol as solidified foam.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].O.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>C(Cl)Cl>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 89.4 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (2.00 g) obtained from Referential Example 7 and potassium carbonate (1.10 g) were suspended in a mixed solvent of methylene chloride (30 ml) and water (20 ml). A solution of benzyl chloroformate (1.35 g) in methylene chloride (10 ml) was added thereto under ice-cooling, and the mixture was stirred for 2 hours at same temperature and then stirred overnight at room temperature. The reaction mixture was separated into organic layer and aqueous layer, the organic layer was successively washed with aqueous 10% oxalic acid solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure, to thereby obtain the 2.61 g of titled compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]3[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=3[CH:41]=2)=[CH:5][CH:4]=1.[CH2:42](I)[CH3:43]>>[CH2:42]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:11][CH:10]2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]3[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=3[CH:41]=2)=[CH:7][CH:8]=1)[CH3:43]
Reactant: CCI
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CO)cc3)cc21
Product: CCOCc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1

Procedure:
Analogously to Method D, 0.100 g of benzyl 4-(4-hydroxymethylphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 270c) and 0.0395 g of ethyl iodide are reacted. The title compound is obtained as a yellow oil. Rf=0.49 (2:1 EtOAc-heptane); Rt=5.60.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][CH3:8])[N:6]=1.[CH:9]1[C:22]2[CH:21]([C:23](Cl)=[O:24])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1>>[CH2:7]([N:5]1[N:4]=[N:3][C:2]([NH:1][C:23]([CH:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][C:13]3[C:22]2=[CH:9][CH:10]=[CH:11][CH:12]=3)=[O:24])=[N:6]1)[CH3:8]
Reactant: O=C(Cl)C1c2ccccc2Cc2ccccc21
Reactant: CCn1nnc(N)n1
Product: CCn1nnc(NC(=O)C2c3ccccc3Cc3ccccc32)n1

Procedure:
The title compound, white solid, m.p. 206-207° and MS: (neg. ions): m/e=318.3 (M+−H) was prepared in accordance with the general method of example 1 from 5-amino-2-ethyl-2H-tetrazole and 9,10-dihydro-anthracene-9-carbonyl chloride.
Reaction SMILES: O[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:5]=[N:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].P(Cl)(Cl)(Cl)(Cl)[Cl:22]>C1(C)C=CC=CC=1>[Cl:22][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:5]=[N:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1Cl
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
Ethyl 5-hydroxy-1-[(4-methoxyphenyl)methyl]-1H-1,2,3-triazole-4-carboxylate (i.e. the product of Step B, 10.0 g, 36.1 mmol) was suspended in anhydrous toluene (300 mL) under a nitrogen atmosphere. Phosphorus pentachloride (8.3 g, 39.8 mmol) was added and the mixture was stirred at 40° C. for 90 min. during which time a clear yellow solution was formed. The reaction was concentrated under reduced pressure to remove most of the toluene. The resulting residue was diluted with diethyl ether (150 mL) and washed with saturated aqueous sodium bicarbonate solution (70 mL) and water (70 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to afford the crude product which was recrystallized twice from hexanes (200 mL, 100 mL) to afford the title compound (6.0 g) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:10]([O:15][CH2:16][CH2:17][CH3:18])(=[O:14])[C:11]([CH3:13])=O>>[CH2:16]([O:15][C:10](=[O:14])[C@H:11]([CH3:13])[NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)[CH2:17][CH3:18]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CCCOC(=O)C(C)=O
Product: CCCOC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and n-propyl pyruvate (prepared by following General Procedure AO above using n-propanol in place of iso-butanol), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.5 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).