Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:9]1[C:10]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:11]2[C:16](=[CH:17][C:18]=1[CH3:19])[N:15]=[C:14]([NH:20][NH2:21])[CH:13]=[CH:12]2)[CH2:7][OH:8])([CH3:4])([CH3:3])[CH3:2].[CH:29](OCC)(OCC)OCC>C(O)CCC.C(OCC)(=O)C>[C:1]([O:5][C@@H:6]([C:9]1[C:10]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:11]2[C:16](=[CH:17][C:18]=1[CH3:19])[N:15]1[CH:29]=[N:21][N:20]=[C:14]1[CH:13]=[CH:12]2)[CH2:7][OH:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2nc(NN)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Reactant: CCOC(OCC)OCC
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: Cc1cc2c(ccc3nncn32)c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 100 °C

Procedure:
The mixture of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-hydrazinyl-7-methylquinolin-6-yl)ethanol and triethyl orthoformate (0.5 mL) in butanol (5 mL) was heated at 100° C. for 12 hours. The solution was diluted with ethyl acetate, and was washed with 1.0 N sodium hydroxide solution and brine, and dried with sodium sulfate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave (S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8-methyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)ethanol (3.3 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C23H25ClN3O2: 410.2. Found: 410.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14](Cl)[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:24]1C=C(NS(C2C=CC(NC(=O)C)=CC=2)(=O)=O)C=C(C(F)(F)F)[N:25]=1>CN.C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14]([NH:25][CH3:24])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(C(F)(F)F)c2)cc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(C(F)(F)F)c2)cc1
Agent: CN
Solvent: CCO
Product: CNc1cc(NS(=O)(=O)c2ccc(N)cc2)cc(C(F)(F)F)n1
Yield: 70 %

Procedure:
0.052 g (0.00015 mol) of 4-amino-N-(2-chloro-6-trifluoromethyl-pyridin-4-yl)-benzenesulfonamide was stirred in 30 ml of 8M methylamine in ethanol in an autoclave at 135° C. for 80 hours. The methylamine was allowed to evaporate, the residue was dissolved in ethanol, treated with 2 g of silica gel, concentrated and the residue was chromatographed on silica gel with ethyl acetate/hexane 1:2. There was obtained 0.036 g (70%) of 4-amino-N-(2-methylamino-6-trifluoromethyl-pyridin-4-yl)-benzenesulfonamide as colorless crystals; m.p.: >68° C. (dec.).
Reaction SMILES: [Na].[SH:2]C(O)C.Cl.[CH3:7][C:8]1[N:9]=[CH:10][NH:11][C:12]=1[CH2:13]Cl.[CH2:15]([OH:17])[CH3:16]>>[CH3:7][C:8]1[NH:9][CH:10]=[N:11][C:12]=1[CH2:13][S:2][CH2:16][CH2:15][OH:17]
Reactant: CC(O)S
Reactant: Cc1nc[nH]c1CCl
Reactant: CCO
Agent: Cl
Agent: [Na]
Product: Cc1[nH]cnc1CSCCO
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Sodium (3.0 g) was added, with stirring under nitrogen, to dry ethanol (75 ml). After the sodium had dissolved mercaptoethanol (9.0 ml) was introduced and to this mixture was added 4-methyl-5-chloromethylimidazole hydrochloride (10 g), as a solid, over a period of 1.5 hours at room temperature. The mixture was then stirred for a further 1 hour at room temperature. After this time the reaction was warmed and the ethanol distilled off at reduced pressure. The residue was taken up in water, acidified with concentrated hydrochloric acid, and continuously extracted with ether to remove the excess mercaptoethanol. The aqueous fraction was then basified using solid sodium carbonate and continuously extracted with ethyl acetate. To the extract was added a further volume of ethyl acetate and the whole warmed to re-dissolve the crude product which had deposited. After drying (MgSO4) and reducing the volume, crystallisation from this solution below 40° and cooling to -15° afforded 2-(5-methyl-4-imidazolylmethylthio)ethanol, m.p. 74°-76°.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH2:12][CH2:13][C:14]([CH3:22])([CH3:21])[CH:15]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:7]1=[C:6]2[CH3:23].B(Br)(Br)[Br:25].C(O)C.CCOCC>C(Cl)(Cl)Cl>[BrH:25].[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH2:12][CH2:13][C:14]([CH3:21])([CH3:22])[CH:15]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:7]1=[C:6]2[CH3:23]
Reactant: BrB(Br)Br
Reactant: COc1ccc2c(c1)c(C)c1n2CCC(C)(C)C1N1CCCC1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: CCO
Product: Br
Product: Cc1c2n(c3ccc(O)cc13)CCC(C)(C)C2N1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
A solution of 6,7,8,9-tetrahydro-2-methoxy-8,8,10-trimethyl-9-(1-pyrrolidinyl)-pyrido[1,2-a]indole (prepared in Example 15, step 5) (2.81 g, 9 mmol) in chloroform (54 mL) was cooled to 0° C. and treated under dry nitrogen with boron tribromide (5.62 g, 22.5 mmol). The mixture was stirred in the dark at 25° C. for 2 hours. Ethanol (54 mL) was added dropwise over 5 minutes at 0° C. Stirring was continued at 0°-5° C. for 1 hour. Ether (34 mL) was added slowly at 5° C. to induce crystallization. The obtained crystals were filtered, washed with ethanol/ether (2:1) and ether, then dried in vacuo at 65° C. affording 2.24 g (66% yield) of the title compound, m.p. 166°-170° C. as an off-white powder. IR (KBr) broad bands at 3280 and 2970 cm-1 ;
Reaction SMILES: [CH2:1]([CH:3]1[CH2:26][NH:25][C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=[C:5]2[CH2:4]1)[CH3:2].O=[CH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:1]([CH:3]1[CH2:26][N:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:6]2=[N:7][C:8]([C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=[C:5]2[CH2:4]1)[CH3:2]
Reactant: CCOC(=O)CCCCCC=O
Reactant: CCC1CNc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)CCCCCCN1CC(CC)Cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Reaction time: 0.17 h

Procedure:
To a mixture comprising 7-ethyl-2,3-di-p-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (Intermediate D)(0.1 g, 0.291 mmol) in 1,2-dichloroethane (2 ml) was added molecular sieves followed by ethyl 7-oxoheptanoate (0.15 g, 0.874 mmol). The mixture was stirred for 10 minutes and treated with NaBH(OAc)3. After stirring at RT overnight, the reaction mixture was passed through Celite® (filter material) and partitioned between EtOAc and water. The organic layer was washed with saturated brine solution, dried over anhydrous sodium sulphate and concentrated under vacuum to afford the titled compound;
Reaction SMILES: O1CCC[CH2:2]1.[Br:6][C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[CH2:13][CH2:14][CH:15]([OH:22])[CH2:16][C:17]=3[C:18]2=[O:21])=[CH:9][CH:8]=1.[OH-].[Na+].COS(OC)(=O)=O>O.C(Cl)(Cl)Cl>[Br:6][C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[CH2:13][CH2:14][CH:15]([O:22][CH3:2])[CH2:16][C:17]=3[C:18]2=[O:21])=[CH:9][CH:8]=1
Reactant: O=c1c2c(oc3ccc(Br)cc13)CCC(O)C2
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: COS(=O)(=O)OC
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC1CCc2oc3ccc(Br)cc3c(=O)c2C1
Temperature: 50 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
To 100 ml of an anhydrous tetrahydrofuran solution containing 5.9 g of 7-bromo-2-hydroxy-1,2,3,4-tetrahydro-9-xanthone obtained in Example 67 was added 1.1 g of sodium hydroxide (as 55% dispersed in an oil). The mixture was stirred at 50° C. for 1 hour to which was then added dropwise 3.3 g of dimethylsulfate. The resulting mixture was agitated at 60° C. for 1.5 hours. After completion of the reaction, the solvent was removed by distillation to give a residue to which were added chloroform and water. The chloroform phase was collected and washed with water, and then dried with anhydrous sodium sulfate and purified by chromatography on silica gel. The crude crystals thus obtained were recrystallized from benzene/hexane to obtain 3.87 g (yield: 62.6%) of 7-bromo-2-methoxy-1,2,3,4-tetrahydro-9-xanthone as colorless needlelike crystals having a melting point of 139° to 142° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[NH:32]1[CH2:37][CH2:36][CH:35]([C:38]([OH:40])=[O:39])[CH2:34][CH2:33]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][N:32]4[CH2:37][CH2:36][CH:35]([C:38]([OH:40])=[O:39])[CH2:34][CH2:33]4)=[CH:30][CH:31]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: O=C(O)C1CCNCC1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Product: O=C(O)C1CCN(Cc2ccc(-c3noc(-c4nnn(-c5ccccc5F)c4-c4ccncc4)n3)cc2)CC1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (100 mg; 0.24 mmol) and piperidine-4-carboxylic acid (62.6 mg; 0.48 mmol) to give Example 128 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.75 (2H, d, J=5.3 Hz), 7.97-7.88 (3H, m), 7.73 (1H, q, J=6.9 Hz), 7.61 (2H, d, J=5.4 Hz), 7.55-7.48 (4H, m), 3.56 (2H, s), 2.78 (2H, d, J=10.9 Hz), 2.27-2.18 (1H, m), 2.05 (2H, m), 1.81 (2H, m), 1.61 (2H, m). LC/MS (Method C): 526 (M+H)+. HPLC (Method E) Rt 2.20 min (Purity: 97.7%).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=O.[C:24]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])(=[O:29])[CH2:25][C:26]([CH3:28])=O.S(=O)(=O)(O)O>C(O)(=O)C>[CH2:31]([O:30][C:24]([C:25]1[C:26]([CH3:28])=[N:1][C:2]2[C:3]([C:4]=1[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=[CH:16][C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=2)=[O:29])[CH2:32][CH2:33][CH3:34]
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Reactant: CCCCOC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCCCOC(=O)c1c(C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Yield: 53 %

Procedure:
To a mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone, butyl acetoacetate and acetic acid, concentrated sulfuric acid was added, followed by the same treatment as in Reference Example 1, to yield 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-methylquinoline-3-carboxylic acid butyl ester (53%), which was then recrystallized from ethyl acetate-hexane to yield a colorless prismatic crystal having a melting point of 119° to 120° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C@@H:7]([C:14]([OH:16])=O)[CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5])[CH3:2].[NH:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=[O:20]>>[CH2:1]([O:3][C:4]([NH:6][C@@H:7]([C:14]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=[O:20])=[O:16])[CH2:8][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N[C@H](CC1CCCC1)C(=O)O
Reactant: O=C(O)[C@@H]1CCCN1
Product: CCOC(=O)N[C@H](CC1CCCC1)C(=O)N1CCC[C@H]1C(=O)O
Yield: 70.5 %

Procedure:
2.43 g (10.5 mmol) of ethoxycarbonyl-3-cyclopentyl-D-alanine (Example 4, Step B) is treated according to the method described in Example 1, Step E, using proportional quantities of reagents and solvents. The resulting 2,4,5-trichlorophenylester is coupled with 1.15 g (10 mmol) of L-proline which yields 2.3 g (71%) of an oily product. Rf(6)=0.53.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][C:30](O)=[O:31])=[CH:28][C:23]=2[O:22][CH2:21]1>>[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][C:30]([NH:1][N:2]3[N:11]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=4)[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]3=[O:19])=[O:31])=[CH:28][C:23]=2[O:22][CH2:21]1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Product: O=C(Cc1ccc2c(c1)OCO2)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product from Example 86A and 2-(benzo[d][1,3]dioxol-5-yl)acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ 8.41 (m, 1H), 8.01-7.95 (m, 2H), 7.72 (m, 1H), 7.63 (m, 4H), 6.96 (d, J=1.6, 1H), 6.88 (d, J=7.9, 1H), 6.84 (dd, J=8.0, 1.6, 1H), 5.99 (s, 2H), 3.61 (s, 2H); MS (APCI+) M/Z 434 (M+H)+.
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:9][C:10]1[C:11](=[O:18])[CH:12]=[C:13]([CH3:17])[C:14](=[O:16])[CH:15]=1.Cl.C(OCC)(=O)C>C1COCC1>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][C:11]1([OH:18])[CH:12]=[C:13]([CH3:17])[C:14](=[O:16])[CH:15]=[C:10]1[CH3:9])[CH3:8]
Reactant: CC1=CC(=O)C(C)=CC1=O
Reactant: CCOC(=O)C[Zn]Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)C=C(C)C(=O)C=C1C
Yield: 87 %

Procedure:
Under nitrogen atmosphere, 6 mL of THF was added to 1.22 g (2 mmol, 0.6 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.45 g (3.33 mmol) of 2,5-dimethyl-p-benzoquinone in 3 mL of THF was added dropwise while stirring at. 0˜5° C. The mixture was stirred at 20˜25° C. for 1 hour. 5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, purification with silica gel column (developing solvent; ethyl acetate/n-hexane=1/3, 1/2) afforded 0.65 g of the desired product (yield 87%).
Reaction SMILES: [C:1]([NH:9][NH:10][C@@H:11]1[C:16]2[CH:17]=[C:18]([C:21]#[N:22])[CH:19]=[CH:20][C:15]=2[O:14][C:13]([CH3:24])([CH3:23])[C@H:12]1[OH:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)(Cl)Cl>[OH2:8].[C:32]([N:10]([C@@H:11]1[C:16]2[CH:17]=[C:18]([C:21]#[N:22])[CH:19]=[CH:20][C:15]=2[O:14][C:13]([CH3:23])([CH3:24])[C@H:12]1[OH:25])[NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](NNC(=O)c2ccccc2)[C@@H]1O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)N(NC(=O)c1ccccc1)[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Product: O

Procedure:
Trans-4-(2-benzoylhydrazino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol (320 mg) was dissolved in 1 ml of chloroform, 0.5 ml of pyridine was added, and 0.28 ml of acetyl chloride was added with stirring under ice cooling. After stirring at room temperature for 80 minutes, the solvent was distilled off under reduced pressure and the residue was dissolved in 5 ml of methanol. The solution was treated with 5 ml of 1N-sodium hydroxide at room temperature for 30 minutes. After the methanol had been distilled off, the residue was shaken together with ethyl acetate-water and the organic layer was washed with an aqueous solution of sodium chloride and subsequently concentrated. This was recrystallized from hexane-ethanol (1:1) to give 170 mg of trans-4-(1-acetyl-2-benzoylhydrazino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol monohydrate as white crystals, m.p. 212°-213° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][CH3:17])[CH2:13][C@H:12]1[C:18]([NH2:21])=[N:19][OH:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([C:28]([O:30][CH3:31])=[O:29])#[C:23][C:24]([O:26][CH3:27])=[O:25]>C(Cl)(Cl)Cl>[CH3:27][O:26][C:24](=[O:25])[C:23]([O:20][N:19]=[C:18]([NH2:21])[C@@H:12]1[CH2:13][C@@H:14]([O:16][CH3:17])[CH2:15][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[CH:22][C:28]([O:30][CH3:31])=[O:29]
Reactant: CO[C@@H]1C[C@@H](C(N)=NO)N(C(=O)OCc2ccccc2)C1
Reactant: COC(=O)C#CC(=O)OC
Solvent: ClC(Cl)Cl
Product: COC(=O)C=C(ON=C(N)[C@@H]1C[C@@H](OC)CN1C(=O)OCc1ccccc1)C(=O)OC
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To benzyl-(2S,4R)-2-[amino(hydroxyimino)methyl]-4methoxypyrrolidine-1-carboxylate, dissolved in chloroform, dimethyl acetylendicarboxylate (1.1 eq.) was added. The mixture was refluxed for 1 hour and left stirring at 40° C. overnight. The chloroform was removed in vacuo and the crude product purified by flash chromatography on silica gel (eluent ethyl acetate:petroleum ether=40:60). Two isomers were present in ratio 7:3.
Reaction SMILES: [N+:1]([O-])([O:3]C(=O)C)=[O:2].[CH3:8][N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:12][CH:11]([F:26])[C:10]1=[O:27].C(Cl)(Cl)(Cl)Cl>C(#N)C>[CH3:8][N:9]1[C:15]2[CH:16]=[CH:17][C:18]([N+:1]([O-:3])=[O:2])=[CH:19][C:14]=2[C:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:12][CH:11]([F:26])[C:10]1=[O:27]
Reactant: CN1C(=O)C(F)N=C(c2ccccc2)c2ccccc21
Reactant: CC(=O)O[N+](=O)[O-]
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: CN1C(=O)C(F)N=C(c2ccccc2)c2cc([N+](=O)[O-])ccc21
Reaction time: 3 h

Procedure:
1.2 g. of acetyl nitrate are added dropwise, at 10° to a stirred solution of 2.67 g. of 1-methyl-3-fluoro-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one in 70 ml. of CCl4 and 20 ml. of acetonitrile. The mixture is stirred for 1 hour more at 10° and for 3 hours at 20° and is poured into ice cold sodium carbonate solution and worked up in the customary manner to give 1-methyl-3-fluoro-5-phenyl-7-nitro-2,3-dihydro-1H-1,4-benzodiazapin-2-one.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[OH:50][CH2:51][C@H]1[C@@H](O)CCN1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:23][CH2:24][C@H:51]([OH:50])[C@@H:27]2[CH2:26][OH:25])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: OC[C@@H]1NCC[C@@H]1O
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2CC[C@H](O)[C@@H]2CO)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (2S,3S)-2-(hydroxymethyl)pyrrolidin-3-ol and isolated as light-yellow gum (10.3 mg, 52%). MS (m/e): 417.4 (MH+).
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:13][C:14]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[C:19]([C:25]([F:28])([F:27])[F:26])[C:15]=1[C:16](Cl)=[O:17].S(=O)(=O)(O)O>C(Cl)(Cl)(Cl)Cl.C(O)C.C1(C)C=CC=CC=1>[F:13][C:14]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[C:19]([C:25]([F:27])([F:28])[F:26])[C:15]=1[C:16]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:17]
Reactant: O=C(Cl)c1c(C(F)(F)F)cc(F)c(F)c1F
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1c(C(F)(F)F)cc(F)c(F)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.47 g (0.019 mol) of magnesium filings are introduced into 1.0 ml of ethanol, the reaction is started up using a few drops of carbon tetrachloride, and a solution of 2.8 g (0.016 mol) of diethyl malonate in 2.0 ml of ethanol and 7.5 ml of toluene is subsequently added dropwise in such a manner that the internal temperature is between 50 and 60° C. Stirring is then continued for one hour at 60° C. A solution of 4.8 g (0.027 mol) of 2,3,4-trifluoro-6-trifluoromethylbenzoyl chloride in 2.0 ml of toluene is added dropwise at -10° to -5° C., and stirring is continued for one hour at 0° C. and subsequently while the mixture comes to room temperature. The batch is poured into 10 ml of ice-water, treated with 1.25 ml of concentrated sulphuric acid, and the mixture is extracted using toluene. The toluene phase is washed using saturated sodium chloride solution, and the solvent is removed in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][C:11]2([CH3:21])[CH3:20])[CH:8]=[N:7][CH:6]=1)=[O:4].[NH4+].[NH4+].[O-:24]S(OOS([O-])(=O)=O)(=O)=O.[OH-].[Na+]>O>[CH3:1][O:2][C:3]([C:5]1[N:9]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:24])[CH2:12][C:11]2([CH3:21])[CH3:20])[CH:8]=[N:7][CH:6]=1)=[O:4]
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: COC(=O)c1cncn1C1c2ccccc2CCC1(C)C
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1cncn1C1c2ccccc2C(=O)CC1(C)C
Reaction time: 1.5 h
Yield: 28.2 %

Procedure:
142 g of 1-(2,2-dimethyltetralin-1-yl)-5-imidazolecarboxylic acid methyl ester are suspended in 1 liter of distilled water. The suspension is heated to +87° C. and, while stirring, a total of 335 g of ammonium peroxodisulfate is added in portions thereto within a period of 1.5 hours in such a manner that the temperature does not exceed +90° C. After the reaction mixture has been cooled to +15° C., the pH value is adjusted to pH 4 by the addition of approximately 335 g of 30% sodium hydroxide solution and the whole is extracted with 500 ml of methylene chloride. The organic phase is separated off, dried over sodium sulfate, treated with activated carbon and concentrated by evaporation. Crystallisation of the residue from ether yields 42 g of 1-(2,2-dimethyl-4-oxotetralin-1-yl)-5-imidazolecarboxylic acid methyl ester having a melting point of 93°-95° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].F[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(O)cc1Cl
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Oc2ccc(C=O)cc2)cc1Cl
Temperature: 120 °C
Yield: 89 %

Procedure:
To a solution of 3-chloro-4-methylphenol (2.5 g, 17.53 mmol) and 4-fluorobenzaldehyde (2.2 g, 17.73 mmol) in DMF (40 ml), was added K2CO3 (2.91 g, 21.04 mmol). The solution was heated at 120° C. overnight: The reaction mixture was diluted in water, extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4 and evaporated in vacuo to afford the title compound (5.5 g, 15.61 mmol, 89% yield). LCMS: rt=3.80 min, [M+H+]=247
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([CH3:18])[C:10]=1[F:19])C1C=CC=CC=1.[CH3:20]OC(OC)N(C)C>[Pd]>[F:19][C:10]1[C:9]([OH:8])=[CH:14][CH:13]=[C:12]2[C:11]=1[CH:18]=[CH:20][NH:15]2
Reactant: Cc1c([N+](=O)[O-])ccc(OCc2ccccc2)c1F
Reactant: COC(OC)N(C)C
Agent: [Pd]
Product: Oc1ccc2[nH]ccc2c1F
Temperature: 180 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
1-Benzyloxy-2-fluoro-3-methyl-4-nitrobenzene (5 g, 19 mmol) is dissolved N,N-dimethylformamide dimethyl acetal (15 mL) and heated in a microwave reactor at 180° C. in a sealed vial for 1 hour. The solution is then concentrated under reduced pressure. The resulting residue is dissolved in THF and Pd/C (1.0 g, 10%, 0.95 mmol) is added. The mixture is stirred under a hydrogen atmosphere at room temperature for 16 h before being filtered through a pad of Celite® and concentrated. The residue is separated by FCC (EtOAc/heptane from 0 to 40%) to give 4-fluoro-1H-indol-5-ol (1.5 g, 52% yield). MS (ESI) m/z 152.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.02 (br. s., 1H), 8.79 (s, 1H), 7.26 (t, J=2.78 Hz, 1H), 7.00 (d, J=8.59 Hz, 1H), 6.75 (t, J=8.46 Hz, 1H), 6.34 (m, 1 H).