Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[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][Cl:24])=[N:21][C:20]([C:25]([NH2:27])=[O:26])=[N:19]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>O1CCCC1.CO>[OH:10][CH:3]([C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[N:18]1[C:22]([CH2:23][Cl:24])=[N:21][C:20]([C:25]([NH2:27])=[O:26])=[N:19]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: NC(=O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1nc(CCl)n(-c2ccc(Cl)cc2C(O)c2ccccc2)n1
Temperature: 25 °C

Procedure:
0.57 g (0.015 mole) of sodium borohydride is added all at once at 0°, with stirring, to the solution of 5.6 g (0.015 mole) of 1-(2-benzoyl-4-chlorophenyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxamide [see Example 1(a)] in 250 ml of tetrahydrofuran and 25 ml of methanol, and the whole is subsequently stirred for a further hour at room temperature. There is then slowly added dropwise, with ice-water cooling, 1 N hydrochloric acid solution until the pH-value of the reaction mixture has reached 4. The mixture obtained is concentrated in vacuo to dryness. Water is added to the residue, and extraction is performed twice with ethyl acetate. The organic phase is washed once with saturated potassium bicarbonate solution, twice with water and once with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated in vacuo. There is obtained amorphous 1-[2-(α-hydroxybenzyl)-4-chlorophenyl]-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxamide, which can be used directly in the next stage. On the silica gel plate, the compound has an Rf value of 0.61 in the system ethyl acetate/methanol (95:5).
Reaction SMILES: [OH-].[Na+].C([O:9][CH2:10][C:11]1[S:12][CH:13]=[C:14]([C:16]([O:18]CC)=[O:17])[N:15]=1)(=O)C(C)(C)C>O.C1COCC1.CO>[OH:9][CH2:10][C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1
Reactant: CCOC(=O)c1csc(COC(=O)C(C)(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1csc(CO)n1
Reaction time: 72 h

Procedure:
A solution of NaOH (1.769 g, 44.23 mmol) in water (20.0 mL) was added to a stirred solution of ethyl 2-(pivaloyloxymethyl)thiazole-4-carboxylate (2.4 g, 8.85 mmol) in a mixture of THF (20 mL) and MeOH (10.0 mL), and the reaction stirred for 72 h. Acidified with 2M HCl (10 mL) and evaporated in vacuo to afford crude 2-(hydroxymethyl)thiazole-4-carboxylic acid as a white solid. Purified by reverse phase chromatography with MeCN/aqTFA as eluent to afford the sub-title compound as a white solid. Yield: 1.4 g
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][N:12]=2)[CH:4]=1)[CH3:2].[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>>[CH2:20]([NH:24][C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[N:12][CH:13]=1)=[O:19])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCN
Reactant: CCc1cc(-c2ccc(C(=O)O)cn2)c(C)[nH]c1=O
Product: CCCCNC(=O)c1ccc(-c2cc(CC)c(=O)[nH]c2C)nc1

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[2,3′]bipyridinyl-5-carboxylic acid and n-butyl amine to afford the title compound. MS: m/e=314 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12].O>CS(C)=O>[C:11]([NH:15][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)Nc1ccc([N+](=O)[O-])cc1
Yield: 72.5 %

Procedure:
A solution of 1-fluoro-4-nitro-benzene (1 g, 7.1 mmol) and tert-butylamine (1.5 g, 21 mmol) in DMSO (5 mL) was stirred at 75° C. overnight. The mixture was poured into water (10 mL) and extracted with EtOAc (7 mL×3). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated under vacuum to dryness. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 30:1) to afford N-tert-butyl-4-nitroaniline (1 g, 73%). 1H NMR (CDCl3, 400 MHz) δ 8.03-8.00 (m, 2H), 6.61-6.57 (m, 2H), 4.67 (brs, 1H), 1.42 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:8])=[O:7])=[CH:4][CH:3]=1.[N:11]1[CH:16]=CC=[CH:13][CH:12]=1.C(OCC)(=[O:19])C>>[ClH:8].[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:19][CH2:13][CH2:12][NH:11][CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: c1ccncc1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(C)=O
Product: CNCCOC(=O)c1ccc(F)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
To a mixture of tert-butyl 2-hydroxyethyl (methyl)carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (10 mL) were added 4-fluorobenzoyl chloride (1.74 g) and pyridine (0.97 mL). The mixture was stirred at room temperature for 6.5 hrs. Ethyl acetate (80 mL) was added to the reaction mixture, and the mixture was washed with water (30 mL), a saturated aqueous sodium hydrogen carbonate solution (30 mL), water (30 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, a 4N hydrogen chloride—ethyl acetate solution (10 mL) was added to the residue. After stirring at room temperature for 1 hr., the precipitated solid was collected by filtration. The solid was washed twice with ethyl acetate (15 mL) and dried under reduced pressure at 60° C. to give the title compound (1.89 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:16])[C:5]([C:12]([O:14][CH3:15])=[O:13])=[N:6][NH:7]2.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H-].[Na+]>CN(C)C=O>[CH2:17]([N:7]1[C:8]2[C:3](=[C:2]([Cl:1])[CH:11]=[CH:10][CH:9]=2)[C:4](=[O:16])[C:5]([C:12]([O:14][CH3:15])=[O:13])=[N:6]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1n[nH]c2cccc(Cl)c2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1nn(Cc2ccccc2)c2cccc(Cl)c2c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.3 %

Procedure:
To 1.00 g (4.2 mmol) of methyl 5-chloro-4-oxo-1,4-dihydrocinnoline-3-carboxylate and 0.86 g (5.0 mmol) of benzyl bromide in 30 mL of dimethylformamide was added 0.20 g (5.0 mmol) of sodium hydride (60% dispersion in mineral oil). The mixture was stirred for 4 h at room temperature and quenched with water. The mixture was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated onto silica gel. The crude material was purified by flash chromatography eluting with a 33-50% ethyl acetate/hexanes gradient mixture to give 0.86 g (62%) of the title compound as a light yellow solid.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[NH2:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[NH2:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[O:12][CH2:2][C:3]#[N:4]
Reactant: Nc1cccc(O)c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: N#CCOc1cccc(N)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59 %

Procedure:
2-Bromoacetonitrile (0.22 g, 1.83 mmol), 3-aminophenol (0.2 g, 1.83 mmol) and potassium carbonate (0.5 g, 3.67 mmol) were combined in dry DMF (10 ml). The reaction was stirred at room temperature for 24 hours. The reaction was diluted with water and ethyl acetate. The organic solution was washed with brine, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 50% ethyl acetate in dichloromethane to afford the title compound as a colourless oil (0.16 g, 58.9%). 1H-NMR (500 MHz, CDCl3): δ 3.76 (s, br, 2H), 4.69 (s, 2H), 6.29 (d, J=2.3 Hz, 1H), 6.37 (dd, J=2.3 Hz, 8.1 Hz, 1H), 6.41 (dd, J=2.3 Hz, 8.1 Hz, 1H), 7.1 (t, J=8.1 Hz, 1H).
Reaction SMILES: [N:1]([N:3]1[CH2:9][CH:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[C:7]2[CH:21]=[CH:22][CH:23]=[CH:24][C:6]=2[CH2:5][CH2:4]1)=O.[C:25]([OH:28])(=[O:27])[CH3:26].[OH2:29]>[Zn]>[C:11]([OH:29])(=[O:10])/[CH:16]=[CH:26]\[C:25]([OH:28])=[O:27].[NH2:1][N:3]1[CH2:9][CH:8]([O:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=2)[C:7]2[CH:21]=[CH:22][CH:23]=[CH:24][C:6]=2[CH2:5][CH2:4]1
Reactant: CC(=O)O
Reactant: O
Reactant: O=NN1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Agent: [Zn]
Product: NN1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Product: O=C(O)/C=C\C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Zinc dust (12 g) was added to a solution of 3-nitroso-2,3,4,5-tetrahydro-1-(4-trifluoromethylphenoxy)-3-benzazepine (9 g) in 150 ml of 2:1 acetic acid/water mixture. After stirring at ambient temperature for three hours, the reaction mixture was filtered, stirred with ice and basified with ammonium hydroxide. The oil which had separated was extracted with dichloromethane. The dried (anhydrous magnesium sulfate) organic extract was filtered and concentrated. The residue was eluted through silica with 3% methanol in dichloromethane via high performance liquid chromatography to yield 6.3 g of white solid, mp 98°-100°. A three gram portion was converted to the maleate salt in 5% methanol/ether to yield 2.7 g of white solid, mp 129°-131°.
Reaction SMILES: C(O)(C)C.Cl[C:6]1[CH:11]=[C:10]([Cl:12])[N:9]=[CH:8][N:7]=1.Cl.[N:14]1([NH2:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15]1>O>[Cl:12][C:10]1[N:9]=[CH:8][N:7]=[C:6]([NH:23][N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)[CH:11]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nn1ccc2ccccc21
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: Clc1cc(Nn2ccc3ccccc32)ncn1
Temperature: 90 °C
Reaction time: 7 h

Procedure:
To 250 ml isopropanol, was added 4,6-dichloropyrimidine (12 g), 1 ml ethereal -HCl, and 1H-indol-1-amine (15 g). After stirring at 90° C. for seven hours, the mixture was poured into 300 ml iced water, stirred for five minutes, then extracted three times with 200 ml of ethyl acetate. The organic layer was washed with water, then dried (saturated NaCl, anhydrous MgSO4).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:18]=2[NH:17][CH2:16][CH2:15]3)=[O:9])=[CH:4][CH:3]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:28]=[N:29][C:30]3[C:35]([CH:36]=2)=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:23]=[CH:22][N:21]=1.C(OCC)(=O)C.O>CS(C)=O>[NH:17]1[C:18]2[C:14](=[CH:13][CH:12]=[CH:11][C:10]=2[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:20]3[N:25]=[C:24]([NH:26][C:27]4[CH:28]=[N:29][C:30]5[C:35]([CH:36]=4)=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH:23]=[CH:22][N:21]=3)=[CH:7][CH:6]=2)=[O:9])[CH2:15][CH2:16]1
Reactant: Clc1nccc(Nc2cnc3ccccc3c2)n1
Reactant: Nc1ccc(C(=O)c2cccc3c2NCC3)cc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: O=C(c1ccc(Nc2nccc(Nc3cnc4ccccc4c3)n2)cc1)c1cccc2c1NCC2

Procedure:
200 mg (0.84 mmol) of (4-aminophenyl)-(2,3-dihydro-1H-indol-7-yl)methanone and 215 mg (0.84 mmol) of (2-chloropyrimidin-4-yl)quinolin-3-ylamine are warmed at 120° C. for 2 h in 2 ml of DMSO. The organic phase is stirred with ethyl acetate and water and purified by chromatography over silica gel after phase separation, drying and evaporation, giving 500 mg of (2,3-di-hydro-1H-indol-7-yl)-{4-[4-(quinolin-3ylaminopyrimidin-2-ylamino]phenyl}-methanone. (M.p.: 235-238° C.)
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:8]([F:22])=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.[CH2:23]([O:25][C:26](=[O:37])[C:27](=[CH:33]OCC)[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:24]>C1(C)C(C)=CC=CC=1>[CH:1]1([N:4]([CH:33]=[C:27]([C:26]([O:25][CH2:23][CH3:24])=[O:37])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:5]2[CH:6]=[CH:7][C:8]([F:22])=[C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:10]=2)[CH2:2][CH2:3]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCOC(=O)N1CCN(c2nc(NC3CC3)ccc2F)CC1
Solvent: Cc1ccccc1C
Product: CCOC(=O)C(=CN(c1ccc(F)c(N2CCN(C(=O)OCC)CC2)n1)C1CC1)C(=O)OCC
Yield: 39.1 %

Procedure:
A solution of 3.8 g (12.3 mmole) of 4-[6-(cyclopropylamino)-3-fluoro-2-pyridinyl]-1-piperazine carboxylic acid, ethyl ester, 2.7 g (12.3 mmole) of diethyl(ethoxymethylene)malonate and 50 ml of xylene was refluxed for 24 hours. The solvent was removed in vacuo and the residue was chromatographed over silica gel eluting with chloroform/ethyl acetate (80/20) to give 2.3 g of the title compound as a viscous oil which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[C:4]([C:9]([O:11][CH3:12])=[O:10])[N:3]=1.NCCCN.[I-:18].[Na+].[CH2:20](O)[CH2:21][CH2:22][CH2:23]C>O.[Cu]I>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:18])=[C:4]([C:9]([O:11][CH2:12][CH2:20][CH2:21][CH2:22][CH3:23])=[O:10])[N:3]=1
Reactant: [I-]
Reactant: COC(=O)c1nc(N)ccc1Br
Reactant: CCCCCO
Agent: [Cu]I
Agent: NCCCN
Agent: [Na+]
Solvent: O
Product: CCCCCOC(=O)c1nc(N)ccc1I
Temperature: 135 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-amino-5-bromo-6-methoxycarbonylpyridine (13.8 g, 59.3 mmol) in n-pentanol (75 mL) was added 1,3-diaminopropane (900 mg, 12.1 mmol), copper (I) iodide (1.15 g, 6.0 mmol) and sodium iodide (18.0 g, 120 mmol). The reaction mixture heated to 135° C. After 16 hours (HPLC analysis shows ˜70% conversion), further portions of copper (I) iodide (600 mg, 3.0 mmol), sodium iodide (9.0 g, 60 mmol) and 1,3-diaminopropane (450 mg, 6.0 mmol) were added. After a further 4 hours, the reaction mixture was cooled to room temperature, diluted with water (200 mL), and extracted with ethyl acetate (2×200 mL). The combined organic extracts were dried over magnesium sulphate and concentrated under reduced pressure. Filtration through a short plug of silica, washing with ethyl acetate:cyclohexane 1:2 affords 2-amino-5-iodo-6-npentyloxycarbonylpyridine (8.94 g, 26.7 mmol, 45%) as a pale yellow solid. 1H NMR (CDCl3) 7.82 (1 H, d, J 12 Hz, C4-H, 6.36 (1 H, d, J 12 Hz, C3-H, 4.65 (2H, m, NH2), 4.36 (2 H, d, J 8 Hz, COCH2), 1.87-0.89 (9 H, m, CH2CH2CH2CH3)
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:3]=1.Cl.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20].C(N(CC)CC)C>C(#N)C>[CH3:22][O:21][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][S:8]([C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1)(=[O:10])=[O:9]
Reactant: COC(=O)CCCCCN
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCNS(=O)(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
Pyridine-3-sulfonyl chloride hydrochloride (92c) (1.8 g, 5.0 mmol) was added to a solution of methyl 6-aminohexanoate hydrochloride (91) (1.82 g, 10 mmol) and triethylamine (3.03 g, 30 mmol) in acetonitrile (30 ml). The mixture was stirred for 1 hour at ambient temperature, filtered and solvents were removed under reduced pressure. The oily product was dissolved in water (15 ml) and extracted with ethyl ether (50 ml). The extract was dried (Na2SO4) and the solvents were removed under reduced pressure. The title compound (1.09 g, 76%) was obtained as oil and was used for the next step without an additional purification. 1H NMR δH (90 MHz, DMSO-d6) δ: 0.80-1.51 (6H, m, CH2); 1.83 (2H, t, J=6.5 Hz, CH2); 2.76 (2H, t, J=6.5 Hz, CH2N); 3.58 (3H, s, CH3); 7.54 (1H, dd, J=5.0 Hz, J=8.2 Hz, C5HN 8.12 (1H, dt, J=2.0 Hz, J=8.2 Hz, C5HN); 8.61 (1H, dd, J=2.0 Hz, J=5.0 Hz, C5HN); 8.81 (1H, d, J=2.0 Hz, C5HN).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[C:13]1[CH:23]=[CH:24][C:25]1[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:33])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:34]1(=[O:40])[NH:38][C:37](=[O:39])[CH:36]=[CH:35]1>>[Cl:33][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:25]=1[CH:24]1[CH:36]2[C:37](=[O:39])[NH:38][C:34](=[O:40])[CH:35]2[C:14]2[C:15]3[CH:16]=[C:17]([O:21][CH3:22])[CH:18]=[CH:19][C:20]=3[NH:12][C:13]=2[CH2:23]1.[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:13]2[CH2:23][CH:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=3[O:31][CH3:32])[CH:36]3[C:37](=[O:39])[NH:38][C:34](=[O:40])[CH:35]3[C:14]=2[C:15]2[CH:16]=[C:17]([O:21][CH3:22])[CH:18]=[CH:19][C:20]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C1C=CC(=O)N1
Reactant: COc1ccc2c(c1)cc(C=Cc1c(Cl)cccc1OC)n2CCCO[Si](C)(C)C(C)(C)C
Product: COc1ccc2[nH]c3c(c2c1)C1C(=O)NC(=O)C1C(c1c(Cl)cccc1OC)C3
Product: COc1ccc2c(c1)c1c(n2CCCO[Si](C)(C)C(C)(C)C)CC(c2ccccc2OC)C2C(=O)NC(=O)C12

Procedure:
The reaction of 1-(3-{[tert-Butyl(dimethyl)silyl]oxy}propyl)-2-[2-(2-chloro-6-methoxyphenyl)ethenyl]-5-methoxy-1H-indole (III; Ar=2-chloro-6-methoxyphenyl, R10═CH2CH2CH2OSiMe2t-Bu) (103) prepared as described in example 56 with maleimide using the procedure described in example 68 gave 6-(3-[tert-Butyl(dimethyl)silyl]oxy}propyl)-4-(2-chloro-6-methoxyphenyl)-9-methoxy-4,5,6,10c-tetrahydropyrrolo[3,4-c]carbazole-1,3(2H,3aH)-dione (IV; Ar=2-chloro-6-methoxyphenyl, R10═CH2CH2CH2OSiMe2t-Bu) (104) in a 77% yield as a cream powder, which was used without further purification.
Reaction SMILES: Br[CH2:2][N:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]1[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].[N-:20]=[N+:21]=[N-:22].[Na+].CC(C)=O>[I-].[K+].O>[N:20]([CH2:2][N:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]1[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)CC1c2ccccc2C(=O)NN1CBr
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)CC1c2ccccc2C(=O)NN1CN=[N+]=[N-]
Yield: 96.1 %

Procedure:
A mixture of ethyl 2-bromomethyl-4-oxo-3H-phthalazine-1-yl-acetate (2.0 g), sodium azide (0.4 g), acetone (20 ml), water (2 ml) and a catalytic amount of potassium iodide (10 mg) was stirred at room temperature for 4 hours. The mixture was concentrated under vacuum to remove the solvents and obtain the title product as a white solid (1.7 g).
Reaction SMILES: [NH:1]1[C:5]([CH:6]=[O:7])=[CH:4][CH:3]=[C:2]1[CH:8]=[O:9].[O-:10][Mn](=O)(=O)=O.[K+].[OH2:16]>>[NH:1]1[C:5]([C:6]([OH:7])=[O:16])=[CH:4][CH:3]=[C:2]1[C:8]([OH:10])=[O:9]
Reactant: O
Reactant: O=Cc1ccc(C=O)[nH]1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: O=C(O)c1ccc(C(=O)O)[nH]1
Temperature: 97.5 °C
Reaction time: 1 h

Procedure:
Pyrrole-2,5-dicarbaldehyde (0.21 g, 1.71 mmol) was dissolved in 35 ml of hot water and placed in a hot water bath (95-100° C.). A solution of KMnO4 (0.788 g, 5.13 mmol) in 10 ml of water was added dropwise in a period of 5 min. The reaction mixture was stirred at 95-100° C. for 1 h, and was then cooled to 70° C. The brown precipitates (MnO2) were filtered off and washed with water. The filtrate was acidified at 0° C. with 5 M HCl to pH 2, evaporated to dryness, and dried under high vacuum. The product was dissolved in 80 ml of anhydrous EtOH and the solution was filtered through a funnel. The filtrate was evaporated to give a brown solid (0.25 g), which was used in next reaction without further purification. ESI MS: 154.00 (M−H+). 1H NMR (DMSO-d6) δ 12.68 (br. S), 12.17 (s), 6.72 (s).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:29][CH:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:27][CH:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH2:29]3)=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CC(N3CCOCC3)C2)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CC(N3CCOCC3)C2)no1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-(3-{[3-(4-morpholinyl)-1-azetidinyl]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoate (Preparation 27) (1.32 g, 2.70 mmol) in dichloromethane (15 ml) was cooled to 0° C. and treated with trifluoroacetic acid (5 ml). The resulting mixture was stirred for 3 hours being allowed to warm to room temperature over this time. The solvent was removed under reduced pressure and the residue azeotroped from toluene (×3) then dichloromethane to afford the title compound as a white foam (1.31 g).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:9]([CH:23]=[C:24]([CH2:26][O:27][C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=4)[N:25]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([O:21]C)=[O:20])=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Li+].[OH-].Cl>C1COCC1.O>[N:1]1([C:7]2[C:8]3[N:9]([CH:23]=[C:24]([CH2:26][O:27][C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=4)[N:25]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
To a solution of compound 15b (500 mg, 0.960 mmol) in THF (20 mL) was added a solution of LiOH (100 mg, 4.18 mmol) in H2O (5 mL). The resulting solution was stirred at rt overnight, and then diluted with H2O (20 mL). The pH of the solution was adjusted to 3 with 2 N HCl solution. The resulting solids were collected by filtration and washed with Et2O to obtain compound 15c as a yellow solid (350 mg, 72% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H23N9O2: 482.2 (M+H). Found 482.0.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:3]=1[NH2:4].[CH3:11][S:12][CH3:13].ClN1C(=O)CCC1=O.[OH-].[Na+]>C(N(CC)CC)C.ClCCl>[CH3:11][S:12][CH2:13][C:5]1[C:6]([F:10])=[C:7]([F:9])[CH:8]=[C:2]([F:1])[C:3]=1[NH2:4]
Reactant: Nc1cc(F)c(F)cc1F
Reactant: CSC
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSCc1c(N)c(F)cc(F)c1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To 2,4,5-trifluoroaniline (35.0 g) are added anhydrous dichloromethane (530 ml) and dimethyl sulfide (24.6 ml) and the mixture is cooled to 0° C. Thereto N-chlorosuccinimide (38.2 g) is gradually added below 5° C. After the mixture is stirred at the same temperature for 15 minutes, triethylamine (47.7 ml) is gradually added. After reflux for 12 hours, the resultant is made alkaline with 5% aqueous sodium hydroxide solution, extracted with dichloromethane, and the extract is dried over sodium sulfate and concentrated. The residue is purified with column chlomatography (silica-gel, dichloromethane:n-hexane=1:4) to give 2-methylthiomethyl-3,4,6-trifluoroaniline (22.3 g).
Reaction SMILES: [C:1]1([C@H:7]([N:9]2[C@H:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@@H:13]3[CH2:20][C@H:10]2[CH:11]=[CH:12]3)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:21]N1C(=O)CCC1=O.[OH2:29]>CS(C)=O>[OH:29][C@H:11]1[C@H:10]2[C@@H:20]([I:21])[C@H:13]([C@@H:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:9]2[C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])[CH2:12]1
Reactant: CCOC(=O)[C@@H]1[C@H]2C=C[C@H](C2)N1[C@H](C)c1ccccc1
Reactant: O
Reactant: O=C1CCC(=O)N1I
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1[C@@H]2C[C@@H](O)[C@@H]([C@H]2I)N1[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl (1S,3S,4R)-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate obtained in Example 5-1 (2.44 g) in dimethyl sulfoxide (12 mL) and water (1.5 mL), was added N-iodosuccinimide (2.06 g). The mixture was stirred at room temperature for 30 minutes.