Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[CH3:8].ClC1C=CC=C(C(OO)=[O:17])C=1>ClCCl>[N+:1]1([O-:17])[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[CH3:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccnc1C
Solvent: ClCCl
Product: Cc1ccc[n+]([O-])c1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
Commercially available 2,3-lutidine (5.00 g) was dissolved in dichloromethane (50 ml) and the solution was cooled to 0° C. After that, the solution was added with meta-chloroperbenzoic acid (12.1 g) and then stirred at room temperature for 2 hours. After completion of the reaction, the solution was added with dichloromethane and washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution, followed by drying with anhydrous sodium sulfate. Then, the solvent was distilled off, thereby obtaining crude 2,3-lutidin-N-oxide (3.16 g). A 2.00 g part thereof was dissolved in dichloromethane (40 ml) and then the solution was cooled to 0° C. Subsequently, the solution was added with trifluoroacetic anhydride (4.49 ml), followed by stirring at room temperature for 4 hours and then at 45° C. for 3 hours. After completion of the reaction, the solvent was distilled off and the residue was dissolved in methanol (30 ml), followed by the addition of a sodium methoxide/methanol solution until the pH of the solution would reach pH=10. After the solution had been stirred at room temperature for 1 hour, the solvent was distilled off and extraction was then carried out with dichloromethane. The extract was dried with anhydrous sodium sulfate and the solvent was then distilled off, thereby obtaining 3-methyl-2-hydroxymethylpyridine (1.30 g). A 605.3 mg part thereof was dissolved in chloroform (30 ml) and then added with manganese dioxide (chemically processed product) (3.03 g), followed by stirring at 70° C. for 2 hours. After completion of the reaction, the catalyst was removed through Celite filtration and the solvent was then concentrated. Then, the residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (419.8 mg) as a pale-orange colored liquid.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[S:15][C:16]2[CH2:24][CH2:23][C:22]3[NH:21][N:20]=[CH:19][C:18]=3[C:17]=2[N:25]=1>C1COCC1>[CH3:3][CH:2]([CH3:4])[C:1]([N:21]1[C:22]2[CH2:23][CH2:24][C:16]3[S:15][C:14]([NH:13][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=4)=[N:25][C:17]=3[C:18]=2[CH:19]=[N:20]1)=[O:5]
Reactant: c1ccc(Nc2nc3c(s2)CCc2[nH]ncc2-3)nc1
Reactant: CC(C)C(=O)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)n1ncc2c1CCc1sc(Nc3ccccn3)nc1-2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
According to Scheme 5: Isobutyryl chloride (0.37 mmol, 39 μL) was added dropwise to a solution of N-(pyridin-2-yl)-5,6-dihydro-4H-thiazolo[4,5-e]indazol-2-amine (0.37 mmol, 100 mg) in THF (2 mL) and the reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was quenched with a saturated solution of NaHCO3 and the aqueous phase was extracted with DCM. The organic phase was dried over Na2SO4, was filtered and was concentrated. The resulting crude product was purified by flash chromatography over silica gel using DCM as eluent to yield after evaporation 2-methyl-1-(2-(pyridin-2-ylamino)-4H-thiazolo[4,5-e]indazol-6(5H)-yl)propan-1-one
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]2=[C:6]([CH:24]=1)[C:7](=[O:23])[N:8]([O:15][Si](C(C)(C)C)(C)C)[C:9]3=[O:14]>Cl.C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]2=[C:6]([CH:24]=1)[C:7](=[O:23])[N:8]([OH:15])[C:9]3=[O:14]
Reactant: CC(C)(C)[Si](C)(C)ON1C(=O)c2cccc3cc(N)cc(c23)C1=O
Agent: Cl
Solvent: CCO
Product: Nc1cc2c3c(cccc3c1)C(=O)N(O)C2=O
Yield: 76.2 %

Procedure:
A solution of compound 5-amino-2-tert-butyldimethylsilyoxy-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinoline (0.8 g, 2.3 mmol, from Example B) in 2% HCl in ethanol (50 mL) was stirred at room temperature for 1 hour. The solid which formed was filtered and dried, to give 0.4 g of the title compound, mp 288-294° C. (dec).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:14][C:15]1(C(O)=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.S(O[O-])([O-])(=O)=O.[NH4+].[NH4+]>C(#N)C.O.C(OCC)C.[N+]([O-])([O-])=O.[Ag+]>[OH:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[C:11]=1[C:15]1([CH3:14])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Reactant: CC1(C(=O)O)CCCCC1
Agent: [Ag+]
Agent: O=S(=O)([O-])O[O-]
Agent: O=[N+]([O-])[O-]
Solvent: CCOCC
Solvent: CC#N
Solvent: O
Product: CC1(C2=C(O)C(=O)c3ccccc3C2=O)CCCCC1
Temperature: 20 °C
Yield: 19.2 %

Procedure:
To a stirred solution of 2-hydroxy-naphthalene-1,4-dione (1.00 g, 5.7 mmol), 1-methylcyclohexanecarboxylic acid (1.22 g, 8.6 mmol) and silver nitrate (600 mg) in a mixture of acetonitrile (20 ml) and water (20 ml) at 65° C. was slowly added a solution of ammonium peroxysulphate (1.96 g, 8.6 mmol) in water (10 ml) over a period of 15 minutes. The mixture was heated for a further hour before cooling to room temperature (about 20° C.) and diluting with diethyl ether (50 ml). The organic phase was separated and washed successively with water, dilute aqueous sodium hydrogen carbonate solution, water and saturated sodium chloride solution before drying over magnesium sulphate. Filtration and evaporation of the solvent under reduced pressure followed by silica gel column chromatography using 2:1 petrol:diethyl ether as eluant gave 2-hydroxy-3-(1-methyl-cyclohexyl)naphthalene-1,4-dione (296 mg) as a yellow crystalline compound, m.pt.: 79° C.
Reaction SMILES: [NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1>[Pd].COCCOCCOC>[NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: Cc1cc(C)c2c(c1)-c1c(nc(N)[nH]c1=O)CC2
Agent: [Pd]
Solvent: COCCOCCOC
Product: Cc1cc(C)c2ccc3nc(N)[nH]c(=O)c3c2c1

Procedure:
A mixture of 3-amino-5,6-dihydro-7,9-dimethylbenzo[f]quinazolin-1(2H)one (0.25 g, 1.04 mmole) and 10% palladium on carbon (0.5 g) in diglyme (25 ml) was vigorously stirred and refluxed under a nitrogen atmosphere for 2.5 hours, and then filtered while still hot through a bed of celite. Diglyme was removed from the filtrate under reduced pressure, and the residue was triturated with hot methanol, filtered, washed with methanol and ether, and dried to give 3-amino-7,9-di-methylbenzo[f]quinazolin-1(2H)-one as an off-white solid. (0.14 g, 55%) 1H NMR (DMSO-d6, 200 MHz) δ: 2.43 (s, 3H, CH3); 2.60 (s, 3H, CH3); 6.48 (s, 2H, NH2); 7.14 (s, 1H, Ar); 7.25 (d, J=9.2 Hz, 1H, Ar); 8.11 (d, J=9.1 Hz, 1H, Ar); 9.38 (s, 1H, Ar); 11.07 (s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][NH:9][CH:8]([CH3:21])[CH2:7][C:6]=2[CH:22]=1.[CH3:23][N:24]=[C:25]=[O:26]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([C:12]3[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)=[N:10][N:9]([C:25](=[O:26])[NH:24][CH3:23])[CH:8]([CH3:21])[CH2:7][C:6]=2[CH:22]=1
Reactant: CC1Cc2cc(Cl)ccc2C(c2ccc([N+](=O)[O-])cc2)=NN1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2ccc(Cl)cc2CC1C
Reaction time: 240 h
Yield: 95.1 %

Procedure:
0.72 g (2.2 mmoles) of 7-chloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine prepared in Example 1, Step D are dissolved in 15 ml of anhydrous dichloromethane, and to the solution obtained, 1.3 ml (22.0 moles) of methyl isocyanate are added, and the reaction mixture is left to stand at 25° C. for 10 days. The mixture is evaporated, and the residue is recrystallized from 3 ml of hot ethanol. The crystals are filtered, washed 3 times using 1 ml of ethanol each time, then dried. Thus, 0.78 g (95%) of the title compound are obtained. M.p.: 224°-226° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([OH:33])=O)[C:25]=1[CH3:34])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH:56]1[CH2:60][CH2:59][C@@H:58]([OH:61])[CH2:57]1>CN(C=O)C.C(Cl)Cl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([N:56]2[CH2:60][CH2:59][C@@H:58]([OH:61])[CH2:57]2)=[O:33])[C:25]=1[CH3:34])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Reactant: O[C@@H]1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)N1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (200 mg), HOBt (1 eq.), EDAC (2 eq.), TEA (3 eq.) and (R)-pyrrolidin-3-ol (3 eq.) in DMF (4 mL) was stirred at rt for overnight. The reaction was diluted with DCM, washed with water (2×) and 10% sodium carbonate (2×). The DCM was dried, concentrated and purified on a silica gel column to give 21 mg of the titled compound. MS m/z 588 [M++1].
Reaction SMILES: BrC1C=CC(S([O:11][C@@H:12]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]2)(=O)=O)=CC=1.[Br:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[C:34]([O:41][CH2:42][CH3:43])[CH:33]=[C:32]2O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[Br:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[C:34]([O:41][CH2:42][CH3:43])[CH:33]=[C:32]2[O:11][C@H:12]1[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]1
Reactant: CCOc1cc(O)c2cc(Br)c(OC)cc2n1
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOc1cc(O[C@@H]2C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C2)c2cc(Br)c(OC)cc2n1

Procedure:
A suspension of 1-t-butyl 2-methyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate (25.0 g, 53.8 mmol), the product of Step 3 (16.1 g, 53.8 mmol) and cesium carbonate (52.6 g, 162 mmol) in NMP (300 mL) was stirred at 75° C., under nitrogen, for 2 hours. At 22° C., the reaction was diluted with water (500 mL) and extracted with EtOAc (3×500 mL). The combined EtOAc layer was washed with water (3×100 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel 60, eluting with 0 to 50% EtOAc in hexane, to give the title product. 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H); 7.16 (s, 1H); 6.02 (s, 1H); 5.05 (m, 1H); 4.49 (m, 3H); 4.00 (s, 3H); 3.91 (m, 2H); 3.78 (s, 3H); 2.67 (m, 1H); 2.37 (m, 1H); 1.47 (s, 3H); 1.44 (s, 9H) ppm. LRMS (ESI) m/z 525.0 [(M+H)+; calcd for C23H30BrN2O7: 298.0].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([O:13]CC)=O)=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH:16]([C:19]1[N:24]=[C:23]([CH2:25][N:26]2[C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([NH2:35])[C:29]=3[C:28]([CH3:36])=[N:27]2)[CH:22]=[CH:21][CH:20]=1)([CH3:18])[CH3:17].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:35][C:30]3[CH:31]=[CH:32][CH:33]=[C:34]4[C:29]=3[C:28]([CH3:36])=[N:27][N:26]4[CH2:25][C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([CH:16]([CH3:17])[CH3:18])[N:24]=3)=[O:13])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: CCOC(=O)c1cnc2cc(Cl)ccn12
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(N)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(Cl)ccn34)c12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 59.8 %

Procedure:
A round bottom flask containing ethyl 7-chloroimidazo[1,2-a]pyridine-3-carboxylate (15.22 g, 67.8 mmol) and 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine (Preparation D; 19.0 g, 67.8 mmol) in 130 mls of THF was chilled to 0° C. LiHMDS (1M in THF, 149 mls, 149 mmol) was then added by syringe over a 15 minute period. Once the addition was complete, the reaction mixture was stirred at 0° C. for 15 minutes, and then quenched with saturated ammonium chloride (250 mls). This mixture was then extracted two times with EtOAc, the extracts were dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (100% EtOAc) afforded 18.6 g (60%) of the title compound.
Reaction SMILES: [CH2:1](Cl)[CH2:2][OH:3].[OH:5][C:6]1[C:11]([CH2:12][CH3:13])=[N:10][C:9]([CH3:14])=[C:8]([CH3:15])[N:7]=1.[OH-].[Na+].C([O-])([O-])=O.[K+].[K+]>C(O)(C)(C)C>[OH:3][CH2:2][CH2:1][N:7]1[C:8]([CH3:15])=[C:9]([CH3:14])[N:10]=[C:11]([CH2:12][CH3:13])[C:6]1=[O:5]
Reactant: CCc1nc(C)c(C)nc1O
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CCc1nc(C)c(C)n(CCO)c1=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
Ethylene chlorohydrin (32.21 g, 0.4M) was added to a solution of 2-hydroxy-3-ethyl-5,6-dimethyl-pyrazine (12.16 g, 80 mM) and 5N NaOH (80 ml) in t-butanol (240 ml), and stirred at 60° C. for 3 hours. Dilute aqueous K2CO3 was added to the reaction mixture, the mixture extracted with chloroform, and the resultant aqueous layer extracted twice with further chloroform. The combined chloroform layers were dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 250 g) packed with chloroform and eluted with chloroform-methanol (from 200:1 to 50:1) to obtain compound 630 (12.31 g, yield: 78.5%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([C:8](=[N:10][OH:11])[NH2:9])[CH:7]=1.[OH:14][CH2:15][C:16]1[CH:21]=[C:20]([C:22](O)=O)[CH:19]=[CH:18][C:17]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31].Cl.C(N=C=NCCCN(C)C)C.CCN(C(C)C)C(C)C>C1COCC1.C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([C:8]2[N:9]=[C:22]([C:20]3[CH:19]=[CH:18][C:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH3:31])=[C:16]([CH2:15][OH:14])[CH:21]=3)[O:11][N:10]=2)[CH:7]=1
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1CO
Reactant: COc1ccc(F)cc1C(N)=NO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1-c1noc(-c2ccc(-c3ccccc3C)c(CO)c2)n1
Temperature: 150 °C

Procedure:
Intermediate 23 (276 mg; 1.5 mmol; 1 eq.), Intermediate 41 (436 mg; 1.8 mmol; 1.2 eq.) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (345 mg; 1.8 mmol; 1.2 eq.) were dissolved in THF (6 mL) and acetonitrile (6 mL) and the reaction mixture was stirred at room temperature for 2 hours. DIEA (0.61 mL; 3.6 mmol; 2.4 eq.) was added and the mixture was heated in the microwave at 150° C. for 30 min. The reaction mixture was then filtered through a SPE-NH2 column (2 g) and through a SPE-SCX column (2 g) and rinsed with ACN. The filtrate was evaporated and the residue washed with ACN to afford the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:14](Cl)(=O)C(Cl)=O>C(#N)C>[CH3:14][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([OH:1])[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1cccc(O)c1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: CC#N
Product: COC(=O)c1cccc(O)c1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
3-Hydroxy-2-nitro-benzoic acid (commercially available) (31.5 g) was suspended in acetonitrile (100 ml). Oxalyl chloride (22 ml) in acetonitrile (20 ml) was added dropwise upon which a vigorous gas stream evolved. After 15 minutes the reaction slowed down and therefore, the reaction mixture was heated with a warm water bath (40° C.) for 40 minutes. The mixture was concentrated and the residue was re-dissolved in dichloromethane (100 ml). A mixture of methanol (50 ml) and triethylamine (20 ml) in dichloromethane (30 ml) was added dropwise while cooling the mixture with an ice bath. The reaction mixture was stirred at ambient temperature for 16 hours. The mixture was concentrated and the residue was purified by column chromatography on silica gel (eluent: 10-55% v/v ethyl acetate in heptane) to give 3-hydroxy-2-nitro-benzoic acid methyl ester (15.9 g). 1H-NMR (400 MHz, CDCl3): 10.15 (bs, 1H), 7.60 (t, 1H), 7.27 (d, 1H), 7.08 (d, 1H), 3.93 (s, 3H) ppm.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:26]=[CH:25][C:8]([CH:9]=[C:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH:14]=[CH:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[CH:7][CH:6]=1)(=O)[CH3:2].IC1C=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(C(C)C)=CC=1>[Cu]>[C:31]1([CH3:34])[CH:30]=[CH:29][C:1]([NH:4][C:5]2[CH:26]=[CH:25][C:8]([CH:9]=[C:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[CH:14]=[CH:13][C:12]4[CH:21]=[CH:22][CH:23]=[CH:24][C:11]3=4)=[CH:7][CH:6]=2)=[CH:2][CH:32]=1
Reactant: Cc1ccc(I)cc1
Reactant: CC(=O)Nc1ccc(C=C2c3ccccc3C=Cc3ccccc32)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccc(C(C)C)cc1
Product: Cc1ccc(Nc2ccc(C=C3c4ccccc4C=Cc4ccccc43)cc2)cc1
Yield: 63.6 %

Procedure:
8.0 g (23.7 m moles) of the thus obtained 5-(4-acetylaminobenzylidene)-5H-dibenzo[a,d]cycloheptene, 7.75 g (35.5 m moles) of p-iodotoluene, 3.70 g (26.8 m moles) of anhydrous potassium carbonate and 1.80 g of copper powder were added to 15 ml of p-cymene and stirred and refluxed for 5 hours. After the end of reaction, the reaction mixture was subjected to filtration by suction, and the filtrate was successively washed with an aqueous 3-5% sodium thiosulfate solution and an aqueous saturated NaCl solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed therefrom under reduced pressure. The residue was dissolved in 40 ml of tetrahydrofuran and admixed with 2.70 (50.0 m moles) of sodium methylate at room temperature. The mixture as such was stirred at room temperature for one hour, and then the reaction mixture was poured into 150 ml of water. The precipitated crystal was recovered therefrom by filtration, and recrystallized from ethanol-methylethylketone solvent mixture, whereby 5.81 g of 5-[4-(p-tolylamino)benzylidene]-5H-dibenzo[a,d]cycloheptene was obtained (yield: 63.6%). The melting point was 174.0°-175.0° C., and elemental analysis as C29H23N was as follows:
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][N:7]1[C:11](/[CH:12]=[C:13]2\[CH2:14][N:15]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:17][C:18]\2=[O:19])=[CH:10][N:9]=[N:8]1)=[O:4].[BH4-].[Na+].[Cl-].[NH4+]>ClCCl.CO>[CH3:1][O:2][C:3]([CH2:5][CH2:6][N:7]1[C:11](/[CH:12]=[C:13]2\[CH2:14][N:15]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17][CH:18]\2[OH:19])=[CH:10][N:9]=[N:8]1)=[O:4]
Reactant: COC(=O)CCn1nncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCn1nncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O
Temperature: 0 °C
Yield: 102.3 %

Procedure:
(E)-3-({1-[2-(Methoxycarbonyl)ethyl]-1H-1,2,3-triazol-5-yl}methylidene)-1-(triphenylmethyl)piperidin-4-one (12.87 g) was dissolved in a mixed solvent of dichloromethane (100 ml) and methanol (100 ml). While the solution was being stirred at 0° C., sodium borohydride (480 mg) was added thereto. The resulting mixture was stirred at 0° C. for 30 minutes, and the reaction was stopped by addition of a saturated aqueous ammonium chloride solution. The product was extracted with dichloromethane. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to afford the crude title compound (13.22 g) as a pale yellow amorphous solid. This product was used in the next process without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17](=[O:30])[CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][C:21]=2[Cl:29])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13]>CCOC(C)=O.[Pt]>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:18][C:17]([NH:16][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:2]([Cl:1])[CH:3]=2)=[O:30])=[C:21]([Cl:29])[CH:22]=1
Reactant: CCN(CC)CCOc1ccc(NC(=O)COc2ccc([N+](=O)[O-])cc2Cl)cc1Cl
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(N)cc2Cl)cc1Cl
Reaction time: 5 h

Procedure:
0.310 g (0.679 mmol) of N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-chloro-4-nitro-phenoxy)-acetamide (from Example 66) was dissolved in 10.0 mL of EtOAc. After the addition of 0.030 g Pt/C (5%) the mixture was hydrogenated at RT under 15 psi H2 atmosphere for 5 hours. The reaction mixture was filtered and the filtrate was evaporated down i. vac. The residue was dissolved with a little EtOH. The precipitate formed was filtered off and dried i. vac.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](O)=[O:16].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C1COCC1.O>[I:1][C:2]1[CH:3]=[C:4]([NH:5][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[C:12]([C:11]([F:10])([F:21])[F:22])[CH:13]=2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N)cc1I
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1I

Procedure:
A solution of 3-iodo-4-methylaniline (1.22 g, 5.25 mmol), 3-(trifluoromethyl)benzoic acid (0.95 g, 5 mmol), HOBt (0.68 g, 5 mmol), and EDCl (1.05 g, 5.5 mmol) in THF (20 mL) was stirred overnight at rt. Water was added and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, concentrated on a rotavap, and then subjected to silica gel column chromatography (3:1 hexane/ethyl acetate) yielding the desired product.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:7]=12.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][OH:26])=[CH:23][CH:22]=1>>[CH:14]1([CH2:13][N:8]2[C:7]3=[C:2]([O:26][CH2:25][C:24]4[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=4)[N:3]=[N:4][CH:5]=[C:6]3[C:10]([CH3:11])=[C:9]2[CH3:12])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: OCc1ccc(F)cc1
Reactant: Cc1c(C)n(CC2CCCCC2)c2c(Cl)nncc12
Product: Cc1c(C)n(CC2CCCCC2)c2c(OCc3ccc(F)cc3)nncc12
Yield: 45.6 %

Procedure:
The title compound was prepared as a white powder in 45.6% yield in a similar procedure to that described in Example 1 by using 7-chloro-1-cyclohexylmethyl-2,3-dimethylpyrrolo[2,3-d]pyridazine and 4-fluorobenzyl alcohol.
Reaction SMILES: [NH2:1][C:2]1[C:3](=O)[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:9]=2[CH3:17])[NH:6][N:7]=1.S(Cl)([Cl:21])=O>>[Cl:21][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:9]=2[CH3:17])[N:6]=[N:7][C:2]=1[NH2:1]
Reactant: Cc1c(-c2nc(=O)c(N)n[nH]2)cccc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Product: Cc1c(-c2nnc(N)c(Cl)n2)cccc1[N+](=O)[O-]
Yield: 102.7 %

Procedure:
A suspension of 6-amino-3-(2-methyl-3-nitrophenyl)-1,2,4-triazin-5(2H)-one (0.95 g, 3.38 mmol) in thionyl chloride (180 mL, 2466 mmol) was heated at reflux for 4 hr, after which period the mixture became a clear solution. The volatiles were removed under vacuum. The residue was dissolved in ice-cold ethyl acetate (250 mL), washed with water (2×60 mL), saturated NaHCO3 solution (60 mL), and brine (60 mL). The organic solution was dried over anhydrous MgSO4 and concentrated under vacuum to dryness to provide the desired product, 5-chloro-3-(2-methyl-3-nitrophenyl)-1,2,4-triazin-6-amine (0.97 g, 3.47 mmol, 77% yield over two steps), as a yellow solid.