Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:10][C:11](=[O:19])[C:12](=[CH:15]OCC)[C:13]#[N:14])[CH3:9]>N1C=CC=CC=1>[CH2:8]([O:10][C:11](=[O:19])[C:12](=[CH:15][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:13]#[N:14])[CH3:9]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: Nc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)C(C#N)=CNc1ccccc1
Yield: 49.9 %

Procedure:
0.91 ml (10 mmol) of aniline and 1.69 g (10 mmol of ethyl(ethoxymethylene)cyanoacetate were dissolved in 10 ml of pyridine and heated under reflux. After 3 h pyridine was removed under vacuum, and the residue was purified by chromatography (silica gel column, eluent 1% methanol in dichloromethane). 1.08 g (50%) of ethyl(anilinomethylene)cyanoacetate were obtained. The compound was cyclized by heating in a biphenyl/phenyl ether mixture. After cooling a precipitate was filtered and washed with diethyl ether to give 4-hydroxyquinoline-3-carbonitrile (49%). Following the procedure outlined in Step 3 of Example 1, but substituting 4-hydroxyquinoline-3-carbonitrile for 9-(10H)acridone, 4-chloro-3-cyanoquinoline (90%) was obtained, which was reacted with 4-(4-methylpiperazin-1-yl)aniline (according to the procedure of Step 4 in Example 1), to afford the title compound with 12% yield (overall yield 3%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[C:24]([OH:26])=O)/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:28][N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][NH2:36])[CH2:31][CH2:30]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C1COCC1.CN(C=O)C>[CH3:28][N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][NH:36][C:24]([C:23]2[CH:22]=[C:21]([CH3:27])[NH:20][C:19]=2/[CH:18]=[C:10]2\[C:11](=[O:17])[NH:12][C:13]3[C:9]\2=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:16]=[CH:15][CH:14]=3)=[O:26])[CH2:31][CH2:30]1
Reactant: CN1CCC(CN)CC1
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)NCC2CCN(C)CC2)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Yield: 55 %

Procedure:
2-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (90.5 mg) was coupled with C-(1-methyl-piperidin-4-yl)-methylamine (1.5 eq.), HOBt (1 eq.), EDC (1.5 eq.) and TEA (3 drops) in THF (2 mL), DMF (0.3 mL) at rt for overnight to give 65 mg (55%) of the titled compound as a yellow solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16](C(O)=O)=[CH:15][CH:14]=2)[C:7]([CH:10]=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[CH2:22]([N:26]1[CH2:32][C:30](=[O:31])[NH:29][C:27]1=[O:28])[CH2:23][CH2:24][CH3:25].[C:33]([OH:36])(=[O:35])C>O.CO>[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C:33]([OH:36])=[O:35])[C:7]([CH:10]=[C:32]2[C:30](=[O:31])[NH:29][C:27](=[O:28])[N:26]2[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O
Reactant: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)O)cc1
Reactant: CCCCN1CC(=O)NC1=O
Solvent: O
Solvent: CO
Product: CCCCc1ncc(C=C2C(=O)NC(=O)N2CCCC)n1Cc1ccccc1C(=O)O
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A solution of 3.44 g (0.012 mole) of 2-butyl-1-(4-carboxybenzyl)-5-formylimidazole, 2.40 g (0.016 mole) of 1-butylhydantoin, 25.92 g (0.071 mole) of 25% tetramethylammonium hydroxide-in-methanol and 12 mL of water is heated with stirring with an oil bath (bath temperature 135°-150° C.), allowing the methanol to distill over. After ca. 1/2 hour, the pot temperature is ca. 115°-120° C. The temperature is maintained 115°-120° C. for 15 minutes. The reaction solution is cooled to 70° C. and 5.04 g (0.084 mole) of glacial acetic acid and then ca. 100 mL of water are added to precipitate the mixed cis (Z) and trans (E) isomers. Separation with 200 mL of methanol, cooling, and filtering off the least soluble (E) isomer. Recrystallization of the (E) isomer is effected by dissolution in 50% methanol-methylene chloride and concentration to remove methylene chloride. The separated pale yellow crystals are filtered; mp 287°-289° C.; tlc (2:10 MeOH--CHCl3), 1 spot, Rf 0.4; nmr (DMSO--d6), vinyl proton at δ 5.86 ppm; MS (CI) 425.1 (M+ +1).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[Cl:15][C:16]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:24]([Cl:32])[C:23]2[C:18](=[C:19]([CH3:35])[CH:20]=[C:21]([CH:33]=[O:34])[CH:22]=2)[N:17]=1>C(Cl)Cl>[Cl:15][C:16]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:24]([Cl:32])[C:23]2[C:18](=[C:19]([CH3:35])[CH:20]=[C:21]([CH:33]([C:2]3[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=3)[OH:34])[CH:22]=2)[N:17]=1
Reactant: Cn1cncc1Br
Reactant: Cc1cc(C=O)cc2c(Cl)c(-c3ccccc3)c(Cl)nc12
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Product: Cc1cc(C(O)c2cncn2C)cc2c(Cl)c(-c3ccccc3)c(Cl)nc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-bromo-1-methyl-1H-imidazole (342 mg, 2.12 mmol) in DCM (2.2 mL) was stirred on an ice bath while iPrMgCl—LiCl (1.77 mL, 1.2 M in THF, 2.1 mmol) was added dropwise over 1-2 min under argon. After 10 min stirring at room temperature, the homogeneous amber reaction was added dropwise over 1-2 min to a slurry of 2,4-dichloro-8-methyl-3-phenylquinoline-6-carbaldehyde (460 mg, 1.46 mmol, Intermediate 47, step b) in LaCl3-2LiCl (7.60 mL, 0.56 M in THF, 1.46 mmol) on an ice bath. The reaction was removed from the ice bath immediately following Grignard addition and stirred for 45 min at ambient temperature, and was then partitioned with 9:1 DCM/MeOH (14 mL) and 5 M NH4Cl (0.72 mL). This was filtered over Celite®, and the filter cake washed with 9:1 DCM/MeOH (1×5 mL). The combined clear dark yellow filtrates were dried (Na2SO4), filtered, and concentrated to provide a beige foam. This was concentrated from DCM (3×15 mL) in prelude to MnO2 oxidation.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([OH:14])[CH:8]=1)[CH3:2].C([O-])(O)=O.[Na+].[Cl:21][CH2:22][C:23](Cl)=[O:24]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:23](=[O:24])[CH2:22][Cl:21])=[C:9]([OH:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(N)c(O)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C=Cc1ccc(NC(=O)CCl)c(O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 11-3 (3.38 g, 16.3 mmol) in CHCl3 (80 mL) was added saturated NaHCO3 (50 mL) and it was then chilled to 0° C. A solution of chloroacetyl chloride (1.94 mL, 24.4 mmol) in CHCl3 (30 mL) was added dropwise to the chilled biphase. Upon addition completion, the reaction was stirred at 0° C. for 1 h. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to give 11-4 which was used without further purification in the next step.
Reaction SMILES: [CH:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2].[CH2:12]([O:14][C:15](=[O:18])[CH:16]=O)[CH3:13].[Cl:19][C:20]1[C:28]([CH:29]=[CH2:30])=[CH:27][C:23]2[O:24][CH2:25][O:26][C:22]=2[CH:21]=1>>[CH2:12]([O:14][C:15]([CH:16]1[CH2:30][CH:29]([C:28]2[C:20]([Cl:19])=[CH:21][C:22]3[O:26][CH2:25][O:24][C:23]=3[CH:27]=2)[C:7]2[C:8](=[CH:10][CH:11]=[C:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[CH:6]=2)[NH:9]1)=[O:18])[CH3:13]
Reactant: CCOC(=O)C=O
Reactant: C=Cc1cc2c(cc1Cl)OCO2
Reactant: CCC(C)c1ccc(N)cc1
Product: CCOC(=O)C1CC(c2cc3c(cc2Cl)OCO3)c2cc(C(C)CC)ccc2N1

Procedure:
Compound 77 was prepared from 4-sec-butylaniline, glyoxylic acid ethyl ester and 5-chloro-6-vinyl-benzo[1,3]dioxol by the automated process.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([O:19][CH3:20])=[CH:6][C:4]=1[NH2:5].[CH3:21][N:22]1[CH2:26][CH2:25][CH2:24][C:23]1=[O:27].[OH:28][C:29]1[C:38]([C:39](Cl)=[O:40])=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:42](Cl)=[O:43])[CH:35]=2)[CH:30]=1>C1(C)C=CC=CC=1>[OH:28][C:29]1[C:38]([C:39]([NH:5][C:4]2[CH:6]=[C:7]([O:19][CH3:20])[C:8]([NH:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][C:3]=2[O:2][CH3:1])=[O:40])=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:42]([NH:5][C:4]3[CH:6]=[C:7]([O:19][CH3:20])[C:21]([NH:22][C:23](=[O:27])[C:24]4[CH:13]=[CH:12][CH:11]=[CH:26][CH:25]=4)=[CH:9][C:3]=3[O:2][CH3:1])=[O:43])[CH:35]=2)[CH:30]=1
Reactant: COc1cc(NC(=O)c2ccccc2)c(OC)cc1N
Reactant: CN1CCCC1=O
Reactant: O=C(Cl)c1ccc2cc(O)c(C(=O)Cl)cc2c1
Solvent: Cc1ccccc1
Product: COc1cc(NC(=O)c2ccc3cc(O)c(C(=O)Nc4cc(OC)c(NC(=O)c5ccccc5)cc4OC)cc3c2)c(OC)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
2,5-Dimethoxy-4-benzoylaminoaniline (16.6 g), N-methyl-2-pyrrolidone (111.2 g) and toluene (30.1 g) were dissolved at room temperature and the acid chloride (5.5 g) obtained in Example 6 was gradually added, and then the mixture was amidated according to Example 8. After the reaction solution was cooled to 25° C. and filtered, toluene was distilled off under reduced pressure. Then, the solution was crystallized by using methanol (377.2 g). The resultant product was subjected to reflux washing using methanol (250.0 g) for 1 hour, filtered and then dried to obtain 12.4 g of 2-hydroxy-3,6-bis(2,5-dimethoxy-4-benzoylaminophenyl-aminocarbonyl)naphthalene as a dull yellow powdered crystal (DSC analysis value: 327.4° C.).
Reaction SMILES: [CH2:1]([C:3]1([CH2:10][CH3:11])[CH2:8][CH:7]([OH:9])[CH2:6][CH2:5][O:4]1)[CH3:2].C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH2:10]([C:3]1([CH2:1][CH3:2])[CH2:8][C:7](=[O:9])[CH2:6][CH2:5][O:4]1)[CH3:11]
Reactant: CCC1(CC)CC(O)CCO1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CCC1(CC)CC(=O)CCO1
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of crude 2,2-diethyloxan-4-ol (500 mg, 3.2 mmol) in CH2Cl2 (10 ml) were added NMO (750 mg, 6.41 mmol) and 4A molecular sieves (2 g). The solution was stirred for 30 mins and then TPAP (34 mg, 0.096 mmol) was added in one portion. The reaction was allowed to stir for 10 h. After checking the TLC, the alcohol was gone. It was filtered through a short pad of SiO2. The filtrate was concentrated and purified by normal phase SiO2 chromatography (0% to 50% EtOAc/hexanes) to give 2,2-diethyloxan-4-one (365 mg, 73%).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]([F:20])([F:19])[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.S(=O)(=O)(O)O>C(O)(=O)C.O>[I:1][C:14]1[CH:13]=[C:12]([O:11][C:10]([F:19])([F:20])[F:9])[CH:17]=[CH:16][C:15]=1[OH:18]
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc(OC(F)(F)F)cc1I
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94 %

Procedure:
To a suspension of N-iodosuccinimide (6.95 g, 31 mmol) in glacial acetic acid (2 ml) was added 4-trifluoromethoxy phenol (4.0 ml, 31 mmol) and, after 5 minutes, concentrated sulphuric acid (0.5 ml, 9 mmol). The pale brown suspension was stirred at room temperature under nitrogen for 48 hours before diluting with water and extracting with dichloromethane. Organic extract was washed with water, saturated aqueous sodium thiosulphate solution, water, dried over magnesium sulfate and decolourising charcoal added. The resulting suspension was left to stand for 30 minutes before filtering through a short pad of silica gel eluting with dichloromethane. The solvent was evaporated in vacuo to give the title compound as an oil, 8.78 g, 94% yield.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][C@@H:7]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:6]2)#[N:2].[S:23]1[C:27]([CH:28]=O)=[CH:26][N:25]=[CH:24]1.C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:28][C:27]1[S:23][CH:24]=[N:25][CH:26]=1)[CH2:8][C@@H:7]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:6]2)#[N:2]
Reactant: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)c1ccccc1)CN2
Reactant: O=Cc1cncs1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)c1ccccc1)CN2Cc1cncs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.8 %

Procedure:
To a solution of 1G (94 mg, 0.3 mmol) and thiazole-5-carbaldehyde (67.9 mg, 0.6 mmol) (prepared following the procedures described in Alessandro Dondoni, et al, Synthesis, 11, 998-1001, (1987)) in a mixed solvents of TFA (0.75 mL) and CH2Cl2 (0.75 mL) was added Et3SiH (0.096 mL, 0.6 mmol). The resulting mixture was stirred at RT under argon for 18 h, then concentrated under reduced pressure. The residue was diluted with saturated aqueous NaHCO3, then extracted with EtOAc (3×20 mL). The combined EtOAc extracts were washed with brine, dried (Na2SO4), and concentrated. The resulting residue was chromatographed (silica gel) eluting with EtOAc (50-90%) in hexane to give the title compound as an off-white solid (70 mg, 57%). HPLC: 99% at 5.43 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient (A 90% H2O—10% MeOH—0.1% H3PO4 and B=10% H2O−90% MeOH−0.1% H3PO4), Flow rate at 2.5 mL/min, UV detection at 220 nm). MS (ES): m/z 411 [M+H]+; Chiral HPLC 100% e.e.; retention time=32.9 min; Conditions: AD (4.6×250 mm); Eluted with 40% isopropanol in hexane for 50 min at 1 mL/min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](I)[CH:15]=3)[C:10]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])=[N:9]2)[CH:5]=[C:4]([NH:23][CH3:24])[N:3]=1.N1CCCCC1.[N:31]1[CH:36]=[CH:35][CH:34]=[N:33][C:32]=1[C:37]([OH:41])([C:39]#[CH:40])[CH3:38]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.C(OCC)(=O)C.CCCCCCC>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:40]#[C:39][C:37]([OH:41])([C:32]4[N:33]=[CH:34][CH:35]=[CH:36][N:31]=4)[CH3:38])[CH:15]=3)[C:10]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])=[N:9]2)[CH:5]=[C:4]([NH:23][CH3:24])[N:3]=1
Reactant: C#CC(C)(O)c1ncccn1
Reactant: CNc1cc(-n2nc(C(=O)N(C)C)c3ccc(I)cc32)nc(N)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: CNc1cc(-n2nc(C(=O)N(C)C)c3ccc(C#CC(C)(O)c4ncccn4)cc32)nc(N)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a sealed tube was added 1-[2-amino-6-(methylamino)pyrimidin-4-yl]-6-iodo-N,N-dimethyl-1H-indazole-3-carboxamide (86 mg, 0.20 mmol), followed by piperidine (2 mL), tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol), copper(I) iodide (4 mg, 0.02 mmol) and 2-(pyrimidin-2-yl)but-3-yn-2-ol (58 mg, 0.39 mmol). The reaction mixture was purged with nitrogen gas, capped and stirred at room temperature for 1.5 hr. After cooling to RT, the reaction mixture was concentrated in vacuo. EtOAc (5 mL) was added and concentration in vacuo repeated. The residue was purified using column chromatography (Biotage, 0-10% gradient of methanol in DCM) to give a brown solid. Trituration of the solid with ethyl acetate/heptane gave the title compound. 1H NMR (DMSO, 500 MHz) delta 1.92 (3H, s), 2.80 (3H, d, J=4.1 Hz), 3.10 (3H, s), 3.31 (3H, s), 6.26 (2H, s), 6.49 (2H, s), 7.11 (1H, s), 7.30 (1H, d, J=8.4 Hz), 7.51 (1H, t, J=4.9 Hz), 7.94 (1H, d, J=8.4 Hz), 8.78-9.04 (3H, m); LC-MS: m/z=+458.10 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=[C:4]([CH3:17])[N:3]=1.[Cl:18][C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([OH:26])=[C:21]([CH3:27])[CH:20]=1.CC(C)([O-])C.[K+]>C1COCC1>[Cl:18][C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([O:26][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=[C:4]([CH3:17])[N:3]=2)=[C:21]([CH3:27])[CH:20]=1
Reactant: CCC(CC)Nc1cc(C)nc(Cl)c1[N+](=O)[O-]
Reactant: Cc1cc(Cl)cc(C)c1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.1 %

Procedure:
To a mixture of (2-chloro-6-methyl-3-nitro-pyridin-4-yl)-(1-ethyl-propyl)-amine (850 mg, 3.30 mmol) and 4-chloro-2,6-dimethylphenol (516 mg, 3.30 mmol) in 25 ml of dry THF was added potassium tert-butoxide (370 mg, 3.30 mmol) and the resulting mixture was stirred at room temperature overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give a yellow solid (1.31 g). The solid was purified through silica gel column chromatography using 6:4 ratio of chloroform:hexane as eluent to give 1.10 g (88%) of the title compound as yellow solid, mp 152–154° C. 1H NMR (CDCl3) δ 7.65 (d, 1H), 7.05 (s, 2H), 6.21 (s, 1H), 3.41 (m, 1H), 2.15 (s, 3H), 2.11 (s, 6H), 1.5–1.8 (m, 4H), 0.99 (t, 6H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[OH:9].[C:10]1([CH2:16][O:17][CH2:18][CH:19](O)[CH:20](O)[CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OC(C)C)(C)C.O>[F:1][C:2]1[C:3]2[O:9][C@@H:19]([CH2:18][O:17][CH2:16][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C@H:20]([CH2:21][O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(F)c1O
Reactant: OC(COCc1ccccc1)C(O)COCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Product: Fc1cccc2c1O[C@@H](COCc1ccccc1)[C@H](COCc1ccccc1)O2

Procedure:
A mixture of 3-fluorobenzene-1,2-diol (5.12 g) and (R*, R*)-(±)-1,4-bis (phenylmethoxy)-2,3-butanediol, bis (4-methylbenzenesulphonate) (24.4 g) was stirred with dimethylformamide (DMF) (160 ml) under a nitrogen stream for 45 min. Anhydrous cesium carbonate (13.0 g) was added and the mixture was heated to 150° under reflux for 18 hours. The dark brown mixture was cooled to 30° and diluted with di-isopropyl ether (370 ml) and water (30 ml). The layers were separated and the aqueous layer was re-extracted with di-isopropyl ether (150 ml and then 100 ml). The extracts were sequentially washed within 1M hydrochloric acid (300 ml), 30% aqueous sodium chloride (100 ml) and were combined and evaporated in vacuo to a dark brown oil (12.6 g) which was dissolved in a light petroleum-dichloromethane (3:1) (40 ml) and chromatographed over Sorbsil (Trade Mark) (126 g) using light petroleum-dichloromethane mixtures of gradually increasing polarity. Combination of appropriate fractions and evaporation of the solvents gave the title compound as a yellow oil (7.0 g), NMR (CDCl3) 2.6-2.8 (10H, m, Ph), 3.18-3.38 (3H, m, 6-H, 7-H, 8-H), 5.32-5.58 (4H, m, CH2Ph), 5.64 (2H, m, 2-H, 3-H), 6.06-6.32 (4H, m, CH2O).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6][C:5]2=[O:18].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][Cl:26].[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[ClH:26].[C:12]1([C:7]2[O:8][C:9]3[CH:10]=[CH:11][C:2]([O:1][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:3][C:4]=3[C:5](=[O:18])[CH:6]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C1CCNCC1
Reactant: ClCCCCCCBr
Reactant: O=c1cc(-c2ccccc2)oc2ccc(O)cc12
Product: Cl
Product: O=c1cc(-c2ccccc2)oc2ccc(OCCCCCCN3CCCCC3)cc12

Procedure:
The compound was prepared by a method similar to Example 3 from 6-hydroxyflavone, 1-bromo-6-chlorohexane and piperidine: mp 176°-178° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:15]=3[CH3:21])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][C:36]=1[C:42]([F:45])([F:44])[F:43]>C1COCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([NH:20][C:23]([NH:41][C:38]4[CH:39]=[CH:40][C:35]([Cl:34])=[C:36]([C:42]([F:43])([F:44])[F:45])[CH:37]=4)=[O:25])[CH:17]=[CH:16][C:15]=3[CH3:21])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1NC(=O)c1csc2c(N)ncnc12
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1NC(=O)c1csc2c(N)ncnc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 175.7 %

Procedure:
4-Amino-N-(5-amino-2-methylphenyl)thieno[3,2-d]pyrimidine-7-carboxamide (50 mg, 0.167 mmol) obtained in Step 3 of Example 39 was dissolved in anhydrous THF (1 mL), TEA (47 μL, 0.334 mmol) and triphosgene (17 mg, 0.059 mmol) were added thereto at 0° C., and the mixture was stirred for 2 hours. 4-Chloro-3-(trifluoromethyl)benzeneamine (49 mg, 0.251 mmol) was added to the reaction mixture, which was stirred at room temperature for 10 hours. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with brine. The organic layer was dried with MgSO4, filtered and then concentrated under reduced pressure. The resulting mixture was purified by silica gel chromatography (MeOH/DCM=3/97) to obtain the title compound (54 mg, 60%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][N:10]2[CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH:13]3[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[N:3]1[C:23]([O:25][CH2:26][CH3:27])=[O:24].C1C(=O)N([Br:35])C(=O)C1>CN(C=O)C.O>[Br:35][C:6]1[CH:7]=[C:8]2[CH:13]3[CH2:14][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:17][CH:12]3[N:10]3[CH2:11][CH:2]([CH3:1])[N:3]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:4]([CH:5]=1)=[C:9]23
Reactant: CCOC(=O)N1CCC2C(C1)c1cccc3c1N2CC(C)N3C(=O)OCC
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC2C(C1)c1cc(Br)cc3c1N2CC(C)N3C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a solution of diethyl 2-methyl-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate (40 mg, 0.1 mmol) in DMF (10 mL) at 0° C. was added NBS (20 mg, 0.11 mmol) and stirred at 0° C. for 2 hours. The solution was diluted with water (10 mL), and extracted with EtOAc (2×20 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to afford diethyl 5-bromo-2-methyl-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate (40 mg, 88%) as a clear oil. MS [M+H]+ 454.