Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)[N:3]=1.O.[CH3:14][N:15](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[NH:12]1[CH:11]=[CH:10][N:9]=[C:8]1[C:4]1[N:3]=[C:2]([C:14]#[N:15])[CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)C=O
Reactant: Clc1cccc(-c2ncc[nH]2)n1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: N#Cc1cccc(-c2ncc[nH]2)n1
Temperature: 40 °C

Procedure:
A mixture of 2-chloro-6-(1H-imidazol-2-yl)-pyridine (800 mg, 4.45 mmol), zinc cyanide (313 mg, 2.68 mmol), Pd2(dba)3 (122 mg, 0.133 mmol), DPPF (144 mg, 0.27 mmol) and water (0.1 mL) in DMF (10 mL) is degassed with argon for 15 minutes. The mixture is then heated at 40° C. overnight in a sealed tube. Solvent is removed and water (30 mL) is added and the mixture is extracted with methylene chloride. On drying (MgSO4), the solvent is removed. Column separation gives the product (172).
Reaction SMILES: [S:1]1[C:5]([CH2:6][O:7][C:8]([NH:10][C@H:11]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:12][NH:13][CH2:14][C@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]2[S:32][CH:31]=[N:30][CH:29]=2)=[O:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:9])=[CH:4][N:3]=[CH:2]1.[CH3:40][CH:41]([CH3:44])[CH:42]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:40][CH:41]([CH3:44])[CH2:42][N:13]([CH2:14][C@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]1[S:32][CH:31]=[N:30][CH:29]=1)=[O:25])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:12][C@H:11]([NH:10][C:8]([O:7][CH2:6][C:5]1[S:1][CH:2]=[N:3][CH:4]=1)=[O:9])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(N[C@@H](CNC[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)Cc1ccccc1)OCc1cncs1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)CN(C[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)C[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1
Yield: 45.6 %

Procedure:
The product from Example 31D (80 mg, 0.141 mmol), 2-methylpropanal (15 μl, 0.170 mmol), acetic acid (10 μl, 0.166 mmol), and sodium triacetoxyborohydride (48 mg, 0.226 mmol) were processed as described in Example 27 to provide the title compound (40 mg, 44%). 1H NMR (CDCl3) δ 8.73 (s, 2H), 7.76 (s, 2H), 7.32-7.12 (m, 10H), 5.35 (br s, 2H), 5.18 (q, 4H), 3.97 (br s, 2H), 2.83 (br s, 2H), 2.70 (dd, 2H), 2.41 (t, 2H), 2.21 (dd, 2H), 2.00 (m, 1H), 1.87 (dd, 1H), 0.72 (s, 6H); MS (ESI+) m/z 622 (M+H)+.
Reaction SMILES: [SH:1][C:2]1O[CH:4]=[CH:5][N:6]=1.[CH:7]([NH2:11])([CH2:9][CH3:10])[CH3:8]>C(O)C>[CH:7]([N:11]1[CH:4]=[CH:5][N:6]=[C:2]1[SH:1])([CH2:9][CH3:10])[CH3:8]
Reactant: Sc1ncco1
Reactant: CCC(C)N
Solvent: CCO
Product: CCC(C)n1ccnc1S
Yield: 53.7 %

Procedure:
1 g (9.89 mmol) of 2-mercaptooxazole and 0.72 g (9.89 mmol) of sec-butylamine were dissolved in 20 ml of ethanol and refluxed for 2 hours. After cooling, the solvent was distilled off under reduced pressure and the residue was treated with column chromatography to obtain 0.83 g of 1-sec-butyl-2-mercaptoimidazole. mp.=108-121° C., yield 54%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]4[CH:22]=[CH:21][C:20]([C:23]5[CH:24]=[N:25][C:26]([O:29]C)=[CH:27][CH:28]=5)=[CH:19][C:17]4=3)[CH:12]=[CH:11][C:10]2=[O:31])[CH:5]=[CH:6][C:7]=1[F:8].[Si](I)(C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]4[CH:22]=[CH:21][C:20]([C:23]5[CH:28]=[CH:27][C:26](=[O:29])[NH:25][CH:24]=5)=[CH:19][C:17]4=3)[CH:12]=[CH:11][C:10]2=[O:31])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(-c2ccc3ncc4ccc(=O)n(-c5ccc(F)c(Cl)c5)c4c3c2)cn1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: O=c1ccc(-c2ccc3ncc4ccc(=O)n(-c5ccc(F)c(Cl)c5)c4c3c2)c[nH]1
Temperature: 50 °C
Reaction time: 48 h
Yield: 14.4 %

Procedure:
To a solution of compound 7.0 1-(3-chloro-4-fluorophenyl)-9-(6-methoxypyridin-3-yl)benzo[h][1,6]naphthyridin-2(1H)-one (21 mg, 0.05 mmol, 1 equiv.) in CH2Cl2(2 mL) at room temperature was added TMSI (70 μL, 0.5 mmol, 10 equiv.). The resulting solution was stirred at 50° C. for 48 h before being cooled to room temperature and quenched with Na2CO3 (sat. 2 mL). After separation, the organic phase was dried over Na2SO4 and evaporated under vacuum. The residue was diluted with DMF (2 mL) and purified via preparative LC-MS (CH3CN:H2O) to afford the desired product 7.1 1-(3-chloro-4-fluorophenyl)-9-(6-oxo-1,6-dihydropyridin-3-yl)benzo [h][1,6]naphthyridin-2(1H)-one (3 mg). LC-MS (M+H): 417.07
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[C:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=O)=[C:17]([F:23])[CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[CH3:7].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[OH-].[Na+]>ClC(Cl)C>[CH:1]1([NH:5][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([N:12]3[CH2:11][CH2:10][N:9]([C:6](=[O:8])[CH3:7])[CH2:14][CH2:13]3)=[CH:16][C:17]=2[F:23])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)N1CCN(c2ccc(C=O)c(F)c2)CC1
Reactant: NC1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)N1CCN(c2ccc(CNC3CCC3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 106 %

Procedure:
To a solution of cyclobutanamine (1.26 mL, 14.7 mmol) and 4-(4-acetylpiperazin-1-yl)-2-fluoro-benzaldehyde (3.68 g, 14.7 mmol) in dichloroethane (50 mL) was added sodium triacetoxyborohydride (4.39 g, 20.6 mmol) followed by acetic acid (0.84 mL, 14.7 mmol) and the reaction was stirred at ambient temperature for 16 hours. 1 N aqueous NaOH was then added to basify the reaction and the product was extracted with Et2O (x3), washed with brine, dried with MgSO4, concentrated and dried in vacuo to give 1-[4-[4[(cyclobutylamino)methyl]-3-fluoro-phenyl]piperazin-1-yl]ethanone (4.76 g, 99% yield). The product was used without purification. LCMS (m/z) ES+ 306 [M+1]+.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[S:11][CH:12]=[C:13](Br)[CH:14]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[Cu][C:17]#[N:18].N>CN1CCCC1>[N:1]1([CH:6]([C:10]2[S:11][CH:12]=[C:13]([C:17]#[N:18])[CH:14]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: N#C[Cu]
Reactant: CCCC(c1cc(Br)cs1)n1ccnc1
Agent: CN1CCCC1
Agent: N
Product: CCCC(c1cc(C#N)cs1)n1ccnc1
Temperature: 180 °C
Reaction time: 5 h
Yield: 78.1 %

Procedure:
0.3 g of 2-[1-(1-imidazolyl)-butyl]-4-bromothiophene is dissolved in 5 ml of N-methylpyrrolidine and mixed with 0.3 g of copper(I) cyanide and stirred for 5 hours at 180° C. Then the reaction mixture is poured into 100 ml of dilute ammonia solution and extracted with ethyl acetate. The ethyl acetate phase is concentrated by evaporation in a vacuum and distilled on a bulb tube, boiling point 180° C./0.03 mbar. 0.190 g of 2-[1-(1-imidazolyl)-butyl]-thiophene-4-carbonitrile is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@@H:13]([O:15][Si](C(C)(C)C)(C)C)[CH2:12][N:11]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@@H:13]([OH:15])[CH2:12][N:11]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN(C(=O)OCc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of (3S,5R)-benzyl 3-(tert-butoxycarbonylamino)-5-(tert-butyldimethylsilyloxy)piperidine-1-carboxylate (1 eq) in 30 mL of THF was added 5.2 mL of TBAF (1.2 eq). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate, washed with brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (5% methanol in EtOAc:hexanes=1:1) to yield (3S,5R)-benzyl 3-(tert-butoxycarbonylamino)-5-hydroxypiperidine-1-carboxylate (100%). LC/MS (m/z): 251.2 (MH+), Rt: 0.89. HPLC: Rt: 3.26 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([OH:9])=[O:8].[CH2:13](O)[CH3:14]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]([O:9][CH2:13][CH3:14])=[O:8])[CH:10]=[CH:11][CH:12]=1
Reactant: CCO
Reactant: O=C(O)C=Cc1cccc(Br)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C=Cc1cccc(Br)c1

Procedure:
Under a nitrogen atmosphere, a stirred solution of 10.1 grams (0.045 mole) of 3-bromocinnamic acid and 40 drops of concentrated sulfuric acid in 75 mL of ethanol was heated at reflux for about 19 hours. After this time the reaction mixture was concentrated under reduced pressure to a residual oil. The oil was dissolved in methylene chloride, and the solution was washed with 50 mL of water and then with 50 mL of an aqueous solution saturated with sodium bicarbonate. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding about 11.4 grams of ethyl 3-(3-bromophenyl)-2-propenoate. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[C:14](=[O:25])[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[F:24])=O)(C)(C)C.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[Cl:23][C:19]1[C:18]([F:24])=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][NH:15][C:14]([C@@H:9]1[CH2:10][C@@H:11]([F:13])[CH2:12][NH:8]1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1cccc(Cl)c1F)[C@@H]1C[C@@H](F)CN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (2S,4R)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (7.94 g, 21.18 mmol) in CH2Cl2 (70.5 mL) was added TFA (16.32 mL, 212 mmol) and the solution was stirred at RT for 16 h. The crude reaction mixture was concentrated under vacuum and the material this obtained was used without further purification in the next step. MS (LC/MS): 274.9 [M+H]+; tR (HPLC conditions b): 2.13 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([OH:15])=[O:14])=[CH:8][CH:7]=[CH:6]2.[C:16](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=[CH:6]2
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2c(C(=O)O)cccc2c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cccc2cc(OC)ccc12
Temperature: 25 °C
Yield: 90.9 %

Procedure:
A mixture of 9.1 g of 6-methoxynaphthoic acid and 7.2 g of anhydrous potassium carbonate in 45 ml of acetone was heated to 50°-55° C. for 15 minutes, and 4.5 ml of dimethyl sulfate were then slowly dripped in over a period of 15 minutes. The mixture was then heated at reflux for one hour and cooled to room temperature, after which all the acetone was stripped under vacuum. After workup, it was determined that the process resulted in the formation of 8.85 g of methyl 6-methoxynaphthoate having an HPLC purity of 83.3%.
Reaction SMILES: [OH:1][CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4].[C:7]([CH2:9][C:10](O)=[O:11])#[N:8]>C1(C)C=CC=CC=1.S(=O)(=O)(O)O>[C:7]([CH2:9][C:10]([O:1][CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4])=[O:11])#[N:8]
Reactant: N#CCC(=O)O
Reactant: C[Si](C)(C)CO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: C[Si](C)(C)COC(=O)CC#N
Yield: 69.7 %

Procedure:
In a reactor fitted with a Dean-Stark apparatus hydroxymethyltrimethylsilane (3.8 g, 0.036 mol) and cyanoacetic acid (3.1 g, 0.036 mol) in 50 ml of toluene are refluxed for 4 hours in the presence of one drop of concentrated sulfuric acid. The organic phase is washed twice with water and is dried over sodium sulfate. It is concentrated under reduced pressure. Distillation under vacuum (b.p. 80° C. under 0.4 hPa) gives 4.3 g (69% yield) of trimethylsilanylmethyl cyanoacetate in the form of a colorless liquid which is used as it is in the following step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]([Cu])#[N:10].[OH-].[Na+].C(OCC)(=O)C>CN1C(=O)CCC1>[Br:8][C:5]1[CH:4]=[N:3][C:2]([C:9]#[N:10])=[CH:7][CH:6]=1
Reactant: Brc1ccc(Br)nc1
Reactant: N#C[Cu]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(Br)cn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 27.4 %

Procedure:
A stirred solution of 2,5-dibromopyridine (39.465 g, 0.17 mol) in anhydrous NMP (100 mL) was treated with CuCN (14.42 g, 0.17 mol) for 20 hours at 110° C. under nitrogen. The reaction mixture was cooled to 40° C. and treated with aqueous sodium hydroxide (2M; 200 mL) and then with ethyl acetate (200 mL). The mixture was stirred for 1 hour and then filtered through Celite to remove the resulting precipitate. The retained solid was washed with aqueous sodium hydroxide (2M; 600 mL) and then with ethyl acetate (600 mL). The organic layers were combined and washed with aqueous ammonium hydroxide (5M; 800 mL), dried over magnesium sulfate, and evaporated to dryness under reduced pressure. The involatile residue was purified by chromatography on silica gel [elution gradient 1% to 7% of ethyl acetate in hexanes] to give the title compound (8.538 g, 28%), as a colorless amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][OH:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.CN(C)C=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]=[O:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(CO)nc3N21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]C(C)(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(C=O)nc3N21
Reaction time: 0.5 h
Yield: 40.1 %

Procedure:
A solution of 2.0 g (5.43 mmol) (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 5, intermediate b) in 15 ml tetrahydrofuran was cooled to −75 deg C. and treated with 4.40 ml (0.65 mmol) tert-butyllithium (1.5 M solution in n-pentane). After 30 min, 0.60 ml (0.63 g, 8.15 mmol) N,N-dimethylformamide was added dropwise. After 2.5 h the reaction mixture was poured onto 10% aqueous citric acid solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash-chromatography on silica gel (0.032–0.063 mm) with ethyl acetate:n-hexane (1:3) as eluant to afford the desired compound as a yellow oil (40.1%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].Cl[CH2:13][CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>>[O:16]([CH2:15][CH2:14][CH2:13][N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[C:5]([I:11])=[N:6]1)[Si:17]([C:20]([CH3:22])([CH3:21])[CH3:23])([CH3:18])[CH3:19]
Reactant: Fc1ccc2[nH]nc(I)c2c1
Reactant: CC(C)(C)[Si](C)(C)OCCCCl
Product: CC(C)(C)[Si](C)(C)OCCCn1nc(I)c2cc(F)ccc21
Yield: 79 %

Procedure:
The title compound was prepared from 5-fluoro-3-iodo-indazole and (3-chloropropoxy)tert-butyldimethylsilane (Org. Lett., 2000, 3473) in 79% yield according to the general procedure for Preparation 31A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 0.06 (6H, s), 0.89 (9H, s), 2.07-2.13 (2H, m), 3.55 (2H, t, J=6.0 Hz), 4.49 (2H, t, J=6.0 Hz), 7.10 (1H, dd, J=2.4, 8.4 Hz), 7.18 (1H, td, J=2.4, 8.8 Hz), 7.40 (1H, dd, J=4.0, 8.8 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:3]=1.ClC(N(C)C)=C(C)C.[NH2:28][C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([N:39]([CH3:41])[CH3:40])[N:30]=1>C1COCC1>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([NH:28][C:29]2[CH:34]=[C:33]([C:35]([F:36])([F:38])[F:37])[CH:32]=[C:31]([N:39]([CH3:41])[CH3:40])[N:30]=2)=[O:8])=[C:4]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:3]=1
Reactant: CN(C)c1cc(C(F)(F)F)cc(N)n1
Reactant: Nc1cc(OCC(F)(F)F)c(C(=O)O)cc1[N+](=O)[O-]
Agent: CC(C)=C(Cl)N(C)C
Solvent: C1CCOC1
Product: CN(C)c1cc(C(F)(F)F)cc(NC(=O)c2cc([N+](=O)[O-])c(N)cc2OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product obtained at (656b) (15.5 g, 2.97 mmol) in 3 mL THF was combined with (1-Chlor-2-methyl-prop-1-en-1-yl)-dimethylamine (0.14 mL, 1.1 mmol) and stirred at ambient temperature for 1 h. Then a mixture of 2-amino-6-dimethylamino-4-trifluoromethyl-pyridine (0.19 g, 0.94 mmol) with TEA (0.50 mL, 3.6 mmol) in 5 mL THF was added and the mixture stirred at ambient temperature for 16 h. The mixture was filtered, evaporated, the residue was mixed with diethylether, filtered off, washed with diethylether and dried.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[NH:23]C(=O)C)(=O)C.O>S(=O)(=O)(O)O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[NH2:23]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cc1-c1cc([N+](=O)[O-])ccc1NC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1ccc([N+](=O)[O-])cc1-c1cc([N+](=O)[O-])ccc1N
Temperature: 110 °C
Yield: 95.3 %

Procedure:
To a solution of 2,2'-bis(acetamido)- 5,5'-dinitrobiphenyl (34.1 g, 0.0953 mole) in concentrated sulfuric acid (500 ml) was added, slowly, 250 ml of water. The reaction mixture was stirred and heated at 110° C. and 1 mm Hg to give 24.9 g (96 %) of 2,2'-diamino- 5,5'-dinitrobiphenyl. An analytical sample, m.p. 315°-317° C., was obtained by recrystallization from ethanol-tetrahydrofuran.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:6]2[CH2:20][O:21][CH3:22].CI.[C:30](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:30])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:6]2[CH2:20][O:21][CH3:22]
Reactant: CCOC(=O)c1cc2c(Cl)ccc(NS(=O)(=O)c3cccs3)c2n1COC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)ccc(N(C)S(=O)(=O)c3cccs3)c2n1COC
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
A mixture of ethyl 4-chloro-1-(methoxymethyl)-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (1.14 g), methyl iodide (0.33 ml), potassium carbonate (0.37 g) and N,N-dimethylformamide (10 ml) was stirred overnight at room temperature. Water was added to the reaction mixture, and the resulting crystals were collected by filtration, washed with water, and dried to give the title compound (1.10 g, yield 93%) as colorless crystals. melting point 137-138° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5](Cl)=[O:6].C[O:15][P:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]=2[O:17]1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5]([P:16]1(=[O:15])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]=2[O:17]1)=[O:6]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: COP1Oc2ccccc2-c2ccccc21
Solvent: Cc1ccccc1
Product: COc1cccc(OC)c1C(=O)P1(=O)Oc2ccccc2-c2ccccc21
Temperature: 125 °C

Procedure:
60.1 g (0.3 mol) of 2,6-dimethoxybenzoyl chloride were warmed to 85° C. under a nitrogen atmosphere. 69 g (0.3 mol) of 6-methoxy-(6H)-dibenz[c,e][1,2]oxaphosphorin were added dropwise while stirring. The temperature was then slowly increased to 125° C. When the reaction was complete and after cooling, 150 ml of toluene were added. After crystallization, 99 g (87% of theory) of the abovementioned compound of melting point 96° to 98° C. were obtained.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:25]=[CH:24][C:14]([O:15][C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:26][O:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[N:36]=[C:37]=[O:38]>C(Cl)Cl>[CH3:26][O:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[NH:36][C:37](=[O:38])[N:8]([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:15][C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:24][CH:25]=1)[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCNCCc1ccc(OC(C)(C)C(=O)OCC)cc1
Reactant: COc1ccc(N=C=O)c(OC)c1
Solvent: ClCCl
Product: CCCCCCCN(CCc1ccc(OC(C)(C)C(=O)OCC)cc1)C(=O)Nc1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The product from step (d) (2.1 g) and 2,4-dimethoxyphenylisocyanate (1.1 g, Aldrich) were dissolved in CH2Cl2 (50 ml). The resulting solution was stirred at room temperature for 17 hours and then evaporated in vacuo. The residue was flash chromatographed through a silica column using hexanes/CH2C1 /EtOAc (50:25:25) as eluant to give the desired product as a very light brown oil (2.0 g).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[CH2:16][OH:17]>C(Cl)Cl>[Cl:1][C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[CH:16]=[O:17]
Reactant: OCc1cccc2c(Cl)c3ccccc3cc12
Solvent: ClCCl
Product: O=Cc1cccc2c(Cl)c3ccccc3cc12
Yield: 69.2 %

Procedure:
10-Chloro-1-anthracenemethanol (37C, 8.8 g, 0.036 mol) was dissolved in CH2Cl2 (200 ml) and treated with BaMnO4 (Aldrich, 15 g, 0.059 mol) for 3 days and briefly brought to reflux. The reaction mixture was filtered, and the filtrate reduced to dryness. The residue was chromatographed by preparative HPLC using PhCH3 as the eluting solvent to give 6.0 g (69%) of crude 10-chloroanthracene-1-carboxaldehyde, which was used without further purification. An analytical sample was recrystallized from CH2Cl2 /hexane mp 139°-140.5° . (C, H, Cl).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:24][CH3:25])=[C:16]([O:22][CH3:23])[C:17]=3[N+:19]([O-])=O)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH4+].[Cl-].O.C(Cl)(Cl)Cl>CO.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:17]([NH2:19])=[C:16]([O:22][CH3:23])[C:15]([O:24][CH3:25])=[CH:14][C:13]=3[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Br)c3)c2c([N+](=O)[O-])c1OC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: COc1cc2ncnc(Nc3cccc(Br)c3)c2c(N)c1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (3-bromo-phenyl)-(6,7-dimethoxy-5-nitro-quinazolin-4-yl)-amine (0.2 g, 0.49 mmol) (from Example 6, Step A, supra) and NH4Cl (0.26 g, 4.94 mmol) in a mixture of MeOH, H2O and CHCl3 (30 mL, 6:1:1) was added Zn powder (0.64 g, 9.87 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was then filtered, the filtrate was concentrated and then extracted with chloroform (100 mL). The organic layer was separated, dried over Na2SO4, and concentrated. This residue was purified by chromatography using EtOAc/CH2Cl2 /NEt3 (1:1:0.05) as eluent to give the desired N4-(3-bromo-phenyl)-6,7-dimethoxy-quinazoline-4,5-diamine as a yellow gum. (Yield 0.1 g, 54%).