Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].CO.[C:15]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)(=[O:17])[CH3:16].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>COC(C)(C)C>[F:9][C:2]([F:1])([F:8])[C:3](=[O:5])[CH2:16][C:15]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=[O:17]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1ccncc1
Agent: C[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CO
Product: O=C(CC(=O)C(F)(F)F)c1ccncc1
Reaction time: 22 h
Yield: 62.2 %

Procedure:
Ethyl trifluoroacetate (6.32 g) was dissolved in tert-butyl methyl ether (10 mL) and a 28% sodium methoxide-methanol solution (9.40 g) and a solution of 4-acetylpyridine (4.90 g) in tert-butyl methyl ether (20 mL) were added successively at room temperature. The mixture was stirred for 22 hr. A 10% a aqueous citric acid solution was added until the reaction solution became about pH 4, and the precipitate was collected by filtration, washed with water and dried to give 4-trifluoroacetoacetylpyridine (5.46 g) as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH:34]=[O:35])=[C:19]([N:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]([C:32]#[N:33])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].O.C([OH:39])C>O.O1CCCC1>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH:34]=[O:35])=[C:19]([N:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]([C:32]([NH2:33])=[O:39])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c5ccccc54)c3C=O)ncc2c1
Reactant: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c5ccccc54)c3C=O)ncc2c1

Procedure:
A round bottom flask containing 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-formylphenyl)-1H-indole-3 carbonitrile (12 mg, 0.03 mmol) was taken up in 10% water/tetrahydrofuran (1.5 ml). Next hydrido(dimethylphosphinousacid-kp)[hydrogen bis-(dimethylphosphinito-kp)]platinum(II) catalyst (2 mg, 0.005 mmol) was added and the mixture was heated to reflux (oil bath). After 1 hour the mixture was cooled to ambient and the volatiles stripped (rotary evaporator) to provide a crude product. This reaction (as described above—but using 10% H2O/ethanol as solvent) was repeated on a 61 mg scale (0.24 mmol) and worked up as described. The combined crude material from the 2 reactions was purified by preparative thin layer chromatography (3 plates, eluting with 5% MeOH/CH2Cl2 and then re-developing again with 5% MeOH/CH2Cl2). The product band was collected to provide 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-formylphenyl)-1H-indole-3-carboxamide as a light yellow solid (51 mg). LC/MS calcd for C28H23FN4O3 (m/e) 482.52, obsd 483.0 (M+H, ES+): 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.40 (s, 9H) 6.03 (br. s, 2H) 7.20-7.36 (m, 3H) 7.44-7.59 (m, 3H) 7.66 (d, J=7.93 Hz, 1H) 7.81 (t, J=7.60 Hz, 1H) 7.91 (s, 1H) 8.19 (m, 1H) 8.23 (d, J=2.64 Hz, 1H) 9.52 (s, 1H)
Reaction SMILES: [O:1]=[C:2]([CH2:8]OCC#C)[CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:13]1(C2C=CC(C=O)=CC=2)C=CC=CC=1.CC1(C)CC(=O)CC(=O)C1.C([O-])(=O)C.[NH4+].II>C(O)C>[O:1]=[C:2]([CH2:8][CH3:13])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: C#CCOCC(=O)CC(=O)OC
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: CC1(C)CC(=O)CC(=O)C1
Agent: II
Solvent: CCO
Product: CCC(=O)CC(=O)OC
Reaction time: 17 h
Yield: 113.2 %

Procedure:
A mixture of methyl 3-oxo-4-(prop-2-ynyloxy)butyrate (2) (220 mg, 1.29 mmol), 4-phenylbenzaldehyde (247 mg, 1.29 mmol), dimedone (183 mg, 1.29 mmol), ammonium acetate (103 mg, 1.29 mmol), I2 (98 mg, 0.39 mmol), and ethanol (15 drops) is stirred under argon for 17 h, quenched with 5% Na2S2O3 (30 mL), and extracted with ethyl acetate (50 mL and 30 mL). The extract is washed (5% Na2S2O3, H2O, and brine), and dried. After solvent removal at reduced pressure, the residue is crystallized (ethanol) to give 190 mg (32%) of 3 (BI-3036) as a cream solid, mp 204-205° C. IR 3370, 2949, 1691, 1638, 1469, 1216 cm−1; NMR (CDCl3) δ 0.99 (s, 3H, CH3), 1.12 (s, 3H, CH3), 2.19-2.48 (m, 4H, COCH2, CH2), 2.56 (t, J=2.4 Hz, 1H, CH≡CCH2), 3.67 (s, 3H, OCH3), 4.34 (d, J=2.4 Hz, 2H, CH≡CCH2), 4.86-4.98 (m, 2H, CH2O), 5.14 (s, 1H, CH), 7.15 (bs, 1H, NH), 7.30-7.60 ppm (m, 9H, 4-BiphenylH).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3](=[O:8])[C:4](Cl)=[N:5][OH:6].[CH2:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])O.[K+]>C1(C)C=CC=CC=1.O>[CH3:1][N:2]([CH3:9])[C:3]([C:4]1[CH2:10][CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:6][N:5]=1)=[O:8]
Reactant: C=Cc1ccccc1
Reactant: CN(C)C(=O)C(Cl)=NO
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)C(=O)C1=NOC(c2ccccc2)C1
Reaction time: 0.17 h

Procedure:
To a solution of 2-(dimethylamino)-N-hydroxy-2-oxoethanimidoyl chloride (prepared according to the procedure of E. Raleigh, U.S. Pat. No. 3,557,089) (6.0 g, 40 mmol), styrene (6.0 g, 60 mmol) in toluene (15 mL) was added a solution of potassium hydrogen carbonate (5.0 g, 50 mmol) in water (25 mL) over 1 h, while keeping the reaction temperature between 7 and 10° C. The reaction mixture was diluted with 10 mL of toluene, and stirred for an additional 10 minutes. The organic layer was separated and washed with water. The organic layer was concentrated under reduced pressure until no styrene remained to give 8.7 g of the title compound as a light yellow oil. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [CH:1]([N:3]1[CH2:7][C@H:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[C:22]([CH3:30])[CH:21]=3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C@H:5]([C:31]([O:33]C(C)(C)C)=[O:32])[CH2:4]1)=[O:2].FC(F)(F)C(O)=O>>[CH:1]([N:3]1[CH2:7][C@H:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[C:22]([CH3:30])[CH:21]=3)=[CH:14][CH:13]=2)(=[O:10])=[O:11])[C@H:5]([C:31]([OH:33])=[O:32])[CH2:4]1)=[O:2]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CN(C=O)C[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CN(C=O)C[C@H]3C(=O)O)cc2)c2ccccc2n1

Procedure:
According to the procedure of Example 17, Step 4, the reaction of 168 mg of tert-butyl cis-1-formyl-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxylate with trifluoroacetic acid provided cis-1-formyl-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxylic acid in quantitative yield. MS: 470.1 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](/[CH:13]=[C:14]2\[CH2:15][N:16]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:18][CH:19]\2O)=[CH:11][N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:40]([OH:43])(=[S:42])[CH3:41].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.O>C1(C)C=CC=CC=1>[C:40]([S:42][CH:19]1[CH2:18][CH2:17][N:16]([C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:15]/[C:14]/1=[CH:13]\[C:12]1[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:9]=[N:10][CH:11]=1)(=[O:43])[CH3:41]
Reactant: CC(C)(C)OC(=O)n1cncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O
Reactant: CC(O)=S
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)SC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1cncn1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (E)-3-{[1-(t-butoxycarbonyl)-1H-imidazol-5-yl]methylidene}-1-(triphenylmethyl)piperidin-4-ol (6.00 g) in toluene (100 ml) were added successively thioacetic acid (1.64 ml) and N,N-dimethylformamide dineopentyl acetal (6.40 ml) under ice-cooling, and the resulting mixture was stirred at room temperature for 1 hour. After stirring, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate, hexane and dichloromethane (1:3:1) as the eluent to afford (E)-4-(acetylsulfanyl)-3-{[1-(t-butoxycarbonyl)-1H-imidazol-5-yl]methylidene}-1-(triphenylmethyl)piperidine (including impurities) as a yellow amorphous solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]#[C:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl>C(O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]#[C:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(C#CCCCO)c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: Nc1cccc(C#CCCCO)c1

Procedure:
A solution of Intermediate 46 (16 mmol) in ethanol (80 mL) was treated successively with 10% aqueous hydrochloric acid solution (4 mL) and iron powder and then was lowered in to a 95° C. oil bath. After 90 minutes of reflux heating, the mixture was deemed complete by LC/MS analysis and was filtered while hot through a pad of Celite diatomaceous earth, eluting with methanol. The filtrate was concentrated to dryness under reduced pressure. The residue was purified via automated flash silica gel chromatography, using a 40 g Silicycle SiliSep flash column (hexanes/ethyl acetate). Concentration of the desired fractions under reduced pressure provided the title compound. ES/MS calcd. for C11H14NO+ 176.1. Found m/z=176.2 (M+H)+.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[N:13]3[CH2:22][CH2:23][C@H:12]3[C:11]=12)=[O:6])[C:2]#[CH:3].IN1C(=O)CCC1=O.[CH2:32]([NH:35][CH2:36][CH2:37][CH3:38])[CH2:33][CH3:34]>C(O)(=O)C>[CH2:32]([N:35]([CH2:3][C:2]1[O:6][C:5]([C:7]2[N:8]=[CH:9][N:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[C:14](=[O:21])[N:13]4[CH2:22][CH2:23][C@H:12]4[C:11]=23)=[N:4][CH:1]=1)[CH2:36][CH2:37][CH3:38])[CH2:33][CH3:34]
Reactant: CCCNCCC
Reactant: C#CCNC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Agent: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1cnc(-c2ncn3c2[C@@H]2CCN2C(=O)c2ccccc2-3)o1
Temperature: 25 °C
Reaction time: 47 h
Yield: 26.9 %

Procedure:
A solution of 3.06 g (0.010 mol) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid prop-2-ynylamide in 200 ml of acetic acid was treated with 3.36 g (0.015 mol) of N-iodosuccinimide while gassing with argon. After stirring at room temperature for 47 hrs. the dark brown suspension obtained was completely freed from the solvents and dried azeotropically several times with toluene. The red-brown solid residue was dissolved in 100 ml of THF, treated with 11.9 ml (0.0865 mol) of dipropylamine and stirred at room temperature for 17 hrs. The suspension obtained was completely freed from the solvents, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with dichloromethane. The organic phase was concentrated, the brown product was chromatographed over basic Alox (grade III) with dichloromethane/ethyl acetate 4:1 as the eluent and recrystallized from hot isopropyl ether. There were obtained 1.09 g (27%) of (S)-1-(5-dipropylaminomethyl-oxazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one as yellowish crystals; m.p. 132°-134° and [α]D20 =-187.8° (MeOH, c=1%).
Reaction SMILES: [NH2:1][C:2]1[C:24]([F:25])=[CH:23][C:5]2[S:6][CH2:7][CH2:8][N:9]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[C:4]=2[CH:3]=1.C(N(CC)CC)C.Cl.[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[C:39](=[NH:42])OC>C(O)C.C(OCC)(=O)C>[F:25][C:24]1[C:2]([NH:1][C:39]([C:35]2[S:34][CH:38]=[CH:37][CH:36]=2)=[NH:42])=[CH:3][C:4]2[N:9]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[CH2:8][CH2:7][S:6][C:5]=2[CH:23]=1
Reactant: COC(=N)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCSc3cc(F)c(N)cc32)CC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCSc3cc(F)c(NC(=N)c4cccs4)cc32)CC1
Temperature: 65 °C

Procedure:
To a stirred solution of tert-butyl 4-(6-amino-7-fluoro-2H-benzo[b][1,4]thiazin-4(3H)-yl)piperidine-1-carboxylate (168 mg, 0.457 mmol) in ethanol (5 mL) and triethylamine (0.643 mL, 4.57 mmol) was added methyl thiophene-2-carbimidate hydrochloride (325 mg, 1.829 mmol). The resulting mixture was stirred at 65° C. over the weekend. The mixture was then cooled to room temperature, diluted with ethyl acetate, and washed with saturated sodium carbonate (3×). The organic phase was dried, filtered, and concentrated, and chromatographed in 1:9 ethyl acetate:hexanes giving a yellow oil (18 mg, 8.26%); 1H NMR (MeOD-d4) δ 7.65-7.61 (m, 1H), 7.59-7.54 (m, 1H), 7.14-7.08 (m, 1H), 6.79 (d, J=10.5 Hz, 1H), 6.49 (d, J=7.5 Hz, 1H), 4.22-4.12 (m, 2H), 3.80-3.67 (m, 1H), 3.43-3.38 (m, 2H), 3.05-3.01 (m, 2H), 2.96-2.79 (m, 2H), 1.83-1.73 (m, 2H), 1.72-1.57 (m, 2H), 1.46 (s, 9H); ESI-MS (m/z, %): 477 (MH+, 100).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:4]=1[O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.Br[CH:20]([CH3:25])[C:21]([O:23][CH3:24])=[O:22]>C(O)C>[Cl:2][C:3]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:4]=1[O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH:20]([CH3:25])[C:21]([O:23][CH3:24])=[O:22])=[CH:11][CH:12]=1
Reactant: Oc1ccc(COc2ccc(Cl)cc2Cl)cc1
Reactant: COC(=O)C(C)Br
Agent: [Na]
Solvent: CCO
Product: COC(=O)C(C)Oc1ccc(COc2ccc(Cl)cc2Cl)cc1
Reaction time: 3 h

Procedure:
2.3 gm of sodium were dissolved in 100 ml of absolute ethanol, 26.9 gm of 4-(2,4-dichlorophenoxy-methyl)-phenol and 16.7 gm of methyl 2-bromo-propionate were added to the solution, and the mixture was boiled for 3 hours. Thereafter, the reaction solution was evaporated, and the residue was worked up as usual with water and chloroform, yielding 80% of theory of the desired compound named in the heading, which had a melting point of 64° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:13])[NH:5][C:6](=[O:12])[NH:7]2.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>COCCOC.O.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>[C:14]1([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[C:4](=[O:13])[NH:5][C:6](=[O:12])[NH:7]3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=c1[nH]c(=O)c2c(Br)cccc2[nH]1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=c1[nH]c(=O)c2c(-c3ccccc3)cccc2[nH]1

Procedure:
See J. Med. Chem., 50(7):1675 (2007), 76759-011. To a mixture of 5-bromoquinazoline-2,4(1H,3H)-dione (900 mg, 3.73 mmol) and Pd(Ph3P)4 (216 mg, 0.187 mmol) in DME (90 mL) was added phenylboronic acid (683 mg, 5.60 mmol) followed by a solution of sodium bicarbonate (941 mg, 11.2 mmol) in water (30 mL) and the reaction heated at reflux for 40 h. At the conclusion of this period, the organic solvent was removed under reduced pressure. The resulting mixture was filtered and the solid washed with water. The solid was concentrated under reduced pressure from MeOH/DCM to remove the water to yield 5-phenylquinazoline-2,4(1H,3H)-dione as an off-white solid. The 5-phenylquinazoline-2,4(1H,3H)-dione (9.64 g, 40.4 mmol) was added to POCl3 (75 mL, 810 mmol) followed by PhN(CH3)2 (10.3 mL, 81.0 mmol). Upon completion of addition, the reaction mixture was heated to reflux (105° C.) where it was stirred for 2 hours. After this time, the reaction mixture was allowed to cool to ambient temperature. Once at the prescribed temperature, the reaction mixture was concentrated under reduced pressure, diluted with DCM and then quenched by the addition of cold 1M K3PO4 solution. The organic layer was separated and the aqueous layer was extracted twice with DCM. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to yield a residue. The residue was purified by ISCO chromatography (330 g column) using hexanes/EtOAc (0-25% over 20 min, flow rate 100 mL/min) to give 2,4-dichloro-5-phenylquinazoline (7.11 g, 63.9% yield) as a yellow solid. 1H NMR (400 MHz, chloroform-d) ppm 8.04 (1H, m) 7.96 (1H, m) 7.59 (1H, dd, J=7.28, 1.25 Hz) 7.45 (3H, dd, J=5.02, 1.76 Hz) 7.32 (2H, m).
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([C:13]([N:15]2[CH2:19][C@@H:18]([N:20]([CH:28]3[CH2:33][CH2:32][C:31]([CH3:35])([CH3:34])[CH2:30][CH2:29]3)[C:21]([C@@H:23]3[CH2:27][CH2:26][CH2:25][O:24]3)=[O:22])[CH2:17][C@H:16]2[C:36]([N:38]2[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]2)=[O:37])=[O:14])[C@H:10]([C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=2)[CH2:9]1)(OC(C)(C)C)=O.Cl>C(Cl)Cl>[Cl:51][C:48]1[CH:47]=[CH:46][C:45]([C@@H:10]2[CH2:9][NH:8][CH2:12][C@H:11]2[C:13]([N:15]2[C@H:16]([C:36]([N:38]3[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]3)=[O:37])[CH2:17][C@H:18]([N:20]([CH:28]3[CH2:33][CH2:32][C:31]([CH3:35])([CH3:34])[CH2:30][CH2:29]3)[C:21]([C@@H:23]3[CH2:27][CH2:26][CH2:25][O:24]3)=[O:22])[CH2:19]2)=[O:14])=[CH:50][CH:49]=1
Reactant: CN1CCN(C(=O)[C@@H]2C[C@H](N(C(=O)[C@@H]3CCCO3)C3CCC(C)(C)CC3)CN2C(=O)[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: ClCCl
Product: CN1CCN(C(=O)[C@@H]2C[C@H](N(C(=O)[C@@H]3CCCO3)C3CCC(C)(C)CC3)CN2C(=O)[C@@H]2CNC[C@H]2c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
1-BOC-(3R,4S)-3-(4-chlorophenyl)-4-({(2S,4S)-4-{(4,4-dimethylcyclohexyl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino}-2-[(4-methylpiperazin-1-yl)carbonyl]pyrrolidin-1-yl}carbonyl)pyrrolidine (1.33 g, 1.83 mmol) obtained in Step A was dissolved in DCM (1 mL) and 4 M HCl (1 mL) was added dropwise thereto. The reaction solution was stirred for 1 hour at room temperature and concentrated in vacuo to give the title compound (1.14 g, 99.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+]>CO>[CH2:16]([NH:15][C:13]1[NH:12][N:11]=[C:10]([NH:9][C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:14]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Clc1cc(Cl)cc(Nc2n[nH]c(NCc3ccccc3)n2)c1
Temperature: -20 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (70 mg, 287 μmol) and benzaldehyde (121.3 mg, 1.14 mmol) in MeOH (3 ml) was stirred at 45° C. for 2 days to give a suspension, cooled to −20° C. and was filtered to collect the solid. The solid was re-suspended in MeOH (5 ml), NaBH4 (65.1 mg, 1.72 mmol) was added and the reaction was stirred for 1 hour. The solvent was removed, and the reaction mixture was redissolved in EtOAc (5 ml) and washed with water (2×4 ml), dried over MgSO4 and concentrated in vacuo. Crystallization from DCM afforded a white solid as desired product (94 mg, 98% yield). MS +m/z: 334 (M+H)+
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:36])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[C:13]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[O:18][C:14]=2[N:15]=[CH:16][N:17]=1.Cl>O1CCOCC1>[F:35][C:31]1[CH:30]=[C:29]([C:19]2[O:18][C:14]3[N:15]=[CH:16][N:17]=[C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:36])=[O:4])[C:13]=3[C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)CCCCCNc1ncnc2oc(-c3cccc(F)c3)c(-c3ccc(OC)cc3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(-c2c(-c3cccc(F)c3)oc3ncnc(NCCCCCC(=O)O)c23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Add 0.5 ml 1 N sodium hydroxide solution to a solution of 45 mg (0.01 mmol) 6-{[6-(3-fluorophenyl)-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester in 2.5 ml dioxan, and stir for 16 h at RT. After adding 0.75 ml 1 N hydrochloric acid, concentrate the reaction solution by vacuum evaporation. Mix the residue with diethyl ether, filter, and dry under vacuum. 42 mg (93% of theor.) of the desired product is obtained.
Reaction SMILES: Br[C:2]1[NH:6][C:5]([CH3:7])=[N:4][C:3]=1[N+:8]([O-:10])=[O:9].[C:11]1([CH3:23])[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1OB(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>COC(OC)C.O.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>[C:11]1([CH3:23])[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1[C:2]1[NH:6][C:5]([CH3:7])=[N:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1nc([N+](=O)[O-])c(Br)[nH]1
Reactant: Cc1cc(C)c(OB(O)O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COC(C)OC
Agent: [Ba+2]
Solvent: O
Product: Cc1cc(C)c(-c2[nH]c(C)nc2[N+](=O)[O-])c(C)c1
Yield: 70.8 %

Procedure:
A solution of 5-bromo-2-methyl-4-nitroimidazole (5.0 g, 24 mmol), mesitylboric acid (3.96 g, 24 mmol), Pd(PPh3)4 (1.4 g, 1.2 mmol) and barium hydroxide octahydrate (19.1 g, 61 mmol) in 2,2-dimethoxyethane (150 mL) and water (25 mL) was heated at reflux for four hours. After filtered through Celite, the filtrate was diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and evaporated. The resulting crystals were washed with ethyl acetate, to give the title compound (4.17 g) as white crystals.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([N+:13]([O-])=O)=[CH:6][C:7]([C:10](=[O:12])[CH3:11])=[N:8][CH:9]=1)[CH3:2]>C(O)C.[Pd]>[NH2:13][C:5]1[C:4]([NH:3][CH2:1][CH3:2])=[CH:9][N:8]=[C:7]([C:10](=[O:12])[CH3:11])[CH:6]=1
Reactant: CCNc1cnc(C(C)=O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCNc1cnc(C(C)=O)cc1N
Reaction time: 1 h

Procedure:
A mixture of 1-(5-ethylamino-4-nitro-pyridin-2-yl)-ethanone (310 mg, 1.5 mmol) and 10% Pd/C (50 mg) in ethanol (10 mL) is stirred under hydrogen for 1 hr. The mixture is filtered through Celite and concentrated in vacuo to give the product as yellow solid. 1H NMR (CD3OD) δ 7.61 (s, 1H), 7.30 (s, 1H), 3.26 (q, 2H), 2.53 (s, 3H), 0.90 (t, 3H). LRMS 180.5 (MH+).