Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:11](O)=[N:10][CH:9]=[CH:8][N:7]3[C:13]=2[CH2:14][C:15]2[CH:34]=[CH:33][C:18]3/[C:19](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:20]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=4[O:22][CH2:23][C:17]=3[CH:16]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:37])=O>>[Cl:37][C:11]1[C:6]2[N:7]([C:13]([CH2:14][C:15]3[CH:34]=[CH:33][C:18]4/[C:19](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:20]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=5[O:22][CH2:23][C:17]=4[CH:16]=3)=[C:4]([CH:1]3[CH2:2][CH2:3]3)[N:5]=2)[CH:8]=[CH:9][N:10]=1
Reactant: C/C(C#N)=C1/c2ccc(Cc3c(C4CC4)nc4c(O)nccn34)cc2COc2cc(F)ccc21
Reactant: O=P(Cl)(Cl)Cl
Product: C/C(C#N)=C1/c2ccc(Cc3c(C4CC4)nc4c(Cl)nccn34)cc2COc2cc(F)ccc21
Temperature: 110 °C
Yield: 94.7 %

Procedure:
[step 5] To (E)-2-{8-[(2-cyclopropyl-8-hydroxyimidazo[1,2-a]pyrazin-3-yl)methyl]-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (3.8 g, 8.3 mmol) obtained in step 4 was added phosphorus oxychloride (19 mL, 207 mmol), and the mixture was stirred with heating at 110° C. for 4 hr. The mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give (E)-2-{8-[(8-chloro-2-cyclopropylimidazo[1,2-a]pyrazin-3-yl)methyl]-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (3.7 g, 96%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[CH:19]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:23][CH:22]=1)O)C1C=CC=CC=1>[Pd].C(O)(=O)C.C(O)C>[CH2:30]([S:27]([C:24]1[CH:23]=[CH:22][C:21]([CH2:19][C:10]2[CH:11]=[C:12]([C:15]([F:17])([F:16])[F:18])[CH:13]=[CH:14][C:9]=2[OH:8])=[CH:26][CH:25]=1)(=[O:28])=[O:29])[CH3:31]
Reactant: CCS(=O)(=O)c1ccc(C(O)c2cc(C(F)(F)F)ccc2OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCS(=O)(=O)c1ccc(Cc2cc(C(F)(F)F)ccc2O)cc1
Reaction time: 2 h

Procedure:
A mixture of the product from example 3 step (iii) (0.225 g), 10% palladium on carbon (0.05 g) and acetic acid (2 drops) in ethanol (20 ml) was hydrogenated at 3 Bar for 2 h then 5 Bar for 5 h. After filtration the solvent was evaporated under reduced pressure. Yield 0.16 g
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH3:32])[C:7]([N:9]1[CH:21]([C:22]([O:24][CH3:25])=[O:23])[CH2:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[CH:10]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:8])(=O)C>CO>[SH:4][CH2:5][CH:6]([CH3:32])[C:7]([N:9]1[CH:21]([C:22]([O:24][CH3:25])=[O:23])[CH2:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[CH:10]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:8]
Reactant: COC(=O)C1Cc2c([nH]c3ccccc23)C(c2ccccc2)N1C(=O)C(C)CSC(C)=O
Solvent: CO
Product: COC(=O)C1Cc2c([nH]c3ccccc23)C(c2ccccc2)N1C(=O)C(C)CS
Reaction time: 1 h
Yield: 8.7 %

Procedure:
2-(3'Acetylthio-2'-methylpropanoyl)-1-phenyl-3-carbomethoxy-1,2,3,4-tetrahydro-β-carboline (2 g, 0.045 mole) was dissolved in methanol (75 ml) and anhydrous ammonia was bubbled through the solution for 15 minutes. The reaction was placed under nitrogen and stirring was continued at room temperature for one hour. The methanol was evaporated and the residue was applied to a cation exchange column (methanol). The methanol was evaporated and the residue was dissolved in chloroform, washed with water, dried over magnesium sulfate, filtered and evaporated to give the product as a colorless oil (1.6 g, 88%).
Reaction SMILES: C(N(CC)CC)C.I[C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][CH2:18][N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])=[CH:11][CH:10]=1.[CH2:30]([O:37][C:38](=[O:44])[NH:39][CH2:40][CH2:41][C:42]#[CH:43])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:30]([O:37][C:38](=[O:44])[NH:39][CH2:40][CH2:41][C:42]#[C:43][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][CH2:18][N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])=[CH:11][CH:10]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C1c2ccccc2C(=O)N1CCC#Cc1ccc(I)cc1
Reactant: C#CCCNC(=O)OCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCC#Cc1ccc(C#CCCN2C(=O)c3ccccc3C2=O)cc1)OCc1ccccc1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
A solution containing triethylamine (100 mL), copper (I) iodide (0.50 g, 2.60 mmol) and 57 (7.00 g, 17.40 mmol) dissolved in anhydrous tetrahydrofuran (100 mL) was stirred at room temperature. The reaction flask was vacuumed and then purged with nitrogen three times. The solution was treated with bis(triphenylphosphine) palladium(II) dichloride (1.20 g, 1.70 mmol) and continued to stir at room temperature for 30 min. The reaction mixture was then treated with but-3-ynylcarbamic acid benzyl ester (4.25 g, 20.90 mmol). The reaction was allowed to stir at room temperature for 16 h. The solution was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography eluting with 0-100% ethyl acetate in hexanes to afford the desired product 58 (6.0 g, 72%) as a brown solid: 1H NMR (500 MHz, CD2Cl2) δ 7.85 (dd, 2H), 7.74 (dd, 2H), 7.35-7.32 (m, 5H), 7.27 (d, 2H), 7.22 (d, 2H), 5.08 (s, 2H), 3.93 (t, 2H), 3.39 (t, 2H), 2.81 (t, 2H), 2.62 (t, 2H); m/z (ESI) 477 [C30H24N2O4+H]+.
Reaction SMILES: [I-:1].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([N:18]2[C:22]([CH2:23]Cl)=[N:21][N:20]=[C:19]2[CH2:25][NH:26][C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])=[C:8]([CH:17]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].O.C1C=CC=CC=1>C(#N)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([N:18]2[C:22]([CH2:23][I:1])=[N:21][N:20]=[C:19]2[CH2:25][NH:26][C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])=[C:8]([CH:17]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10]
Reactant: O=C(NCc1nnc(CCl)n1-c1ccc(Cl)cc1C(=O)c1ccccc1)OCc1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: c1ccccc1
Product: O=C(NCc1nnc(CI)n1-c1ccc(Cl)cc1C(=O)c1ccccc1)OCc1ccccc1
Yield: 61.1 %

Procedure:
To a solution of sodium iodide (1.51 g) in acetonitrile (30 ml), 5-chloro-2-(3-carbobenzoxyaminomethyl-5-chloromethyl-4H-1,2,4-triazol-4-yl)-benzophenone (5.0 g) is added, and the resultant mixture is stirred at room temperature for 18 hours. The reaction mixture is poured into water (100 ml) and shaken with benzene (50 ml) twice. The benzene layer is washed with water (100 ml) twice, dried over magnesium sulfate and evaporated under reduced pressure to remove the benzene. The residue is chromatographed on a column of silica gel, which is eluted with ethyl acetate to give 5-chloro-2-(3-carbobenzoxyaminomethyl-5-iodomethyl-4H-1,2,4-triazol-4-yl)-benzophenone (3.61 g). The product is recrystallized from methylene chloride/ether to give crystals melting at 133° to 134° C. (decomp.).
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:7]=1)=[O:4].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Cl.C(N(C(C)C)CC)(C)C.N>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)(Cl)Cl.O1CCOCC1>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][N:15]1[CH2:16][CH2:17][CH:12]([C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:18])[CH3:1])[CH:11]=[CH:10][CH:9]=2)[CH2:13][CH2:14]1
Reactant: COc1cccc(CCl)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COc1cccc(CN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c1
Yield: 27.8 %

Procedure:
A mixture of 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (28.3 mg, 0.100 mmol), 3-methoxybenzyl chloride (19.6 mg, 0.125 mmol), diisopropylethylamine (0.50 mL), catalytic amount of tetrabutylammonium iodide and dioxane (2.0 mL). Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] afforded the desired product (10.2 mg, 27.9% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.35 (apparent d, 1H, J=8.3 Hz), 7.27–7.21 (m, 2H), 6.95 (apparent t, 3H, J=6.9 Hz), 6.82 (apparent dd, 1H, J=2.4, 8.3 Hz), 3.84 (m, 3H), 3.56 (s, 2H), 3.05 (d, 2H, J=10.5 Hz), 2.51 (apparent sept, partially hidden, 0.4H, J=7.2 Hz), 2.13 (apparent t, 2H, J=9.7 Hz), 1.88 (m, 2H), 1.25 (d, 6H, J=6.7 Hz); ESMS m/e: 367.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[NH2:15][NH2:16]>C1COCC1>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:7]=[C:2]([NH:15][NH2:16])[N:3]=[CH:4][N:5]=2)=[CH:9][CH:10]=1
Reactant: NN
Reactant: Clc1ccc(-c2cc(Cl)ncn2)cc1
Solvent: C1CCOC1
Product: NNc1cc(-c2ccc(Cl)cc2)ncn1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 67.3 %

Procedure:
To a stirred solution of 4-chloro-6-(4-chlorophenyl)pyrimidine (1.25 g, 5.6 mmol) in THF (10 mL) at room temperature under argon was added H2NNH2 (538 mg, 16.8 mmol). The reaction mixture was heated at 60° C. under argon for 2 h. Analysis by HPLC/MS indicated that the reaction was complete. About three fourths of the solvent was evaporated and Et2O (5 mL) was added to the resulting suspension. After stirring at room temperature for 20 min, solid was collected by filtration and further washed with Et2O (15 mL), then dried under vacuum to obtain 831 mg of the title compound as a white solid. HPLC/MS: retention time=1.88 min, [M+H]30 =221.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C@H:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22]C(=O)C)=[CH:18][CH:17]=1)[O:14][CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>CCO>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][C@H:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[O:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@H](CNC(=O)OCc1ccccc1)c1ccc(OC(C)=O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CO[C@H](CNC(=O)OCc1ccccc1)c1ccc(O)cc1
Temperature: 24 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a solution of 6 (160 mg, 0.46 mmol) in EtOH (5 mL) 0.568 g of a freshly prepared solution of potassium hydroxide (253.2 mg in 5.013 g H2O, 0.045 M) was added. The mixture was stirred at 23-25° C. for 1 h (completion monitored by TLC) and neutralized with 0.1% HCl (neutral by pH indicator paper). Solvent was evaporated in vacuo and the residue dissolved in ethyl acetate and flash filtered through a pad of silica gel to remove inorganic impurities. The silica gel was washed with ethyl acetate, fractions combined and solvent evaporated in vacuo to afford 136 mg (97%) of 6d.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9]1.[C:23]1([CH:29]2[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([C@H:29]2[CH2:34][CH2:33][C@H:32]([N:8]3[CH2:12][CH2:11][CH:10]([S:13]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=4)(=[O:15])=[O:14])[CH2:9]3)[CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=S(=O)(c1ccc(O)cc1)C1CCNC1
Reactant: O=C1CCC(c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(O)cc1)C1CCN([C@H]2CC[C@H](c3ccccc3)CC2)C1

Procedure:
The title compound, MS: m/e=386.3 (M+H+) was prepared from (RS)-4-(pyrrolidine-3-sulfonyl)-phenol trifluoroacetic acid and 4-phenylcyclohexanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:12]([OH:16])(=[O:15])[CH:13]=[CH2:14]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:14][CH2:13][C:12]([OH:16])=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(S)cc1OC
Reactant: C=CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(SCCC(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 22.4 h
Yield: 76.7 %

Procedure:
3,4-Dimethoxythiophenol (5.00 g, 29 mmol) was placed in a flask with acrylic acid (2.27 g, 32 mmol) and stirred at room temperature for 22.4 hours. The reaction mixture solidified, was dissolved in ethyl acetate and extracted with 10% Na2CO3. The aqueous layer was acidified with concentrated hydrochloric acid, extracted with ether, dried over MgSO4, and concentrated in vacuo to give 3-(3,4-dimethoxyphenylthio)propanoic acid (5.39 g, 76%), contaminated with some acrylic acid, as a white solid which was used without further purification in the next step: mp 62°-64° C.; 1H NMR (CDCl3) 300 MHz 9.80 (br s, 1H) 7.01 (d, J=8.3 Hz, 1H) 6.98 (s, 1H) 6.82 (d, J=8.3 Hz, 1H) 3.87 (s, 3H) 3.86 (s, 3H) 3.06 (t, J=7.3 Hz, 2H) 2.63 (t, J=7.3 Hz, 2H). Mass spectrum: M+=242.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][OH:15])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[C:17]1[NH:21][C:20]2[CH:22]=[C:23]([C:35]([F:38])([F:37])[F:36])[CH:24]=[C:25]([C:26]3[CH:31]=[C:30]([F:32])[C:29]([F:33])=[C:28]([F:34])[CH:27]=3)[C:19]=2[N:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][OH:15])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:17]2[NH:18][C:19]3[C:25]([C:26]4[CH:27]=[C:28]([F:34])[C:29]([F:33])=[C:30]([F:32])[CH:31]=4)=[CH:24][C:23]([C:35]([F:38])([F:36])[F:37])=[CH:22][C:20]=3[N:21]=2)[CH2:10][CH2:9]1
Reactant: Fc1cc(-c2cc(C(F)(F)F)cc3[nH]c(Cl)nc23)cc(F)c1F
Reactant: OCc1cnc(N2CCNCC2)c(Cl)c1
Product: OCc1cnc(N2CCN(c3nc4cc(C(F)(F)F)cc(-c5cc(F)c(F)c(F)c5)c4[nH]3)CC2)c(Cl)c1

Procedure:
The piperazine from step (a) above (114 mg, 0.5 mmol) reacted with 2-chloro-6-(trifluoromethyl)-4-(3,4,5-trifluorophenyl)-1H-benzoimidazole (140 mg, 0.4 mmol, Example 51b) under the conditions of Example 3c to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 542 (M+1).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Br:20])[NH:8][C:9](=[O:12])[C:10]=1[OH:11])=[O:4].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:3]([C:5]2[N:6]=[C:7]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Br:20])[NH:8][C:9](=[O:12])[C:10]=2[OH:11])=[O:4])=[CH:24][CH:23]=1
Reactant: COC(=O)c1nc(Cc2ccccc2Br)[nH]c(=O)c1O
Reactant: NCc1ccc(Cl)cc1
Product: O=C(NCc1ccc(Cl)cc1)c1nc(Cc2ccccc2Br)[nH]c(=O)c1O

Procedure:
The compound was prepared according to the same procedure as in Example 21 using 2-(2-bromo-benzyl)-5-hydroxy-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid methyl ester (0.08 g; 0.236 mmol) and 4-chlorobenzylamine (0.5 ml; 4.1 mmol). The title compound was prepared as a white solid (0.042 g; 39%). LCMS: m/z=449 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[NH2:19][C:20](N)=S>CS(C)=O>[C:6]1([C:4]2[C:3]3[C:2](=[CH:15][CH:14]=[C:13]([N+:16]([O-:18])=[O:17])[CH:12]=3)[N:1]=[CH:20][N:19]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC(N)=S
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc2ncnc(-c3ccccc3)c2c1
Temperature: 140 °C
Yield: 39.6 %

Procedure:
To a 20 mL microwave reaction vial with a micro magnetic stir bar, were added 0.297 g of 2-amino-5-nitrobenzophenone, 0.186 g of thiourea and 3.0 mL of DMSO. Then the vial was sealed and heated with microwave at 140° C. for 20 hours. Two layers of liquid formed with brown liquid on the top and a dark brown gel like layer at the bottom. The reaction mixture was extracted with EtOAc and purified on column chromatography using hexane/EtOAc (5:1 to 4:1) as eluent, and 0.122 g of 4-phenyl-6-nitro-quinazoline was obtained, in a yield of 39.7%.
Reaction SMILES: [CH:1]([C:3]1[N:4]([C:8]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH:5]=[CH:6][N:7]=1)=[O:2].[CH2:19](O)[CH2:20][OH:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1.[OH-].[Na+]>>[O:2]1[CH2:19][CH2:20][O:21][CH:1]1[CH:3]1[NH:7][CH2:6][CH2:5][N:4]1[C:8]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1-n1ccnc1C=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: N#Cc1ccc([N+](=O)[O-])cc1N1CCNC1C1OCCO1
Temperature: 25 °C
Yield: 65.3 %

Procedure:
Into a round bottom flask equipped with a Dean Stark trap, 2-(2-formyl-imidazol-1-yl)-4-nitro-benzonitrile (10.48 g, 0.04327 mol), 1,2-ethanediol (15.0 mL, 0.269 mol), p-toluenesulfonic acid monohydrate (8.23 g, 0.0433 mol), and benzene (150 mL, 1.7 mol) were added. The reaction was heated to reflux for 6 hours. The reaction was cooled to room temperature. 1N NaOH was added to adjust the pH to 10. The reaction was partitioned with water and EtOAc. The organic was separated, washed with Brine, and dried over magnesium sulfate. The solid was filtered and washed with EtOAc. The solvent was removed under vacuum. The product was isolated via ISCO column chromatography with DCM and methanol as eluant (0 to 5% methanol). The collected fractions afforded 2-(2-[1,3]dioxolan-2-yl-imidazolidin-1-yl)-4-nitro-benzonitrile as a yellow solid (8.20 g, 66%). 1H-NMR (DMSO-D6, 400 MHz): δ8.53 (d, 1H), 8.42 (s, 1H), 8.35 (d, 1H), 7.65 (s, 1H), 7.14 (s, 1H), 5.82 (s, 1H), 3.65 (bs, 2H), 3.45 (bs, 2H).
Reaction SMILES: C1C[O:4][CH2:3]C1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:18][C:19]1[C:28]([NH2:29])=[C:27]([NH:30][CH2:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.O>N1C=CC=CC=1>[Cl:18][C:19]1[C:28]2[N:29]=[C:3]([OH:4])[N:30]([CH2:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: C1CCOC1
Reactant: Nc1c(Cl)nc2ccccc2c1NCC1CCOCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: c1ccncc1
Product: Oc1nc2c(Cl)nc3ccccc3c2n1CC1CCOCC1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
THF (50 mL) and 1,1′-carbonyldiimidazole (4.2 g, 26 mmol) were sequentially added to a solution of 2-chloro-N4-(tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine (5 g, 17 mmol) in pyridine (50 mL), and the reaction was heated at 90° C. overnight. The reaction was cooled to approximately 0° C., and water (400 mL) was added. The mixture was stirred for 30 minutes. A precipitate was present and was isolated by filtration and washed with water and diethyl ether to provide 4 g of 4-chloro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-2-ol. A small portion of the product was triturated with hot acetonitrile, isolated by filtration, and washed with cold acetonitrile and diethyl ether to provide beige needles with the following analytical data, mp greater than 275° C.
Reaction SMILES: OO.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH:12]([N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:6][CH:5]=1.[OH2:24].C(O)(=[O:27])C>S(=O)(=O)(O)O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH2:11][CH:12]([N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:27])=[O:24])=[CH:8][CH:9]=1
Reactant: O
Reactant: CC(=O)O
Reactant: CC(C)(C)C(=O)C(CSc1ccc(Cl)cc1)n1cncn1
Agent: O=S(=O)(O)O
Agent: OO
Product: CC(C)(C)C(=O)C(CS(=O)(=O)c1ccc(Cl)cc1)n1cncn1
Temperature: 60 °C
Reaction time: 18 h
Yield: 22 %

Procedure:
8.3 g (0.074 mol) of 30% strength hydrogen peroxide were slowly added dropwise to a solution of 22.6 g (0.07 mol) of 1-(4-chlorophenylthio)-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pentan-3-one (prepared as described in Example 1) in 100 ml of acetic acid and 2 drops of concentrated sulphuric acid. The reaction mixture was stirred for a further 18 hours at 60° C., and 8.3 g (0.074 mol) of 30% strength hydrogen peroxide were again added. The reaction mixture was then stirred for a further 18 hours at 80° C. Thereafter, the reaction solution was introduced into water, and the mixture was extracted with methylene chloride. The organic phase was dried over sodium sulphate, filtered, and concentrated in vacuo. The oily residue crystallized after being stirred with diisopropyl ether. 4.9 g (22% of theory) of 1-(4-chlorophenylsulphonyl)-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pentan-3-one of melting point 134° C. were obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([NH2:12])[N:3]=1.Cl.[OH:14][CH:15]([CH2:18][CH2:19][CH3:20])[CH2:16][NH2:17].C(N(CC)CC)C.N>C(Cl)(Cl)Cl.CN(C=O)C>[NH2:12][C:4]1[N:3]=[C:2]([NH:17][CH2:16][CH:15]([OH:14])[CH2:18][CH2:19][CH3:20])[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=1
Reactant: CCCC(O)CN
Reactant: Nc1nc(Cl)c2c(n1)CCCC2
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCC(O)CNc1nc(N)nc2c1CCCC2
Temperature: 90 °C
Yield: 51.1 %

Procedure:
A mixture of 4-chloro-5,6,7,8-tetrahydroquinazoline-2-ylamine (184 mg, 1 mmol), 2-hydroxypentylamine hydrochloride (140 mg, 1 mmol), triethylamine (202 mg, 2 mmol) and DMF (1 ml) was warmed for 5 hours in a bath (bath temperature, 90° C.). The solvent in the filtrate was removed in vacuo and the residue was purified by silica gel column chromatography (CHCl3:MeOH:NH4OHaq=100:10:0.4) to give the crude product (210 mg). To the crude product was aqueous ammonia solution (5 ml) and chloroform (30 ml) and it was extracted. The organic layer was washed with saturated brine (20 ml), dried over sodium sulfate, filtered and the solvent in the filtrate was removed in vacuo to give the object compound (128 mg, 51%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C[O:29][C:30](=[O:60])[CH2:31][C@H:32]([NH2:59])[C:33]([N:35]([CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[C:49]2[NH:53][N:52]=[N:51][N:50]=2)=[CH:39][CH:38]=1)=[O:34].C([S:64][CH2:65][CH:66]([CH2:70][CH:71]([CH3:73])[CH3:72])[C:67](O)=[O:68])(=O)C.CCN(C(C)C)C(C)C>CN(C=O)C>[SH:64][CH2:65][CH:66]([CH2:70][CH:71]([CH3:73])[CH3:72])[C:67]([NH:59][C@H:32]([C:33]([N:35]([CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[C:49]2[NH:53][N:52]=[N:51][N:50]=2)=[CH:41][CH:42]=1)=[O:34])[CH2:31][C:30]([OH:29])=[O:60])=[O:68]
Reactant: CCCCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)[C@@H](N)CC(=O)OC
Reactant: CC(=O)SCC(CC(C)C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)[C@H](CC(=O)O)NC(=O)C(CS)CC(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.2 %

Procedure:
BOP (88 mg, 0.2 mmol) was added to a solution of (S)-3-amino-N-pentyl-N-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]succinamic acid methyl ester (100 mg, 0.2 mmol), 2-acetylsulfanylmethyl-4-methylpentanoic acid (41 mg, 0.2 mmol) and DIPEA (34 μL) in DMF (1.5 mL) at room temperature. After 10 minutes, DIPEA (30 μL) was added. After 4 hours, the mixture was concentrate in vacuo. A solution of the concentrate in MeOH (1.0 mL), 1M aq. NaOH (1.0 mL) and 6M aq. NaOH (0.1 mL) was stirred under a nitrogen atmosphere at room temperature. After 3 hours, the mixture was neutralized with 6M aq. HCl, and was concentrated in vacuo. Reverse phase HPLC afforded the title compound (11.9 mg). MS m/z: [M+H]+ calcd for C30H40N6O4S, 581.28. found 581.4.