Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][S:9][C:10]2[NH:14][C:13]3=[CH:15][S:16][CH:17]=[C:12]3[N:11]=2)=[N:6][CH:7]=1.[H-].[Na+].[C:20](=O)([O:31]C1C=CC=CC=1)[O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>CN(C=O)C>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][O:21][C:20]([N:11]2[C:12]3=[CH:17][S:16][CH:15]=[C:13]3[N:14]=[C:10]2[S:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)=[O:31])=[CH:24][CH:25]=1
Reactant: Cc1ccc(CSc2nc3cscc3[nH]2)nc1
Reactant: COc1ccc(COC(=O)Oc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)n2c(SCc3ccc(C)cn3)nc3cscc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1.3 g (5 mmol) of 2-(5-methyl-2-picolylmercapto)-1H-thieno[3,4-d]imidazole dissolved in 15 ml of anhydrous DMF were added, under nitrogen, 275 mg (6 mmol) of sodium hydride. After the mixture had been heated at 40°-50° C. for 10 min, at room temperature 1.92 g (7.5 mmol) of 4-methoxybenzyl phenyl carbonate (prepared from 4-methoxybenzyl alcohol and phenyl chloroformate) were added, and the mixture was heated at 30°-40° C. for 10 minutes and stirred at room temperature for 1 hour. The solvent was removed by distillation in vacuo, and water was added to the residue. The oily/resinous precipitate was taken up in CH2Cl2, and the solution was dried over MgSO4 and the solvent was evaporated off. The residue crystallized from diethyl ether and was recrystallized from isopropanol. Melting point 120°-121° C.
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][O:25][CH3:26])[C:13]([C:27]#[N:28])=[CH:12]2)=[CH:7][C:6]=1[OH:29])C.C(O)C.[OH-].[Li+].Cl>O.O1CCCC1>[C:27]([C:13]1[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:15][N:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:30])=[O:3])=[C:6]([OH:29])[CH:7]=2)[CH:12]=1)#[N:28]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3OCCOC)c2)cc1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COCCOc1ccccc1-c1cn(-c2ccc(C(=O)O)c(O)c2)cc1C#N
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.1 %

Procedure:
To a solution of 4-{3-cyano-4-[2-(2-methoxyethoxy)phenyl]pyrrole-1-yl}-2-hydroxy benzoic acid ethyl ester (0.072 g) in a mixed solvent of ethanol (9 mL) and tetrahydrofuran (3 mL) was added 1 mol/mL aqueous lithium hydroxide solution (2.7 mL), and this mixture was stirred at room temperature for 48 hours. This reaction mixture was poured into 1 mol/L hydrochloric acid (2.7 mL), and to this mixture was added water (30 mL). The precipitated solid was collected by filtration. This obtained solid was washed with water, dried under reduced pressure at 50° C. to give the title compound (0.051 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:13][C:14](=[O:16])[CH3:15])([CH3:12])[CH3:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+].Cl>CO>[OH:3][CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:13][C:14](=[O:16])[CH3:15])([CH3:11])[CH3:12])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)NC(C)(C)c1ccc(C(C)=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)NC(C)(C)c1ccc(C(C)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
To a solution of N-(1-(4-acetylphenyl)-1-methylethyl)acetamide (50.0 g) in methanol (400 ml) was added dropwise sodium borohydride (4.3 g) at below 5° C. over 30 min. The mixture was stirred at room temperature for 2 hr and 2N hydrochloric acid (60 ml) was added. The mixture was treated by a conventional method and the obtained crude crystals were recrystallized from ethanol to give the title compound (42.17 g) as white crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]([OH:16])=O)([O-:3])=[O:2].[CH3:17][O:18][C:19]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22]>>[CH3:17][O:18][C:19]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH:22][C:14]([C:9]1[C:10]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1)=[O:16]
Reactant: O=C(O)c1cccc2c([N+](=O)[O-])cccc12
Reactant: COc1cccc(CN)c1OC
Product: COc1cccc(CNC(=O)c2cccc3c([N+](=O)[O-])cccc23)c1OC
Yield: 55.1 %

Procedure:
Using 5-nitronaphthalene-1-carboxylic acid (250 mg, 1.15 mmol) and 2,3-dimethoxybenzylamine (0.18 ml, 1.20 mmol), the same operation as the Example 104(2) gave the title compound as a gray white solid (232 mg, 55.0%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:27])=[C:4]2[C:24](=[CH:25][CH:26]=1)[C:8]1[NH:9][C:10]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17](OC(C)(C)C)=[O:18])=[N:11][C:7]=1[CH:6]=[CH:5]2.Cl.[CH3:29][O:30][C:31]([NH:33][C@@H:34]([CH:38]([CH3:40])[CH3:39])C(O)=O)=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O.CN(C=O)C.CO>[Br:1][C:2]1[C:3]([F:27])=[C:4]2[C:24](=[CH:25][CH:26]=1)[C:8]1[NH:9][C:10]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17](=[O:18])[C@@H:34]([NH:33][C:31](=[O:32])[O:30][CH3:29])[CH:38]([CH3:40])[CH3:39])=[N:11][C:7]=1[CH:6]=[CH:5]2
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc3c(F)c(Br)ccc3c2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3c(F)c(Br)ccc3c2[nH]1)C(C)C
Reaction time: 16 h
Yield: 103.1 %

Procedure:
(S)-tert-butyl 2-(7-bromo-6-fluoro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (204 mg, 0.47 mmol) was dissolved in DCM (5 mL), MeOH (1 mL) and HCl (4 M in dioxane, 1 mL) was added. The reaction mixture was stirred for 16 h and then concentrated under reduced pressure. The crude residue was treated with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (82 mg, 0.47 mmol), HATU (179 mg, 0.47 mmol) and DMF (6 mL), then DIPEA (0.41 mL, 2.35 mmol) was added dropwise. After 3 h, the mixture was diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0% to 30% MeOH/EtOAc) to afford methyl (S)-1-((S)-2-(7-bromo-6-fluoro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (238 mg, 49%).
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:90]=[CH:91][CH:92]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([N:71]5[CH2:76][CH2:75][N:74]([CH2:77][CH2:78][OH:79])[CH2:73][CH2:72]5)=[CH:67][CH:66]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:90]=[CH:91][CH:92]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([N:71]5[CH2:72][CH2:73][N:74]([CH2:77][CH2:78][OH:79])[CH2:75][CH2:76]5)=[CH:69][CH:70]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(CCO)CC5)cc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: OCCN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cc2)CC1
Yield: 87.6 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 2-(4-(4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl)ethanol (60 mg, 0.092 mmol) was hydrolyzed by lithium hydroxide (20 mg, 0.461 mmol) in THF/methanol/water (5/1/1 ml) to yield 40 mg (13.3% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.747-8.742 (d, 2H), 8.586-8.583 (d, 1H), 8.30 (s, 1H), 7.99 (s, 1H), 7.82 (s, 1H), 7.72-7.69 (d, 2H), 7.38-7.35 (q, 1H), 7.19-7.17 (d, 2H), 7.13-7.11 (d, 1H), 7.08-7.01 (m, 2H), 5.44 (s, 2H), 3.99-3.90 (m, 5H), 3.85-3.75 (m, 2H), 3.39-3.33 (m, 3H), 3.30-3.20 (m, 2H). MS: m/z=496.9 (M+1), HPLC: 96.51% in method A.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH:9]([C:11]([CH3:13])=O)=[CH2:10]>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:13][C:11]1[C:5]2[C:3](=[C:2]([CH3:1])[CH:8]=[CH:7][CH:6]=2)[N:4]=[CH:10][CH:9]=1
Reactant: C=CC(C)=O
Reactant: Cc1ccccc1N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: Cc1ccnc2c(C)cccc12
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 65 %

Procedure:
To a stirred solution of 2-methylaniline (1 g. 9.3 mmol.) in acetic acid (10 ml), activated silferc (1.5 g., ferric chloride 9.3 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred for 5 minutes and methyl vinyl ketone (MVK) (0.72 g, 10.2 mmol) was added slowly over a period of 15 minutes. The reaction mixture was heated to 70° C. and maintained between 70-75° C. for one hour. Anhydrous zinc chloride (1.27 g. 9.3 mmol) was added and the reaction was further refluxed for two hours. The reaction mixture was cooled, filtered, basified with 10% NaOH solution, extracted with ethyl acetate (3×20 ml), dried over Na2SO4 and evaporated to give the product; Yield 65%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C@@H:27]([NH:32][C:33]([C:35]4[O:36][C:37]([C:40]5[CH:45]=[CH:44][C:43]([CH:46]([CH3:48])[CH3:47])=[CH:42][CH:41]=5)=[CH:38][CH:39]=4)=[O:34])[C:28]([O:30]C)=[O:29])=[CH:22][C:21]=3[F:49])[N:16]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.C(C1C=CC(C2C=COC=2C(O)=O)=CC=1)(C)C.C(Cl)(=O)C.C(OC(=O)C(N)CC1C=CC(C2N=C(C3C=CC(NC(OC(C)(C)C)=O)=CC=3)ON=2)=C(F)C=1)C>>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C@@H:27]([NH:32][C:33]([C:35]4[O:36][C:37]([C:40]5[CH:45]=[CH:44][C:43]([CH:46]([CH3:47])[CH3:48])=[CH:42][CH:41]=5)=[CH:38][CH:39]=4)=[O:34])[C:28]([OH:30])=[O:29])=[CH:22][C:21]=3[F:49])[N:16]=2)=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](Cc1ccc(-c2noc(-c3ccc(NC(=O)OC(C)(C)C)cc3)n2)c(F)c1)NC(=O)c1ccc(-c2ccc(C(C)C)cc2)o1
Agent: CC(C)c1ccc(-c2ccoc2C(=O)O)cc1
Agent: CCOC(=O)C(N)Cc1ccc(-c2noc(-c3ccc(NC(=O)OC(C)(C)C)cc3)n2)c(F)c1
Solvent: CC(=O)Cl
Solvent: O=S(Cl)Cl
Product: CC(C)c1ccc(-c2ccc(C(=O)N[C@H](Cc3ccc(-c4noc(-c5ccc(NC(=O)OC(C)(C)C)cc5)n4)c(F)c3)C(=O)O)o2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(R)-methyl 3-(4-(5-(4-((tert-butoxycarbonyl)amino)phenyl)-1,2,4-oxadiazol-3-yl)-3-fluorophenyl)-2-(5-(4-isopropylphenyl)furan-2-carboxamido)propanoate. Thionyl chloride (5 mL) was added to p-isopropylphenyl-furan-2-carboxylic acid (1.7 g, 7.23 mmol) and the mixture was heated under reflux for 10 min. After removal of excess thionyl chloride under vacuum, the resulting acetyl chloride was added to the mixture of 2-amino-3-{4-[5-(4-tert-butoxycarbonylamino-phenyl)-[1,2,4]oxadiazol-3-yl]-3-fluorophenyl}-propionic acid ethyl ester (3 g, 6.58 mmol), disopropylethylamine (1.3 g, 9.87 mmol) and the mixture was stirred for 30 min at room temperature. The mixture was partitioned between EtOAc and water. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was chromatographed on silica gel to give the title compound as a yellow solid (2.94 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([S:14][CH:15]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=4)[CH2:22][CH2:21]3)[CH2:16][CH2:17][CH2:18][NH-:19])[S:12][CH:13]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43]>ClCCl.C(Cl)(Cl)Cl>[ClH:33].[C:42]([NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([S:14][CH:15]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=4)[CH2:22][CH2:21]3)[CH2:16][CH2:17][CH2:18][NH-:19])[S:12][CH:13]=2)=[CH:5][CH:4]=1)(=[O:44])[CH3:43]
Reactant: [NH-]CCCC(Sc1nc(-c2ccc(N)cc2)cs1)C1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(-c2csc(SC(CCC[NH-])C3CCN(Cc4ccc(Cl)c(Cl)c4)CC3)n2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The product (106 mg) of Example 5 was dissolved in dichloromethane (80 mL), and triethylamine (30 μL) and acetyl chloride (15 μL) were added to the solution. The mixture was stirred at room temperature for 12 hrs. The reaction mixture was diluted with chloroform, washed with 0.1 mol/L sodium hydroxide and then saturated brine, and dried. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in ethanol (10 mL). 1 mol/L Hydrogen chloride diethyl ether solution (2 mL) was added, which was followed by filtration to give the title compound (62 mg) as a white amorphous solid.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[C:25]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])#[N:26].N1CCCC1>C(O)C>[C:25](/[C:27](=[CH:19]/[C:18]1[CH:21]=[CH:22][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:23])([F:1])[F:24])=[CH:5][CH:6]=3)[N:11]=2)=[CH:16][CH:17]=1)/[C:28]([O:30][CH2:31][CH3:32])=[O:29])#[N:26]
Reactant: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CCOC(=O)CC#N
Solvent: CCO
Solvent: C1CCNC1
Product: CCOC(=O)/C(C#N)=C\c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.1 %

Procedure:
To 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzaldehyde (3.0 g, 9.0 mmol) in ethanol (11.5 mL) was added ethyl 2-cyanoacetate (0.95 mL, 8.9 mmol) and pyrrolidine (0.97 mL, 12 mmol). A yellow precipitate formed immediately and additional ethanol (10 mL) was added. The reaction was stirred at room temperature for 18 hours and then concentrated onto Celite®. Purification by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes as eluent afforded the title compound as a white solid (2.1 g, 50%): 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.36-8.31 (m, 2H), 8.29 (s, 1H), 8.12 (d, J=8.4 Hz, 2H), 7.85-7.79 (m, 2H), 7.41 (d, J=8.3 Hz, 2H), 4.41 (q, J=7.1 Hz, 2H), 1.42 (t, J=7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 162.46, 162.24, 154.18, 141.89, 135.36, 134.76, 132.41, 131.53, 127.22, 122.47, 121.33, 115.51, 103.28, 62.82, 14.19; ESIMS m/z 429 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([NH:12][CH3:13])[C:9]([N+:14]([O-:16])=[O:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:17](Cl)[C:18](=[CH2:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:19][C:18](=[CH2:17])[CH2:20][O:1][C:2]1[CH:11]=[C:10]([NH:12][CH3:13])[C:9]([N+:14]([O-:16])=[O:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CNc1cc(O)c(C(=O)OC)cc1[N+](=O)[O-]
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)COc1cc(NC)c([N+](=O)[O-])cc1C(=O)OC
Yield: 70952.6 %

Procedure:
The title compound was prepared following the procedure described for Step-6 of Intermediate-1 using methyl 2-hydroxy-4-(methylamino)-5-nitrobenzoate (4.00 g, 0.0176 mmol), methallyl chloride (2.8 g, 0.0318 mmol), potassium carbonate (4.38 g, 0.037 mmol) and DMF (50.0 mL) to afford 3.500 g of desired product. 1HNMR (DMSO-d6): δ 1.81 (s, 3H), 3.00 (d, J=4.8 Hz, 3H), 3.76 (s, 3H), 4.65 (s, 2H), 5.00 (s, 1H), 5.24 (s, 1H), 6.30 (s, 1H), 8.59 (s, 2H); [M+H]+: 281.00.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[C:4]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[C:18](N1C=CN=C1)(N1C=CN=C1)=[O:19].O>CN(C)C=O>[CH:15]1[CH:14]=[CH:13][C:12]([CH2:11][O:10][C:4]2[C:5]3[NH:9][C:18]([NH:8][C:6]=3[N:7]=[C:2]([NH2:1])[N:3]=2)=[O:19])=[CH:17][CH:16]=1
Reactant: Nc1nc(N)c(N)c(OCc2ccccc2)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(OCc2ccccc2)c2[nH]c(=O)[nH]c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4,5-Triamino-6-benzyloxypyrimidine (Pfleiderer et al., Chem. Ber., 94, 12-18 (1961)) (1.85 g, 8 mmol) and 1,1′-carbonyldiimidazole (1.30 g, 8 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL) under argon. The solution was stirred at room temperature overnight and was mixed with water (200 mL) to precipitate a white solid. The solid was collected by filtration, and dissolved in 250 mL of aqueous 2 N NaOH solution. Undissolved material was removed by filtration, and the filtrate was neutralized with glacial acetic acid to precipitate a white solid. The solid was collected by filtration, was washed with water, and was recrystallized from 50% aqueous ethanol to afford analytically pure 1c: yield, 1.63 g (79%); mp 256-257° C. dec.; UV (pH 1) λmax 243 nm (ε=0.717×104), 306 (1.499×104); (pH 6.9) 243 (0.915×104), 290 (1.108×104); (pH 13) 249 (sh) (0.443×104), 293 (1.368×104); 1H NMR δ 5.41 (s, 2H, ArCH2), 6.13 (s, 2H, NH2, exchange with D2O), 7.33-7.51 (m, 5H, ArH), 10.46 (s, 1H, exchanges with D2O), 11.04 (s, 1H, exchanges with D2O); MS (EI) Calcd. m/z for C12H11N5O2: 257.0912. Found: 257.0914. Anal. (C12H11N5O2. 1/2 H2O) C, N, H.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.I.[NH2:12][NH:13][C:14]([NH:16][CH2:17][C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1)=[NH:15].C(O)C.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[N:12][NH:13][C:14]([NH:16][CH2:17][C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1)=[NH:15]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: N=C(NN)NCc1cnccn1
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: N=C(NCc1cnccn1)NN=Cc1c(Cl)cccc1Cl

Procedure:
A solution of 2.83 g. of 2,6-dichlorobenzaldehyde and 1-amino-3-(pyrazinylmethyl)guanidine hydriodide from Example 10 in 50 ml. of absolute ethanol and 5.0 ml. of glacial acetic acid is heated at reflux for 4 hours. The cooled solution is made basic by addition of 10N sodium hydroxide and extracted with ether. The ether extract is evaporated to give a residual orange gum which is crystallized from absolute ethanol to give the desired product as colorless crystals, m.p. 168°-169° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([C:42]2[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=2)[C:38]2=[N:48][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:53][CH2:52][C:16]([CH3:54])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:51])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:50])=[CH:28][C:29]=2[C:30]2[CH:49]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=C(Cl)N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([C:42]2[CH:43]=[CH:44][N:45]=[CH:46][CH:47]=2)[C:38]2=[N:48][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:54])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:51])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:50])=[CH:28][C:29]=2[C:30]2[CH:49]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:52][CH2:53]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(-c2ccncc2)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Agent: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Product: Cc1c([C@H](OC(C)(C)C)C(=O)O)c2n3cc(nc3c1-c1ccncc1)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 27.2 %

Procedure:
Prepared in 27.2% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-4,22,28-trimethyl-5-(pyridin-4-yl)-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.70 (d, J=5.5 Hz, 2H), 8.13 (s, 1H), 8.05 (s, 1H), 7.87 (d, J=7.7 Hz, 1H), 7.45 (d, J=5.5 Hz, 3H), 7.31 (d, J=7.7 Hz, 1H), 7.22-7.12 (m, 3H), 5.91 (br. s., 1H), 4.60 (br. s., 1H), 3.92-3.81 (m, 1H), 3.62 (d, J=12.1 Hz, 1H), 3.44 (br. s., 4H), 2.19 (s, 3H), 1.93-1.65 (m, 9H), 1.54 (br. s., 1H), 1.20 (s, 3H), 1.18 (s, 9H), 1.06 (d, J=6.2 Hz, 3H). LCMS (ESI, M): 720.4.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[CH3:28][S-:29].[Na+]>CN(C=O)C>[CH3:21][S:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([S:29][CH3:28])[N:3]=[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:5]=3[CH:10]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: C[S-]
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(N2CCOCC2)c2cc(CN3CCN(S(C)(=O)=O)CC3)sc2n1
Temperature: 1100 °C

Procedure:
To a solution 2-chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine (450 mg) in DMF (6 mL) was added sodium thiomethoxide (183 mg) and the reaction heated at 1100° C. for 16 h. After cooling to room temperature the reaction mixture was poured into ice water and the resulting precipitate filtered and air dried to give 6-(4-methanesulfonyl-piperazin-1-ylmethyl)-2-methylsulfanyl-4-morpholin-4-yl-thieno[2,3-d]pyrimidine as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:12][C:13]([O:15]CC)=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:27][NH:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[NH:37])[NH2:36])=[CH:31][CH:30]=1.[OH-].[Na+]>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:20])=[O:19])[CH2:12][C:13]([OH:15])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:27][NH:28][C:29]1[CH:30]=[CH:31][C:32]([C:35](=[NH:36])[NH2:37])=[CH:33][CH:34]=1
Reactant: CCOC(=O)CN(c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(N(CC(=O)O)S(=O)(=O)c3ccccc3)ccc21

Procedure:
Prepared analogously to Example 3 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-5-[N-(ethoxycarbonylmethyl)-benzenesulphonylamino]-benzimidazole and sodium hydroxide solution.
Reaction SMILES: CCN(CC)CC.[CH2:8]1[CH:12]2[CH2:13][NH:14][CH2:15][CH:11]2[CH2:10][N:9]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[C:23]([N:14]1[CH2:13][CH:12]2[CH2:8][N:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH:11]2[CH2:15]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3ccccc3)CC2C1
Temperature: 115 °C

Procedure:
Et3N (0.5 mL) was added into a solution of tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.2 g) and benzoyl chloride (0.11 mL) in THF (10 mL). The mixture was heated to 115° C. for 24 hours. The reaction was quenched with water (10 mL). The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic phase was dried over MgSO4 and concentrated to give a residue which was purified by silica gel chromatography to give tert-butyl 5-benzoylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate.