Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:32]([CH3:33])=[N:31][N:30](C4CCCCO4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=3[F:29])[CH:21]=2)=[O:15])[C:10]([CH3:41])([CH3:40])[CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[CH3:40][C:10]1([CH3:41])[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[C:14]([C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=2[F:29])[N:19]=[C:18]2[NH:30][N:31]=[C:32]([CH3:33])[C:17]=12)=[O:15]
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3F)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3(C)C)c12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3F)cc(C(=O)N3CCNCC3(C)C)c12
Yield: 109.3 %

Procedure:
130 mg of 4-[6-(2-fluoro-4-Hydroxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester were dissolved in 4.6 mL of 4M hydrochloric acid in dioxane. After complete conversion, dioxan was removed in vacuo, water was added and the solution was extracted twice with dichloromethane/isopropanol (10/1). The aqueous layer was lyophilized, taken up in water three times and lyophilized again to give 96 mg (100%) of the title compound as the hydrochloride salt.
Reaction SMILES: [NH2:1][NH2:2].[CH3:3][N:4]([CH3:25])[S:5]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][CH3:16])[N:10]=[C:9]1[CH2:19][CH2:20][C:21](OC)=[O:22])(=[O:7])=[O:6]>CO>[CH3:17][C:14]([CH3:18])([CH2:15][CH3:16])[CH2:13][C:11]1[N:10]=[C:9]([CH2:19][CH2:20][C:21]([NH:1][NH2:2])=[O:22])[N:8]([S:5]([N:4]([CH3:25])[CH3:3])(=[O:7])=[O:6])[CH:12]=1
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(CCC(=O)OC)n1
Reactant: NN
Solvent: CO
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(CCC(=O)NN)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Hydrazine (0.45 mL, 14.5 mmol) was added to a solution of methyl 3-[1-[(dimethyl-amino)sulfonyl]-4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]propanoate (1 g, 2.9 mmol) in dry methanol (2 mL). After stirring at rt for 3 hr, volatiles were removed in vacuo, and chromatography of the resulting residue over silica eluting with 0-40% ethyl acetate/hexane afforded the title compound.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23]([O:25]C)=[O:24])[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH-].[K+].O>C(O)C>[CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23]([OH:25])=[O:24])[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1cccc(CC(=O)OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCOc1cccc(CC(=O)O)c1
Yield: 81.7 %

Procedure:
A mixture of 40.5 g of 3-(tetradecyloxy)benzeneacetic acid, methyl ester, 18.8 g of potassium hydroxide, 15 ml of water and 300 ml of ethyl alcohol is refluxed for 4 hours. The solvent is removed and the residue partitioned between chloroform and dilute hydrochloric acid. The organic layer is dried and evaporated to a residue which is crystallized from carbon tetrachloride:hexane to give 31.8 g of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14]Cl)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39].[CH3:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.O>CN(C)C(=O)C>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][N:44]2[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]2)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(OCCCCl)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN1CCN(CCCOc2cc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c(c2Cl)CNC3=O)CC1
Yield: 61.5 %

Procedure:
In a similar manner to Step 2 of Example 440, 4-chloro-5-(3-chloropropoxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (87.1 mg, 0.152 mmol) was dissolved in N,N-dimethylacetoamide (0.9 mL), and the solution was treated with N-methylpiperazine (0.138 mL, 1.58 mmol). The reaction mixture was added with water. The obtained solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 4-chloro-5-[3-(4-methylpyperazin-1-yl)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (59.5 mg, yield 68%).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[C:20]([C:24]1[CH:25]=[C:26]([NH2:36])[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[N:28]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[C:26]([NH:36][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:15][CH:14]=2)[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[N:28]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2Cl)n1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Product: CC(C)(C)c1cc(NC(=O)Cc2ccc(-n3cnc4cccnc43)cc2)n(-c2ccccc2Cl)n1

Procedure:
The title compound is prepared as described in Example 28 but using 2-(4-imidazo[4,5-b]pyridine-3-yl-phenyl)-acetic acid and 5-tert-butyl-2-(2-chloro-phenyl)-2H-pyrazol-3-ylamine. Title compound: ES-MS: 485.03 [M+H]+; tR=3.08 min (System 3).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH2:8].[CH3:9][N:10]([CH3:31])[CH2:11][CH:12]([N:14]1[C:27]2[CH:26]=[C:25]([C:28](=S)N)[CH:24]=[CH:23][C:22]=2[S:21][C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13]>C(OCC)(=O)C>[CH3:31][N:10]([CH3:9])[CH2:11][CH:12]([N:14]1[C:27]2[CH:26]=[C:25]([C:28]3[NH:8][CH:3]4[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]4[N:1]=3)[CH:24]=[CH:23][C:22]=2[S:21][C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13]
Reactant: CC(CN(C)C)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reactant: NC1CCCCC1N
Solvent: CCOC(C)=O
Product: CC(CN(C)C)N1c2ccccc2Sc2ccc(C3=NC4CCCCC4N3)cc21
Temperature: 160 °C
Yield: 36.2 %

Procedure:
1,2-Diaminocyclohexane (9.3 g) is added to an ethanolic solution (35 cc) of 10-[(2RS)-1-dimethylamino-2-propyl]-2-phenothiazinecarbothioamide (2.8 g). The mixture is heated in an autoclave to 160° C. for 4.5 hours. The reaction mixture is diluted with ethyl acetate (100 cc) and washed with distilled water (3×100 cc). The organic phase is separated after settling has taken place, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is purified by chromatography on a column (height: 22 cm; diameter: 4 cm) of silica gel (0.04-0.06 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with 1,2-dichloroethane (1 liter) and mixtures of 1,2-dichloroethane and methanol in proportions (by volume) of 90:10 (3 liters), 80:20 (2 liters), 70:30 (2 liters) and 50:50 (1 liter) and with pure methanol (1 liter) and collecting 125-cc fractions. Fractions 63 to 80 containing the pure product are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give 10-[(2RS)-1-dimethylamino-2-propyl]-2-(3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl)phenothiazine (1.2 g) in the form of a yellow product of meringue-like consistency.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[N:15]=[N:16][N:17]=[C:7]2[C:6]=1[NH2:18].[C:20](OC(OCC)OCC)(=O)C.[OH-].[Na+]>O>[CH3:1][CH:2]([CH3:19])[CH2:3][N:4]1[C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]3[N:15]=[N:16][N:17]=[C:7]3[C:6]=2[N:18]=[CH:20]1
Reactant: CC(C)CNc1c(N)c2nnnn2c2ccccc12
Reactant: CCOC(OCC)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)Cn1cnc2c1c1ccccc1n1nnnc21

Procedure:
N5 -(2-Methylpropyl)tetrazolo[1,5-a]quinoline-4,5-diamine (0.2 g, 0.78 mmole, Example 16) was combined with diethoxymethyl acetate (2 mL) and heated on a steam bath for 3 hours. Water (10 mL) and 10% sodium hydroxide (2 mL) were added and the reaction mixture was heated on a steam bath for 1 hour. A solid was isolated by filtration then recrystallized from methanol/ethyl acetate to provide 0.16 g of 6-(2-methylpropyl)-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline as a white crystalline solid, m.p. 210-212° C. Analysis: Calculated for C14H14N6 : %C, 63.14; %H, 5.30; %N, 31.56; Found: %C, 63.12; %H, 5.32; %N, 31.61.
Reaction SMILES: [N:1]([CH:4]1[CH2:33][C:8]2=[CH:9][N:10]([S:15]([C:18]3[C:23]([CH:24]([CH3:26])[CH3:25])=[CH:22][C:21]([CH:27]([CH3:29])[CH3:28])=[CH:20][C:19]=3[CH:30]([CH3:32])[CH3:31])(=[O:17])=[O:16])[C:11]3[CH:12]=[CH:13][CH:14]=[C:6]([C:7]=32)[C:5]1=[O:34])=[N+]=[N-].[C:35](OC(=O)C)(=[O:37])[CH3:36]>C1COCC1.[Pd]>[C:35]([NH:1][CH:4]1[CH2:33][C:8]2=[CH:9][N:10]([S:15]([C:18]3[C:23]([CH:24]([CH3:26])[CH3:25])=[CH:22][C:21]([CH:27]([CH3:29])[CH3:28])=[CH:20][C:19]=3[CH:30]([CH3:32])[CH3:31])(=[O:17])=[O:16])[C:11]3[CH:12]=[CH:13][CH:14]=[C:6]([C:7]=32)[C:5]1=[O:34])(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)n2cc3c4c(cccc42)C(=O)C(N=[N+]=[N-])C3)c(C(C)C)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(=O)NC1Cc2cn(S(=O)(=O)c3c(C(C)C)cc(C(C)C)cc3C(C)C)c3cccc(c23)C1=O
Yield: 90.8 %

Procedure:
A solution of 4-azido-3,4-dihydro-1-(2,4,6-triisopropylphenylsulfonyl)benz[cd]indol-5(1H)-one (5.36 g, 11.2 mmol), acetic anhydride (2.29 g, 22.4 mmol) and 10% Pd-C (1.7 g in THF (60 ml) was stirred for 4 hours at 4 hours under 4 atmospheres pressure under hydrogen atmosphere. After completion of the reaction, the catalyst was filtered off. The filtrate was concentrated under reduced pressure. To the concentrate was added isopropyl ether to give 5.03 g (91%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]3[S:15][C:14]([N:16](C(OC(C)(C)C)=O)[CH2:17][C@@H:18]([NH:30]C(=O)OC(C)(C)C)[CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[N:13][N:12]=3)[CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=[O:45].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:30][C@@H:18]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=1)[CH2:17][NH:16][C:14]1[S:15][C:11]([C:8]2[CH:9]=[CH:10][C:5]3[NH:4][C:3](=[O:45])[N:2]([CH3:1])[C:6]=3[CH:7]=2)=[N:12][N:13]=1
Reactant: Cn1c(=O)[nH]c2ccc(-c3nnc(N(C[C@H](Cc4ccc(C(F)(F)F)cc4)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)[nH]c2ccc(-c3nnc(NC[C@@H](N)Cc4ccc(C(F)(F)F)cc4)s3)cc21
Yield: 74.3 %

Procedure:
tert-Butyl (S)-1-(5-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1,3,4-thiadiazol-2-yl-boc-amino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (0.36 g, 0.6 mmol) in 20 mL DCM was treated with TFA (20 mL, 260 mmol) for 30 minutes. After removing the solvent, the remaining residue was dissolved in 100 mL EtOAc. The resulting solution was washed with a mixture of aqueous saturated sodium bicarbonate and 5% 5N NaOH, and then twice with saturated sodium bicarbonate. After removing the solvent, a tan solid was obtained as the pure product 6-(5-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)-1,3,4-thiadiazol-2-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one (0.2 g, 79% yield). LCMS (API-ES) m/z (%): 449.1 (100%, M++H); 1H NMR (400 MHz, CDCl3) δ ppm 2.72 (b, 3H), 2.97 (dd, J=13.2, 7.7 Hz, 1H) 3.27 (dd, J=13.2, 7.7 Hz, 1H) 3.36-3.46 (m, 5H) 3.56 (m, 1H) 7.03 (d, J=8.22 Hz, 1H) 7.32-7.37 (m, 3H) 7.49 (s, 1H) 7.57 (d, J=7.82 Hz, 2H).
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16](N5CCNCC5)=[N:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[N:27]1([C:18]2[C:13]3[NH:12][CH:11]=[C:10]4[C:25](=[O:26])[N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:8]=[C:9]4[C:14]=3[CH:15]=[CH:16][N:17]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: C1COCCN1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Product: O=c1c2c[nH]c3c(N4CCOCC4)nccc3c-2nn1-c1ccccc1

Procedure:
The title compound was prepared following the procedure described in Step 4 for synthesis for 6a using 16 and morpholine. 1H-NMR (DMSO-d6) δ (ppm): 3.17 (4H, brm), 3.87 (4H, brm), 7.15 (1H, m), 7.43 (2H, m), 7.76 (1H, d, J=5.5 Hz), 8.17 (2H, d, J=8.8 Hz), 8.33 (1H, d, J=5.2 Hz), 8.44 (1H, s). m/z 348.1 (MH+).
Reaction SMILES: NN.[CH3:3][C:4]1([CH3:29])[C:12]2[C:7](=[CH:8][C:9]([N:17]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:10][C:11]=2[C:13]([F:16])([F:15])[F:14])[NH:6][C:5]1=[O:28]>CO.C(Cl)(Cl)Cl>[NH2:17][C:9]1[CH:8]=[C:7]2[C:12]([C:4]([CH3:29])([CH3:3])[C:5](=[O:28])[NH:6]2)=[C:11]([C:13]([F:16])([F:14])[F:15])[CH:10]=1
Reactant: CC1(C)C(=O)Nc2cc(N3C(=O)c4ccccc4C3=O)cc(C(F)(F)F)c21
Agent: NN
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC1(C)C(=O)Nc2cc(N)cc(C(F)(F)F)c21

Procedure:
By adding a hydrazine aqueous solution to a methanol-chloroform solution of 2-[3,3-dimethyl-2-oxo-4-(trifluoromethyl)-2,3-dihydro-1H-indol-6-yl]-1H-isoindol-1,3-(2H)-dione and carrying out the reaction at room temperature for 10 hours, 6-amino-3,3-dimethyl-4-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one was obtained.
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9](=O)[CH3:10])[C:3]([O:5]CC)=[O:4].Cl.[NH2:13]O>Cl>[CH3:10][C:9]1[CH:8]=[C:2]([C:3]([OH:5])=[O:4])[O:1][N:13]=1
Reactant: NO
Reactant: CCOC(=O)C(=O)CC(C)=O
Agent: Cl
Product: Cc1cc(C(=O)O)on1
Reaction time: 7 h
Yield: 58.7 %

Procedure:
Concentrated HCl (450 ml) was added to ethyl 2,4-dioxovalerate ( 177.8 g, 1.1 mol ) followed by hydroxylamine hydrochloride (103.7 g, 1.68 mol). The reaction mixture was stirred for 7 hours, then allowed to stand for 60 hours. The solvent was removed in vacuo and the residue was chilled on ice. A solid formed which was collected by filtration and washed with cold water. The solid was dissolved in THF (11), the solution was filtered and the solvent was removed in vacuo. The residue was slurried with ethyl acetate (200 ml) and the solid collected by filtration. Concentration of filtrate to approximately 30 ml afforded a second crop of the product. The two crops were combined and recrystallized from methanol to afford 82.1 g (58%) of 3-methylisoxazole-5-carboxylic acid, m.p. 209°-211° C.
Reaction SMILES: C([S:4][C@H:5]1[CH2:9][C@@H:8]([CH2:10][C:11]2[S:15][C:14]3=[CH:16][N:17]=[C:18]([CH3:19])[N:13]3[CH:12]=2)[N:7]([C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])[CH2:6]1)(=O)C.C1(OP(O[C:43]2[C@H:44]([CH3:60])[C@@H:45]3[C@@H:55]([C@H:56]([OH:58])[CH3:57])[C:54](=[O:59])[N:46]3[C:47]=2[C:48]([O:50][CH2:51][CH:52]=[CH2:53])=[O:49])(OC2C=CC=CC=2)=O)C=CC=CC=1>>[CH2:23]([O:22][C:20]([N:7]1[C@H:8]([CH2:10][C:11]2[S:15][C:14]3=[CH:16][N:17]=[C:18]([CH3:19])[N:13]3[CH:12]=2)[CH2:9][C@H:5]([S:4][C:43]2[C@H:44]([CH3:60])[C@@H:45]3[C@@H:55]([C@H:56]([OH:58])[CH3:57])[C:54](=[O:59])[N:46]3[C:47]=2[C:48]([O:50][CH2:51][CH:52]=[CH2:53])=[O:49])[CH2:6]1)=[O:21])[CH:24]=[CH2:25]
Reactant: C=CCOC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1Cc1cn2c(C)ncc2s1
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3cn4c(C)ncc4s3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 53.5 %

Procedure:
The procedure of Example 23-a) is repeated to prepare 653.0 mg of a mercaptan compound as a yellow oil from 766.4 mg of (3S,5S)-3-acetylthio-1-allyloxycarbonyl-5-(5-methylimidazo[5,1-b]thiazol-2-yl)methylpyrrolidine described in Synthesis Example 11. Allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-(5-methylimidazo[5,1-b]thiazol-2-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate (560.2 mg) is prepared as a colorless amorphous material from this mercaptan and 891.6 mg of allyl(1R,5R,6S)-2-(diphenylphosphono)oxy-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH2:18][OH:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[CH:26][C:27](=O)[NH:28][CH:29]=1>COCCOC>[CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH2:18][O:19][C:27]1[CH:26]=[CH:25][C:24]([C:23]([F:32])([F:31])[F:22])=[CH:29][N:28]=1)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:14])([F:15])[F:16])[CH:6]=1
Reactant: O=c1ccc(C(F)(F)F)c[nH]1
Reactant: CC(C)(C)CN(CCO)c1ccc(C#N)c(C(F)(F)F)c1
Solvent: COCCOC
Product: CC(C)(C)CN(CCOc1ccc(C(F)(F)F)cn1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 27B from 4-[(2,2-dimethylpropyl)(2-hydroxyethyl)amino]-2-(trifluoromethyl)benzonitrile (Example 61C) and 5-(trifluoromethyl)-2(1H)-pyridinone, using dry DME as the reaction solvent: 1H NMR (400 MHz, CDCl3) δ 8.43 (m, 1H), 7.79 (app. dd, J=8.8, 2.6 Hz, 1H), 7.56 (d, J=8.9 Hz, 1H), 7.27 (d, J≈2.6 Hz, 1H; partially obscured by solvent), 6.97 (dd, J=9.0, 2.8 Hz, 1H), 6.78 (partially resolved ddd, J=8.7, ˜0.6, ˜0.6 Hz, 1H), 4.52 (t, J=6.6 Hz, 2H), 3.90 (t, J=6.7 Hz, 2H), 3.34 (s, 2H), 1.00 (s, 9H).
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH2:2][CH3:3].[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=2)[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:19][CH2:20][CH3:21])=[CH:25][CH:24]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCCN(CCC)CCCCNCc1ccc(C#N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCN(CCC)CCCCN(Cc1ccc(Br)cc1)Cc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 22 h
Yield: 80.1 %

Procedure:
0.40 g (1.39 mmol) of 4-[(4-dipropylaminobutyl)amino]methylbenzonitrile (2a), 8.0 ml of ethanol, and 514 mg (2.78 mmol, 2.0 equivalents) of 4-bromobenzaldehyde were charged in a 50 ml recovery flask under a nitrogen stream. The mixture was then cooled to 0° C. After the addition of 0.707 g (3.34 mmol, 2.4 equivalents) of sodium triacetoxyborohydride, the mixture was stirred for 22 hours. After confirming the disappearance of the raw material by TLC, the reaction solution was added to 50 ml of a saturated sodium bicarbonate aqueous solution, and extracted twice with 50 ml of chloroform. The chloroform layer was washed with 100 ml of a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (Chromatorex NH (manufactured by FujiSilysia Chemical Ltd.), n-hexane:ethyl acetate=3:1), thereby obtaining 0.508 g of 4-{[(4-bromobenzyl)-(4-dipropylaminobutyl)amino]methyl}benzonitrile (15) as a light yellow oily substance (yield: 80.0%). [HPLC: 96.2% (HPLC measurement conditions B)]
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([C:20]([C:23]#[N:24])([CH3:22])[CH3:21])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=2)=O)C.[BH4-].[Na+]>CO.C1COCC1>[CH2:18]([O:17][C:15]([C:10]1[CH:11]=[CH:12][C:13]2[CH:14]=[C:6]3[C:4](=[O:3])[NH:24][CH2:23][C:20]([CH3:22])([CH3:21])[N:7]3[C:8]=2[CH:9]=1)=[O:16])[CH3:19]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(C(C)(C)C#N)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1ccc2cc3n(c2c1)C(C)(C)CNC3=O
Temperature: 0 °C
Yield: 31.3 %

Procedure:
1-(Cyano-dimethyl-methyl)-1H-indole-2,6-dicarboxylic acid diethyl ester (238, 0.725 mmol) was suspended in 3 mL of MeOH and 2 mL of THF, and 188 mg (1.45 mmol) of CoCl2 was added. While the mixture was stirred in a 0° C. bath, 274 mg (7.25 mmol) of NaBH4 was carefully added in small portions. The cold bath was removed and the mixture was stirred for 30 min. The vessel was sealed and heated to 60° C. with stirring for 4 h. The mixture was cooled and partitioned between EtOAc and saturated aqueous NaHCO3. The organic phase was then washed with 1 M NaHSO4 and brine, dried with Na2SO4, filtered, and concentrated. The residue was chromatographed (1-5% MeOH in CH2Cl2) to provided 65 mg of 4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-7-carboxylic acid ethyl ester. ESI-MS m/z 287 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:17]=[C:16](OS(C2C=CC(C)=CC=2)(=O)=O)[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:4]=2[N:3]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(N(CC)CC)C>C(#N)C>[N:29]1([C:16]2[C:5]3[CH2:6][CH2:7][CH2:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:4]=3[N:3]=[C:2]([NH2:1])[N:17]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1
Reactant: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCCc2ccccc2-3)cc1
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1nc2c(c(N3CCNCC3)n1)CCCCc1ccccc1-2

Procedure:
A solution of Example 20C (80 mg 0.20 mmol), piperazine (26 mg, 0.30 mmol) and triethylamine (0.1 mL, 0.72 mmol) in anhydrous acetonitrile (3 mL) was heated at 160° C. in a microwave reactor for 20 minutes. The mixture was concentrated under reduced pressure and chromatographed on silica gel eluting with NH4OH:MeOH:CH2Cl2 (0.6:6:94) to provide the title compound. 1H NMR (CD3OD) δ 1.45 (m, 2H), 1.86 (m, 1H), 2.00-2.15 (m, 2H), 2.34 (m, 1H), 2.73 (dd, J=14.58, 8.48 Hz, 1H), 2.80-3.02 (m, 5H), 3.37 (m, 4H), 7.22 (m, 1H), 7.24-7.31 (m, 2H), 7.33-7.41 (m, 1H). MS (M+H)+ m/z 310.
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH-:11].[K+]>C(O)(C)(C)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:1]([NH2:10])=[O:11])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(C#N)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: N#Cc1ccc(C(N)=O)cc1
Yield: 105.3 %

Procedure:
Terephthalonitrile (12.8 g, 0.1 mol) and tert-butanol (243.2 g) were mixed, and the resultant mixture was heated to 80° C. with stirring. To the mixture, a 26% aqueous solution of potassium hydroxide (4.3 g) was added over three hours. Liquid chromatographic analysis revealed the reaction mixture contained 11.8 g of p-cyanobenzamide (yield 81%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][CH:15]=[C:16]([C:18]2[CH:19]=[C:20]([CH:45]=[CH:46][CH:47]=2)[O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[NH:32][C:31]([C@@H:33]4[CH2:37][CH2:36][CH2:35][N:34]4C(OC(C)(C)C)=O)=[N:30][CH:29]=3)=[CH:24][CH:23]=2)[N:17]=1)=O)(C)(C)C.[ClH:48]>ClCCl>[ClH:48].[NH:34]1[CH2:35][CH2:36][CH2:37][C@H:33]1[C:31]1[NH:32][C:28]([C:25]2[CH:26]=[CH:27][C:22]([O:21][C:20]3[CH:45]=[CH:46][CH:47]=[C:18]([C:16]4[N:17]=[C:13]([C@@H:9]5[CH2:10][CH2:11][CH2:12][NH:8]5)[NH:14][CH:15]=4)[CH:19]=3)=[CH:23][CH:24]=2)=[CH:29][N:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2cccc(Oc3ccc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)c2)c[nH]1
Agent: Cl
Solvent: ClCCl
Product: c1cc(Oc2ccc(-c3cnc([C@@H]4CCCN4)[nH]3)cc2)cc(-c2c[nH]c([C@@H]3CCCN3)n2)c1
Temperature: 25 °C

Procedure:
To a solution of (S)-tert-butyl 2-(5-(4-(3-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)phenoxy)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (500 mg, 0.78 mmol) in dichloromethane was added HCl (1 M, 3 mL), the reaction product precipitated after stirring at room temperature. Filtration and drying in the vacuum oven afforded 2-((S)-pyrrolidin-2-yl)-5-(4-(3-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-4-yl)phenoxy)phenyl)-1H-imidazole hydrochloride (220 mg).