Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4/[CH:28]=[CH:29]/[N+:30]([O-:32])=[O:31])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]>O1CCOCC1.C(O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][N+:30]([O-:32])=[O:31])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(/C=C/[N+](=O)[O-])c[nH]c34)no2)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CC[N+](=O)[O-])c[nH]c34)no2)cc1Cl
Temperature: 25 °C
Yield: 84.2 %

Procedure:
To a suspension of NaBH4 (0.7 g) in 1,4-dioxane (150 mL) and ethanol (50 mL) stirred in air at room temperature was added a solution of 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-3-[(E)-2-nitroethenyl]-1H-indole (D82) (2.6 g) in 1,4-dioxane (150 mL) dropwise. The reaction mixture was stirred at 20° C. for 1 h. The excess NaBH4 was quenched with dilute H2SO4. The reaction solution was concentrated. Ethyl acetate (300 mL) was added to the residue, washed with water and brine, and then dried over MgSO4. Solvent was evaporated off to give the desired product 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-3-(2-nitroethyl)-1H-indole (D83) (2.2 g) as a yellow solid. δH (CDCl3, 400 MHz): 1.46 (6H, d), 3.55 (2H, t), 4.69-4.74 (3H, m), 7.07 (1H, d), 7.23 (1H, d), 7.30 (1H, t), 7.75 (1H, d), 8.08 (1H, dd), 8.12 (1H, d), 8.26 (1H, d), 9.74 (1H, s). MS (ES): C21H19ClN4O4 requires 426; found 427.2 (M+H+).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]2[C:11]3[CH:12]=[C:13]([C:18]#[N:19])[CH:14]=[CH:15][C:16]=3[CH2:17][C@H:6]12)=O.[OH-].[Na+]>CO.[Cl-].[Na+].O>[NH:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]2[C:11]3[CH:12]=[C:13]([C:18]#[N:19])[CH:14]=[CH:15][C:16]=3[CH2:17][C@H:6]12
Reactant: N#Cc1ccc2c(c1)[C@H]1CCCN(C(=O)C(F)(F)F)[C@H]1C2
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1ccc2c(c1)[C@H]1CCCN[C@H]1C2

Procedure:
A solution of cis-1-(2,2,2-trifluoroacetyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile (5.50 g) and 4 M NaOH solution (5.6 mL) in methanol (30 mL) is stirred at room temperature for 2 h. Brine (150 mL) is then added and the resulting mixture is extracted with ethyl acetate (3×75 mL). The combined extract is dried (MgSO4) and concentrated to give the title compound as an oil that solidified upon standing. Yield: 3.70 g (quantitative); Mass spectrum (ESI+): m/z=295 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[O:6][N:5]=[C:4]([C:7]([O:9]CC)=[O:8])[C:3]=1[CH3:12].[OH-].[Na+].Cl>CO>[Br:1][C:2]1[O:6][N:5]=[C:4]([C:7]([OH:9])=[O:8])[C:3]=1[CH3:12]
Reactant: CCOC(=O)c1noc(Br)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)O)noc1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl 5-bromo-4-methylisoxazole-3-carboxylate (Intermediate A) (8.65 g, 37.0 mmol) in MeOH (100 mL) was added 2M NaOH (aq) (18.48 mL, 37.0 mmol). The reaction mixture was stirred at room temperature for 10 minutes and the resulting mixture was acidified using 1M HCl (aq) and concentrated under reduced pressure to remove MeOH. The aqueous was diluted with water and extracted with EtOAc (×3) and the combined organic extracts were dried over MgSO4 and filtered. The solvent was removed under reduced pressure to afford the title compound;
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:23](=[O:29])[C:24]([O:26]CC)=[O:25])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:15]=2)[C:10]([C:23](=[O:29])[C:24]([OH:26])=[O:25])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccccc3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccccc3)cc12
Yield: 62.3 %

Procedure:
{1-Benzyl-5-phenyl-1H-indol-3-yl}(oxo)acetic acid was prepared from ethyl {1-benzyl-5-phenyl-1H-indol-3-yl}(oxo)acetate (0.680 g, 1.77 mmol), and potassium hydroxide (0.322 g, 5.74 mmol) in THF (10 mL) and water (10 mL), following the procedure described in Step 4 of Example 5. Crystallization from acetonitrile, and drying for 3.5 hours at 70° C., yielded the title compound as a yellow solid (0.392 g, 62%), mp: 193-195° C. (dec.). Mass spectrum (+ES, [M+H]+) m/z 356; 1HNMR (500 MHz, DMSO-d6): δ 13.7-14.2 (br s, 1H), 8.7 (s, 1H), 8.45 (d, 1H, J=0.61 Hz), 7.65 (m, 3H), 7.55 (dd, 1H, J=8.7 Hz and 1.1 Hz), 7.45 (t, 2H, J=7.6 Hz), 7.25-7.35 (m, 6H), and 5.65 ppm (s, 2H). Elemental Analysis for C23H17NO3: Calculated: C, 77.73; H, 4.82; N, 3.94. Found: C, 77.52; H, 4.81; N, 3.95.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:33]3[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:32]=3[O:31][CH2:30]2)[CH2:26][CH2:25]1)=[O:23].[CH2:39]([S:41]([NH2:44])(=[O:43])=[O:42])[CH3:40]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:44][S:41]([CH2:39][CH3:40])(=[O:43])=[O:42])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][C:27]2([C:33]3[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:32]=3[O:31][CH2:30]2)[CH2:28][CH2:29]1)=[O:23]
Reactant: CCS(N)(=O)=O
Reactant: Cc1ccc(F)c(Nc2c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc3c(C(=O)O)cnn23)c1
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc12
Yield: 47.6 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-fluoro-5-methylphenylamino)-6-(6-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.109 g, 0.210 mmol) obtained in step 2 and ethanesulfonamide (0.114 g, 1.05 mmol), the title compound (0.061 g, 48%) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24](O)=[O:25])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24](=[O:25])[NH:34][CH2:33][C:32]2[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)=[CH:12][N:11]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1ccc(CN)cc1
Reactant: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)O)c2c1
Product: COc1ccc(CNC(=O)c2cnc(CNC(=O)OC(C)(C)C)c3c(OC)cc(OC)cc23)cc1

Procedure:
As described in example 1E, 50 mg of 1-(tert-butoxycarbonylamino-methyl)-6,8-dimethoxy-isoquinoline-4-carboxylic acid was coupled with 4-methoxy-benzylamine to give 48 mg of [6,8-dimethoxy-4-(4-methoxy-benzylcarbamoyl)-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl ester. H1-NMR (CDCl3): δ, 8.43 (s, 1H), 7.35 (d, J=8.6 Hz, 2H), 6.91 (d, J=8.6 Hz, 2H), 6.87 (s, 1H), 6.68 (br s, 1H), 6.56 (s, 1H), 6.36 (br s, 1H), 5.00 (d, J=3.5 Hz, 2H), 4.66 (d, J=5.9 Hz, 2H), 3.95 (s, 3H), 3.88 (s, 3H), 3.82 (s, 3H), 1.51 (s, 9H); MS: APCI (M+H) calc'd for C26H31N3O6+H 482.5; found 482.0.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2Br)=[CH:3][CH:2]=1.C([Li])CCC.[C:21]([N:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1)([O:23][CH2:24][CH3:25])=[O:22]>O1CCCC1>[C:21]([N:26]1[CH2:27][CH2:28][C:29]([OH:32])([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7][C:4]2[CH:5]=[CH:6][C:1]([CH3:15])=[CH:2][CH:3]=2)[CH2:30][CH2:31]1)([O:23][CH2:24][CH3:25])=[O:22]
Reactant: Cc1ccc(Sc2ccccc2Br)cc1
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(O)(c2ccccc2Sc2ccc(C)cc2)CC1
Temperature: -15 °C

Procedure:
2-(4-tolylsulfanyl)-phenyl bromide (6.98 g, 25 mmol) was dissolved in heptanes (40 mL) and dry tetrahydrofuran (4.1 mL) and after 1.5 hrs the reaction mixture was cooled down to 0° C. under an atmosphere of nitrogen. n-Butyllithium in heptanes 2.7 M (9.8 mL, 26.5 mmol) was added at 0° C. and after 45 min the reaction mixture was cooled to −15° C. A solution of N-carbethoxy-4-piperidone (3.8 mL, 25 mmol) in tetrahydrofuran (15 mL) was added maintaining the temperature below −15° C. Once the addition was complete the reaction was allowed to warm to room temperature. The reaction was quenched with a dilute hydrogen chloride solution. A sample from the organic phase shows a ratio of 1-carbethoxy-4-hydroxy-4-[2-(4-methylphenylsulfanyl)phenyl]piperidine to 1-methyl-4-phenylsulfanyl-benzene of 28:58.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:10][CH2:11][OH:12])[C:5]([CH2:17][CH2:18][CH2:19][NH2:20])=[C:4]([CH3:21])[N:3]=1.[CH3:22][O:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:10][CH2:11][OH:12])[C:5]([CH2:17][CH2:18][CH2:19][NH:20][CH2:32][C:29]2[CH:28]=[CH:27][C:26]([CH2:25][C:24]([O:23][CH3:22])=[O:34])=[CH:31][CH:30]=2)=[C:4]([CH3:21])[N:3]=1
Reactant: CCCC[C@@H](CCO)Nc1nc(N)nc(C)c1CCCN
Reactant: COC(=O)Cc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCC[C@@H](CCO)Nc1nc(N)nc(C)c1CCCNCc1ccc(CC(=O)OC)cc1
Reaction time: 5 h
Yield: 3.1 %

Procedure:
To a solution of the product from step (ix) (57 mg) in THF (5 mL) was added (4-formylphenyl)acetic acid methyl ester (51 mg) and acetic acid (0.011 mL). The resulting mixture was stirred for 5 h, sodium triacetoxyborohydride (90 mg) was added and the resulting solution stirred at rt for 16 h. TEA (0.013 mL) was added and the reaction mixture stirred for a further 2 h. The solvents were evaporated, the residue redissolved in MeOH and purified by RPHPLC to afford the title compound 2.7 mg.
Reaction SMILES: Cl[C:2]1[C:21]([I:22])=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.Cl.[CH3:24][C:25]1([OH:29])[CH2:28][NH:27][CH2:26]1>>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([I:22])[C:2]([N:27]3[CH2:28][C:25]([OH:29])([CH3:24])[CH2:26]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: CC1(O)CNC1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(I)c1
Agent: Cl
Product: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2I)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 88.1 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-iodonicotinamide (Stage 48.3) and 3-methylazetidine-3-ol hydrochloride to afford a beige foam. HPLC (Condition 7) tR=6.84 min, UPLC-MS (Condition 8) tR=1.14 min, m/z=510.0/512.0 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]1[CH:7]([C:8]([OH:10])=O)[NH:6][C:5](=[O:11])[NH:4]1)[CH3:2].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[CH2:1]([CH:3]1[NH:4][C:5](=[O:11])[NH:6][CH:7]1[C:8](=[O:10])[C:16]1[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=1)[CH3:2]
Reactant: Fc1ccccc1
Reactant: CCC1NC(=O)NC1C(=O)O
Solvent: O
Product: CCC1NC(=O)NC1C(=O)c1ccc(F)cc1
Temperature: 100 °C

Procedure:
In 100 g PPA are suspended 15.8 g 4-ethyl-2-oxoimidazolidine-5-carboxylic acid and 10 g fluorobenzene. The mixture is heated to 100° C. for 10 hours with rapid stirring and poured into water. The product separates and is collected.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][CH:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[CH3:28]I>CO>[CH3:28][N:12]([CH2:13][CH2:14][CH:15]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:11][CH2:10][CH2:9][S:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: Oc1ccc(SCCCNCCC(c2ccccc2)c2ccccc2)cc1
Reactant: CI
Solvent: CO
Product: CN(CCCSc1ccc(O)cc1)CCC(c1ccccc1)c1ccccc1

Procedure:
To a solution of 0.8 g (0.0021 moles) of N-(3'-p-hydroxyphenylthiopropyl)-3,3-diphenylpropylamine in 20 ml methanol containing 0.3 ml triethylamine are gradually added 0.13 ml (0.0021 moles) methyl iodide. After 36 hours at room temperature the solvent is evaporated under vacuum and the residue is dissolved in 20 ml benzene. The solution is washed three times with water, dried and evaporated.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)=[O:2].ClCCl.[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2
Reactant: CCOC(=O)c1cc(C=O)c2ccccn2c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1cc(CO)c2ccccn2c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The ethyl 1-formyl-4-oxo-4H-quinolizine-3-carboxylate (5 g, 20.4 mmol) was stirred in a 2:1 dichloromethane:MeOH solution (102 mL) and cooled to 0° C. The reaction was treated with sodium borohydride (0.309 g, 8.16 mmol), warmed to ambient temperature, and stirred for 20 hours. The mixture was quenched with a 10% sodium carbonate solution, extracted with dichloromethane (3×100 mL), and partitioned between water and dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and concentrated to afford ethyl 1-(hydroxymethyl)-4-oxo-4H-quinolizine-3-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:33])([CH3:32])[C:13](=[O:31])[N:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[OH:30])=[O:23])[CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:41][C:42]([NH2:44])=[O:43]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:33])([CH3:32])[C:13](=[O:31])[N:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:41][C:42]([NH2:44])=[O:43])=[O:23])[CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: NC(=O)CCl
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)c4ccccc4O)CC3)C(=O)C2(C)C)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccccc4OCC(N)=O)CC3)C(=O)C2(C)C)cc1OC

Procedure:
1.0 g of 5-(3,4-dimethoxyphenyl)-2-{1-[(2-hydroxyphenyl)carbonyl]piperidin-4-yl}-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound described in example 94) and 1.0 g potassium carbonate are suspended in 20 ml of acetonitrile. 0.3 g of 2-chloroacetamide are added and the reaction mixture is heated to reflux for 5 h until the reaction is completed according to TLC analysis. The solvent is evaporated under reduced pressure, and the remaining residue is taken up in DCM. The organic phase is washed with water, dried over MgSO4, and the solvent is removed under reduced pressure. Purification of the resulting crude product by crystallization from EA yields the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=2[CH3:21])=[O:11])[CH2:3]1.[C:22]([C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1)#[N:23]>>[C:22]([C:24]1[CH:25]=[C:26]([S:30]([N:7]2[C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=3[CH3:21])=[O:11])[CH2:3][C@H:2]2[CH3:1])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1)#[N:23]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: COc1cccc(NC(=O)CN2C[C@@H](C)N[C@@H](C)C2)c1C
Product: COc1cccc(NC(=O)CN2C[C@@H](C)N(S(=O)(=O)c3cccc(C#N)c3)[C@@H](C)C2)c1C

Procedure:
The title compound was prepared from the product of Example 65 step (i) (0.503 mmol) and 3-cyanobenzenesulphonyl chloride (0.503 mmol) by the method of Example 58 step (ii) as a white solid. Yield: 21 mg
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:20])[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[CH2:27]([O:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:20])[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
To a solution of N-(2-hydroxy-4-methylphenyl)-4-nitrobenzamide (3.8 g) in N,N-dimethylformamide (25 ml) was added potassium carbonate (3.85 g) and benzyl bromide (2.63 g). The reaction mixture was stirred at ambient temperature for 3 hours. The mixture was extracted with ethyl acetate and washed with water and brine. The organic solution was dried over magnesium sulfate. The solvent was removed by evaporation to give N-(2-benzyloxy-4-methylphenyl)-4-nitrobenzamide (4.8 g).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH:13]=[C:12]([C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[NH:26])[NH2:25])=[CH:20][CH:19]=2)=[O:15])[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:34]([O:36][CH3:37])=[O:35]>O.O1CCCC1>[NH2:26]/[C:24](=[N:25]\[C:34](=[O:35])[O:36][CH3:37])/[C:21]1[CH:20]=[CH:19][C:18]([CH2:17][NH:16][C:14]([C:12]2[CH:11]=[N:10][N:9]([CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:13]=2)=[O:15])=[CH:23][CH:22]=1
Reactant: COC(=O)Cl
Reactant: N=C(N)c1ccc(CNC(=O)c2cnn(Cc3ccccc3)c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)/N=C(\N)c1ccc(CNC(=O)c2cnn(Cc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
57 mg of 1-benzyl-N-[(4-carbamimidoylphenyl)methyl]pyrazole-4-carboxamide hydrochloride and 59 mg of potassium carbonate were dissolved in 0.72 ml of water and 3.6 ml of tetrahydrofuran. The mixture was stirred at room temperature, and 0.012 ml of methyl chloroformate (Sigma-Aldrich) added. Stirring is continued for 1 h, following which the organic layer is removed, and dried in vacuo to obtain the synthetic target. The mass of the compound was verified using LC/MS/MS.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[CH3:8].Cl.[NH2:13][OH:14].C[O-].[Na+].CO>CO>[OH:14][N:13]=[C:10]([NH2:11])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1ccc(CC#N)cc1C
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(CC(N)=NO)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.7 %

Procedure:
3,4-Dimethylphenylacetonitrile (10 g, 0.069 mol) was added to a mixture of hydroxylamine hydrochloride (9.57 g, 0.14 mol), methanol (100 mL) and 25% sodium methoxide/methanol (31.5 mL, 0.14 mol) at room temperature. After stirring for 16 hours at room temperature, the reaction mixture was concentrated in vacuo. The resultant oil was partitioned between methylene chloride and water. The organic phase was separated, washed with water, dried over magnesium sulfate and concentrated in vacuo to yield the desired product (11.4 g, 93%) as a white solid. Recrystallization from toluene afforded an analytical sample m.p. 59°-60° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([N:14]2[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C(=O)O)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)n1
Reaction time: 0.25 h
Yield: 95.5 %

Procedure:
6-Methylpicolinic acid (2.15 g) and t-butyl piperazine-1-carboxylate (3.21 g) was dissolved in 45 mL of DMF, and 4.24 g of HOBt was added to the solution at ice temperature. After stirring for 15 minutes, additionally 3.0 g of WSC was added thereto and the mixture was stirred at room temperature overnight. After the solvent was removed under reduced pressure from the reaction mixture, then water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, then the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel (methylene chloride-ethanol=30:1) to give 4.57 g of t-butyl 4-(6-methylpyridine-2-carbonyl)piperazine-1-carboxylate as a colorless oil.
Reaction SMILES: Cl.Cl.[C:3]([N:6]1[CH2:11][CH2:10][N:9]([NH2:12])[CH2:8][CH2:7]1)(=[O:5])[CH3:4].C(N(CC)CC)C.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>ClCCl>[C:3]([N:6]1[CH2:11][CH2:10][N:9]([NH:12][C:21](=[O:22])[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: CC(=O)N1CCN(N)CC1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(NC(=O)Oc2ccccc2)CC1
Reaction time: 1 h

Procedure:
To a solution of 1-acetyl-4-aminopiperazine dihydrochloride (300 mg) in dichloromethane (9 ml) was added triethylamine (0.77 ml) and phenyl chloroformate (0.261 ml) at ambient temperature. The mixture was stirred at the same temperature for 1 hour, and washed with water (×2). The organic layer was separated, dried over magnesium sulfate, and concentrated. The residue was crystallized from ethyl acetate and diethyl ether to give phenyl N-(4-acetyl-1-piperazinyl)carbamate (0.29 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[K+].[C:11](=S)=[S:12]>CCO>[O:1]1[C:2]2[C:3](=[N:4][CH:5]=[CH:6][CH:7]=2)[NH:8][C:11]1=[S:12]
Reactant: Nc1ncccc1O
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: S=c1[nH]c2ncccc2o1
Temperature: 25 °C
Yield: 91 %

Procedure:
3-Hydroxy-2-aminopyridine (2.00 g, 18.2 mmol) and potassium hydroxide (1.22 g, 21.8 mmol) were dissolved in carbon disulfide (15 mL) and EtOH (25 mL), and the reaction mixture was heated to reflux overnight. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure. The resulting solid was suspended in 1 M aqueous HCl, collected by filtration, washed with water (2×) and air-dried. Further drying in a 35° C. vacuum oven gave 2.52 g (91%) of the title compound as a tan solid. LC-MS: RT=4.82 min., [M+H]+=153.1
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][C:16]2[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:32][C:33]1[N:38]=[C:37](Cl)[C:36]([Cl:40])=[CH:35][N:34]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][C:16]2[CH:21]=[C:20]([NH:22][C:35]3[C:36]([Cl:40])=[CH:37][N:38]=[C:33]([Cl:32])[N:34]=3)[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: COc1ccc(N)cc1CCc1cccc(NC(=O)OC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Nc2nc(Cl)ncc2Cl)cc1CCc1cccc(NC(=O)OC(C)(C)C)c1
Yield: 95.8 %

Procedure:
tert-Butyl{3-[2-(5-amino-2-methoxyphenyl)ethyl]phenyl}carbamate (55 mg, 0.16 mmol), potassium carbonate (67 mg, 0.48 mmol), and 2,4,5-trichloropyrimidine (18 μL, 0.16 mmol) were stirred in N,N-dimethylformamide (1.5 mL) for 30 minutes. Purification by preparative LCMS (pH 2) gave the desired compound (75 mg, 95%). 1H NMR (300 MHz, DMSO-d6): δ 9.40 (s, 1H), 9.25 (s, 1H), 8.30 (s, 1H), 7.40 (m, 3H), 7.20 (m, 1H), 7.12 (m, 1H), 6.99 (d, 1H) 6.80 (d, 1H), 3.80 (s, 3H), 2.77 (m, 4H), 1.42 (s, 9H). LCMS for C24H27Cl2N4O3 (M+H)+: m/z=489.1.