Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7].[CH3:33][C@H:34]1[CH2:39][O:38][CH2:37][C@H:36]([CH3:40])[N:35]1[CH2:41][C:42]#[C:43][CH2:44]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:44][C:43]#[C:42][CH2:41][N:35]2[C@@H:36]([CH3:40])[CH2:37][O:38][CH2:39][C@@H:34]2[CH3:33])[CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7]
Reactant: C[C@H]1COC[C@H](C)N1CC#CCCl
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H]1COC[C@H](C)N1CC#CCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]piperazine (0.20 g), (3S, 5S)-3,5-dimethyl-4-(4-chloro-2-butynyl)morpholine (0.11 g) and potassium carbonate (0.31 g) in N,N-dimethylformamide (4 ml) was stirred at 60° C. for 3 hours. After cooling, the solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and sodium hydrogen carbonate solution. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with 3% of methanol in ethyl acetate as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-((3S,5S)-3,5-dimethylmorpholino)-2-butynyl]-2-[(1H-indol-3-yl)methyl]piperazine. It was dissolved in ethyl acetate and the solution was added 4N hydrogen chloride in ethyl acetate. The mixture was evaporated in vacuo and the residue was triturated with isopropyl ether to give (2R)-1-[3,5-bis-trifluoromethyl)benzoyl]-4-[4-((3S,5S)-3,5-dimethylmorpholino)-2-butynyl]-2-[(1H-indol-3-yl)methyl]piperazine dihydrochloride (0.11 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:25])[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:6][CH:7]=1.Cl[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]([OH:35])=[O:34])[CH:28]=1.C(N(CC)CC)C>C(O)C>[C:33]([C:29]1[CH:28]=[C:27]([N:22]2[CH2:21][CH2:20][CH:19]([CH2:18][NH:17][C:11]3[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=3[C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[O:25])[CH2:24][CH2:23]2)[CH:32]=[CH:31][N:30]=1)([OH:35])=[O:34]
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(F)ccc1NCC1CCNCC1
Reactant: O=C(O)c1cc(Cl)ccn1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(O)c1cc(N2CCC(CNc3ccc(F)cc3C(=O)Nc3ccc(Cl)cn3)CC2)ccn1
Yield: 45.1 %

Procedure:
Using a similar procedure to that described in Example 52, N-(5-chloropyridin-2-yl)-5-fluoro-2-(piperidin-4-ylmethyl)aminobenzamide (200 mg, 0.55 mmol), 4-chloropicolinic acid (130 mg, 0.83 mmol), triethylamine (111 mg, 1.10 mmol), and ethanol (4 mL) yielded 120 mg (45%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=3)=[CH:16][C:15]=2[CH:29]=O)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:32]([NH2:34])[CH3:33]>>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=3)=[CH:16][C:15]=2[CH2:29][NH:34][CH2:32][CH3:33])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCN
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ccc(OCC)nc3)cc2C=O)c1
Product: CCNCc1cc(-c2ccc(OCC)nc2)ccc1-c1cc(CC(=O)OCC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using the following starting materials: [4′-(6-ethoxy-pyridin-3-yl)-2′-formyl-6-methoxy-biphenyl-3-yl]-acetic acid ethyl ester and ethylamine (2M in THF).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].Cl.[CH3:20][C:21]([CH3:25])=[CH:22][CH2:23][NH2:24].C(N(CC)CC)C>C(#N)C>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:24][CH2:23][CH:22]=[C:21]([CH3:25])[CH3:20])[N:6]=1)[CH:2]=[CH2:3]
Reactant: CC(C)=CCN
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CCNc1nc(NCC=C(C)C)nc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Yield: 74.5 %

Procedure:
To 10 ml of a solution of 150 mg (0.57 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline in acetonitrile were added 137 mg (1.13 mmol) of 3-methyl-2-butenylamine hydrochloride and 288 mg (2.85 mmol) of triethylamine, followed by heating at room temperature for 4.5 hours. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with chloroform (10 ml×3). After the organic layer was washed with brine and then dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by a silica gel chromatography to give 133 mg (yield: 75.1%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([NH2:13])=[O:12].[Cl:14][CH2:15][C:16]([CH2:18]Cl)=O>>[Cl:14][CH2:15][C:16]1[N:13]=[C:11](/[CH:10]=[CH:9]/[C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[O:12][CH:18]=1
Reactant: NC(=O)/C=C/c1ccc(F)cc1F
Reactant: O=C(CCl)CCl
Product: Fc1ccc(/C=C/c2nc(CCl)co2)c(F)c1
Yield: 49.4 %

Procedure:
Using (E)-3-(2,4-difluorophenyl)-2-propenamide (9.16 g) and 1,3-dichloroacetone (7.62 g), the same reaction as Reference Example 1-(ii) was carried out to yield the titled compound (6.31 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:20])[CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+].Cl>C(O)C>[CH3:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:2]([CH3:1])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:20])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)CCC(=O)c1cccc(OCc2c(C)cccc2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C)c1COc1cccc(C(=O)CCC(=O)O)c1
Reaction time: 3 h

Procedure:
To a solution of Ethyl 4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxobutyrate (Step C, 12.31 g, 36.2 mmol) in abs ethanol (160 ml) was added 1N NaOH (50 ml) at room temperature. The reaction mixture was stirred for 3 hours and then acidified with 1M HCl. The occurring white precipitate was filtered, washed with water and dried under vacuum to provide the title compound as a white solid.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[N:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[S:10][CH2:11][CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(N(CC)CC)C.[Cl:28][C:29]([Cl:33])([Cl:32])[S:30]Cl>O1CCCC1>[CH2:14]([N:13]([S:30][C:29]([Cl:33])([Cl:32])[Cl:28])[C:9](=[N:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[S:10][CH2:11][CH3:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: ClSC(Cl)(Cl)Cl
Reactant: CCCCCCCN=C(NCCCCCCC)SCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCN=C(SCC)N(CCCCCCC)SC(Cl)(Cl)Cl
Reaction time: 0.17 h
Yield: 101.1 %

Procedure:
3 g (0.01 mole) 1,3-di-n-heptyl-2-ethyl isothiourea was mixed with 50 ml tetrahydrofuran in a stirred round bottom flask and cooled in an ice bath. 1.4 ml (0.01 mole) triethylamine was added and the mixture stirred for 10 minutes. 1.1 ml (0.01 mole) trichloromethyl sulfenyl chloride was added to the mixture dropwise over 2 minutes. A white precipitate formed and the mixture was stirred for 1 hour while coming to ambient temperature. The resultant reaction mixture was allowed to sit overnight. The mixture was suction filtered to remove the white solid which was rinsed twice with 10 ml of fresh tetrahydrofuran. The filtrate was evaporated under vacuum resulting in 4.55 g of the title product at a yield of 101.2 percent. The resulting liquid had a nD30 of 1.5084 and was identified as the title compound by IR spectrum and mass spectroscopy. Compound No. 297 in Table I.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)O)=[O:4].[OH-].[Na+].Cl[C:16]([O:18]CC)=[O:17]>>[C:7]1([N:5]2[C:3](=[O:4])[N:2]([CH3:1])[C:16](=[O:17])[O:18]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)Cl
Reactant: CNC(=O)N(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(=O)on(-c2ccccc2)c1=O
Reaction time: 0.5 h

Procedure:
1-Methyl-3-phenyl-3-hydroxyurea (10 g; 0.06 mole) was dissolved in a cooled (10° C.) 2 N aqueous sodium hydroxide (0.068 mole) solution (34 ml.). Ethyl chloroformate (6.3 ml; 0.066 mole) was added dropwise at 10°-15° C. with stirring. The stirring was continued for about 1/2 hour after the addition was completed. The desired compound, which precipitated as formed, was removed by filtration, washed with water and dried. The compound was recrystallized from methanol and dried under vacuum to yield solid 2-phenyl-4-methyl-1,2,4-oxadiazolidine-3,5-dione having a melting point of 98°-99° C. and the following elemental analysis as calculated for C9H8N2O3 :
Reaction SMILES: C[O:2][C:3](=[O:41])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]2[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:40])=[O:32])=[CH:26][CH:25]=1)[NH:5][C:6]([C:8]1([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[OH-].[Na+]>C(O)C>[Cl:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:40])[C:33]=1[C:31]([NH:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][C@@H:4]([C:3]([OH:41])=[O:2])[NH:5][C:6]([C:8]2([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[O:7])=[CH:29][CH:28]=1)=[O:32]
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)C1(Cc2ccc(OC)cc2)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CC2(C(=O)N[C@@H](Cc3ccc(NC(=O)c4c(Cl)cccc4Cl)cc3)C(=O)O)CCCCC2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a suspension of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-(4-methoxyphenyl-methyl)cyclohexy]carbonyl]-L-phenylalanine methyl ester (0.15 g, 0.25 mmol) in ethanol (2 mL) was added aqueous 1.0 N sodium hydroxide (1.5 mL, 3 mmol) at room temperature. The mixture was heated to 50° C. and the resulting clear solution was stirred overnight. The mixture was concentrated, the residue was diluted with 5 mL of water and extracted with 25 mL of ether to remove any neutral impurities. The aqueous layer was acidified with 1 N HCl and the precipitated white solid was collected by filtration and washed with water (20 mL) and hexane (20 mL). After air-drying, 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-(4-methoxyphenylmethyl)cyclohexyl]carbonyl]-L-phenylalanine (0.12 g, 82%) was obtained as a white solid, mp 136-140° C. HR MS: Obs mass, 583.1763. Calcd mass, 583.1766 (M+H).
Reaction SMILES: [CH2:1]([CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:2]([CH3:4])[CH3:3].[H-].[Na+].Cl[C:19]1[CH:20]=[CH:21][C:22]([N+:29]([O-:31])=[O:30])=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1>CN(C=O)C>[CH2:1]([C:5]([C:19]1[CH:20]=[CH:21][C:22]([N+:29]([O-:31])=[O:30])=[C:23]([C:25]([F:26])([F:28])[F:27])[CH:24]=1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C(F)(F)F
Reactant: CCOC(=O)C(CC(C)C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(C)C)(C(=O)OCC)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 87.4 %

Procedure:
To a solution of diethyl isobutylmalonate (50.0 g, 231 mmol) in anhydrous DMF (200 mL) cooled in an ice bath was added NaH (60%, 11.1 g, 277 mmol) in small portions. After the addition, the reaction mixture was stirred at 0° C. for 10 min and then at room temperature for 30 min. 5-Chloro-2-nitrobenzotrifluoride (47.3 g, 210 mmol) in anhydrous DMF (50 mL) was added dropwise and the mixture was stirred at room temperature for two days. The DMF was removed under high vacuum and the residue was diluted with ethyl acetate (400 mL). Water (400 mL) was added dropwise; ammonium chloride (25 g) was added and the layers were separated. The organic layer was washed with brine (400 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a red-brown oil, which was purified by silica-gel flash chromatography eluting with heptane/ethyl acetate (12:1) to give the desired product diethyl 2-isobutyl-2-(4-nitro-3-(trifluoromethyl)phenyl)malonate (74.4 g, 87%) as a yellow oil: 1H NMR (300 MHz, CDCl3): δ 8.07 (s, 1H), 7.94 (d, 2H, J=8.7 Hz), 7.88 (d, 2H, J=8.7 Hz), 4.25 (m, 4H), 2.33 (d, 2H, J=6.6 Hz), 1.51 (m, 1H), 1.26 (t, 6H, J=7.2 Hz), 0.84 (d, 6H, J=6.6 Hz); 13C NMR (75 MHz, CDCl3): δ 169.23, 146.71, 142.86, 132.94, 127.94 (q, J=5 Hz), 124.55, 123.12 (q, J=33 Hz), 121.79 (q, J=272 Hz), 62.19, 61.59, 44.16, 24.66, 23.66, 13.89.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:17])[CH:9]=2)[C:5]([F:18])=[CH:4][N:3]=1.[CH3:19][O:20][C:21]1[CH:27]=[C:26]([N:28]2[CH2:33][CH2:32][CH:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)[CH2:30][CH2:29]2)[CH:25]=[CH:24][C:22]=1[NH2:23]>>[F:18][C:5]1[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:17])[CH:9]=2)=[N:7][C:2]([NH:23][C:22]2[CH:24]=[CH:25][C:26]([N:28]3[CH2:33][CH2:32][CH:31]([N:34]4[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]4)[CH2:30][CH2:29]3)=[CH:27][C:21]=2[O:20][CH3:19])=[N:3][CH:4]=1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Reactant: Cn1cc(-c2nc(Cl)ncc2F)c2ccccc21
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc(F)c(-c2cn(C)c3ccccc23)n1

Procedure:
Starting materials: 3-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-indole (INTERMEDIATE 50) and 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (INTERMEDIATE 27).
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>[Fe].O>[NH2:19][C:18]1[C:9]([S:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1SCc1ccccc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cccc(N)c1SCc1ccccc1
Reaction time: 3 h
Yield: 78.3 %

Procedure:
69.8 g of iron powder are added in portions to a mixture of 68.0 g (0.22 mol) of methyl 2-benzylmercapto-3-nitrobenzoate, 215 ml of glacial acetic acid and 480 ml of water. The reaction solution is then stirred at 50°-60° C. for 3 h. The solid is separated off by filtration and then the mother liquor is washed with water and salt and subsequently dried over MgSO4. After concentration of the solution under reduced pressure, 47.1 g of a yellow oil (77%) are obtained; 1H NMR (CDCl3, 80 MHz): δ=3.8 (s, 3H, OCH3), 3.9 (s, 2H, SCH2Ph), 5.9 (s, 2H, NH2), 6.6-7.3 (m, 8H, Harom.).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[O:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][NH2:29])[CH2:23][CH2:22]1.[BH4-].[Na+]>CO>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:29][CH2:28][CH2:27][CH:24]2[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=1
Reactant: COc1cc(C=O)ccc1Oc1cnc(C(N)=O)cn1
Reactant: NCCC1CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCC2CCOCC2)ccc1Oc1cnc(C(N)=O)cn1
Reaction time: 8 h
Yield: 59.4 %

Procedure:
Place 5-(4-Formyl-2-methoxyphenoxy)pyrazine-2-carboxamide (Example 719, Part A) (0.200 g, 0.732 mmol), 2-(tetrahydropyran-4-yl)ethylamine (0.0993 g, 0.769 mmol) and 3 Å molecular sieves in a vial. Add methanol (3.6 mL), cap and stir overnight. Add NaBH4 (ca. 3-5 eq in two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® C. pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column 5% to 20% (2.0 M NH3 in methanol) in ethyl acetate. Concentrate the fractions containing the product. Take the solid up in ethyl acetate (50 mL) and wash with 1.0 N NaOH to give the title compound (0.168 g, 59.4%): TOF MS ES+ 387.2031 (M+H)+, HRMS calcd for C20H27N4O4 387.2032 (M+H)+, found 387.2031, time 0.52 min; HPLC [Waters XTerra™ C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 23 min], tR=8.7 min, 100% purity.
Reaction SMILES: Cl.[F:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([C:15]([NH2:17])=[NH:16])=[N:7]1.Cl.C[O-].[Na+].C(O[CH:29]=[C:30]([C:36](=O)[C:37]([F:40])([F:39])[F:38])[C:31]([O:33][CH2:34][CH3:35])=[O:32])C>CO>[CH2:34]([O:33][C:31]([C:30]1[C:36]([C:37]([F:38])([F:39])[F:40])=[N:16][C:15]([C:8]2[C:9]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:6]([CH2:5][C:4]3[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=3[F:2])[N:7]=2)=[N:17][CH:29]=1)=[O:32])[CH3:35]
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)(F)F
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1C(F)(F)F
Reaction time: 12 h

Procedure:
600 mg of the crude 1-(2-fluorobenzyl)1H-pyrazolo[3,4-b]pyridine-3-carboxamidine hydrochloride (preparable from the amidine 25A by reaction with HCl) are stirred in 30 ml of methanol with 106 mg of sodium methoxide and admixed with 472 mg (1.96 mmol) of ethyl 3-ethoxy-2-trifluoroacetyl-acrylate. The mixture is boiled for 12 hours and the precipitate is then filtered off with suction and washed with ether. This gives 249 mg (27.5% of theory) of crystals.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][C:9]2[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[CH:15]=[CH:14][C:10]=2[C:11](O)=[O:12])=O)=[CH:4][CH:3]=1.C([NH2:25])=O>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]2[N:25]=[C:11]([OH:12])[C:10]3[C:9](=[C:17]([CH3:18])[C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: NC=O
Reactant: COc1ccc(C(=O)O)c(NC(=O)c2ccc(F)cc2)c1C
Product: COc1ccc2c(O)nc(-c3ccc(F)cc3)nc2c1C
Yield: 83 %

Procedure:
2-(4-Fluoro-benzoylamino)-4-methoxy-3-methyl-benzoic acid (91) (830 mg, 2.7 mmol) was heated to 150° C. in formamide (20 ml) for 4 h. The excess formamide was removed by distillation. Water was added and the precipitated product was filtered of to give pure title compound (642 mg, 83%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[S:6][C:5]=1[C:15]([NH2:17])=[O:16])[CH3:2].[C:18]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:1]([N:3]1[C:4]2[CH:8]=[C:7]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)[S:6][C:5]=2[C:15](=[O:16])[NH:17][C:18]21[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH3:2]
Reactant: O=C1CCCCC1
Reactant: CCNc1cc(-c2ccncc2)sc1C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCN1c2cc(-c3ccncc3)sc2C(=O)NC12CCCCC2
Temperature: 100 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
A mixture of 3-(ethylamino)-5-(pyridin-4-yl)thiophene-2-carboxamide (0.100 g, 0.400 mmol), cyclohexanone (2.0 mL, 1.9 g, 19 mmol), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (2.0 mL) was stirred overnight at 100° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (150 mL). Extraction with ethyl acetate (100 mL, 30 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave a solid. The solid was triturated with DMF/dichloromethane, then the precipitate was collected by filtration to afford the title compound (0.0738 g, 56%) as a yellow solid:
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[P:14]([O-:18])([O-:17])([O-:16])=[O:15].[Na+].[Na+].[Na+].[OH-].[Na+]>O>[C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[P:14]([O-:18])([O-:17])([O-:16])=[O:15]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Temperature: 25 °C

Procedure:
A citrate-phosphate buffer (pH 3.0) is prepared from 39.8 ml of 0.1 M citric acid and 10.2 ml of 0.2 M dibasic sodium phosphate diluted to 100 ml with distilled water. The lyophilized Fraction A from Preparation 1 is dissolved in this buffer solution in a proportion of 20 mg of Fraction A per ml of buffer. To this is added an aliquot of 5 mg of pepsin in 1 ml of distilled water to give a ration of Fraction A to pepsin of 100 to 1. The solution is maintained for 24 hours at room temperature and then brought to pH 7.4 by the addition of 0.1 M sodium hydroxide. The resulting ragweed pollen specific immunosuppressant has the ability to block immune response to antigen E but is in itself somewhat immunogenic.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH:12]([CH2:20][CH3:21])[C:13]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:14]>>[CH2:16]([O:15][C:13](=[O:14])[CH:12]([NH:11][C:8](=[O:10])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:20][CH3:21])[CH:17]([CH3:18])[CH3:19]
Reactant: CCC(N)C(=O)OCC(C)C
Reactant: O=C(O)Cc1ccccc1
Product: CCC(NC(=O)Cc1ccccc1)C(=O)OCC(C)C

Procedure:
Following General Procedure BH above and using phenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by chromatography on silica gel using 9:1 toluene:EtOAc as the eluant.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7]C[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.Cl.NC1CCN(CCN2CCC([OH:51])CC2)CC1>>[OH:51][CH:4]1[CH2:3][CH2:2][N:1]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:14][CH2:15]2)[CH2:7][CH2:5]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Reactant: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12
Agent: Cl
Product: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCC(O)CC4)CC3)cc12

Procedure:
This compound is synthesized analogously to Example 1 from 4-Isobutoxy-1H-indole-2-carboxylic acid 80 (preparation see Example 8) and amine 21.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][O:7][B:8]([OH:9])[C:4]=2[CH:3]=1.[H-].[Na+].Br[C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>CN(C=O)C>[CH2:19]([O:18][C:16](=[O:17])[C:15]([O:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][O:7][B:8]([OH:9])[C:4]=2[CH:3]=1)([CH3:22])[CH3:21])[CH3:20]
Reactant: OB1OCc2ccc(O)cc21
Reactant: CCOC(=O)C(C)(C)Br
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)B(O)OC2
Temperature: 0 °C
Reaction time: 24 h
Yield: 61 %

Procedure:
H181 (150 mg, 1.0 mmol) was dissolved in DMF (7.0 mL) and cooled to 0° C. with ice bath. To this solution under nitrogen were added in sequence NaH (60% in mineral oil, 160 mg, 4.0 mmol) and ethyl 2-bromo-2-methylpropanoate (0.59 mL, 4.0 mmol). The reaction mixture was stirred for 1 d then treated with 1.0 M HCl (10.0 mL). After extraction with ethyl acetate, the organic phase was washed with water and brine, and dried over anhydrous Na2SO4. The residue after rotary evaporation was purified by column chromatography over silica gel to give the title compound (161 mg, 61% yield). 1H NMR (300 MHz, CDCl3): δ 7.23 (d, J=8.1 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 7.04 (dd, J=8.4 & 2.7 Hz, 1H), 5.04 (s, 2H), 4.25 (q, J=6.9 Hz, 2H), 1.60 (s, 6H) and 1.26 (t, J=7.2 Hz, 3H) ppm; Mp: 63-66° C.