Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][OH:7].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.B.O1CCCC1>CO.O1CCCC1>[NH2:1][C:2]1[CH:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][OH:7]
Reactant: Nc1ccc(OCCO)c(N)c1
Reactant: O=Cc1ccccc1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(NCc2ccccc2)ccc1OCCO
Reaction time: 7 h

Procedure:
2.66 g (10 mmol) of 2-(2,4-diaminophenoxy)ethanol and 1.06 g (10 mmol) of benzaldehyde were dissolved in methanol (dried over molecular sieve). After addition of 10 mg of molecular sieve, the reaction mixture was allowed to agitate 7 hours. Then, 20 mL of a solution of borane-tetrahydrofuran com-plex (1 M in tetrahydrofuran) was added at 0° C., and the reaction mixture was allowed to agitate one hour at room temperature. At the end of the reaction, the reaction mixture was filtered and hydrolyzed. The precipitate was filtered off, washed with water and then dried.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:11]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[NH:16][C:15]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6]C(C)C)=[O:5].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:11]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[NH:16][C:15]2=[O:25])=[CH:10][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)ccc1Cl
Reaction time: 2 h

Procedure:
A mixture of 58.9 grams (0.156 mole) of isopropyl 2-chloro-5-[3,6-dihydro-4-trifluoromethyl-2,6-dioxo-1(2H) pyrimidinyl]benzoate and 11.2 grams (0.28 mole) of sodium hydroxide in 1200 ml. of 50% ethanol was heated at 65° C. for 30 minutes and stirred for 2 hours. Evaporation under a reduced pressure removed the solvent. The residue was treated with 2.3 ml. of concentrated hydrochloric acid in 130 ml. of water. Filtration collected 45 grams of crude solid. The solid product was further dissolved in a solution of 10 grams (0.25 (mole) of sodium hydroxide in 600 ml. of water. The solution was cooled with an ice-water bath and then acidified to pH 2 with concentrated hydrochloric acid. The colorless precipitate was collected by filtration, rinsed with water and air-dried. The sample of 2-chloro-5-[3,6-dihydro-4-trifluoromethyl-2,6-dioxo-1 (2H) pyrimidinyl] benzoic acid weighed 40.7 grams (78%); m.p. 311°-2° C. 'H NMR (300 MHzm/DMSO-d6) δ 3.36 (broad,1H); 6.37 (S,1H); 7.45 (dd, J=9.3, 2.1 Hz,1H); 7.67 (d,J=9.3 Hz,1H); 7.79 (d, J=2.1 Hz, 1H), 12.48 (broad, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](OC)=[O:9])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:5]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:21]=[C:4]2[N:3]=1.CC(C[AlH]CC(C)C)C.C1COCC1>C(Cl)Cl>[CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:5]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:21]=[C:4]2[N:3]=1
Reactant: COC(=O)c1c(C)nc2cc(-c3ccccc3)nn2c1-c1ccc(C)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(CO)c(C)nc3cc(-c4ccccc4)nn23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
To a stirred solution of methyl 5-methyl-2-phenyl-7-p-tolylpyrazolo[1,5-a]pyrimidine-6-carboxylate (800 mg, 2.238 mmol) in CH2Cl2 (50 mL) was added DIBAL-H, 1M in THF (6.72 mL, 6.72 mmol) dropwise. The reaction mixture was stirred at room temperature for 1 h before being quenched with saturated NH4Cl solution. The aqueous layer was extracted with CH2Cl2 and the combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (344 mg, 46.7%). 1H-NMR (500 MHz, CDCl3) δ ppm 1.61 (1H, t, J=5.0 Hz), 2.49 (3H, s), 2.78 (3H, s), 4.59 (2H, d, J=5.0 Hz), 6.88 (1H, s), 7.29-7.42 (5H, m), 7.56 (2H, d, J=8.2 Hz), 7.81-7.96 (2H, m).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:7][C:6]=1[N+:22]([O-])=O)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)C.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])=[CH:7][C:6]=1[NH2:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(/C=C/CO[Si](C)(C)C(C)(C)C)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOCC
Product: CC(C)(C)c1ccc(CCCO[Si](C)(C)C(C)(C)C)cc1N
Yield: 84.9 %

Procedure:
A solution of 16.0 g of 2-t-butyl-5-[(1E)-3-(t-butyldimethylsilyloxy)propenyl]-1-nitrobenzene [prepared as described in step (iv) above] in 800 ml of diethyl ether was stirred at room temperature for 3 hours in the presence of 8.0 g of 10% palladium-on-charcoal under a stream of hydrogen. At the end of this time, the reaction mixture was filtered and the filtrate was freed from the solvent by distillation under reduced pressure . The residue was purified by column chromatography through silica gel, using a 1:10 by volume mixture of ethyl acetate and hexane as the eluent, to give 12.5 g of the title compound as an oily substance.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.O=[C:11]([CH3:20])[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].N1CCC[C@H]1C(O)=O>CCO>[N:1]1[C:2]2[C:3](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[CH:20][C:11]=1[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: Nc1ncccc1C=O
Reactant: CCOC(=O)CCCC(C)=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)CCCc1ccc2cccnc2n1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
A solution consisting of 2-aminonicotinaldehyde (0.7 g; 5.8 mmol), ethyl 5-oxohexanoate (1.83 g; 11.6 mmol; 1.85 ml), L-proline (0.166 g; 1.45 mmol) and 50 ml of EtOH is heated at 90° C., with stirring, for 6 hours. The reaction mixture is then concentrated and the residue is purified by chromatography on silica gel (eluant: EtOAc) to yield the title product in the form of a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH3:9].C(Br)C.[NH3:13].O=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]#[N:13]
Reactant: Cc1c(Cl)cccc1Cl
Reactant: N
Agent: O=O
Solvent: CCBr
Product: N#Cc1c(Cl)cccc1Cl
Yield: 82.3 %

Procedure:
270 g of this catalyst was charged into the same fluidized bed reactor as used in Example 1. The catalyst layer was kept at 390° C. To the catalyst layer were fed air, 2,6-dichlorotoluene containing 2% of ethyl bromide, and ammonia at rates of 71.6 N liters, 25.0 g, and 17 N liters per hour, respectively. The ratio of 2,6-dichlorotoluene:oxygen:ammonia was 1.0:4.2:5.0. 2,6-dichlorobenzonitrile was obtained in an amount of 21.5 g per hour. The quantity of unreacted 2,6-dichlorotoluene was 1.6 g. Conversion was 94.5%, yield was 82.3%, and selectivity was 87.1%.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:35][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1
Reactant: N#Cc1c(N)nc2ccc(N3CCN(Cc4ccccc4)CC3)cc2c1Cl
Reactant: NCc1ccccc1
Solvent: O
Product: N#Cc1c(N)nc2ccc(N3CCN(Cc4ccccc4)CC3)cc2c1NCc1ccccc1

Procedure:
14 g of 2-amino-3-cyano-4-chloro-6-(4-benzylpiperazin-1-yl)quinoline and 28 mL of benzylamine are stirred at 125° C. for 4 hours. The reaction mixture is poured onto 100 mL of water. The precipitated material is filtered off, washed with 2×50 mL of water. After drying 8 g of the title compound is obtained, m.p.: 202° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[N:7][CH:6]=[CH:5]2.CO[Si](C)(C)C.F[C:20](=[O:35])[C@H:21]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:22]1[CH:26]=[CH:25][S:24][CH:23]=1.CCOC(C)=O>CN(C=O)C>[OH:12][C:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:20](=[O:35])[C@H:21]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[C:22]3[CH:26]=[CH:25][S:24][CH:23]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1ccc2c(O)nccc2c1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)F)c1ccsc1
Agent: CO[Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)Nc1ccc2c(O)nccc2c1)c1ccsc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To 6-aminoisoquinolin-1-ol in DMF was added methoxytrimethylsilane and (R)-tert-butyl 2-fluoro-2 oxo-1-(thiophen-3-yl)ethylcarbamate and the solution was stirred at room temperature for 6 h. The mixture was poured into EtOAc, washed with NH4Cl(sat)/HCl (1N) followed by NaHCO3 (0.05%), dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, 5% MeOH, CH2Cl2) gave pure (R)-tert-butyl 2-(1-hydroxyisoquinolin-6-ylamino)-2-oxo-1-(thiophen-3-yl)ethylcarbamate) (91.8% ee by Chiracel OD-RH).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][C:5]=1C.Br[CH2:16][CH2:17][O:18][CH2:19][CH2:20]Br.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:11]#[N:12])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(CC#N)cc1C
Reactant: BrCCOCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C2(C#N)CCOCC2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methyl 4-(cyanomethyl)-benzoic acid methyl ester (1.92 g, 11.01 mmol) and 1-bromo-2-(2-bromo-ethoxy)-ethane (12.56 mL, 55.04 mmol) were combined in THF (15 mL) and cooled down to 0° C. Potassium bis(trimethylsilyl)-amide (0.5M in toluene, 48.3 mL, 24.21 mmol, 2.2 eq) was added over a period of 15 minutes and then warmed up to room temperature and stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was dried with MgSO4 and evaporated under vacuum. The crude product was purified by chromatography on silica gel (25% EtOAc/hexanes) to afford 4-(4-cyano-tetrahydro-pyran-4-yl)-benzoic acid methyl ester. To a solution of 4-(4-cyano-tetrahydro-pyran-4-yl)-benzoic acid methyl ester (1.55 g 6.32 mmol) in MeOH (10 mL) was added Et3N (3 mL). H2S was bubbled into the solution. The reaction vessel was stirred at room temperature for 3 days. The reaction mixture was then evaporated and purified by silica gel chromatography (33% EtOAc/hexanes) to afford 4-(4-thiocarbamoyl-tetrahydro-pyran-4-yl)-benzoic acid methyl ester.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7](/[CH:26]=[N:27]/O)=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CN(C=O)C.C([O-])(O)=O.[Na+]>[C:1]([NH:5][C:6]1[C:7]([C:26]#[N:27])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1/C=N/O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1C#N
Temperature: 25 °C
Yield: 36.2 %

Procedure:
A solution of (E)-3-(tert-butylamino)-5-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxaline-2-carbaldehyde oxime (308) (26.3 mg, 0.069 mmol) and 1-propanephosphonic acid cyclic anhydride (Alfa Aesar, Ward Hill, Mass.; 50 wt % solution in EtOAc; 0.16 mL, 0.28 mmol) in DMF (2.0 mL) was stirred at 100° C. for 3.5 h. The reaction mixture was then cooled to RT, diluted with saturated aq. NaHCO3 (30 mL), and extracted with 5% MeOH/DCM (2×30 mL). The combined extracts were sequentially washed with water (2×20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was taken up in DMSO (2.0 mL) and purified by rpHPLC (Phenomenex Gemini C18 column (150×30 mm, 10 mm), 35 mL/min, 5-100% CH3CN/H2O+0.1% TFA). Product-containing fractions were combined and neutralized with saturated aq. NaHCO3 (30 mL). The resulting mixture was extracted with 5% MeOH/DCM (2×30 mL), and the combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo to provide 3-(tert-butylamino)-5-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxaline-2-carbonitrile (8.9 mg, 0.025 mmol, 36% yield) as a red-orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.61 (1H, br. s.), 7.98 (1H, dd, J=7.4, 1.2 Hz), 7.73 (1H, dd, J=8.2, 1.2 Hz), 7.52 (1H, t, J=7.8 Hz), 7.12 (1H, d, J=2.3 Hz), 6.95 (1H, br. s.), 6.60 (1H, s), 3.42 (2H, td, J=6.8, 2.2 Hz), 2.84 (2H, t, J=6.8 Hz), 1.53 (9H, s). m/z (ESI, +ve) 361.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C@@H:7]([NH2:9])[CH3:8])=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15](Cl)[N:14]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:9][C@H:7]([C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH3:8])[CH:16]=[N:17][CH:18]=1
Reactant: Clc1cncc(Cl)n1
Reactant: COc1ccc([C@H](C)N)cc1
Product: COc1ccc([C@H](C)Nc2cncc(Cl)n2)cc1
Yield: 78.8 %

Procedure:
In a procedure analogous to Example 1, reaction of 4-methoxy-α-(S)-methylbenzylamine (0.70 mg, 4.6 mmol) and 2,6-dichloropyrazine (0.6259 g, 4.20 mmol) furnished the product (873 mg, 79%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[NH2:11][C:12]1[CH:13]=[C:14]2[C:18]3=[C:19]([CH2:21][O:22][CH2:23][CH2:24][N:17]3[C@H:16]3[CH2:25][CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][C@@H:15]23)[CH:20]=1>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][NH:11][C:12]1[CH:13]=[C:14]2[C:18]3=[C:19]([CH2:21][O:22][CH2:23][CH2:24][N:17]3[C@H:16]3[CH2:25][CH2:26][NH:27][CH2:28][C@@H:15]23)[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Reactant: O=Cc1c(F)cccc1F
Product: Fc1cccc(F)c1CNc1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCOC2

Procedure:
Using 2,6-difluorobenzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B was converted into the title compound of EXAMPLE 140. 1H NMR (CDCl3) δ: 7.25-7.15 (m, 2H), 6.90-6.82 (m, 2H), 6.50 (d, 1H, J=2.2 Hz), 6.30 (d, 1H, J=2.2 Hz), 4.58 (ABq, 2H, JAB=14.0 Hz), 4.35 (s, 2H), 4.20-4.13 (m, 1H), 3.72 (dd, 1H, J=11.5, 10.8 Hz), 3.33-3.25 (m, 1H), 3.22-3.08 (m, 2H), 3.02 (dd, 1H, J=12.4, 6.6 Hz), 2.95-2.85 (m, 2H), 2.65-2.57 (m, 1H), 2.44 (dd, 1H, J=12.3, 10.4 Hz), 1.95-1.80 (m, 2H). LRMS (ES)+: 372.4 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)=O.[C:19]([C:22]1[CH:23]=[CH:24][C:25]([OH:31])=[C:26]([CH:30]=1)[C:27]([OH:29])=[O:28])(=[O:21])[CH3:20]>[OH-].[Na+].O.C(O)(=O)C>[OH:31][C:25]1[CH:24]=[CH:23][C:22]([C:19](=[O:21])[CH:20]=[CH:1][C:3]2[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)(=[O:11])=[O:10])=[CH:5][CH:4]=2)=[CH:30][C:26]=1[C:27]([OH:29])=[O:28]
Reactant: O=Cc1ccc(S(=O)(=O)Nc2ccccn2)cc1
Reactant: CC(=O)c1ccc(O)c(C(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(C=Cc1ccc(S(=O)(=O)Nc2ccccn2)cc1)c1ccc(O)c(C(=O)O)c1

Procedure:
4-Formyl-N-(2-pyridinyl)benzenesulfonamide (5.7 g, 0.022 mol), 5-acetyl-2-hydroxybenzoic acid (6.64 g, 0.044 mol) in 5M sodium hydroxide (20 ml) were stirred for 3 days at room temperature. The solution was diluted with water (100 ml) and acetic acid added dropwise in excess. The precipitate was collected by filtration and washed with water. After drying, the material was recrystallized from acetic acid and dried at 120° C. in vacuo. Yield 6.4 g, 66%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]1([S:36]([N:39]2[CH2:43][CH2:42][CH2:41][CH:40]2[CH:44]=[CH2:45])(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN(CC)CC.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:30]1([S:36]([N:39]2[CH2:43][CH2:42][CH2:41][CH:40]2/[CH:44]=[CH:45]/[C:13]2[CH:12]=[CH:11][C:10]([N:16]3[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]3)=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:14]=2)(=[O:38])=[O:37])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: C=CC1CCCN1S(=O)(=O)c1ccccc1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/C3CCCN3S(=O)(=O)c3ccccc3)cc2OCc2ccccc2)S1(=O)=O
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a solution of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (100 mg, 0.183 mmol) in acetonitrile (2 mL) is added 1-benzenesulfonyl-2-vinylpyrrolidine (43 mg, 0.183 mmol), NEt3 (0.038 mL, 0.274 mmol), Pd(OAc)2 (2 mg, 0.034 mmol), and 2-(di-t-butylphosphino)biphenyl (4 mg) and the mixture stirred at 80° C. for 48 h. The reaction is cooled to RT and partitioned between 1N HCl and EtOAc. The organic phase is washed with brine and dried over magnesium sulfate. The solvent is removed under reduced pressure and the crude material purified by column chromatography using a gradient of 10-25% EtOAc/hexane to afford the title compound.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.OP([O-])(O)=O.[K+].OC(C[CH2:23][CH2:24][CH2:25][C@H:26]1[C@@H:34]2[C@@H:29](N[C:31]([NH:33]2)=O)[CH2:28]S1)=O.CC1[N+](CC2C=NC(C)=NC=2N)=CSC=1CCO.Cl.[NH2:54][C@H:55]([C:58]([OH:60])=[O:59])[CH2:56]O.C(O)(=O)C1C(=CC=CC=1)N.C([O-])([O-])=O.[Ca+2]>O>[NH2:54][C@H:55]([C:58]([OH:60])=[O:59])[CH2:56][C:28]1[C:29]2[C:34](=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:33][CH:31]=1
Reactant: N[C@@H](CO)C(=O)O
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: Cc1ncc(C[n+]2csc(CCO)c2C)c(N)n1
Agent: Cl
Agent: Nc1ccccc1C(=O)O
Solvent: O
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reaction time: 70 h

Procedure:
A culture medium containing 100 g of glucose, 40 g of (NH4)2SO4, 1 g of KH2PO4, 0.4 g of MgSO4.7H2O, 10 mg of FeSO4.7H2O, 10 mg of MnSO4.4H2O, 1 g of "Casamino acid", 300 microgram/l of biotin, 200 microgram/l of thiamine.HCl, 5 g of serine, 5 g of anthranilic acid and 50 g of CaCO3 in 1 l of water and having a pH value of 7.0 was used for the culture. Each the strains was inoculated into 3 ml of the above-mentioned culture medium placed in a test tube and then cultured at 30° C. for 70 hours with shaking. L-tryptophan in the supernatant of the culture liquid obtained by centrifugation after the culture was determined by a liquid chromatography.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].[C:18]([O:22][C:23]([N:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].Cl.C(N=C=NCCCN(C)C)C>>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:28]1[CH2:29][CH2:30][CH2:31][N:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH2:26][CH2:27]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CCOC(=O)c1cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc2[nH]1

Procedure:
The title compound was synthesized in analogy to Example 1, from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester, [1,4]diazepane-1-carboxylic acid tert-butyl ester and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, to afford the product as a white solid (69%).
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:51][CH2:52][C:53]1[O:57][C:56]([C:58]2[CH:63]=[CH:62][C:61]([C:64]3[C:69]([CH3:70])=[CH:68][CH:67]=[C:66]([C:71]([NH:73][CH:74]4[CH2:76][CH2:75]4)=[O:72])[CH:65]=3)=[CH:60][CH:59]=2)=[N:55][N:54]=1>CN(C=O)C>[CH:74]1([NH:73][C:71]([C:66]2[CH:65]=[C:64]([C:61]3[CH:62]=[CH:63][C:58]([C:56]4[O:57][C:53]([CH2:52][NH:51][C:5](=[O:7])[CH2:4][CH:1]5[CH2:2][CH2:3]5)=[N:54][N:55]=4)=[CH:59][CH:60]=3)[C:69]([CH3:70])=[CH:68][CH:67]=2)=[O:72])[CH2:76][CH2:75]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN)o2)cc1
Reactant: O=C(O)CC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CNC(=O)CC3CC3)o2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Cyclopropylacetic acid (8.6 mg) and HATU (33 mg) in DMF (1 ml) were stirred for 10 minutes at room temperature. To this solution was added HOBt (11.6 mg), DIPEA (.0.45 ml) and 4′-[5-(aminomethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Example 53) (30 mg) in DMF (2 ml) and the reaction stirred at room temperature for 18 hours. The solvent was evaporated under vacuum and the residue dissolved in DCM and washed with water (2×4 ml). The organic phase was reduced to dryness and the residue purified by bond-elut (SCX, 5 g) eluting with methanol and methanolic ammonia. The methanolic ammonia fraction was further purified by preparative HPLC to give, after evaporation of the solvents, N-cyclopropyl-4′-(5-{[(cyclopropylacetyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([O:20][CH3:21])[C:13]=1[C:14]1[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=1)[C:7]([O:9]C)=[O:8])[CH3:2].Cl>CO.C1COCC1.[OH-].[Na+]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([O:20][CH3:21])[C:13]=1[C:14]1[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=1)[C:7]([OH:9])=[O:8])[CH3:2]
Reactant: CCOc1cc(C(=O)OC)cc(OC)c1-c1cnn(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cc(C(=O)O)cc(OC)c1-c1cnn(C)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Methyl 3-ethoxy-5-methoxy-4-(1-methyl-1H-pyrazol-4-yl)benzoate (157 mg) was dissolved in a mixed solvent of methanol/THF (9 mL, 1/2), and aqueous 1 M NaOH solution (2.1 mL) was added to it and stirred at room temperature for 5 hours. Aqueous 1 M HCl solution (2.1 mL) was added to it, and the solvent was concentrated under reduced pressure. The obtained solid was removed through filtration, washed with water and ether, and dried under reduced pressure to obtain the title compound as a white solid.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[C:10]([C:12]1[C:13]([CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:14][C:15]([CH2:21][CH:22]([CH3:24])[CH3:23])=[C:16]([CH2:18][C:19]#[N:20])[CH:17]=1)#[N:11]>>[C:10]([C:12]1[C:13]([CH2:25][CH:26]([CH3:28])[CH3:27])=[C:14]([N+:6]([O-:9])=[O:7])[C:15]([CH2:21][CH:22]([CH3:23])[CH3:24])=[C:16]([CH2:18][C:19]#[N:20])[CH:17]=1)#[N:11]
Reactant: O=[N+]([O-])O
Reactant: CC(C)Cc1cc(CC(C)C)c(CC#N)cc1C#N
Agent: O=S(=O)(O)O
Product: CC(C)Cc1c(C#N)cc(CC#N)c(CC(C)C)c1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
A round bottom flask is charged with 25 parts of 98% sulfuric acid and 25 parts of 20% fuming sulfuric acid and cooled to 0°; then, 20 parts of 90% fuming nitric acid is added. Twenty parts of 5-cyano-2,4-diisobutylbenzeneacetonitrile is added in portions, and the mixture is warmed to 50° with stirring. After two hours, the solution is poured onto ice and the precipitate of 5-cyano-2,4-diisobutyl-3-nitrobenzeneacetonitrile is collected and dried.