Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=NC=1NC(NC1C=CC=CC=1C(F)(F)F)=O.[NH2:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[S:29]([NH2:32])(=[O:31])=[O:30].[F:33][C:34]([F:45])([F:44])[C:35]1[CH:36]=[C:37]([N:41]=[C:42]=[O:43])[CH:38]=[CH:39][CH:40]=1>>[Cl:28][C:26]1[CH:25]=[CH:24][C:23]([S:29]([NH2:32])(=[O:31])=[O:30])=[C:22]([NH:21][C:42]([NH:41][C:37]2[CH:38]=[CH:39][CH:40]=[C:35]([C:34]([F:33])([F:44])[F:45])[CH:36]=2)=[O:43])[CH:27]=1
Reactant: Nc1cc(Cl)ccc1S(N)(=O)=O
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Agent: O=C(Nc1ncccn1)Nc1ccccc1C(F)(F)F
Product: NS(=O)(=O)c1ccc(Cl)cc1NC(=O)Nc1cccc(C(F)(F)F)c1

Procedure:
This compound was prepared in a manner analogous to 1-Pyrimidin-2-yl-3-(2-trifluoromethyl-phenyl)-urea (Compound 2) from 2-amino-4-chloro-benzenesulfonamide and 3-trifluoromethylphenylisocyanate, yielding 4-chloro-2-[3-(3-trifluromethyl-phenyl)-ureido]-benzenesulfonamide (550 mg). Mp.=163-165° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:10][C:9](O)([C:11]([Cl:14])([Cl:13])[Cl:12])[N:8]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[N:7]=1)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O>C(OC)(C)(C)C>[C:1]([O:4][CH2:5][C:6]1[CH:10]=[C:9]([C:11]([Cl:12])([Cl:13])[Cl:14])[N:8]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[N:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=NN(c2ncccc2Cl)C(O)(C(Cl)(Cl)Cl)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: COC(C)(C)C
Product: CC(=O)OCc1cc(C(Cl)(Cl)Cl)n(-c2ncccc2Cl)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
38.7 g of [1-(3-chloropyridin-2-yl)-5-hydroxy-5-(trichloromethyl)-4,5-dihydro-1H-pyrazol-3-yl]-methyl acetate were dissolved in 200 ml of methyl tert-butyl ether, and 12.6 g of oxalyl chloride were added dropwise within 2 h (vigorous evolution of gas). The mixture was stirred at 25° C. for a further 5 h and concentrated completely under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2=[N:6][C:7](=[O:9])[N:8]=[C:4]2[CH:3]=1.[CH2:12]=[C:13]1[O:17][C:15](=[O:16])[CH2:14]1.C(C1C=CC2=NC(=O)N=C2C=1N)(=O)CC(C)=O>O>[C:15]([NH:1][C:2]1[CH:11]=[CH:10][C:5]2=[N:6][C:7](=[O:9])[N:8]=[C:4]2[CH:3]=1)(=[O:16])[CH2:14][C:13]([CH3:12])=[O:17]
Reactant: C=C1CC(=O)O1
Reactant: Nc1ccc2c(c1)=NC(=O)N=2
Agent: CC(=O)CC(=O)c1ccc2c(c1N)=NC(=O)N=2
Solvent: O
Product: CC(=O)CC(=O)Nc1ccc2c(c1)=NC(=O)N=2
Temperature: 40 °C

Procedure:
Via the bottom inlet tube of a glass vessel having a capacity of 80 liters, a clarified solution of 150 kg of 5-aminobenzimidazolone in 4200 l of water, which solution has a temperature of 90° C., is fed in at a rate of 2100 l/h with agitation. Simultaneously, via a cover inlet tube, diketene is added at a rate of 50 l/h. Immediately, a colorless precipitate of 5-acetoacetyl-aminobenzimidazolone forms. The suspension thus obtained flows via a lateral tube which limits the reaction volume to 40 l into a 8 m3 agitation vessel of stainless steel containing already 1000 l of water having a temperature of 80° C. The reaction temperature in the glass vessel is maintained at 80°-85° C. by spraying water having a temperature of 5° C. onto the surface of the suspension by means of a spray ring (amount of water about 500-600 l/h). After the reaction is complete, the reaction mixture is cooled to 40° C., and the 5-acetoacetylaminobenzimidazolone is isolated by means of a suitable filter. 550 kg of a reaction product of about 40% strength are thus obtained which may be directly used for pigment synthesis without a further purification step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16]C)[CH:14]=2)[CH2:9][CH2:8][CH:7]1[N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][CH:6]1[C:15]2[CH:14]=[C:13]([OH:16])[CH:12]=[CH:11][C:10]=2[CH2:9][CH2:8][CH:7]1[N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1ccc2c(c1)C(Cc1cccc(Cl)c1)C(N1CCCC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Oc1ccc2c(c1)C(Cc1cccc(Cl)c1)C(N1CCCC1)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(1-(3-Chlorobenzyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)pyrrolidine (6.6 g, 18.54 mmol) was dissolved in dichloromethane (100 mL). A 1 M solution of bortribromide in dichloromethane (55.6 mL, 55.6 mmol) was added dropwise under cooling maintaining the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction was poured on ice, made alkaline with sodium hydroxide. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were washed successively with sodium bicarbonate and brine. The combined extracts were dried (MgSO4) and the solvent was evaporated in vacuo. The crude product (5.5 g) was used for the next step without further purification.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:37])[C:11]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:12][N:13]([CH2:26][CH:27](OC)OC)[C:14]=1[C:15](=[O:25])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)C1C=CC=CC=1>FC(F)(F)C(O)=O>[Cl:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:16]1[CH:27]=[CH:26][N:13]2[CH:12]=[C:11]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:10](=[O:37])[C:9]([OH:8])=[C:14]2[C:15]1=[O:25]
Reactant: COC(=O)Cc1cn(CC(OC)OC)c(C(=O)NCc2cccc(Cl)c2)c(OCc2ccccc2)c1=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1cn2ccn(Cc3cccc(Cl)c3)c(=O)c2c(O)c1=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
Methyl [5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridin-3-yl]acetate (30 mg) was dissolved in trifluoroacetic acid (1 ml) and the mixture was stirred at 70° C. for 4 hr. The mixture was cooled and concentrated. Toluene was added to the residue and the mixture was concentrated again, which operations were performed twice. Crystallization from ethyl acetate-diisopropyl ether gave methyl [2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazin-7-yl]acetate (17 mg).
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][C:7]=1[CH:8]=[O:9].O>C(Cl)Cl>[F:5][C:6]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:7]=1[CH:8]=[O:9]
Reactant: COc1ccc(F)c(C=O)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=Cc1cc(O)ccc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
BBr3 (4 mL, 4 mmol, 1.0 M in heptane) was added dropwise to a solution of 2-fluoro-5-(methyloxy)benzaldehyde in CH2Cl2 at −78° C. The reaction mixture was stirred at −78° C. for 1 hour, slowly warmed to 0° C. and stirred for 2 hours. The reaction mixture was poured into water, extracted with EtOAc (3×10 mL). The extracts were combined, washed with water, brine, and dried (Na2SO4). The solvent was evaporated, and the residue was purified on silica gel, using 0-20% EtOAc-Hexane to give the desired product (142 mg, 25%) as a white solid. MS m/z 141 [M+H]+
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[C:19]1([S:29](Cl)(=[O:31])=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[N:12]([S:29]([C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=[CH:21][CH:20]=4)(=[O:31])=[O:30])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: C1=C(c2c[nH]c3ccncc23)CC2CCCN2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)n1cc(C2=CCN3CCCC3C2)c2cnccc21

Procedure:
from 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-5-Azaindole (10 mg, 0.0418 mmol), 1-naphthalenesulfonyl chloride (20 mg, 0.088 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: CC([O-])(C)C.[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([F:26])=[C:12]([C:14]([NH:21][C:22](=[O:25])[CH2:23]Cl)([C:16]([F:20])([F:19])[CH2:17][OH:18])[CH3:15])[CH:13]=1>CC(O)(C)C>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([F:26])=[C:12]([C:14]2([CH3:15])[C:16]([F:20])([F:19])[CH2:17][O:18][CH2:23][C:22](=[O:25])[NH:21]2)[CH:13]=1
Reactant: CC(NC(=O)CCl)(c1cc(Br)ccc1F)C(F)(F)CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC1(c2cc(Br)ccc2F)NC(=O)COCC1(F)F

Procedure:
To a solution of t-BuOK (0.36 g, 3.2 mmol) in t-BuOH (10 mL) was added N-(2-(5-bromo-2-fluorophenyl)-3,3-difluoro-4-hydroxybutan-2-yl)-2-chloroacetamide (1.0 g, 2.6 mmol) t-BuOH (10 mL) at rt and heated to reflux temperature for 1 h 30 min. Reaction mixture was monitored by TLC analysis. Reaction mixture was concentrated under reduced pressure and adjusted pH to ˜2 using 2 N HCl. Ethyl acetate was added to extract the product, organic layer was washed with water, brine solution followed by drying over anhy. Na2SO4 and concentrated under reduced pressure. The crude compound (0.9 g) was carried forward for the next step without purification. LCMS: RtH8=1.616 [M+H]+=337.8, 339.9 (56%); 1.482 [M+H]+=675.1, 676.8 (34%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:15])=[O:14])=[CH:11][CH:10]=1.[OH-].[Na+]>O.O1CCCC1.CO>[ClH:15].[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([N:2]2[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)=[O:14])=[CH:11][CH:10]=1
Reactant: C1CNCCN1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cc1)N1CCNCC1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
With ice cooling, 100 mL (1.2 mol) of concentrated hydrochloric acid was added in portions to a solution of 100.0 g (1.16 mol) of piperazine in water (200 mL)-methanol (300 ml) and the mixture was stirred for 30 minutes. To the resulting solution was added dropwise a solution of 127.4 g (0.58 mol) of 4-bromobenzoyl chloride in tetrahydrofuran (300 mL) over about 40 minutes, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran. To the residue was added water (2 L) and the mixture was stirred for 2 hours at 70° C. At this temperature, insoluble materials were filtered off and the residue was washed with hot water (20 mL). The filtrate and the washing were combined. After cooling to about 20° C., 74.4 g (1.86 mol) of sodium hydroxide was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Isopropanol (400 mL) was added to the residue and the mixture was concentrated under reduced pressure. Isopropanol (1 L) was added again to the residue. The mixture was stirred at 50° C. to obtain a homogenous solution. Over about 20 minutes, 50 mL (0.60 mol) of concentrated hydrochloric acid was added dropwise to the resulting solution. After stirring for 10 minutes at 50° C., the mixture was cooled to room temperature, and stirred in an ice bath. The precipitates were collected by filtration and washed with isopropanol, whereby 140.1 g of 1-(4-bromobenzoyl)piperazine hydrochloride was obtained as colorless fine needles (yield: 79%).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH2:6][CH2:7][CH2:8][S:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C.CC(O)=O>C(Cl)Cl>[Br:1][CH2:2][C:3]([NH:6][CH2:7][CH2:8][S:9][C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:4]
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Br)CBr
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CBr)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromoacetylbromide (54 μl, 0.62 mmol) was dissolved in 0.5 ml CH2Cl2 and added to a solution of H2N—CH2—CH2-STrt (200 mg, 0.56 mmol) and DIEA (196 μl, 1.1 mmol) in CH2Cl2 (1 ml). The mixture was stirred for 1 h at RT. The reaction mixture was acidified with AcOH (100 μl) and the solvent was removed in vacuo. The residue was purified over silica gel (heptane/EtOAc=1:1) to obtain product Br—CH2—CONH—(CH2)2-STrt.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[O:3]1.[Si:19]([O:26][C@@H:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>>[Si:19]([O:26][C@@H:27]1[CH2:31][CH2:30][N:29]([C:13]([C:12]2[CH:11]=[CH:10][C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:1])([CH3:18])[O:3]3)=[CH:17][CH:16]=2)=[O:15])[CH2:28]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCNC1
Product: CC1(C)OB(c2ccc(C(=O)N3CC[C@@H](O[Si](C)(C)C(C)(C)C)C3)cc2)OC1(C)C

Procedure:
The title compound was prepared by the procedure as described in Example 101 (Step H) using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and (R)-3-(tert-butyldimethylsilyloxy)pyrrolidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)(=[O:20])[CH3:19]>>[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:26])=[CH:23][CH:22]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CC(=O)c1ccc(C(=O)Nc2ccc3[nH]c4c(c3c2)CC(N(C)C)CC4)cc1
Yield: 51.9 %

Procedure:
Beginning with 9.2 mg (0.040 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 16.6 mg (0.101 mMol) 4-acetylbenzoic acid, 7.8 mg (52%) of the title compound were recovered as a beige solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]([NH:17][NH2:18])[CH:8]=1)=[O:6])[CH3:3].[CH3:19][C:20]([CH3:27])([CH3:26])[C:21](=O)[CH2:22][C:23]#[N:24]>CCO.Cl>[NH2:24][C:23]1[N:17]([C:9]2[CH:8]=[C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[C:16]3[C:11]([CH:10]=2)=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:18]=[C:21]([C:20]([CH3:27])([CH3:26])[CH3:19])[CH:22]=1
Reactant: CCOC(=O)c1cc(NN)cc2ccccc12
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-n2nc(C(C)(C)C)cc2N)cc2ccccc12
Yield: 95.3 %

Procedure:
A mixture of 3-hydrazinonaphthalene-1-carboxylic acid ethyl ester hydrochloride (1.5 g, 5.6 mmol) and 4,4-dimethyl-3-oxopentanenitrile (875 mg, 7.0 mmol) in EtOH (50 mL) and conc. HCl (5 mL) was heated at reflux overnight. After removal of the solvent, the residue was purified by column chromatography to yield ethyl 3-(5-amino-3-t-butyl-1H-pyrazol-1-yl)-1-naphthoate (1.8 g, 95% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.74 (d, J=6.3 Hz, 1H), 8.47 (s, 1H), 8.24 (s, 1H), 8.15 (d, J=6.0 Hz, 1H), 7.76 (t, J=5.7 Hz, 1H), 7.71 (t, J=5.7 Hz, 1H), 5.68 (s, 1H), 4.44 (q, J=5.4 Hz, 2H), 1.37 (t, J=5.4 Hz, 3H), 1.30 (s, 9H).
Reaction SMILES: Cl[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]([CH2:21][CH3:22])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11](=[O:23])[NH:10][C:9]1=[O:24])=[O:3].[N:25]1([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)CC)C.ClCCl>C(Cl)(Cl)Cl>[CH2:34]([O:33][C:31]([N:25]1[CH2:30][CH2:29][N:28]([C:2]([CH2:4][CH2:5][CH2:6][CH2:7][N:8]2[C:13](=[O:14])[C:12]([CH2:21][CH3:22])([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11](=[O:23])[NH:10][C:9]2=[O:24])=[O:3])[CH2:27][CH2:26]1)=[O:32])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCC1(c2ccccc2)C(=O)NC(=O)N(CCCCC(=O)Cl)C1=O
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC1(c2ccccc2)C(=O)NC(=O)N(CCCCC(=O)N2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The acid chloride of step 3 (0.2 mole) in chloroform (75 mL) was added dropwise over 15 minutes to a mixture of benzyl 1-piperazinecarboxylate (6.0 g, 0.030 mole) and triethylamine (4.0 g, 0.04 mole) in chloroform (100 mL). This mixture was stirred at room temperature for 20 hrs, and dichloromethane was then added (300 mL). The mixture was washed with 10% hydrochloric acid solution (3×100 mL), washed with saturated sodium chloride solution (100 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent removed. The residue was then chromatographed on SiO2 to give a solid.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([O:12][CH3:13])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.C(Cl)(Cl)[Cl:16]>C(Cl)Cl>[NH2:1][C@H:2]([C:10]([NH:1][C@H:2]([C:10]([O:12][CH3:13])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[ClH:16]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: ClC(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)Cc1ccccc1

Procedure:
The C-terminal tetrapeptide (ε-INOC)Lys-Asn-Phe-Phe-OMe.2HCl is prepared by reacting Phe-OMe hydrochloride with BOC-PheHSE, which reaction is conducted in a suitable organic solvent, such as chloroform or methylene chloride, overnight at a basic pH. Insoluble materials are separated and the organic solution evaporated to dryness and the residue recrystallized. The blocked dipeptide is treated with anhydrous hydrogen chloride in ethyl acetate, thereby cleaving the BOC substituent to form Phe-Phe-OMe hydrochloride.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[O:23][CH3:24])=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[NH:8]2.[C:25]1([OH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:4]2[C:3]([CH2:2][O:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:12]3[C:7]([NH:8][C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[NH:11]3)=[CH:6][CH:5]=2)=[C:17]([O:23][CH3:24])[CH:18]=1
Reactant: COc1cc(F)ccc1-c1ccc2c(c1CCl)NC(=O)C(C)(C)N2
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1-c1ccc2c(c1COc1ccccc1)NC(=O)C(C)(C)N2
Temperature: 80 °C
Reaction time: 19 h
Yield: 67 %

Procedure:
A mixture of 8-chloromethyl-7-(4-fluoro-2-methoxyphenyl)-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 4-1, 47.1 mg, 0.14 mmol), phenol (37.5 mg, 0.40 mmol), and potassium carbonate (73.0 mg, 0.53 mmol) was suspended in anhydrous N,N-dimethylformamide (1.5 mL) and stirred at 80° C. for 19 hours. After cooling down, ethyl acetate (30 mL) and water (30 mL) were added to the reaction mixture and partitioned. The organic layer was washed with water (30 mL) and saturated brine (30 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (35.7 mg) as a pale yellow solid. (Yield 67%)
Reaction SMILES: [C:1]([CH2:3][S:4][C:5]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:6]=1[O:7][CH2:8][C:9]#[N:10])#[N:2].C[O-].[Na+].C(O)(=O)C>CN(C)C=O>[NH2:10][C:9]1[CH2:8][O:7][C:6]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:5]=2[S:4][C:3]=1[C:1]#[N:2]
Reactant: COc1ccc(OCC#N)c(SCC#N)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)SC(C#N)=C(N)CO2
Temperature: 0 °C

Procedure:
In 120 ml of N,N-dimethylformamide is dissolved 30 g of 2-cyanomethylthio-4-methoxyphenoxyacetonitrile, and 30 g of 28% sodium methoxide is added dropwise to the solution under ice-cooling and under a nitrogen gas stream with stirring, followed by stirring for 2 hours. The reaction mixture is poured in ice-cold water containing 12 g of acetic acid, and the precipitate is collected by filtration, washed with water and recrystallized from chloroform to give colorless prisms of 3-amino-7-methoxy-2H-1,5-benzoxathiepin-4-carbonitrile. Yield of 19.5 g, m.p. of 203°-205° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:21]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:22][C:23]([CH3:25])=[O:24]>C(O)C>[C:23]([CH:22]([CH:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])[C:21]([O:27][CH2:28][CH3:29])=[O:26])(=[O:24])[CH3:25]
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1ccc(C=CC(=O)c2ccccc2)cc1OC
Solvent: CCO
Product: CCOC(=O)C(C(C)=O)C(CC(=O)c1ccccc1)c1ccc(OC)c(OC)c1
Temperature: 20 °C
Reaction time: 20 h
Yield: 68 %

Procedure:
3,4-Dimethoxychalcone (m,p,--(CH3O)2C5H3 --CH=CH--CO--C5H5) (26.8 g; 0.1 mole) and ethyl acetoacetate (13 g; 0.1 mole) are dissolved in ethanol (300 ml). Activated baryta (1 g) is added, and the mixture stirred at 20° C. for 20 hours. The oxovalerate precipitate is filtered off, washed with ethanol and dried. Compound no. 501 (27 g; yield: 68%) is obtained, m.p. 135° C.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:28])=[C:7]([C:10]([NH:12][NH:13][C:14](=O)[C:15]2[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:23][CH:24]=[CH2:25])=[C:17]([CH3:26])[CH:16]=2)=[O:11])[S:8][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O.C(OCC)C>C1COCC1>[CH2:23]([O:22][C:18]1[C:19]([CH3:21])=[CH:20][C:15]([C:14]2[O:11][C:10]([C:7]3[S:8][CH:9]=[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[C:6]=3[CH3:28])=[N:12][N:13]=2)=[CH:16][C:17]=1[CH3:26])[CH:24]=[CH2:25]
Reactant: C=CCOc1c(C)cc(C(=O)NNC(=O)c2scc(CC(C)C)c2C)cc1C
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCOc1c(C)cc(-c2nnc(-c3scc(CC(C)C)c3C)o2)cc1C
Yield: 118.3 %

Procedure:
A solution of 4-allyloxy-3,5-dimethyl-benzoic acid N′-(4-isobutyl-3-methyl-thiophene-2-carbonyl)-hydrazide (160 mg, 0.4 mmol) and (methoxycarbonyl-sulfamoyl)triethylammonium hydroxide (350 mg, 1.27 mmol) in dry THF (5 mL) is heated at 110° C. in a microwave oven for 6 min. The mixture is poured into diethyl ether (10 mL) and washed with 1M aq. HCl (10 mL). The aq. phase is re-extracted with ether (10 mL). The combined organic extracts are dried (Na2SO4), filtered and evaporated to give 181 mg of crude 2-(4-allyloxy-3,5-dimethyl-phenyl)-5-(4-isobutyl-3-methyl-thiophen-2-yl)-[1,3,4]oxadiazole; LC-MS: tR=1.23 min, [M+1]+=383.35.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:16]([F:19])([F:18])[F:17])([CH3:15])[CH2:13][OH:14])=[CH:8][CH:7]=1)[CH3:4].[I-].[Na+].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][C:24]=1[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(COC)OC>[CH2:3]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([C:16]([F:17])([F:18])[F:19])([CH3:15])[CH2:13][O:14][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([F:22])=[C:24]([O:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:25]=2)=[CH:10][CH:11]=1)[CH3:4]
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Reactant: CCOc1ccc(C(C)(CO)C(F)(F)F)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOc1ccc(C(C)(COCc2ccc(F)c(Oc3ccccc3)c2)C(F)(F)F)cc1
Temperature: 0 °C
Yield: 91.1 %

Procedure:
Sodium hydride (144 mg; 6 mmol) was suspended in dimethoxyethane (16 ml) and then in turn, with stirring, there was added 2-(4-ethoxyphenyl)-2-trifluoromethyl-1-propanol (1.25 g; 5.044 mmol), a spatula of sodium iodide and 4-fluoro-3-phenoxybenzyl bromide (1.4 g; 5.04 mmol). After stirring for 5 hours at room temperature, the mixture was added to ice-water, extracted 3 times with ether and the extracts washed with water dried over sodium sulphate and evaporated. After chromatography on silica gel using a mixture of ethyl acetate and hexane, there was obtained 2.06 g of product (=91.1% of theory).