Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[N+](C1C=CC=CC=1)([O-])=O.[Br:21]Br.Cl>>[Br:21][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=[N:3][CH:4]=1
Reactant: BrBr
Reactant: c1ccc2cnccc2c1
Agent: Cl
Solvent: O=[N+]([O-])c1ccccc1
Product: Brc1cncc2ccccc12
Temperature: 180 °C
Reaction time: 3 h

Procedure:
The same general procedure set forth in Example 1 above was followed. In a flask equipped with a reflux condenser, dropping funnel, thermometer, and stirrer was placed 33.3 g. (0.20 mole) of isoquinoline hydrochloride, together with 50 ml. of nitrobenzene, and the mixture was stirred and heated to about 180°C. to give a clear yellow solution. To this solution was added dropwise, via the dropping funnel, over a period of 1 hour and 13 minutes, 35.2 g. (0.22 mole) of bromine. The evolution of hydrogen chloride was smooth from the start to the completion of the addition of the bromine. After all the bromine had been added, the reaction mixture was of a single phase, amber red in color. Heating at about 180°C. and stirring were continued after addition of the bromine had been completed. An hour later, a few crystals of a solid material started to collect in the flask near the condenser. After 3 hours and 15 minutes of heating and stirring a very thin slurry of crystals had begun to form and hydrogen chloride evolution had become very slow. After 4 hours and 45 minutes of heating and stirring, the evolution of hydrogen chloride had practically ceased.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].S(Cl)(Cl)=O.[CH3:19]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:19])=[O:7])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C(O)c1ccc(Br)c(C(F)(F)F)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Br)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91 %

Procedure:
To a suspension of 4-bromo-3-(trifluoromethyl)benzoic acid (APAC Pharmaceuticals, 20 g, 74.35 mmol) in MeOH (400 ml) at 0° C. was added thionyl chloride (21.6 ml, 297 mmol) dropwise. The reaction mixture was stirred at RT for 24 hours. The solvent was concentrated under vacuum and the crude residue was diluted with EtOAc (250 mL). The organic layer was washed with a saturated NaHCO3 solution (100 mL), water (100 mL), brine (100 mL), dried over MgSO4, filtered off and concentrated under vacuum to afford the title compound as a yellow solid (19.13 g, 91%). HPLC (Method A) Rt 5.12 min (Purity: 99.2%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].C(N(CC)CC)C.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][O:8][Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:24])[CH3:23])[NH2:6]
Reactant: COC(=O)[C@@H](N)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](N)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
L-Serine methyl ester hydrochloride (7.09 g) was suspended in dichloromethane (100 mL), and to the suspension 4-(dimethylamino)pyridine (700 mg) and triethylamine (9.69 g) were added, and tert-butyldimethylchlorosilane (7.0 g) were added portionwise at 0° C. to the mixture to conduct stirring at room temperature. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=20:1) to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([C:10](=[O:29])[C:11]1[CH:16]=[C:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=2[F:25])[C:14]([O:26][CH3:27])=[CH:13][C:12]=1[F:28])=[CH:6]N(C)C)[CH3:2].[NH2:31][C@@H:32]([CH:35]([CH3:37])[CH3:36])[CH2:33][OH:34].Cl>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:30])[C:5]([C:10](=[O:29])[C:11]1[CH:16]=[C:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=2[F:25])[C:14]([O:26][CH3:27])=[CH:13][C:12]=1[F:28])=[CH:6][NH:31][C@H:32]([CH2:33][OH:34])[CH:35]([CH3:37])[CH3:36])[CH3:2]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Cc2cccc(Cl)c2F)c(OC)cc1F
Reactant: CC(C)[C@H](N)CO
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN[C@H](CO)C(C)C)C(=O)c1cc(Cc2cccc(Cl)c2F)c(OC)cc1F
Temperature: 25 °C

Procedure:
To a solution of 2-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl)-3-dimethylaminoacrylic acid ethyl ester prepared in Step XII in toluene was added (S)-2-amino-3-methylbutan-1-ol (3.96 g) with stirring at room temperature. After stirring for 30 min, 1N hydrochloric acid (60 ml) was added, and the mixture was further stirred for 1 hr. The organic layer was separated, and washed successively with water (60 ml), 5% sodium hydrogencarbonate (60 ml) and water (60 ml). The organic layer was concentrated under reduced pressure. N,N-dimethylformamide (40 ml) was added to the residue, and the mixture was concentrated again under reduced pressure. The residue was dissolved in N,N-dimethylformamide (60 ml) to give a solution of 2-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl)-3-((S)-1-hydroxymethyl-2-methylpropylamino)acrylic acid ethyl ester in N,N-dimethylformamide. This was identified as the title compound by HPLC.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C@@H:10]([CH3:26])[CH2:11][N:12]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([Cl:25])[CH:18]=3)=[N:13]2)=[O:8])[N:6]=1.[CH3:27][N:28]([CH3:33])[CH2:29][C:30](O)=[O:31].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:25][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][N:12]([CH2:11][C@@H:10]([NH:9][C:7]([C:5]3[N:6]=[C:2]([NH:1][C:30](=[O:31])[CH2:29][N:28]([CH3:33])[CH3:27])[S:3][CH:4]=3)=[O:8])[CH3:26])[N:13]=2)[CH:22]=[CH:21][C:20]=1[C:23]#[N:24]
Reactant: CN(C)CC(=O)O
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(NC(=O)CN(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.7 %

Procedure:
A solution of (S)-2-amino-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide of Example 57 (46 mg, 0.12 mmol) in 1 ml of DCM was added to a suspension of N,N-dimethylglycine (25 mg, 0.24 mmol), DIPEA (0.041 ml; 0.24 mmol), anhydrous HOBt (32 mg, 0.24 mmol) and EDCI (46 mg, 0.24 mmol) in 1 ml of DCM. The reaction mixture was stirred at RT over three nights. N,N-dimethylglycine (25 mg), DIPEA (0.021 ml), anhydrous HOBt (16 mg) and EDCI (23 mg) were added to the reaction mixture, and stirring was continued overnight. N,N-dimethylglycine (25 mg), DIPEA (0.082 ml) and EDCI (46 mg) were added twice the following two days. Three days after last addition of reagents the reaction was quenched by adding DCM and washing with water. Organic phase was dried over Na2SO4, filtered and evaporated. Crude product was purified twice by CombiFlash (1st column: silica, eluent: 0-10% MeOH in DCM; 2nd column: silica, eluent: 20-100% EtOAc in heptane) to obtain 3.2 mg (6%) of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.26 (d, 3H), 2.42 (s, 6H), 3.25 (s, 2H), 4.32 (dd, 1H), 4.42 (dd, 1H), 4.53-4.63 (m, 1H), 6.62 (d, 1H), 7.49 (d, 1H), 7.62 (d, 1H), 7.68 (d, 1H), 7.78 (s, 1H), 7.82 (dd, 1H), 7.96 (d, 1H).
Reaction SMILES: [C:1]1([C:11]([C:14]2[N:15]=[CH:16][N:17](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:18]=2)(O)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)(=O)C.O>[C:1]1([C:11]([C:14]2[N:15]=[CH:16][NH:17][CH:18]=2)=[CH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(O)(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: C=C(c1c[nH]cn1)c1cccc2ccccc12

Procedure:
1-Naphthalen-1-yl-1-(1-trityl-1H-imidazol-4-yl)-ethanol (Intermediate H1) in acetic acid:water (˜2:1) was heated to 100° C. for 1 h. The mixture was basified with 1 M NaOH and extracted (6×) with CHCl3: iPrOH (3:1). The organic solution was dried over MgSO4, filtered, and concentrated onto silica gel. The material was eluted from a column of silica with 5% NH3-MeOH: CH2Cl2 to give 4-(1-naphthalen-1-yl-vinyl)-1H-imidazole.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[N:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[CH:24]=[O:25])=[CH:18][CH:17]=1.CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[N:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][CH2:24][OH:25])=[CH:18][CH:17]=1
Reactant: O=C/C=C/c1ccc(-c2ncccn2)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Solvent: ClCCl
Product: OCC=Cc1ccc(-c2ncccn2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
DIBAL (1.0 M in THF, 18.0 mL) was added over 10 min to a −78° C. suspension of (2E)-3-[4-(2-pyrimidinyl)phenyl]-2-propenal (2.50 g, 11.89 mmol, prepared as described in Reference Example 2) in dichloromethane (100 mL). The resulting suspension was stirred for 30 min at −78° C., methanol (2 mL) was added cautiously, and stirring was continued for 5 min at −78° C. The mixture was poured into a mixture of 10% aq. citric acid (300 mL) and dichloromethane (200 mL) and allowed to stir for 1 h. The organic layer was separated, washed with sat. aq. NaHCO3 (200 mL) and brine (200 mL), dried (MgSO4), filtered through Celite, and concentrated. The resulting material was triturated with ether and dried in vacuo to provide 2.08 g (82%) of the title compound. MS 213 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[CH:3]=[N:2]1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>C(Cl)(Cl)Cl>[NH:1]1[CH:5]=[C:4]([C:6]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:8])[CH:3]=[N:2]1
Reactant: C1COCCN1
Reactant: O=C(O)c1cn[nH]c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(c1cn[nH]c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
A suspension of 1H-pyrazole-4-carboxylic acid (1.05 g), 1-{3-(dimethylamino)propyl}-3-ethylcarbodiimide hydrochloride (2.5 g), 1-hydroxybenzotriazole hydrate (1.6 g) and morpholine (1.2 g) in chloroform (18 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: chloroform:methanol=100:0 to 95:5) and silica gel column chromatography (eluting solvent: chloroform:methanol=100:0 to 90:10). The resulting colorless solid was washed with ethyl acetate to give the titled compound (1.00 g) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7](OC)=[N:6][S:5](=[O:10])[N:4]=1.[CH3:11][N:12]([CH3:21])[CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20]>>[CH3:1][O:2][C:3]1[C:7]([NH:20][CH2:19][CH2:18][CH2:17][CH2:16][C:15]#[C:14][CH2:13][N:12]([CH3:11])[CH3:21])=[N:6][S:5](=[O:10])[N:4]=1
Reactant: COC1=NS(=O)N=C1OC
Reactant: CN(C)CC#CCCCCN
Product: COC1=NS(=O)N=C1NCCCCC#CCN(C)C

Procedure:
In a similar manner to Example 1, 3,4-dimethoxy-1,2,5--thiadiazole-1-oxide (1.57 g) and 7-(dimethylamino)hept-5ynylamine (1.5 g) were reacted to give a solution of 3-methoxy-4-[7-dimethylaminohept-5-ynylamino]-1,2,5-thiadiazole-1-oxide. Reaction with ammonia gas and purification as in Example 1 gave the title compound (1.8 g), m.p. 154°-5° C. (recrystallisation from isopropanolethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18](O)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:22][O:23][C:24]1[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][CH:32]=[C:33]([O:34][CH3:35])[C:24]=4[O:23][CH3:22])[CH2:29]3)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2)nc2ccccc12
Reactant: COc1ccc2c(c1OC)CCNC2
Agent: Cl
Product: COc1ccc2c(c1OC)CCN(C(=O)c1nc(-c3ccc(Cl)cc3)nc3ccccc13)C2
Yield: 10 %

Procedure:
Reaction of 2-(4-chlorophenyl)quinazoline-4-carboxylic acid with 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 29 (10% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.71 and 2.98 (2t, 2H), 3.49 and 4.03 (2t, 2H), 3.68-3.81 (4s, 6H), 4.42 and 4.93 (2s, 2H), 6.62 and 7.01 (2d, 1H), 6.81 and 7.08 (2d, 1H), 7.63-7.67 (m, 2H), 7.71-7.81 (m, 1H), 7.89-8.00 (2d, 1H), 8.08-8.16 (m, 2H), 8.50-8.57 (m, 2H); MS (ESI) m/z 460 ([M+H]+).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:6][CH:7]=1.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([NH:23][NH2:24])=O)=[CH:16][CH:15]=1>C(O)CCC>[S:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]2[N:3]([C:21]([CH2:20][C:17]3[CH:18]=[CH:19][C:14]([OH:13])=[CH:15][CH:16]=3)=[N:23][N:24]=2)[N:4]=1
Reactant: Clc1ccc(-c2cccs2)nn1
Reactant: NNC(=O)Cc1ccc(O)cc1
Solvent: CCCCO
Product: Oc1ccc(Cc2nnc3ccc(-c4cccs4)nn23)cc1
Temperature: 25 °C

Procedure:
A solution containing 3-Chloro-6-thiophene-2-yl-pyridazine (58 mg, 0.29 mmol) Example 17: step a and (4-Hydroxy-phenyl)-acetic acid hydrazide (120 mg, 0.58 mmol) in butanol (5 mL) was heated to reflux overnight. The reaction was cooled to rt and the solids were filtered and washed with MeOH. The solid was recrystallized from MeOH to yield the title compound as a tan solid. 1H-NMR (CD3OD/CDCl3): δ 8.12-8.10 (1H, d, J=9.34 Hz), 7.83-7.82 (1H, d, J=3.7 Hz), 7.78-7.76 (1H, d, J=9.8 Hz), 7.67-7.65 (1H, d, J=5.0 Hz), 7.34-7.32 (2H, d, J=6.5 Hz), 7.22-7.21 (1H, m), 6.77-6.75 (2H, d, J=8.3 Hz), 4.49 (2H, s). ESI-MS (m/z): Calcd. For C16H12N4OS: 308.07; found: 309.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH2:10][CH2:11]O)[CH:5]=[CH:6][CH:7]=1.CCN(S(F)(F)[F:19])CC.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH2:10][CH2:11][F:19])[CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OCCC#Cc1cccc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FCCC#Cc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
A solution of 1.5 gm (6.67 mmol) of 4-(3-bromophenyl)but-3-yn-1-ol in CH2Cl2 at 0° C. was treated with 2.0 mL (15.3 mmol) of DAST, stirred at 0° C. for 1 h, allowed to warm to room temperature for 1 h, poured into saturated sodium bicarbonate and extracted with EtOAc. The combined extracts were washed sequentially with water and brine, dried over Na2SO4 and concentrated under reduced pressure. Chromatography of the resultant concentrate on silica gel with a gradient of 0% to 24% EtOAc-hexanes gave 1-Bromo-3-(4-fluoro-but-1-ynyl)benzene as a volatile liquid, 0.96 gm (64% yield); 1H NMR (400 MHz, CDCl3) δ: 2.82 (dt, 2H, J=6.6, 19.8 Hz), 4.56 (dt, 2H, J=6.6,46.4 Hz), 7.14 (t, 2H, J=7.9 Hz), 7.31 (m, 1H), 7.41 (m, 1H), 7.55 (t, 1H, J=1.7 Hz).
Reaction SMILES: [CH2:1]([N:5]([CH2:20][CH2:21][CH2:22][CH3:23])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=O)=[C:8]([O:18][CH3:19])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:24]([C:26]1[C:27](=[C:34]([C:37]#[N:38])[C:35]#[N:36])[O:28][C:29]([CH3:33])([CH3:32])[C:30]=1[CH3:31])#[N:25].C([O-])(=O)C.[NH4+]>C(O)C.O1CCCC1>[CH2:1]([N:5]([CH2:20][CH2:21][CH2:22][CH3:23])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=[CH:31][C:30]2[C:29]([CH3:32])([CH3:33])[O:28][C:27](=[C:34]([C:35]#[N:36])[C:37]#[N:38])[C:26]=2[C:24]#[N:25])=[C:8]([O:18][CH3:19])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)c1ccc(C=CC=CC=O)c(OC)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=CC=CC=CC2=C(C#N)C(=C(C#N)C#N)OC2(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 61.3 %

Procedure:
In 3 ml of ethanol and 1 ml of tetrahydrofuran were dissolved 146 mg (0.46 mmol) of 5-(4-dibutylamino-2-methoxyphenyl)-2,4-pentadienal and 101 mg (0.51 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene)propanedinitrile. To this mixture was added 36 mg of ammonium acetate, and the mixture was stirred at room temperature for 19 hours. The precipitate was separated by filtration, washed with ethanol, and purified by silica gel column chromatography to give 140 mg of a dark greenish brown crystal (yield: 60.9%; mp: 156-160° C.)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1.[H][H]>[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: COc1ccc(C(=O)O)c(C=Cc2cccc(Cl)c2)c1
Agent: [Pd]
Product: COc1ccc(C(=O)O)c(CCc2cccc(Cl)c2)c1

Procedure:
For the synthesis of the title compound, 6.0 g of 2-[2-(3-chlorophenyl)-vinyl]-4-methoxybenzoic acid, 0.6 g of Pd/C (10%) and 41 of hydrogen are employed in method J (variant 2). The solvent mixture comprises 75 ml of acetonitrile, 75 ml of ethyl acetate and 20 ml of methanol. C16H15ClO3(Mr=290.75)
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[NH:6][C:7]([C:9]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8].C(N(CC)CC)C.[C:31]([S:34][C@@H:35]([CH:39]([CH3:41])[CH3:40])[C:36](O)=[O:37])(=[O:33])[CH3:32].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2N=CC=CC=2N=N1>ClCCl>[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1)[NH:6][C:7]([C:9]1([NH:14][C:36](=[O:37])[C@@H:35]([S:34][C:31](=[O:33])[CH3:32])[CH:39]([CH3:41])[CH3:40])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8]
Reactant: CC(=O)S[C@H](C(=O)O)C(C)C
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(N)CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(NC(=O)[C@@H](SC(C)=O)C(C)C)CCCC1
Reaction time: 0.08 h

Procedure:
To a solution of [(1-amino(1-cyclopentyl)carbonyl]-L-tyrosine methyl ester hydrochloride (1.36 g, 3.97 mmol) in dichloromethane (50 mL) is added triethylamine (0.55 mL, 3.97 mmol). The mixture is stirred for 5 minutes and then (S)-2-acetylthio-3-methylbutanoic acid (0.70 g, 3.97 mmol), 1,3-dicyclohexylcarbodiimide (0.82 g, 3.97 mmol) and 1-hydroxy-7-azabenzotriazole (0.54 g, 3.97 mmol) are added. The mixture is stirred for 16 hours and then the solid precipitate is filtered off. The organic phase is washed with a saturated solution of sodium bicarbonate (30 mL), brine, dried over MgSO4, filtered and concentrated under reduced pressure to give a white foam. The foam is purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate (1:1). The pure fractions are concentrated and the resulting foam is crystallized from ethyl acetate-hexane to afford N-[[1-[(2(S)-acetylmercapto-3-methyl-1-oxobutyl)amino]-1-cyclopentyl]carbonyl]-L-tyrosine methyl ester as a white solid, m.p. 157°-158° C., the compound of formula III wherein R1 is 4-hydroxyphenyl, R2 is methyl, R3 is acetyl and R4 is isopropyl.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([N+:26]([O-:28])=[O:27])[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:30]=[C:31]([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)[NH2:32]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:12]2[O:13][N:32]=[C:31]([C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)[N:30]=2)[CH:15]=[C:16]([N+:26]([O-:28])=[O:27])[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c([N+](=O)[O-])c1
Reactant: NC(=NO)c1ccncc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(-c2nc(-c3ccncc3)no2)cc(OCc2ccccc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3,4-dibenzyloxy-5-nitrobenzoic acid (0.5 g, 1.32 mmol) in dimethylformamide (5 mL) at room temperature was added 1,1-carbonyldiimidazole (0.246 g, 1.52 mmol) in one portion. After stirring for one hour, N′-hydroxypyridine-4-carboximidamide (0.208 g, 1.52 mmol) was added in one portion and the resulting mixture was stirred at room temperature overnight. The mixture was then stirred at 110° C. for three hours and then allowed to cool to room temperature. The mixture was poured onto ice-water (100 mL) and extracted with 20% isopropanol/dichloromethane. The organic extracts were washed with water and brine, then dried (Na2SO4), filtered and evaporated to leave a solid residue that was recrystallised from ethanol. 4-[5-(3,4-Bis-benzyloxy-5-nitro-phenyl)-[1,2,4]oxadiazol-3-yl]-pyridine was obtained as a beige solid (0.395 g, 62%).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([OH:13])[C:9]([CH2:14][C:15]([CH3:17])=[CH2:16])=[CH:8][C:7]=2[CH3:18])[CH3:2].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.CCCCCC>[Br:20][CH2:16][C:15]1([CH3:17])[O:13][C:10]2=[C:11]3[C:6](=[C:7]([CH3:18])[CH:8]=[C:9]2[CH2:14]1)[NH:5][C:4](=[O:19])[C:3]([CH2:1][CH3:2])=[CH:12]3
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(C)Cc1cc(C)c2[nH]c(=O)c(CC)cc2c1O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CCc1cc2c3c(cc(C)c2[nH]c1=O)CC(C)(CBr)O3
Yield: 99.1 %

Procedure:
Using 3-ethyl-6-(2-methyl-2-propenyl)-5-hydroxy-8-methylcarbostyril (710 mg, 2.76 mmol) and N-bromosuccinimide (516 mg, 2.90 mmol), the procedure of Example 227 was followed (reaction, post-treatment, and recrystallization from chloroform-n-hexane) to obtain 920 mg of the title compound as pale yellow crystals (99.2%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:13]#[N:14])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[OH-:17].[Na+].OO>CO>[F:1][C:2]([F:15])([F:16])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:13]([NH2:14])=[O:17])[CH2:11][CH2:12]2)=[CH:8][CH:9]=1
Reactant: [OH-]
Reactant: N#CC1(c2ccc(OC(F)(F)F)cc2)CC1
Agent: OO
Agent: [Na+]
Solvent: CO
Product: NC(=O)C1(c2ccc(OC(F)(F)F)cc2)CC1
Temperature: 55 °C

Procedure:
A mixture of 1-(4-trifluoromethoxyphenyl)cyclopropanecarbonitrile (4.0 g), 25% aqueous sodium hydroxide (0.46 mL), 30% aqueous hydrogen peroxide (25 mL), and methanol (100 mL) was heated at 55° C. for 1 h with stirring. The reaction mixture was concentrated under reduced pressure, the precipitated crystals were collected by filtration, to obtain white solid 1-(4-(trifluoromethoxy)phenyl)cyclopropanecarbamide (4.5 g). (3) A mixture of 1-(4-trifluoromethoxyphenyl)cyclopropanecarbamide (4.5 g), 15% aqueous sodium hydroxide (150 mL), and methanol (60 mL) was heated at 78° C. for 18 h with stirring. The reaction mixture was left stand for cooling, then the reaction solution was adjusted to pH 2 using 15% hydrochloric acid and concentrated under reduced pressure. The precipitated crystals were collected by filtration to obtain white solid 1-(4-(trifluoromethoxy)phenyl)cyclopropanecarboxylic acid (4.5 g).