Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[C:8](C)=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].CC1[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]([N+:19]([O-])=[O:20])[C:12]=1N.NC1C=CC=CC=1.[CH3:29][C:30]1[C:35]([CH3:36])=[CH:34][CH:33]=[C:32]([N+:37]([O-:39])=[O:38])[C:31]=1[N:40]=[C:41]=[S:42].OCCN.Cl.ClCC1(N)CCCC1>>[OH:20][CH2:5][C:3]1([NH2:4])[CH2:2][CH2:8][CH2:7][CH2:6]1.[CH3:29][C:30]1[C:35]([CH3:36])=[CH:34][CH:33]=[C:32]([N+:37]([O-:39])=[O:38])[C:31]=1[N:40]=[C:41]1[S:42][CH2:12][C:14]2([CH2:15][CH2:16][CH2:17][CH2:18]2)[NH:19]1
Reactant: Cc1cccc(N)c1C
Reactant: Cc1ccc([N+](=O)[O-])c(N)c1C
Reactant: Cc1ccc([N+](=O)[O-])c(N=C=S)c1C
Agent: Cl
Agent: NC1(CCl)CCCC1
Solvent: NCCO
Solvent: Nc1ccccc1
Product: Cc1ccc([N+](=O)[O-])c(N=C2NC3(CCCC3)CS2)c1C
Product: NC1(CO)CCCC1

Procedure:
2,3-Dimethylaniline was converted to 2,3-dimethyl-6-nitroaniline according to Method A4a. The aniline was converted to 2,3-dimethyl-6-nitrophenyl isothiocyanate according to Method A2d. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2,3-dimethyl-6-nitrophenyl isothiocyanate according to Method C1e to give 2-(2,3-dimethyl-6-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2b to afford 2-(2,3-dimethyl-6-nitrophenylimino)-1-isobutyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[N:14]\[O:15][CH3:16])/[C:10]([NH:12][CH3:13])=[O:11].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[OH:25].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(OCC)(=O)C>[CH3:16][O:15]/[N:14]=[C:9](\[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:25][C:19]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=1[CH3:17])/[C:10]([NH:12][CH3:13])=[O:11]
Reactant: Cc1ccc(C)c(O)c1
Reactant: CNC(=O)/C(=N/OC)c1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1cc(C)ccc1C
Temperature: 60 °C
Reaction time: 45 h
Yield: 53.1 %

Procedure:
A mixture of (E)-2-(2-chloromethylphenyl)-2-methoxyimino-N-methylacetamide (500 mg), 2,5-dimethylphenol (700 mg), potassium carbonate (700 mg) and acetone (5.0 ml) was stirred in a sealed tube at 60° C. for 45 hours. After the mixture was cooled by allowing it to stand, ethyl acetate was added thereto. The mixture was washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The resulting residue was subjected to column chromatography on silica gel (ethyl acetate:hexane=1:2) to obtain the title compound (360 mg, 53%). In this chromatographic separation, some of the starting compound was recovered.
Reaction SMILES: [C:1]1([PH+:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC[C:22]1[CH:27]=[CH:26][C:25]([C:28]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[C:29]([C:36]2[CH:41]=[CH:40][C:39](CBr)=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][CH:23]=1.[C:50]1([P:56]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.C1(C)C=CC=CC=1>CN(C=O)C>[C:25]1([C:28]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[C:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:24]=[CH:23][CH:22]=[CH:27][CH:26]=1.[C:14]1([PH+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.[C:63]1([PH+:56]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1
Reactant: BrCc1ccc(C(=C(c2ccccc2)c2ccc(CBr)cc2)c2ccccc2)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: c1ccc(C(=C(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Reaction time: 24 h
Yield: 80 %

Procedure:
Triphenylphosphonium salt, TPE-TPP, was prepared from 3 (0.5 g, 1.0 mmol) and triphenylphosphine (1.0 g, 4.0 mmol) in DMF at 100° C. After stirring for 24 h, the solution was poured into large amount of toluene. The white precipitate was collected in 80% yield. 1H NMR (400 MHz, DMSO-d6), δ (TMS, ppm): 7.90-7.55 (m, 30H), 7.16-6.66 (m, 18H), 5.039 (d, 4H). 13C NMR (100 MHz, DMSO-d6), δ (TMS, ppm): 143.4, 142.5 140.1, 135.2, 134.0, 131.1, 130.6, 130.3, 130.1, 128.0, 127.0, 126.1, 118.1, 17.2, 40.21. m/z (MALDI-TOF) 882.49 [M−2Br)+]; calc. 882.35. Anal. Calcd. C64H52Br2P2: C, 73.7; H, 5.0. Found: C, 73.7; H, 4.9.
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[C:12](=[O:15])([O-])[O-].[K+].[K+].C=O.[CH:20](Br)([CH3:22])[CH3:21]>CN(C=O)C.O.C(OCC)(=O)C>[OH:15][CH2:12][C:3]1[C:4]([C:8]([F:11])([F:10])[F:9])=[N:5][N:6]([CH3:7])[C:2]=1[O:1][CH:20]([CH3:22])[CH3:21]
Reactant: Cn1nc(C(F)(F)F)cc1O
Reactant: CC(C)Br
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1c(CO)c(C(F)(F)F)nn1C
Temperature: 25 °C
Yield: 53.5 %

Procedure:
In 100 ml of DMF were suspended 16.6 g (0.10 mole) of the 5-hydroxy-1-methyl-3-trifluoromethylpyrazole synthesized in Reference Example 1 and 20.9 g (0.15 mole) of potassium carbonate. In this suspension being stirred at room temperature was placed 4.5 g (0.15 mole) of paraformaldehyde, followed by stirring at the same temperature for 1 hour. Then, 41.8 g (0.30 mole) of potassium carbonate was added. Thereto was dropwise added 36.9 g (0.30 mole) of isopropyl bromide. The reaction mixture was heated to 60° C. and stirred for 12 hours to give rise to a reaction. After the reaction, 200 ml of ethyl acetate and 200 ml of water were added. The organic layer, which appeared by phase separation, was separated. The aqueous layer was subjected to re-extraction with 50 ml of ethyl acetate. The two organic layers were combined and washed with 50 ml of water, 30 ml of a saturated aqueous ammonium chloride solution and 30 ml of a saturated aqueous sodium chloride solution in this order. The resulting organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 21.7 g (purity: 59.4%, yield: 53.5%) of a crude solution of title compound. The crude solution was subjected to vacuum distillation to obtain a title compound as a light yellow transparent solution.
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH2:8](O)[CH3:9]>>[CH2:8]([O:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)[CH3:9]
Reactant: OCc1ccco1
Reactant: CCO
Product: CCOCc1ccco1
Reaction time: 2.5 h

Procedure:
Six batches of ethylfurfuryl ether comprising liquid were prepared as follows. A feed mixture of 120 grams ethanol and 110 grams furfuryl alcohol (molar ratio ethanol/furfuryl alcohol of 2.5) was added to 10 grams acidic ZSM-5 particles with a silica-alumina ratio of 30. The mixture was contracted with the catalyst for 2.5 hours at 125° C. under stirring.
Reaction SMILES: C(OCC)(=O)[CH2:2][C:3](OCC)=[O:4].[Na].[S:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH:18]=[CH:19][C:20](=[O:22])[CH3:21].[OH-].[K+]>C(O)C>[OH:4][C:3]1[CH2:2][CH:18]([C:14]2[S:13][CH:17]=[CH:16][N:15]=2)[CH2:19][C:20](=[O:22])[CH:21]=1
Reactant: CC(=O)C=Cc1nccs1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Product: O=C1C=C(O)CC(c2nccs2)C1
Temperature: 70 °C

Procedure:
(i) Diethyl malonate (1.16 g) was added to a solution of sodium (158 mg) in dry absolute ethanol (10 ml) and the mixture was heated to reflux. 1-(2-Thiazolyl)but-1-en-3-one (1.0 g) in dry absolute ethanol (5 ml) was added dropwise to the solution. After refluxing for 2.5 hr, an aqueous potassium hydroxide solution (862 mg in 12 ml) was added and the mixture was extracted with diethyl ether. The aqueous layer was heated to 70° C. and neutralised with dilute hydrochloric acid and the water was then evaporated under reduced pressure. The residue was extracted with dry dimethylformamide. Evaporation of the solvent gave 3-hydroxy-5-(2-thiazolyl)cyclohex-2-en-1-one.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH:4]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][C:17]3[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][C:20]([CH2:21]Br)=[CH:19][C:18]=3[C:29]([F:32])([F:31])[F:30])[CH:14]=2)[NH:9][CH:8]=1)([CH3:6])[CH3:5]>CN(C)C=O.O>[CH:4]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][C:17]3[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][C:20]([CH2:21][C:1]#[N:2])=[CH:19][C:18]=3[C:29]([F:32])([F:31])[F:30])[CH:14]=2)[NH:9][CH:8]=1)([CH3:6])[CH3:5]
Reactant: [C-]#N
Reactant: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(CBr)cc3C(F)(F)F)cc12
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(CC#N)cc3C(F)(F)F)cc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
72.9 mg (1.49 mmol) of sodium cyanide are added at 50° C. to a solution of 0.57 g (1.19 mmol) of benzyl bromide from Example VII in 3.5 ml of dimethylformamide and 0.38 ml of water and the mixture is stirred for 60 minutes at 50° C. Dimethylformamide is subsequently distilled off, the concentrate is diluted with ethyl acetate and water, and the aqueous phase is separated off and extracted again with ethyl acetate. The combined organic phases are washed with sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The purification of the crude product is carried out on silica gel 60 by means of toluene/ethyl acetate (toluene, toluene/ethyl acetate=18:1 and 18:1.5).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][CH3:11])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.C(O)(=O)[CH2:13][OH:14].O.[C:18]1(C)C=CC=CC=1>>[OH:14][CH2:13][C:11]1[N:10]([CH3:18])[C:3]2=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=[C:2]2[N:1]=1
Reactant: O=C(O)CO
Reactant: CNc1nc(OC)ccc1N
Reactant: Cc1ccccc1
Solvent: O
Product: COc1ccc2nc(CO)n(C)c2n1

Procedure:
A solution of 2.20 g of 3-amino-6-methoxy-2-methylaminopyridine (prepared as described in Preparation 68) and 3.30 g of glycolic acid in 40 ml of toluene was heated under reflux for 4 hours. At the end of this time, the reaction mixture was poured into water, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 30:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 620 mg of the title compound, melting at 138°-140° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:5])C.[CH:16]([O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)([CH3:18])[CH3:17].Br[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH:37]([CH3:39])[CH3:38])=[CH:32][CH:31]=1>>[CH:16]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N:7]2[C:8]3[C:13](=[CH:12][C:11]([C:30]4[CH:35]=[CH:34][C:33]([O:36][CH:37]([CH3:39])[CH3:38])=[CH:32][CH:31]=4)=[CH:10][CH:9]=3)[CH:14]=[C:6]2[C:4]([OH:3])=[O:5])=[CH:22][CH:21]=1)([CH3:18])[CH3:17]
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Reactant: CC(C)Oc1ccc(Br)cc1
Product: CC(C)Oc1ccc(-c2ccc3c(c2)cc(C(=O)O)n3-c2ccc(OC(C)C)cc2)cc1

Procedure:
The title compound was prepared in accordance with Example 1, using 5-bromoindole-2-carboxylic acid ethyl ester, 4-isopropoxyphenylboronic acid and 4-bromo-1-isopropoxybenzene.
Reaction SMILES: [O:1]=[C:2]1[NH:6][N:5]=[CH:4][N:3]1[C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][N:16]=1)[C:10]([O:12][CH3:13])=[O:11].[H-].[Na+].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1>CN(C)C=O>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:6]2[C:2](=[O:1])[N:3]([C:7]3[CH:8]=[C:9]([CH:14]=[CH:15][N:16]=3)[C:10]([O:12][CH3:13])=[O:11])[CH:4]=[N:5]2)=[CH:22][CH:23]=1
Reactant: COC(=O)c1ccnc(-n2cn[nH]c2=O)c1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccnc(-n2cnn(Cc3ccc(F)cc3)c2=O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)isonicotinate (1.68 g, 7.63 mmol) in N,N-dimethylformamide (76 mL) was added sodium hydride (60% dispersion in mineral oil, 0.67 g, 16.80 mmol) at 0° C. The resulting reaction mixture was stirred for 1 hour at 0° C., followed by the addition of 1-(bromomethyl)-4-fluorobenzene (3.23 g, 17.09 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 48 hours and concentrated in vacuo to dryness to give methyl 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)isonicotinate, and used in the further reaction without purification
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5]Cl.C(=O)([O-])[O-].[K+].[K+].[N+:14]([C:17]1[CH:18]=[N:19][NH:20][CH:21]=1)([O-:16])=[O:15]>CC(C)=O>[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][N:19]1[CH:18]=[C:17]([N+:14]([O-:16])=[O:15])[CH:21]=[N:20]1
Reactant: CN(C)CCCl
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C)CCn1cc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Dimethylaminoethyl chloride hydrochloride (955 mg, 6.63 mmol), potassium carbonate (1.83 g, 8.84 mmol) and 4-nitro-1H-pyrazole (750 mg, 6.63 mmol) were combined in acetone (30 ml) and the reaction was stirred overnight at reflux. After cooling to room temperature, the crude reaction mixture was filtered to remove inorganics, and the filtrate was concentrated to give the product.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[O:9][CH:8]([C:14]([F:17])([F:16])[F:15])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]2)[CH3:2].S(Cl)([Cl:24])(=O)=O>ClCCl.C(O)(=O)C.[Zn]>[Cl:24][C:11]1[C:12]([OH:13])=[C:3]([CH2:1][CH3:2])[CH:4]=[C:5]2[C:10]=1[O:9][CH:8]([C:14]([F:15])([F:16])[F:17])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]2
Reactant: CCc1cc2c(cc1O)OC(C(F)(F)F)C(C(=O)O)=C2
Reactant: O=S(=O)(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1cc2c(c(Cl)c1O)OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 18.2 %

Procedure:
To a mixture of 1.0 g (3.4 mmol) of 6-ethyl-7-hydroxy-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid in anhydrous dichloromethane (30 mL) was added 4.2 mL (1.0 M in DCM, 22 mmol) sulfuryl chloride dropwise. The resulting mixture was stirred at room temperature for 24 h. The sample was concd and the residue dissolved in 30 mL of acetic acid, followed by addition of 0.5 g granular Zn. The mixture was stirred at room temperature for 3 h, filtered and the filtrate evaporated. The residue was purified by chromatography to afford 0.20 g (18%) of a white solid: 1H NMR(CDCl3/400 MHz) 7.79 (s, 1H), 7.26 (s, 1H), 5.77 (q, J=6.8 Hz, 1H), 2.63(q, J=7.6 Hz, 2H), 1.21(t, J=7.6 Hz, 3H). MS (ESI+) 323.0 (M+1, 100).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][C:26]=4[N+:34]([O-:36])=[O:35])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:38][C:39]1[S:40][C:41]([C:44]([F:47])([F:46])[F:45])=[N:42][N:43]=1.C(N(C(C)C)CC)(C)C>O1CCCC1.C(OCC)(=O)C>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:32])[NH:38][C:39]5[S:40][C:41]([C:44]([F:47])([F:46])[F:45])=[N:42][N:43]=5)=[CH:27][C:26]=4[N+:34]([O-:36])=[O:35])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1nnc(C(F)(F)F)s1
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)Cl)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Sc2ccc(C(=O)Nc3nnc(C(F)(F)F)s3)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
A solution of the product of Example 19C (290 mg, 0.546 mmol) in anhydrous tetrahydrofuran (5 mL) was treated with 2-amino-5-trifluoromethyl-1,3,4-thiadiazole (102 mg, 0.601 mmol) and diisopropylethylamine (0.143 mL, 0.819 mmol), and stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction was diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (25 mL), water (2×25 mL), and brine (25 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Trituration with methylene chloride provided the title compound (308 mg, 85%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([N:7]=[C:8](Cl)[Cl:9])=[CH:3][CH:2]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[C:18]([NH2:26])(=[NH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CCOCC.O1CCCC1>[ClH:9].[NH2:26][C:18](=[N:25][C:8]([N:15]1[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]1)=[N:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N=C(N)c1ccccc1
Reactant: ClC(Cl)=Nc1ccccc1
Reactant: CN1CCNCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN1CCN(C(N=C(N)c2ccccc2)=Nc2ccccc2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.1 %

Procedure:
To 3.48 g (0.02 mol) of phenylisocyanide dichloride in 25 ml of anhydrous ether at 0° C. under a nitrogen atmosphere was added 4.0 g (0.04 mol) of 1-methylpiperazine in 20 ml of anhydrous ether dropwise. The mixture was stirred for one hour at ambient temperature and filtered to remove the precipitated 1-methylpiperazine hydrochloride. The filtrate was added dropwise to a solution of 4.8 g (0.04 mol) of benzamidine in 15 ml of tetrahydrofuran. The mixture was stirred for 20 hours at ambient temperature. The precipitated product was collected and reprecipitated twice by pouring a methanolic solution of the product into a large excess of anhydrous ether. The product was subsequently recrystallized from methanol-ether to afford 2.30 g (32%) of N-(1-amino-1-phenylmethylene)-N'-(phenyl)-1-methyl-4-piperazinecarboximidamide hydrochloride, mp 247°-248° C.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:6][C:7]1[CH:12]=C[CH:10]=[C:9](N)[CH:8]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.CI.ClCCl.[CH3:31][N:32]([CH:34]=O)[CH3:33]>>[C:1]([NH:4][CH:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:34]([N:32]([CH3:31])[CH3:33])[CH:12]=1)(=[O:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(Cc1cccc(N)c1)NC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CI
Product: CCOC(=O)C(Cc1cccc(N(C)C)c1)NC(C)=O
Temperature: 30 °C

Procedure:
4 g of ethyl (RS)-N-acetyl-3-aminophenylalaninate, prepared as described in Example 35-8, in 15 ml of DMF are placed in a three-necked flask under a nitrogen atmosphere, and 5.5 ml of triethylamine, and then 2.5 ml of methyl iodide and 4 ml of dichloromethane, are added while maintaining the temperature in the region of 30° C. using an icebath. The mixture is then warmed at 35° C. for 18 h. 1 ml of methyl iodide dissolved in 1 ml of DMF is then added slowly while maintaining the temperature in the region of 30° C.; 2.2 ml of triethylamine are then added and the mixture is subsequently warmed for a further 5 h at 35° C. The mixture is brought to room temperature and then extracted with 100 ml of ethyl acetate and 150 ml of distilled water. The aqueous phase is separated off after settling and then rewashed with 2 times 70 ml of ethyl acetate. The organic phases are combined, washed with 2 times 80 ml of distilled water and then with 50 ml of distilled water which is saturated with NaCl. The organic phase is separated off after settling, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure in order to yield 2.4 g of a product which is purified by flash chromatography (dichloromethane, MeOH 90/10). 0.72 g (16%) of ethyl (RS)-3-N-acetyl-3-dimethylamino phenylalaninate is thus obtained in the form of yellow crystals.
Reaction SMILES: [NH:1]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:2]([C:4]([NH:6][C@H:7]([C:9]([NH2:11])=[O:10])C)=[O:5])[CH3:3]>CO>[NH:1]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:2]([C:4]([NH:6][CH2:7][C:9]([NH2:11])=[O:10])=[O:5])[CH2:3][CH2:3][CH2:2][CH2:4][NH2:6]
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(N)=O
Solvent: CO
Product: NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(N)=O

Procedure:
Z-L-Ala-L-Ala-NH2 (12) (Katakai et al., Macromolecules, 6:827-831 (1973), which is hereby incorporated by reference): 1H NMR (DMSO-d6) δ1.20 (2×d, J=7 Hz, 6H, 2×CH3), 4.10, 4.20 (m, 2H, 2×NHCHCO), 5.00 (s, 2H, OCH2Ph), 7.20-7.40 (m, 5H, Ph); 13C NMR (DMSO-d6) δ18.1, 18.4, 47.9, 50.1, 65.4, 127.7, 128.4, 137.0, 155.8, 172.0, 174.1. HRMS (FAB+) MH+ calcd294.1454 found 294.1457. [α]25D=−20.4 (c 0.77, MeOH).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[I:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[I:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=2)=[CH:17][CH:16]=1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(I)cc2)cc1C(F)(F)F
Yield: 68.7 %

Procedure:
4-Fluoro-2-(trifluoromethyl)benzonitrile (53 g, 280.4 mmol, AK Scientific) was treated with 4-iodophenol (61.7 g, 280.4 mmol, Aldrich) and sodium carbonate (44.6 g, 420.6 mmol) in 90 mL anhydrous DMF at 100° C. for 20 hours. The reaction mixture was diluted with 250 mL water and extracted with 2×200 mL EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 4-(4-iodophenoxy)-2-(trifluoromethyl)benzonitrile as a white solid (75 g, 69%). 1H NMR (400 MHz, CDCl3): 7.80-7.72 (3 H, m), 7.36-7.32 (1 H, m), 7.17-7.10 (1 H, m), 6.89-6.82 (2 H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][S:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=1)(=[O:9])=[O:8].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][S:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][O:18][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:13][CH:12]=1)(=[O:9])=[O:8]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CNS(=O)(=O)Cc2ccc(CO)cc2)c(OC)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(CNS(=O)(=O)Cc2ccc(COS(C)(=O)=O)cc2)c(OC)c1
Reaction time: 1.5 h

Procedure:
To a solution of N-(2,4-dimethoxybenzyl)-C-(4-hydroxymethylphenyl)methanesulfonamide (6 g) were added, at 0° C., triethylamine (4.5 ml) and, gradually, methanesulfonyl chloride in dichloromethane (2.2 ml in 50 ml). The mixture was stirred for 1.5 h and then diluted with ethyl acetate. After washing with water, 1 M hydrochloric acid and sodium chloride solution, the organic phase was dried over magnesium sulfate and concentrated. This gave the product (7 g) with a molecular weight of 429.5 g/mol (C18H23NO7S2).