Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([CH2:11][C:12]1([N:25]2[CH:29]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:27]=[N:26]2)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)#[N:10].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:28]2[CH:27]=[N:26][N:25]([C:12]3([CH2:11][C:9]#[N:10])[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17]3)[CH:29]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Clc1ccnc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(-c3ccnc(Cl)n3)cn2)CC1
Temperature: 100 °C
Yield: 81 %

Procedure:
A mixture of 2,4-dichloropyrimidine (1.00 g, 6.71 mmol), tert-butyl 4-(cyanomethyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (2.8 g, 6.7 mol), tetrakis(triphenylphosphine)palladium (0.5 g, 0.4 mmol), and potassium phosphate (4.3 g, 20 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was heated at 100° C. overnight. After cooling to room temperature, the mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified on silica gel, eluting with 0 to 100% EtOAc in hexanes, to give the desired product (2.19 g, 82%). LCMS (M+H) 403.0.
Reaction SMILES: C1C([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[O:16])=[CH:10][CH:9]=2)=CC=C(N=C=O)C=1.[N-:20]=[C:21]=[O:22].[N-]=C=O.CC1C(C)=C(C)C(C)=C(C)C=1C.[N-]=C=O.[N-]=C=O.COC1C=CC=CC=1C1C=CC=CC=1OC.C1(N=C=O)C(N=C=O)=CC=CC=1.[N-]=C=O.[N-]=C=O.C1C=CC(C2C=CC=CC=2)=CC=1.CC(C)(CC(C)CCN=C=O)CN=C=O.CC(CC(C)(C)CCN=C=O)CN=C=O>>[CH3:7][C:8]1[C:9](=[CH:10][C:11](=[CH:12][CH:13]=1)[N:14]=[C:15]=[O:16])[N:20]=[C:21]=[O:22]
Reactant: O=C=Nc1ccc(Cc2ccc(N=C=O)cc2)cc1
Reactant: [N-]=C=O
Agent: CC(CCN=C=O)CC(C)(C)CN=C=O
Agent: CC(CN=C=O)CC(C)(C)CCN=C=O
Agent: COc1ccccc1-c1ccccc1OC
Solvent: c1ccc(-c2ccccc2)cc1
Product: Cc1ccc(N=C=O)cc1N=C=O

Procedure:
diphenylmethane-4,4′-diisocyanate (MDI); hydrogenated diphenylmethane-4,4′-diisocyanate (H12MDI); tetra-methyl xylene diisocyanate (TMXDI); hexamethylene-1,6-diisocyanate (HDI), of the formula OCN—(CH2)6—NCO naphthalene-1,5-diisocyanate; 3,3′-dimethoxy-4,4′-biphenyldiisocyanate; 3,3′-dimethyl-4,4′-bimethyl-4,4′-biphenyldiisocyanate; phenylene diisocyanate; 4,4′-biphenyldiisocyanate; 2,2,4-trimethylhexamethylene diisocyanate and 2,4,4-trimethylhexamethylene diisocyanate, of the formulae
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[SH:20]>C1C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]2[S:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccccc1S
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc(-c2nc3ccccc3s2)cc1
Reaction time: 16 h
Yield: 73.2 %

Procedure:
A solution of 4-nitrobenzoyl chloride (1.49 g, 8.0 mmol) in benzene (anhydrous, 10 mL) was added dropwise to 2-aminothiophenol (1.0 g, 8.0 mmol in 10 ml of benzene) at room temperature. The reaction mixture was allowed to stir for 16 hr. The reaction was quenched with water (20 mL). The aqueous layer was separated and extracted with ethyl acetate (3×10 ml). The combined organic layers were dried and evaporated. The crude product was purified with flush column, (hexane:ethyl acetate=85:15) to give 1.5 g (73.2%) of product as light yellow solid.
Reaction SMILES: [N:1]([C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:10])[C:5]([O:7]CC)=O)=[C:2]=[S:3].[C:17]1([NH:23]N)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C(C)=CC=CC=1>[C:17]1([N:23]2[C:5](=[O:7])[C:4]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)([CH3:10])[NH:1][C:2]2=[S:3])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)C(C)(N=C=S)c1ccccc1
Solvent: Cc1ccccc1C
Product: CC1(c2ccccc2)NC(=S)N(c2ccccc2)C1=O
Temperature: 25 °C
Yield: 81.5 %

Procedure:
4.7 g (20 mmol) of ethyl 2-isothiocyanato-2-phenylpropionate are dissolved in 40 ml of xylene. 2.16 g (20 mmol) of phenylhydrazine are added and the mixture is heated for 4 hours at reflux. The mixture is cooled to room temperature and a beige solid precipitates. The precipitate is filtered, washed with 5 ml of diisopropyl ether and then dried under vacuum. 4.6 g (yield=77%) of 3,5-diphenyl-5-methyl-2-thiohydantoin are thus obtained in the form of a beige powder melting at 164° C.
Reaction SMILES: [NH3:1].[CH3:2][N:3]([CH3:11])[C:4]([N:6]=[C:7](Cl)[S:8][CH3:9])=[O:5]>>[CH3:2][N:3]([CH3:11])[C:4](=[O:5])[NH:6][C:7](=[NH:1])[S:8][CH3:9]
Reactant: N
Reactant: CSC(Cl)=NC(=O)N(C)C
Product: CSC(=N)NC(=O)N(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To 50 parts of conc. aqueous ammonia are added within 10 min. at 20°-25° C., 18.1 parts of N-dimethylcarbamoyl-1-methylthioformimidoyl chloride with agitation. When all has been added, the suspension of crystals which forms is stirred for 10 minutes to assure completion of the reaction. The reaction mass is then cooled to 0° C., the solids filtered and recrystallized from acetone to give 10.6 parts of methyl 4,4-dimethylthioallophanimidate (a compound of formula II), m.p. 136°-138° C.
Reaction SMILES: [CH3:1][Mg+].[Br-].[Cl:4][C:5]1[CH:27]=[C:26]([CH3:28])[C:8]([O:9][C:10]2[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]([NH:20][CH:21]([CH:24]=[O:25])[CH2:22][CH3:23])[C:11]=2[C:12]([NH2:14])=[O:13])=[C:7]([CH3:29])[CH:6]=1>C1COCC1>[Cl:4][C:5]1[CH:6]=[C:7]([CH3:29])[C:8]([O:9][C:10]2[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]([NH:20][CH:21]([CH2:22][CH3:23])[CH:24]([OH:25])[CH3:1])[C:11]=2[C:12]([NH2:14])=[O:13])=[C:26]([CH3:28])[CH:27]=1
Reactant: C[Mg+]
Reactant: CCC(C=O)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(N)=O
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC(Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(N)=O)C(C)O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of MeMgBr in dry THF was added a solution of 2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-formyl-propylamino)-6-methyl-nicotinamide in dry THF at −78° C. The mixture was stirred at −78° C. for 2 hr, then quenched with dilute acid. After standard extraction and purification, the title compound was obtained. 1H NMR(CDCl3) d 9.8(d,1H), 7.9(nbrs,1H), 7.05(s,2H), 6.27(s,0.5H), 6.24(s,0.5H), 5.6(brs,1H), 3.91(m,0.5H), 3.89(m,0.5H), 3.51(m,0.5H), 3.3(m,0.5H), 2.09(s,9H), 1.5-1.8(m,2H), 1.26(d,3H), 0.98(t,3H) ppm.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:47])[NH:6][C:7]2[CH:45]=[CH:44][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][N:28]6[CH2:33][CH2:32][CH:31]([NH:34][C:35](=[O:43])[NH:36][CH2:37][C:38]([O:40]CC)=[O:39])[CH2:30][CH2:29]6)=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:46])[CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([NH:4][C:5](=[O:47])[NH:6][C:7]2[CH:45]=[CH:44][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][N:28]6[CH2:29][CH2:30][CH:31]([NH:34][C:35](=[O:43])[NH:36][CH2:37][C:38]([OH:40])=[O:39])[CH2:32][CH2:33]6)=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:46])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)CNC(=O)NC1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CNC(=O)NC1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 425 (78 mg, 0.12 mmol) in MeOH (3 mL) was added 1N NaOH (0.6 mL, 0.6 mmol). The reaction mixture was stirred at RT for 20 h. The reaction mixture was then concentrated, diluted with water and the pH was adjusted to 6-7 by addition of 1N HCl. To the resulting suspension was added MeOH to dissolve the mixture clearly, and purified via Biotage [KP-C18-HS 30 g, gradient 20-95% (methanol/water)]. Title compound 426 was obtained as a white solid (79.5 mg, 60% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): one H of carboxylic acid is missing, 10.17 (brs, 1H), 8.53 (d, J=1.6 Hz, 1H), 8.51 (d, J=5.2 Hz, 1H), 8.29 (s, 1H), 8.20 (d, J=8.0 Hz, 1H), 8.02 (brs, 1H), 7.81 (dd, J=8.0, 2.0 Hz, 1H), 7.76 (dd, J=14.0, 2.4 Hz, 1H), 7.33 (t, J=9.0 Hz, 1H), 7.28 (dd, J=9.2, 2.0 Hz, 1H), 6.65 (d, J=4.4 Hz, 1H), 6.25 (d, J=7.6 Hz, 1H), 5.59 (t, J=3.6 Hz, 1H), 4.15-4.09 (m, 1H), 3.51 (s, 2H), 3.28 (d, J=4.4 Hz, 2H), 2.72-2.65 (m, 2H), 2.58-2.51 (m, 1H), 2.11-2.02 (m, 2H), 1.76-1.66 (m, 2H), 1.38-1.25 (m, 2H), 0.63-0.56 (m, 2H), 0.44-0.38 (m, 2H). MS (m/z): 634.5 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.[Cl:15][C:16]1[CH:17]=[C:18]([S:23]([CH2:25][CH2:26][CH2:27][CH2:28]Br)=[O:24])[CH:19]=[CH:20][C:21]=1[Cl:22].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:15][C:16]1[CH:17]=[C:18]([S:23]([CH2:25][CH2:26][CH2:27][CH2:28][O:1][C:2]2[CH:3]=[CH:4][C:5]3[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:12])([CH3:13])[C:6]=3[CH:14]=2)=[O:24])[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: CC1(C)OC(=O)Nc2ccc(O)cc21
Reactant: O=S(CCCCBr)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A solution of 1.9 gm (0.01 mol) of 6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4.1 gm (0.0125 mol) of 4-(3,4-dichlorophenyl-sulfinyl)-butylbromide (m.p.: 63°-64° C.) in 40 ml of dimethylsulfoxide is mixed with 3.5 gm (0.025 mol) of potassium carbonate, and the mixture is stirred for three hours at 40° C. After cooling, copious amounts of ice water are added, and the mixture is extracted with chloroform. The extract is washed with water and dried with sodium sulfate, and the chloroform is distilled off. The residue is recrystallized from isopropanol/diisopropylether.
Reaction SMILES: [CH2:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH2:2][CH2:3][CH3:4].[Br:15][CH2:16][C:17](Br)=[O:18]>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[CH:11]=[CH:10][C:8]([NH:9][C:17](=[O:18])[CH2:16][Br:15])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Br)CBr
Reactant: CCCCc1ccc(N)c([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: CCCCc1ccc(NC(=O)CBr)c([N+](=O)[O-])c1
Yield: 86.8 %

Procedure:
A solution of 4-n-butyl-2-nitroaniline (29.1 g) in toluene (100 ml) was treated with bromoacetyl bromide (33.3 g). The mixture was boiled under reflux for 3/4 hour and the toluene evaporated off. The residual oil was poured into petroleum spirit (b.p. 60°-80° C; 400 ml). Crystals were deposited and these were removed by filtration to give N-(4-n-butyl-2-nitrophenyl)-2-bromoacetamide (41 g), m.p. 56°-57° C.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[C:23]1([CH3:35])[CH:28]=[CH:27][C:26]([S:29]([N:32]=[C:33]=[O:34])(=[O:31])=[O:30])=[CH:25][CH:24]=1>ClCCl>[CH3:35][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:32][C:33](=[O:34])[O:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([N:13]3[C:6]4=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]4[N:4]=[C:3]3[CH2:1][CH3:2])=[CH:19][CH:18]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCO)cc1
Solvent: ClCCl
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCOC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a solution of 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol (step 6 of Example 1, 300 mg, 1.0 mmol) in dichloromethane (10 mL) was added p-toluenesulfonyl isocyanate (237 mg, 1.2 mmol). The resulting mixture was stirred at room temperature overnight. After removal of solvent, the residual solids were recrystallized from ethyl acetate to afford 454 mg (92%) of the title compound as white solids: 1H-NMR (CDCl3) δ 7.93 (2H, d, J=8.4 Hz), 7.33 (2H, d, J=8.4 Hz), 7.22 (4H, s), 6.92 (1H, s), 4.87 (1H, br.s), 4.35 (2H, t, J=6.6 Hz), 2.96 (2H, t, J=6.6 Hz), 2.78 (2H, q, J=7.7 Hz), 2.66 (3H, s), 2.50 (3H, s), 2.43 (3H, s), 1.24 (3H, t, J=7.7 Hz).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:15])=[C:4]([C:8]([CH2:12][CH2:13][CH3:14])=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[Cl:16][C:17]([Cl:21])([Cl:20])[CH2:18]O.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:3]([CH3:15])=[C:4]([C:8]([CH2:12][CH2:13][CH3:14])=[C:9]([OH:11])[CH:10]=1)[C:5]([O:7][CH2:18][C:17]([Cl:21])([Cl:20])[Cl:16])=[O:6]
Reactant: CCCc1c(O)cc(O)c(C)c1C(=O)O
Reactant: OCC(Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCCc1c(O)cc(O)c(C)c1C(=O)OCC(Cl)(Cl)Cl
Yield: 87.4 %

Procedure:
A mixture of 5.0 g of 3,5-dihydroxy-2-methyl-6-propyl benzoic acid, 4.48 g of 2,2,2-trichloroethanol, and 0, 1 ml of 98% sulfuric acid in 40 ml of toluene was heated at reflux for 3 hours, water being constantly removed by a Dean-Stark trap. The mixture was cooled, diluted with 80 ml of ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated in vacuo. Chromatography of the residue on silica gel using acetone/hexane (1:6, v/v) as eluent afforded 7.1 g of 2,2,2-trichloroethyl 3,5-dihydroxy-2-methyl-6-propylbenzoate as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[NH:15][N:14]=1>>[F:23][C:12]([F:11])([F:22])[C:13]1[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[N:15]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=2)[N:14]=1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Reactant: N#CCc1ccc(Br)cc1
Product: N#CCc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from (4-bromophenyl)acetonitrile and 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similar procedure to that described for Example 7.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1)[CH3:2].[CH:28]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1[N:38]1[C:42](=[O:43])[CH2:41][S:40]/[C:39]/1=[N:44]\[C:45](=O)[O:46]C1C=CC([N+]([O-])=O)=CC=1)([CH3:30])[CH3:29]>>[CH2:1]([N:3]([CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:19][CH:18]=3)[N:13]=2)=[CH:10][CH:11]=1)[C:45](/[N:44]=[C:39]1\[S:40][CH2:41][C:42](=[O:43])[N:38]\1[C:32]1[CH:33]=[C:34]([CH3:37])[CH:35]=[CH:36][C:31]=1[CH:28]([CH3:29])[CH3:30])=[O:46])[CH3:2]
Reactant: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: CCNCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Product: CCN(CCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)C(=O)/N=C1\SCC(=O)N1c1cc(C)ccc1C(C)C

Procedure:
The title compound was prepared as described in Example 95 using N-ethyl-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)ethanamine (CB25) and (Z)-4-nitrophenyl (3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate (CA50), purified by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent and isolated as a red solid (0.075 g, 56%).
Reaction SMILES: Cl.COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@H](CCSC)N.COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@H](CCSC)N[P:43]([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:44].C(N(CC)CC)C.C(Cl)(Cl)(Cl)[Cl:74]>C(Cl)Cl>[CH2:45]([P:43]([Cl:74])([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:44])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@H](CCSC)NP(=O)(Cc1ccccc1)Cc1ccccc1
Reactant: ClC(Cl)(Cl)Cl
Agent: COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCSC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=P(Cl)(Cc1ccccc1)Cc1ccccc1
Temperature: -30 °C

Procedure:
Dibenzylphosphoryl-L-methionyl-L-prolyl-L-proline methylester L-methionyl-L-prolyl-L-proline methylester hydrochloride (2.0 g, 5.1 m mole) was dissolved in methylene chloride (20 ml), and triethyl amine (1.54 g, 15.2 m mole) was added thereto. The solution was cooled at -30° C., and to the cooled solution, a carbon tetrachloride solution (10 ml) of dibenzylphosphorylchloride produced from dibenzylhydrogen phosphite (1.41 g, 5.1 m mole) was added dropwise, and the mixture was further stirred overnight at room temperature. To the reaction solution, methylene chloride (100 ml) was added, and the mixture was washed with 1N hydrochloric acid, water, 5% sodium bicarbonate and water in this order. The mixture was dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a candy-like residue (3.23 g). The residue was purified by column chromatography (silica gel, developing solvent; ethyl acetate:methanol=20:1) to obtain dibenzylphosphoryl-L-methionyl-L-prolyl-L-proline methylester (1.87 g, yield: 59.6%). A single spot with Rf =0.1 was obtained by thin layer chromatography (developing solvent, ethyl acetate:methanol32 20:1, Colour forming method, spraying of 25% hydrobromic acid and 0.1 ninhydrin, and heating).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1Br.C([Li])CCC.[C:15]([O:18][CH2:19][C:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])=[O:21])(=[O:17])[CH3:16].Cl>C(OCC)C.CCCCCC>[C:24]([O:23][CH2:22][C:20]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([OH:21])[CH2:19][O:18][C:15](=[O:17])[CH3:16])(=[O:26])[CH3:25]
Reactant: Fc1ccc(Br)c(F)c1
Reactant: CC(=O)OCC(=O)COC(C)=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(=O)OCC(O)(COC(C)=O)c1ccc(F)cc1F
Temperature: -30 °C
Reaction time: 1 h
Yield: 27.8 %

Procedure:
Under an atmosphere of argon, 22.5 g of 2,4-difluorobromobenzene was dissolved in 200 ml of diethyl ether and to the resulting solution was added dropwise 73 ml of 1.63M n-hexane solution of n-butyllithium at -30° C. The resulting liquid was stirred for 1 hour and stored at -60° C. This liquid was carefully added dropwise using an injection cylinge to 150 ml of diethyl ether solution of 17.4 g of 1,3-diacetoxyacetone which was previously cooled to -30° C. After the resulting liquid was stirred at -60° C. for 2 hours, a temperature thereof was gradually raised to room temperature. Then, the reaction mixture was transferred to 100 ml of 1.2N aqueous solution of hydrochloric acid at 5° C. or below, and the organic layer was separated therefrom and the aqueous layer was extracted twice with 100 ml of ethyl acetate. The organic layers were combined and washed with saturated aqueous solution with sodium chloride, dried over anhydrous magnesium sulfate. The resulting organic layer was filtered and the solvent was removed under reduced pressure. Thus obtained concentrate was purified by column chromatography on silica gel (hexane: ethyl acetate=1:1) to give 8 g of the desired compound.
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:13]([OH:17])(=[O:16])[CH:14]=[CH2:15]>>[C:13]([O:17][CH:2]([O:12][CH2:11][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2)[CH:1]([CH3:10])[CH3:8])(=[O:16])[CH:14]=[CH2:15]
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: C=CC(=O)O
Product: C=CC(=O)OC(OCC12CC3CC(CC(C3)C1)C2)C(C)C
Yield: 78 %

Procedure:
By following the same procedures as in Examples 1-1-1 to 1-1-3 aside from using 1-adamantanemethanol instead of 2-adamantanol and acrylic acid instead of methacrylic acid, 1-[(1-adamantyl)methoxy]-2-methylpropyl acrylate was produced (four step yield 78%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Br)([O-])=O.Br[C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1>>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: Brc1ncccn1
Product: Nc1ccccc1-c1ncccn1

Procedure:
2-Nitrobromobenzene (2.02 g) and 2-bromopyrimidine (0.80 g) were coupled as in Example 83, and the product reduced as in Example 64 to give 2-(2-aminophenyl)pyrimidine. This was reacted with CMI under conditions described in the general procedure for CMI couplings to give N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-2-(2-pyrimidinyl)aniline.
Reaction SMILES: Cl.C[O:3]C(=O)[C@H](CC1C=CC=CC=1)N.COC(=O)[C@H](CC1C=CC=CC=1)N[C:20]([CH2:22][C:23]1[N:27]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[C:26]([CH2:36][CH2:37][CH2:38][CH3:39])=[N:25][CH:24]=1)=[O:21]>>[ClH:35].[CH2:36]([C:26]1[N:27]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[C:23]([CH2:22][C:20]([OH:21])=[O:3])=[CH:24][N:25]=1)[CH2:37][CH2:38][CH3:39]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CCCCc1ncc(CC(=O)N[C@@H](Cc2ccccc2)C(=O)OC)n1Cc1ccccc1Cl
Agent: Cl
Product: CCCCc1ncc(CC(=O)O)n1Cc1ccccc1Cl

Procedure:
The procedure of Example 12 (ii-iii) was followed using L-phenylalanine methyl ester hydrochloride in place of glycine methyl ester hydrochloride. From 5.59 g (16.3 mmol) of 2-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]acetic acid hydrochloride, there was obtained 6.88 g (90%) of the intermediate N-[{2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-yl}methylcarbonyl]-L-phenylalanine methyl ester; mp 88°-90° C. (from ethanol/water). Hydrolysis of this ester provided the title compound in a 79% yield; mp 168°-170° C.; [α]25 (c=1, methanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]#[N:11].[OH-].[Na+].Br[CH:15]([CH3:17])[CH3:16]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([CH:15]([CH3:17])[CH3:16])[C:10]#[N:11]
Reactant: CC(C)Br
Reactant: N#CCc1c(F)cccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: CC(C)C(C#N)c1c(F)cccc1F
Yield: 914.5 %

Procedure:
A mixture of 2,6-difluorophenylacetonitrile (10.0 g, 5.4 mmoles), 50% aqueous sodium hydroxide (4.6 g), sodium hydroxide (653 mg), tetra-n-butylammonium bromide (2.90 g and 2-bromopropane (8.85 g, 71.9 mmoles) was stirred while heating to 80°-85° over 1.0 hours, and then maintained at that temperature for 2.0 hours. After cooling, the mixture was partitioned between diethyl ether and water, the aqueous layer extracted with ether and the combined organic extracts washed with brine, dried over magnesium sulfate, filtered and the solvent evaporated. The residue was distilled to give a product compound (9.64 g) as a water-white liquid, b.p. 92°-94° (3 mm) which was characterized by NMR as follows: 1 1H NMR (CDCl)3 d 7.32 (m, 1H), 6.95 (m, 2H), 3.84 (d, 1H), 2.32 (m, 1H), 1.24 (d, 3H), 0.89 (d, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=[CH:3]1.OS(O)(=O)=O.[CH3:16]O>>[O:1]=[C:2]1[NH:7][C:6]([C:8]([O:10][CH3:16])=[O:9])=[CH:5][CH:4]=[CH:3]1
Reactant: CO
Reactant: O=C(O)c1cccc(=O)[nH]1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(=O)[nH]1

Procedure:
A mixture of commercially available 6-oxo-1,6-dihydropyridine-2-carboxylic acid (4.000 g; 28.75 mmol) and concentrated H2SO4 (3.5 ml) in anh. MeOH (65 ml) was refluxed, under nitrogen, for 22 h. MeOH was removed under reduced pressure, and the residue was basified by addition of a solution of 10% aq. NaHCO3. The mixture was then extracted with DCM (3×), and the mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording methyl 6-oxo-1,6-dihydropyridine-2-carboxylate as a beige solid. LC-MS (conditions D): tR=0.54 min.; no ionisation.