Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[CH:2](Br)=[CH2:3].[CH3:5][C:6]([CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:7][CH2:8][CH2:9][C:10](=[O:13])[CH2:11][CH3:12].S(=O)(=O)(O)O>O1CCCC1>[CH2:11]([C:10]([OH:13])([CH2:9][CH2:8][CH:7]=[C:6]([CH3:5])[CH2:14][CH:15]([CH3:16])[CH3:17])[CH:2]=[CH2:3])[CH3:12]
Reactant: CCC(=O)CCC=C(C)CC(C)C
Reactant: C=CBr
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CC(O)(CC)CCC=C(C)CC(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a Grignard solution, prepared from 12.5 g. of magnesium and 57.8 g. of vinyl bromide in 130 ml. of tetrahydrofuran, is slowly added dropwise at 0°-5° C. a solution of 40.11 g. of 7,9-dimethyl-6-decen-3-one in 90 ml. of tetrahydrofuran. The mixture is left to stir for 2 hours at room temperature, then poured on to 300 ml. of ice-water, acidified with dilute sulphuric acid and extracted three times with ether. The extracts are washed with 10% by weight aqueous sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulphate and evaporated. By distillation there is obtained pure 3-ethyl-7,9-dimethyl-1,6-decadien-3-ol; nD24 = 1.4631; boiling point - 71° C./0.65 mm Hg.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]2[C:9](N3CCOCC3)([C:10](=[O:15])[NH:11][CH2:12][CH2:13]2)[N:8]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:7]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][NH:11][C:10](=[O:15])[C:9]=2[N:8]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=NN(c2ccc(OC)cc2)C2(N3CCOCC3)C(=O)NCCC12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCNC2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Method B. A solution of 1-(4-methoxy-phenyl)-7a-morpholin-4-yl-7-oxo-3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[3,4-c]pyridin-3-carboxylic acid ethyl ester (51, 402 mg, 1.0 mmol) in methylene chloride (CH2Cl2, 4 mL) was treated with trifluoroacetic acid (TFA, 1.0 mL) at 25° C., and the resulting reaction mixture was stirred at 25° C. for an additional 30 min. When HPLC and TLC showed the reaction was complete, the solvents were removed in vacuo. The residue was directly purified by flash column chromatography (SiO2, 5–30% EtOAc/hexane gradient elution) to afford the desired elimination product (50, 299 mg, 315 mg theoretical, 95%) as a pale-yellow oil, which solidified upon standing at room temperature in vacuo. This material was found to be identical with the product obtained from method A in every comparable aspect.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:21]=[C:22]([NH:26][C:27]([NH2:29])=[NH:28])[CH:23]=[CH:24][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:28]=[C:27]([NH:26][C:22]4[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=4)[N:29]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Reactant: N=C(N)Nc1cccc(Cl)c1
Product: O=C1Cc2cnc(Nc3cccc(Cl)c3)nc2-c2ccc(Cl)cc2N1

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and 1-(3-chlorophenyl)guanidine were converted to I-13 (26%): HRMS Calcd. for C18H12Cl2N4O: 371.0466, Found 371.0489.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[O:22][N:21]=[C:20]([CH3:23])[CH:19]=2)=[CH:8][CH:7]=1)=O)C.O.[NH2:27][NH2:28]>>[NH:27]([C:4]([C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[O:22][N:21]=[C:20]([CH3:23])[CH:19]=2)=[CH:8][CH:7]=1)=[O:3])[NH2:28]
Reactant: CCOC(=O)c1ccc(OCCCCCCCc2cc(C)no2)cc1
Reactant: NN
Solvent: O
Product: Cc1cc(CCCCCCCOc2ccc(C(=O)NN)cc2)on1
Temperature: 0 °C

Procedure:
A mixture of 3.0 g (0.086 mole) of 5-[7-(4-ethoxycarbonylphenoxy)heptyl]-3-methylisoxazole (Example 22) and 10 ml of hydrazine hydrate was heated at reflux for six hours. The reaction mixture was cooled to 0° C. whereupon the solid product separated. The latter was collected, washed and dried in vacuo to give 2.6 g of 5-[7-(4-hydrazinocarbonylphenoxy)heptyl]-3-methylisoxazole, m.p. 121°-122° C., MIC vs. rhinovirus Type 2 in vitro=0.64 μg/ml.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:21].[Na+].Cl>CS(C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([OH:21])=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2O)CC1
Temperature: 25 °C

Procedure:
To a solution of 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (1.85 g, 6.19 mmol, prepared in Example 5a) in DMSO (6 mL) was added a 2.5M aqueous solution of NaOH (30 mL). The resulting suspension was heated to reflux for 12 h before allowing to cool to room temperature. The suspension was then diluted with water (20 mL), acidified to pH=5 with 6M HCl, and extracted with EtOAc. The organic phase was concentrated in vacuo and the resulting solids were purified by flash chromatography (silica gel, 5.5:1 EtOAc:Hexanes). Product 3′-Hydroxy-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester was obtained as white solids (538 mg, 31.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:20]([S:28][CH2:29][CH2:30][C:31](=[O:35])[N:32]([CH3:34])[CH3:33])[S:21][CH2:22][CH2:23][C:24]([O:26]C)=[O:25])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[Li+].[OH-]>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:20]([S:28][CH2:29][CH2:30][C:31](=[O:35])[N:32]([CH3:34])[CH3:33])[S:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCSC(SCCC(=O)N(C)C)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CN(C)C(=O)CCSC(SCCC(=O)O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1

Procedure:
To a solution of (+)-methyl 5-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-8-dimethylcarbamyl-4,6-dithiaoctanoate (step 4) (640 mg, 1.21 mmol.) in peroxide free 1,2-dimethoxyethane (15 mL) and water (1.5 mL) was added LiOH (1M, 1.8 mL, 1.8 mmol.). The solution was stirred for 3 hrs at room temperature Water was added and the mixture was washed with EtOAc. The aqueous layer was acidified with 1N HCl, extracted with EtOAC, the extracts were washed with brine (2×), dried over Na2SO4, filtered and evaporated to dryness. The oily residue was coevaporated 3 or 4 times with EtOAc and finally was allowed to crystallize in this solvent overnight at 0° C. Filtration afforded the title compound.
Reaction SMILES: O[CH2:2][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[N:4]1.S(Cl)([Cl:14])=O>>[Cl:14][CH2:2][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[N:4]1
Reactant: OCn1nnc2ccccc21
Reactant: O=S(Cl)Cl
Product: ClCn1nnc2ccccc21

Procedure:
To 1-hydroxymethylbenzotriazole (59.6 g), prepared above, kept at ice-bath temp., 175 ml of thionyl chloride was added dropwise as long as a vigorous reaction continued. The reminder was added more rapidly. The mixture was then stirred and refluxed for 90 minutes. Excess thionyl chloride was removed by distillation, the last traces were removed by heating for a short time with 200 ml of methanol. After cooling and collecting on a funnel, the product weighted 45 g. (67%); melting point: 136° C; (lit. 136°-138° C.).
Reaction SMILES: [OH:1][CH2:2][C-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:13].[C:14]([O-])(=[O:18])[C:15]([CH3:17])=[CH2:16].[Cl-]>C(Cl)Cl>[C:14]([O:1][CH2:2][C-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1)(=[O:18])[C:15]([CH3:17])=[CH2:16].[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:13]
Reactant: C=C(C)C(=O)[O-]
Reactant: OC[c-]1cccc1
Agent: [Fe+2]
Agent: [Cl-]
Agent: c1cc[cH-]c1
Solvent: ClCCl
Product: C=C(C)C(=O)OC[c-]1cccc1
Yield: 73.4 %

Procedure:
To 1.00 g (4.63 mmol) of hydroxymethylferrocene of formula (30) below dissolved in 20 ml of methylene chloride was added dropwise 0.73 g (7.00 mmol) of chloride methacrylate in 5 ml of methylene chloride. The reaction solution was washed with an aqueous solution of NaCl, dilute hydrochloric acid and an aqueous solution of dilute sodium hydroxide and dried over sodium sulfate, followed by distillation of the solvent thereby obtaining 0.97 g (3.4 mmol) of ferrocenylmethyl methacrylate of formula (31):
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=1[CH3:12].C(N(CC)C(C)C)(C)C.[NH2:26][C@@H:27]([CH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[CH2:28][N:29]1[C:37](=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]1=[O:39].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:26][C@H:27]([CH2:28][N:29]2[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]2=[O:39])[CH2:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)=[O:15])[S:10][C:11]=1[CH3:12]
Reactant: N[C@@H](CC1CCCCC1)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1sc(C(=O)N[C@@H](CC2CCCCC2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (159 mg, 0.62 mmol), N,N-diisopropylethylamine (0.54 ml, 3.10 mmol) and 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (200 mg, 0.62 mmol) [Prepared according to the procedure of Preparation 6, except substituting 3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-alanine (5 g, 18.4 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (347 mg, 0.74 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 45% EtOAc in hexanes) yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide (231 mg, 0.44 mmol, 71% yield) as a clear oil: LCMS (ES) m/e 525, 527 (M, M+2)+.
Reaction SMILES: S([C:5]1[N:6]=[C:7]2[N:11]([C:12]=1C(OCC)=O)[CH:10]=[CH:9][S:8]2)(C)(=O)=O.[CH:18]([SH:21])([CH3:20])[CH3:19]>>[CH:18]([S:21][C:5]1[N:6]=[C:7]2[N:11]([CH:12]=1)[CH:10]=[CH:9][S:8]2)([CH3:20])[CH3:19]
Reactant: CC(C)S
Reactant: CCOC(=O)c1c(S(C)(=O)=O)nc2sccn12
Product: CC(C)Sc1cn2ccsc2n1

Procedure:
In a manner similar to the procedure in Reference Example 1, the oily title compound was prepared from ethyl 6-mesylimidazo[2,1-b]thiazole-5-carboxlate and isopropyl mercaptan. ##STR10## NMR(CDCl3) δ: 1.30(s, 6H), 3.15-3.65(m, 1H), 6.85(d, 1H), 7.38(d, 1H), 7.62(s, 1H)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[CH3:24][O:25][C:26]1[N:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:29]5[CH:30]=[N:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=5)=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: COc1ccc(B(O)O)cn1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Product: COc1ccc(-c2ccc3c(c2)-c2nc(-c4ncnn4C(C)C)sc2CCO3)cn1
Yield: 17 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 6-methoxypyridin-3-ylboronic acid were reacted to give 305 (0.027 g, 17%). 1H NMR (400 MHz, DMSO) δ 8.62 (d, J=2.3, 1H), 8.48 (d, J=2.0, 1H), 8.11 (s, 1H), 7.99 (dd, J=8.6, 2.5, 1H), 7.60 (dd, J=8.4, 2.3, 1H), 7.18 (d, J=8.4, 1H), 6.96 (d, J=8.6, 1H), 5.77 (dt, J=13.3, 6.8, 1H), 4.42 (t, J=4.9, 2H), 3.91 (s, 3H), 3.48 (t, J=4.8, 2H), 1.57 (d, J=6.6, 6H). MS (ESI(+)): m/z 420.1 (M+H)
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[C:21]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[C:21]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:22]=[CH:23][C:24]([CH2:27][NH:28][C:15]([CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=2)=[O:17])=[CH:25][CH:26]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: NCc1ccc(-c2ccccc2)cc1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)NCc2ccc(-c3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and C-biphenyl-4-yl-methylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C25H25NO5 [M+H]+: 420.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[N:19]=[C:18]2[CH:20]=[CH:21][N:22]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:17]2=[CH:16][CH:15]=1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34].Cl>C1COCC1>[Cl:13][C:14]1[N:19]=[C:18]2[CH:20]=[C:21]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:22]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:17]2=[CH:16][CH:15]=1
Reactant: CCOC(=O)Cl
Reactant: O=S(=O)(c1ccccc1)n1ccc2nc(Cl)ccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2nc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.6 M n-Butyllithium in hexanes (9.6 mL, 15 mmol) was added to a solution of N,N-diisopropylamine (2.3 mL, 16 mmol) in THF (43 mL) at −78° C. Upon complete addition, the reaction was warmed to 0° C. for 30 minutes and then was re-cooled to −78° C. A solution of 5-chloro-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine (3.00 g, 10.2 mmol, from Example 2, Step 1) in THF (8 mL) was added dropwise. After stirring for one hour at −78° C., ethyl chloroformate (1.4 mL, 14 mmol, Alfa Aesar) was added and the reaction was stirred at −78° C. for 2 hours, after which time it was allowed to warm to room temperature. The reaction was poured into dilute HCl and the product was extracted with three portions of ethyl acetate. The combined extracts were dried over sodium sulfate, decanted, and the solvent removed in vacuo. Flash chromatography, eluting with a gradient from 0-30% EtOAc in hexanes afforded product as a yellow solid (2.15 g, 57%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[O:8][C:9]([CH2:22][CH2:23][C:24](OC)=[O:25])=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:11]=2)[CH:4]=[CH:5][N:6]=1.O.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+].O.O.[Na+].[K+].C(C(C(C([O-])=O)O)O)([O-])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]([C:7]2[O:8][C:9]([CH2:22][CH2:23][CH2:24][OH:25])=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)[N:11]=2)[CH:4]=[CH:5][N:6]=1
Reactant: COC(=O)CCc1oc(-n2ccnc2C)nc1-c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nccn1-c1nc(-c2ccc(C(F)(F)F)cc2)c(CCCO)o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
Methyl 2-(2-methyl-1-imidazolyl)-4-(4-trifluoromethylphenyl)-5-oxazolepropionate (1.00 g) was dissolved in toluene (15 ml). To the obtained solution was added dropwise a mixture of a 70% toluene solution (1.20 g) of sodium dihydrobis(2-methoxyethoxy)aluminate, and toluene (5 ml) at 0° C., which was stirred at 0° C. for 30 minutes. To the reaction mixture was carefully added a 10% aqueous solution of (+)-sodium potassium tartrate sesquihydrate (50 ml), which was stirred at room temperature for 1 hour. The precipitated crystals were filtered, washed in sequence with a 10% aqueous solution of (+)-sodium potassium tartrate sesquihydrate, pure water, and isopropyl ether, and air-dried to give crystals of 2-(2-methyl-1-imidazolyl)-4-(4-trifluoromethylphenyl)-5-oxazolepropanol (0.75 g, 81%). Recrystallization from ethyl acetate-isopropyl ether gave pale yellow prisms. Melting point 127-129° C.
Reaction SMILES: C(N1C2C([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([CH2:21][C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=5)[NH:24][CH:23]=4)[CH2:17][CH2:16]3)=CC=CC=2NC1=O)(C)=C.[C:33]([N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38](CCCl)[C:37]1=[O:48])([CH3:35])=[CH2:34].FC1C=C2C(=CC=1)NC=C2CC1CCNCC1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1>[C:33]([N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]([CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([CH2:21][C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=4)[NH:24][CH:23]=3)[CH2:19][CH2:20]2)[C:37]1=[O:48])([CH3:35])=[CH2:34]
Reactant: C=C(C)n1c(=O)n(CCCl)c2ccccc21
Reactant: C=C(C)n1c(=O)[nH]c2cccc(CCN3CCC(Cc4c[nH]c5ccc(F)cc45)CC3)c21
Agent: Fc1ccc2[nH]cc(CC3CCNCC3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=C(C)n1c(=O)n(CCN2CCC(Cc3c[nH]c4ccc(F)cc34)CC2)c2ccccc21
Temperature: 20 °C
Reaction time: 10 h

Procedure:
3-Isopropenyl-{2-[4-((5-fluoro-3-indolyl)methyl)piperidino]ethyl}-2H-benzimidazolin-2-one may be prepared in the following manner: the procedure is as in Example 25, starting with 3-isopropenyl-1-(2-chloroethyl)-2H-benzimidazolin-2-one (2.4 g), 4-[(5-fluoro-3-indolyl)methyl]piperidine (2.3 g) and sodium bicarbonate (0.8 g) in a mixture of dimethylformamide (40 cc) and tetrahydrofuran (20 cc). The mixture is heated to boiling for 10 hours and then cooled to a temperature in the region of 20° C. After purification by flash chromatography on a silica column under a stream of nitrogen and moderate pressure (0.5-1.5 bar) with dichloromethane and ethyl acetate as eluents, 3-isopropenyl-1-{2-[4-((5-fluoro-3-indolyl)methyl)piperidino]ethyl}-2H-benzimidazolin-2-one (3 g), m.p. 132° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH3:11])=[C:6]([NH2:12])[CH:5]=1.[CH:14]([N:17](CC)C(C)C)(C)[CH3:15].BrCC#N.O>C1COCC1>[C:14]([CH2:15][NH:12][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([F:10])[C:7]=1[CH3:11])[C:3]([O:2][CH3:1])=[O:13])#[N:17]
Reactant: COC(=O)c1cc(N)c(C)c(F)c1
Reactant: CCN(C(C)C)C(C)C
Agent: N#CCBr
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)c(C)c(NCC#N)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 3-amino-5-fluoro-4-methyl-benzoic acid methyl ester (Example 252e, 34.7 g) in THF (300 mL) at room temperature was added N,N-diisopropylethylamine (61.2 mL) followed by bromoacetonitrile (24.41 mL). The mixture was heated at reflux for 16 h, further bromoacetonitrile (4.8 mL) and N,N-diisopropylethylamine (12.5 mL) were added and heating was continued for 6 h. The reaction was cooled to room temperature and concentrated. 1N HCl (600 mL) and dichloromethane (800 mL) were added. This gave some solid precipitate which did not dissolve. Water (300 mL) was added to help identify layers. The lower organic layer containing solid and a bit of water was separated and this organic fraction was washed with 1M HCl/brine (400 mL of 1:1 mixture) before being dried (MgSO4). A second drying (Na2SO4) was needed. After the drying agent was filtered off (washed through with 400 ml dichloromethane) the filtrate was concentrated (˜60 g). This was azeotroped with toluene (400 mL) and final solvent removal gave subtitle compound (39.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1.CO>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:31]([NH:30][C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)=[O:32])=[CH:18][CH:17]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)c2cc1OC
Yield: 36 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in chloroform (3 ml), and p-fluorophenyl isocyanate (23 μl) was then added to the solution. The mixture was heated under reflux overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 26 mg (yield 36%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C1(C)C=CC=CC=1>[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH3:16])[C:5]([C:6]#[N:7])=[CH:4][N:3]=2)[CH2:20][CH2:19]1
Reactant: CN1CCNCC1
Reactant: Cc1ccccc1-c1cc(Cl)ncc1C#N
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1cc(N2CCN(C)CC2)ncc1C#N
Temperature: 112 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
500 mg (2.1865 mmol) 6-chloro-4-o-tolyl-nicotinonitrile were dissolved in 10.0 ml toluene and heated to 112° C. At this temperature 2.19 g (21.865 mmol) 1-methylpiperazine were added, and the reaction mixture was stirred for further 60 minutes. The mixture was cooled down to 50° C. and concentrated under reduced pressure. 5 ml toluene were added to the obtained residue at a temperature of 20-25° C., followed by 900 mg sulfuric acid (95%). The organic phase was washed with 5 ml water. Evaporation in vacuo gave 520 mg of 6-(4-methyl-piperazin-1-yl)-4-o-tolyl-nicotinonitrile as a beige foam.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5](P(OC)(OC)=O)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].C1CCN2C(=NCCC2)CC1.[F:34][C:35]([F:40])([F:39])[CH2:36][CH:37]=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:4])[C:5]([NH:6][C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])=[CH:37][CH2:36][C:35]([F:40])([F:39])[F:34]
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Reactant: O=CCC(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)C(=CCC(F)(F)F)NC(=O)OCc1ccccc1
Temperature: -30 °C

Procedure:
N-(Benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester and DBU were dissolved in dry methylene chloride (50 mL) and the reaction mixture was chilled to −30° C. 3,3,3-Trifluoropropanal (1 eq) was added dropwise to the chilled and stirred solution and the reaction was allowed to stir for an additional hour at −30° C., and then overnight at ambient temperature. Methylene chloride (ca. 100 mL) was added and the organic phase was washed with 1N HCl (ca. 100 mL), then saturated brine (ca. 100 mL). The organic phase was dried over MgSO4, filtered, and concentrated by rotary evaporation. This crude product was purified by silica gel chromatography with a gradient of 10-30% ethyl acetate in hexanes to yield 2-benzyloxycarbonylamino-5,5,5-trifluoro-pent-2-enoic acid methyl ester as a white, crystalline solid.