Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H+].[B-](F)(F)(F)F.[CH3:7][N:8]1[CH:12]([CH3:13])[CH2:11][CH2:10][C:9]1=[NH:14].[Cl:15][C:16]1[CH:17]=[C:18]([N:22]=[C:23]=[O:24])[CH:19]=[CH:20][CH:21]=1>C1C=CC=CC=1>[Cl:15][C:16]1[CH:17]=[C:18]([NH:22][C:23]([N:14]=[C:9]2[CH2:10][CH2:11][CH:12]([CH3:13])[N:8]2[CH3:7])=[O:24])[CH:19]=[CH:20][CH:21]=1
Reactant: CC1CCC(=N)N1C
Reactant: O=C=Nc1cccc(Cl)c1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: c1ccccc1
Product: CC1CCC(=NC(=O)Nc2cccc(Cl)c2)N1C
Reaction time: 2 h

Procedure:
The HBF4 salt of 1,5-dimethyl-2-iminopyrrolidine (6.75 g.; 0.0337 mole) is converted to free base in benzene in the usual manner. Then 5.16 g. (0.0337 mole) of m-chlorophenylisocyanate, dissolved in anhydrous benzene, is added. The reaction mixture is stirred for 2 hours and then the solvent is evaporated in vacuo leaving a solid residue of 1-m-chlorophenyl-3-(1,5-dimethyl-2-pyrrolidylidene)urea, m.p. = 129°-130° C. After recrystallization from ethyl acetate, the m.p. is still 129°-130° C.
Reaction SMILES: [C:1]1([CH3:10])[C:2]([C:7](O)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.C(Cl)(=O)C([Cl:14])=O>C1C=CC=CC=1.CN(C=O)C>[CH3:10][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([Cl:14])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccccc1C(=O)O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: Cc1ccccc1C(=O)Cl

Procedure:
Meanwhile, the 2-methylbenzoyl chloride acylating agent was prepared by suspending 4.750 g (42.2 mmol) of o-toluic acid in 100 ml benzene. To this solution was added 2.0 equiv. (7.37 ml) of oxalyl chloride, dropwise via a pressure-equalizing dropping funnel at 0° C. DMF (2-3 drops) was added to the reaction mixture catalytically and the ice bath was removed. The progress of the reaction was monitored via infrared spectroscopy. The solvent was removed by rotary vacuum evaporation and the residual oil was pumped down under high vacuum overnight.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([C@@H:10]1[CH2:14][C@@H:13]([C@@H:15]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:16][C:17]([CH3:29])([CH3:28])[CH2:18][CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:12][C:11]1=[O:38])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(NC(=O)[C@H](C(C)C)C[C@H](O)[C@@H](NC(OC(C)(C)C)=O)CC(C)(C)CC(N1C2C=CC=CC=2SC(C(NCC)=O)C1)=O)CCC>O1CCCC1>[CH3:1][NH:2][C:11](=[O:38])[C@H:10]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:14][C@H:13]([OH:12])[C@@H:15]([NH:30][C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[CH2:16][C:17]([CH3:29])([CH3:28])[CH2:18][CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(CCOCc1ccccc1)C[C@H](NC(=O)OC(C)(C)C)[C@@H]1C[C@@H](Cc2ccccc2)C(=O)O1
Reactant: CN
Agent: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](CC(C)(C)CC(=O)N1CC(C(=O)NCC)Sc2ccccc21)NC(=O)OC(C)(C)C)C(C)C
Solvent: C1CCOC1
Product: CNC(=O)[C@H](Cc1ccccc1)C[C@H](O)[C@H](CC(C)(C)CCOCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 30 h

Procedure:
8 ml of methylamine are passed into a solution of 476 mg of 3(R)-benzyl-5(S)-[5-benzyloxy-1(S)-tert-butoxycarbonylamino-3,3-dimethyl-pentyl]-2-oxotetrahydrofuran (Example 74d)) in 4 ml of tetrahydrofuran at 0° C. and a condensation reaction is carried out. The solution is stirred at room temperature for 30 h and concentrated and the residue is further reacted without chromatography: Rf (L)=0.48; FAB-MS:(M+H)+ =527.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11](=[O:35])[CH2:12][C@@H:13]([NH:15][C@@H:16]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:20]=1[F:34])[CH2:17][CH3:18])[CH3:14])(C)(C)C.Cl.C(OCC)C>C(OCC)(=O)C>[NH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:35])[CH2:12][C@H:13]([NH:15][C@@H:16]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:20]=1[F:34])[CH2:17][CH3:18])[CH3:14]
Reactant: CC[C@@H](N[C@@H](C)CC(=O)NCCNC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccccc2)c1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC[C@@H](N[C@H](C)CC(=O)NCCN)c1ccc(Cl)c(C(=O)c2ccccc2)c1F
Reaction time: 0.33 h

Procedure:
To (2-{(S)-3-[(R)-1-(3-benzoyl-4-chloro-2-fluoro-phenyl)-propylamino]-butyrylamino}-ethyl)-carbamic acid tert-butyl ester (13 mg, 0.025 mmol) residue was added hydrogen chloride in ethyl acetate (2N, 2 ml). The mixture was stood at room temperature for 20 minutes, diethyl ether was added to precipitate solids. These were isolated by filtration and dried in a vacuum oven to furnish the desired material as a white solid
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([C@H:19]([NH:28][C:29]([C:31]1[NH:32][C:33]2[C:38]([CH:39]=1)=[CH:37][C:36]([Cl:40])=[CH:35][CH:34]=2)=[O:30])[C:20](=[O:27])[N:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl.C(OCC)(=O)C>[CH2:12]([C@H:19]([NH:28][C:29]([C:31]1[NH:32][C:33]2[C:38]([CH:39]=1)=[CH:37][C:36]([Cl:40])=[CH:35][CH:34]=2)=[O:30])[C:20](=[O:27])[N:21]1[CH2:22][CH2:23][S:24](=[O:6])[CH2:25][CH2:26]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCSCC1)c1cc2cc(Cl)ccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCS(=O)CC1)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 1 h
Yield: 76 %

Procedure:
m-Chloroperoxybenzoic acid (80 mg of 50%, 0.23 mmol) was added at 25° C. to a solution of 5-chloro-1H-indole-2-carboxylic acid ((1S)-benzyl-2-oxo-2-thiomorpholin-4-yl-ethyl)-amide (100 mg, 0.23 mmol) in dichloromethane (2 mL). After 1 hour, the mixture diluted with ethyl acetate and washed three times with a 50/50 mixture of saturated aqueous sodium bicarbonate and 10% aqueous sodium thiosulfate, once with saturated aqueous sodium bicarbonate, brine, and dried. The crude product was purified by column chromatography on silica gel eluted with 0.5-8% ethanol in dichloromethane to give the title compound. Yield 76%; HPLC (60/40) 3.97 minutes (97%); mp 230-234° C.; TSPMS 444/446 (MH+, 100%);
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH3:12][C:13]1(O)[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14]1.C(=O)([O-])[O-:24].[K+].[K+].CS(C)=O>O>[CH3:12][CH:13]1[CH2:17][C:16]2[CH:18]=[C:19]([O:24][C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=3)[CH:20]=[CH:21][C:15]=2[O:14]1
Reactant: O=C([O-])[O-]
Reactant: CC1(O)Cc2ccccc2O1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC1Cc2cc(Oc3ccc(C(F)(F)F)cn3)ccc2O1
Reaction time: 8 h
Yield: 73.4 %

Procedure:
A stirred mixture of 2.18 grams (0.012 mole) of 2-chloro-5-trifluoromethyl pyridine, 1.80 grams (0.012 mole) of 2,3-dihydro-2-methyl benzofuranol, 2.07 grams (0.015 mole) of potassium carbonate and 80 milliliters of dimethylsulfoxide was heated, under anhydrous conditions, at a temperature in the range of 65°-72° C. for about 72 hours. After heating was discontinued, the mixture was stirred overnight, then poured into 800 milliliters of water and extracted with 2×250 milliliter portions of diethylether. The combined organic extracts were washed with 2×300 milliliter portions of water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo affording 2.60 grams of brown oil. The crude product was purified by column chromatography and eluted with 5:95 v/v ethyl acetate:hexane affording 1.64 grams of white crystals confirmed by spectroscopic analysis as the desired product.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][N:12]([CH3:31])[CH2:13][C:14]1[C:15]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:16][N:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:18]=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C.[CH3:39][CH:40]([CH3:45])[CH2:41][C:42](Cl)=[O:43]>ClCCl>[CH3:1][N:2]([CH2:10][CH2:11][N:12]([CH3:31])[CH2:13][C:14]1[C:15]([CH:25]2[CH2:30][CH2:29][N:28]([C:42](=[O:43])[CH2:41][CH:40]([CH3:45])[CH3:39])[CH2:27][CH2:26]2)=[N:16][N:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:18]=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: CN(CCN(C)C(=O)OC(C)(C)C)Cc1cn(C2CCCCO2)nc1C1CCNCC1
Reactant: CC(C)CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC(=O)N1CCC(c2nn(C3CCCCO3)cc2CN(C)CCN(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.6 %

Procedure:
To a solution of (R/S) tert-butyl methyl(2-(methyl((3-(piperidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methyl)amino)ethyl)carbamate (200 mg, 0.46 mmol, 1.00 equiv) and triethylamine (1.14 g, 11.26 mmol, 24.52 equiv) in dichloromethane (15 mL) was added 3-methylbutanoyl chloride (67 mg, 0.56 mmol, 1.21 equiv). The resulting solution was stirred at room temperature for 2 h. The reaction was then quenched by the addition of 2 mL of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give 250 mg of crude (R/S) tert-butyl methyl(2-(methyl((3-(1-(3-methylbutanoyl)piperidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methyl)amino)ethyl)carbamate as a yellow solid. LCMS (method D, ESI): RT=1.22 min, m/z=520.0 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][Mg]Br.[CH:20](=[O:24])[CH2:21][CH2:22][CH3:23]>>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][CH:20]([OH:24])[CH2:21][CH2:22][CH3:23]
Reactant: Br[Mg]C#CCCCCCCCCOC1CCCCO1
Reactant: CCCC=O
Product: CCCC(O)C#CCCCCCCCCOC1CCCCO1

Procedure:
For example, according to the above-cited British patent, one starts from 10-(2-tetrahydropyranyloxy-)dec-1-ynyl magnesium bromide, which is reacted with butyraldehyde to obtain 14-(-2-tetrahydropyranyloxy-)-tetradec-5-yn-4-ol, which is then dehydrated to 2-(-tetradec-11-en-9-ynyloxy-)-tetrahydropyranyl(cis, trans mixture); the latter, after acetylation and reduction, provides a cis-cis and cis-trans mixture of 9,11-tetradecadienyl-acetate. To obtain the desired cis-trans compound, a difficult and expensive separation of the isomers is required.
Reaction SMILES: Cl.[F:2][C:3]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:19])[CH:6]=[C:7]([O:15][CH:16](C)C)[C:8]2=[O:14]>CO>[F:2][C:3]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:19])[CH:6]=[C:7]([O:15][CH3:16])[C:8]2=[O:14]
Reactant: CC(C)OC1=CC(=O)c2c(F)cc(F)cc2C1=O
Agent: Cl
Solvent: CO
Product: COC1=CC(=O)c2c(F)cc(F)cc2C1=O
Temperature: 25 °C
Yield: 83.6 %

Procedure:
A solution of 0.48 g (13.2 mM) of anhydrous hydrogen chloride in 15 mL of methanol was treated with 0.175 g (0.694 mM) of 5,7-difluoro-2-isopropoxy-1,4-naphthoquinone. The mixture was heated to solvent reflux temperature for 0.33 hours, cooled to room temperature and concentrated in vacuo to give 0.13 g of product. 1H NMR (dmso-d6): δ=7.8 (m, 1H), 7.68 (dd, 1H, JH-Fortho =7.5Hz),6.31 (s, 1H), 3.86(s, 3H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11].[CH:20]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[N:29]=[N:30][C:31](Cl)=[CH:32][CH:33]=2)=[O:27])[CH2:22][CH2:21]1>>[CH:20]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[N:29]=[N:30][C:31]([N:15]3[CH2:16][CH2:17][CH:12]([C:10](=[O:11])[NH:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:2]([F:1])([F:18])[F:19])[CH2:13][CH2:14]3)=[CH:32][CH:33]=2)=[O:27])[CH2:22][CH2:21]1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Reactant: O=C(Nc1ccccc1C(F)(F)F)C1CCNCC1
Product: O=C(NCCC1CC1)c1ccc(N2CCC(C(=O)Nc3ccccc3C(F)(F)F)CC2)nn1
Yield: 89 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use piperidine-4-carboxylic acid (2-trifluoromethylphenyl)amide in place of piperidin-4-yl-(2-trifluoromethylphenyl)amine to react with 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder in 89% yield. 1H NMR (300 MHz, CDCl3) δ 8.06 (d, J=7.9 Hz, 1H), 7.96 (d, J=9.4 Hz, 2H), 7.58-7.48 (m, 3H), 7.24-7.18 (m, 1H), 6.97 (d, J=9.5 Hz, 1H), 4.53-4.49 (m, 2H), 3.54-3.47 (m, 2H), 3.18-3.00 (m, 2H), 2.66-2.57 (m, 1H), 2.07-1.99 (m, 2H), 1.93-1.79 (m, 2H), 1.49-1.43 (m, 2H), 0.73-0.67 (m, 1H), 0.45-0.39 (m, 2H), 0.07-0.02 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 172.4, 163.2, 159.9, 144.6, 134.9, 132.9, 126.9, 126.2, 126.1, 125.2, 124.9, 122.2, 112.2, 44.4, 43.8, 39.6, 34.5, 27.9, 43.8, 8.6, 4.2. MS (ES+) m/z 462 (M+1).
Reaction SMILES: [Cl:1][C:2]([F:8])(I)[C:3]([F:6])([F:5])[Cl:4].[CH2:9]([Si](C)(C)C)[CH:10]=[CH2:11].N(C(C)(C)C#N)=NC(C)(C)C#N>>[Cl:1][C:2]([F:8])([C:3]([Cl:4])([F:6])[F:5])[CH2:11][CH:10]=[CH2:9]
Reactant: FC(F)(Cl)C(F)(Cl)I
Reactant: C=CC[Si](C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: C=CCC(F)(Cl)C(F)(F)Cl
Temperature: 80 °C

Procedure:
A mixture of 279 mg (1.0 mmol) of 1,2-dichloro-1-iodotrifluoroethane, 114 mg (1.0 mmol) of allyltrimethylsilane and 10 mg (0.06 mmol) of azobisisobutyronitrile (AIBN) was heated in a sealed glass tube at 80° C. for 3 hours. After cooling, 10 mg (0.06 mmol) of AIBN was added to the mixture, followed by heating in a sealed tube at 80° C. for 3 hours to obtain 4,5-dichloro-4,5,5-trifluoro-1-pentene (Compound 39) in a yield of 40%.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]([C:27]#[N:28])([CH2:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][C:12]=1[N+:24]([O-:26])=[O:25])[CH2:6][CH2:7][CH:8]=[CH2:9])C.[Li+].[OH-].Cl>CO.O>[C:27]([C:5]([CH2:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][C:12]=1[N+:24]([O-:26])=[O:25])([CH2:6][CH2:7][CH:8]=[CH2:9])[C:4]([OH:29])=[O:3])#[N:28]
Reactant: C=CCCC(C#N)(Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-])C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCCC(C#N)(Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-])C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-cyano-2-(2-nitro-5-phenoxy-benzyl)-hex-5-enoic acid ethyl ester (2.84 g, 7.20 mmol) was dissolved in methanol (42 mL). In a separate flask, LiOH (1.5 g, 36.0 mmol) was dissolved in water (21 mL). The LiOH solution was added to the methanolic solution containing 2-cyano-2-(2-nitro-5-phenoxy-benzyl)-hex-5-enoic acid ethyl ester and the reaction was allowed to stir at room temperature for 2 hours. Next, 12N HCl (3 mL) was added to the reaction mixture followed by removal of the methanol under reduced pressure. The reaction mixture was poured into a separatory funnel, ethyl acetate was added and the organic layer was washed 2 times with 1N HCl and one time with saturated brine solution. The organic layer was separated, dried with sodium sulfate, filtered and the solvent was removed to yield a residue.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:12]=[O:13].N1C=CN=C1.[C:19]1(=[O:24])[CH2:23][CH2:22][CH:21]=[CH:20]1>CO.O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:12]([OH:13])[C:20]1[C:19](=[O:24])[CH2:23][CH2:22][CH:21]=1
Reactant: O=C1C=CCC1
Reactant: COC(=O)c1ccc(C=O)c(Cl)n1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(C(O)C2=CCCC2=O)c(Cl)n1
Yield: 90 %

Procedure:
The clear solution of Methyl 6-chloro-5-formyl-2-pyridincarboxylate (10 mmol, 1.99 g) and imidazole (10 mmol) in 50 ml. of MeOH was slowly charged with 50 ml. of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclopenten-1-one (10.2 mmol., 0.88 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 90% yield (2.53 g).
Reaction SMILES: Cl[C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[NH:14]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)C(=O)[C:15]1=O.F[C:26]1C=C2C(=CC=1)NC(=O)C2=O>>[CH3:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:19]=1[C:10](=[O:12])[N:11]1[C:5]3[C:6](=[CH:13][CH:2]=[CH:3][CH:4]=3)[C:7](=[O:9])[C:15]1=[N:14]2
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: O=C1Nc2ccccc2C1=O
Product: Cc1cccc2nc3n(c(=O)c12)-c1ccccc1C3=O
Yield: 31 %

Procedure:
Using the procedure in Example 12 and substituting 6-methylisatoic anhydride for 5-chloroisatoic anhydride and isatin for 5-fluoroisatin gave the title compound in 31% yield: mp 304°-307° C.; 1H NMR (300 MHz, CDCl3) δ 8.65 (d, 1H), 7.9 (t, 1H), 7.9 (t, 1H), 7.88 (t, 1H), 7.78 (t, 1H), 7.68 (t, 1H), 7.42 (dt, 1H), 7.41 (t, 1H), 3.0 (s, 3H); MS (M+H)+ 263.1, (M+CH4CN)+ 304.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH2:19][CH2:20][OH:21])[CH:5]=[CH:4][N:3]=1.[CH3:22][C:23]1[O:27][N:26]=[C:25]([C:28]([OH:32])([C:30]#[CH:31])[CH3:29])[CH:24]=1.C(N(CC)CC)C>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:31]#[C:30][C:28]([C:25]4[CH:24]=[C:23]([CH3:22])[O:27][N:26]=4)([OH:32])[CH3:29])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH2:19][CH2:20][OH:21])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(-n2c(OCCO)nc3ccc(Br)cc32)n1
Reactant: C#CC(C)(O)c1cc(C)on1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cc(C(C)(O)C#Cc2ccc3nc(OCCO)n(-c4ccnc(N)n4)c3c2)no1
Yield: 30 %

Procedure:
A solution of 2-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]ethan-1-ol (80 mg, 0.19 mmol), 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (80 mg, 0.53 mmol), bis(triphenylphosphine)palladium(II) dichloride (20 mg, 0.03 mmol) and triethylamine (0.7 mL) in dimethylsulfoxide (3 mL) under nitrogen in a 10-mL sealed tube was irradiated with microwave radiation for 30 min at 70° C. The reaction mixture was concentrated and the crude product (80 mg) was purified by Flash-Preparative HPLC to give 24 mg (28%) of 4-[1-(2-aminopyrimidin-4-yl)-2-(2-hydroxyethoxy)-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol as a yellow solid. 1H NMR (400 MHz, DMSO-d6) delta 8.39 (d, J=5.6 Hz, 1H), 8.19 (s, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.06 (s, 3H), 6.43 (s, 1H), 6.37 (s, 1H), 5.03 (t, J=5.2 Hz, 1H), 4.62 (s, 2H), 3.82 (d, J=4.0 Hz, 2H), 2.41 (s, 3H), 1.81 (s, 3H); LC-MS: m/z=+455 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[OH-].[K+].[C:12](#[N:15])[CH:13]=[CH2:14]>C(O)(C)(C)C.CCOCC>[C:12]([CH2:13][CH2:14][O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)#[N:15]
Reactant: C=CC#N
Reactant: COc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: COc1ccc(OCCC#N)cc1
Temperature: 75 °C
Reaction time: 5 h

Procedure:
4-Methoxyphenol (248 g), KOH (5.6 g) and acrylonitrile (397 ml) were dissolved in 1 liter of t-butanol and heated with stirring at 75° C. for 5 hours. The mixture was then cooled to room temperature and stripped in vacuo to solid residue, which was repulped in ether and insolubles recovered by filtration. The latter were taken up in 2 liters of ethyl acetate, washed in sequence with 1 liter each of H2O, saturated NaHCO3 and saturated NaCl, dried over MgSO4 and restripped to yield purified title product, 199.4 g, m.p. 62°-64° C.
Reaction SMILES: [CH:1]([NH2:3])=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:5].Br[CH2:19][C:20]([C:22]1[CH:49]=[CH:48][C:25]([O:26][CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:44]=[CH:43][C:34]3[CH2:35][CH2:36][CH:37]([C:39]([O:41][CH3:42])=[O:40])[O:38][C:33]=3[C:32]=2[CH2:45][CH2:46][CH3:47])=[C:24]([CH2:50][CH:51]=[CH2:52])[C:23]=1[O:53][CH3:54])=O.C(=O)([O-])[O-].[Mg+2]>O1CCOCC1.C(OCC)C>[CH3:54][O:53][C:23]1[C:24]([CH2:50][CH:51]=[CH2:52])=[C:25]([CH:48]=[CH:49][C:22]=1[C:20]1[N:3]=[CH:1][S:5][CH:19]=1)[O:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:44]=[CH:43][C:34]2[CH2:35][CH2:36][CH:37]([C:39]([O:41][CH3:42])=[O:40])[O:38][C:33]=2[C:32]=1[CH2:45][CH2:46][CH3:47]
Reactant: C=CCc1c(OCCCOc2ccc3c(c2CCC)OC(C(=O)OC)CC3)ccc(C(=O)CBr)c1OC
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: NC=O
Agent: O=C([O-])[O-]
Agent: [Mg+2]
Solvent: C1COCCO1
Solvent: CCOCC
Product: C=CCc1c(OCCCOc2ccc3c(c2CCC)OC(C(=O)OC)CC3)ccc(-c2cscn2)c1OC
Yield: 51 %

Procedure:
Formamide (0.15 mL, 4.3 mmol) and phosphorus pentasulfide (0.33 g, 0.73 mmol) in 15 mL dioxane were refluxed for 2 hr., and 4 mL of this solution was added to 59 mg of the compound of Example 15 in 2 mL dioxane with 100 mg magnesium carbonate. The reaction mixture was refluxed for 1.75 hr. and poured into ethyl ether/1N sodium hydroxide. The ether layer was washed with brine, dried over sodium sulfate, and concentrated. Flash chromatography on silica gel using 8:1 hexane/ethyl acetate as eluant gave the product (28 mg, 52 μmmol, 51% yield). High resolution mass spectrum, m/e 537.2195 (calculated for C30H35NO6S, 537.2185).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[N:14]=[CH:13][C:12]([N:15]2[CH2:19][CH:18]([C:20]([O:22]C(C)(C)C)=[O:21])[N:17]([CH3:27])[C:16]2=[O:28])=[CH:11][CH:10]=1>ClCCl>[OH:5][C:3]([C:2]([F:7])([F:6])[F:1])=[O:4].[F:8][C:9]1[N:14]=[CH:13][C:12]([N:15]2[CH2:19][CH:18]([C:20]([OH:22])=[O:21])[N:17]([CH3:27])[C:16]2=[O:28])=[CH:11][CH:10]=1
Reactant: CN1C(=O)N(c2ccc(F)nc2)CC1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)N(c2ccc(F)nc2)CC1C(=O)O
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (400 mg, 1.998 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 5-bromo-2-fluoropyridine (352 mg, 1.998 mmol) in 1,4-dioxane (20 ml) was added trans-N,N-dimethylcyclohexane-1,2-diamine (0.062 ml, 0.400 mmol), potassium phosphate (1272 mg, 5.99 mmol) and copper(I) iodide (38.0 mg, 0.200 mmol) and the reaction mixture was heated at reflux under argon overnight. The reaction mixture was allowed to cool and the solvent was evaporated. The residue was partitioned between dichloromethane and water. The organic layer was separated and washed with water (˜50 ml) containing 0.880 ammonia solution (˜5 ml), then brine and passed through a hydrophobic frit and the organic layer was reduced under vacuum. The residue was purified by SP4 automated silica gel chromatography eluting with 10-80% ethyl acetate in isohexane to give 1,1-dimethylethyl 1-(6-fluoro-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (422 mg, 68.7% yield). LC/MS [M+H]+=296. (ii) Trifluoroacetic acid (2 ml) was added to a solution of 1,1-dimethylethyl 1-(6-fluoro-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (420 mg, 1.422 mmol) in dichloromethane (5 ml) and the mixture was stirred at room temperature for 36 hours. The reaction mixture was reduced under vacuum and the residue was azeotroped with toluene and dried under heated vacuum to give 1-(6-fluoro-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylic acid TFA salt (assume ˜1.4 mmol) which was used in the next step. LC/MS [M+H]+=240.
Reaction SMILES: C([Li:5])C[CH2:3][CH3:4].[CH:6]([N-:9][CH:10]([CH3:12])[CH3:11])([CH3:8])[CH3:7].[CH3:13][C:14](C)([O-:16])C.[K+].C(=O)CCCCC>CCCCCC.CCOCC>[CH:6]([N-:9][CH:10]([CH3:12])[CH3:11])([CH3:8])[CH3:7].[Li+:5].[CH3:13][CH2:14][O:16][CH2:3][CH3:4]
Reactant: CC(C)(C)[O-]
Reactant: [Li]CCCC
Agent: CC(C)[N-]C(C)C
Agent: CCCCCC=O
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOCC
Product: [Li+]
Reaction time: 0.5 h

Procedure:
67 ml (0.11 M) of a 1.6 N solution of butyllithium in hexane were treated at 0° with 11.1 g (0.11 M) of diisopropylamide, and the reaction mixture was kept at 0° under stirring during 30 min. To this reaction mixture there was then added 1 g of potassium ter-butoxide followed by 24.5 g (0.05 M) of 4-bromo-pent-2trans-en-1-yl triphenylphosphonium bromide and the mixture obtained was kept under stirring during 18 h at 23°, whereupon a solution of 5 g (0.05 M) of hexanal in 35 ml of anhydrous ether at 8°-15° was added thereto.