Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH:30]([C:32]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:33]=1[C:34]([OH:36])=[O:35])=O>C(OCC)C.C(O)(C)(C)C.O>[Cl:41][C:38]1[CH:39]=[CH:40][C:32]([CH:30]=[CH:2][O:3][CH3:4])=[C:33]([CH:37]=1)[C:34]([OH:36])=[O:35]
Reactant: O=Cc1ccc(Cl)cc1C(=O)O
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: COC=Cc1ccc(Cl)cc1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
To a cooled (0° C.) slurry of methoxymethyltriphenylphosphonium chloride (39 g) in a mixture of diethyl ether (200 ml) and tert-butanol (50 ml) was added potassium tert-butoxide (12.8 g) portion wise. The resulting mixture was stirred at 0° C. for 1 hour, then a solution of 2-formyl-5-chlorobenzoic acid (prepared as described in J. Org. Chem. 61, 3402 (1996)) (10 g) in diethyl ether (50 ml) was added dropwise over 15 minutes. The resulting mixture was stirred for 1 hour at 0° C., then warmed to ambient and stirred for an additional 90 minutes. The mixture was diluted with water (200 ml) and the organic phase removed. The aqueous phase was acidified to pH 1 with 1M HCl and extracted with ethyl acetate (3×50 ml). The combined extracts were washed with brine, dried (magnesium sulfate), filtered and concentrated. The residue was purified by flash chromatography (50% ethyl acetate/hexane) to afford the sub-title compound as a yellow solid (9.13 g, 80%). 1H NMR (400 MHz, CDCl3) δ 3.70-3.81 (3H, s), 6.20(0.3H, d, cis alkene), 6.30 (0.3H, d, cis alkene), 6.80(0.7H, d, trans alkene), 7.01 (0.7H, d, trans alkene), 7.30-8.15 (3H, m) ppm.
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][CH2:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11]O)[N:10]=1.Cl.[NH2:14][CH2:15][CH2:16][SH:17].[BrH:18]>>[BrH:18].[BrH:18].[BrH:18].[CH3:3][NH:4][CH2:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][S:17][CH2:16][CH2:15][NH2:14])[N:10]=1
Reactant: CNCc1nc(CO)cs1
Reactant: NCCS
Agent: Br
Agent: Cl
Product: CNCc1nc(CSCCN)cs1

Procedure:
Following the above procedure, 10.1 millimoles of 2-(methylaminomethyl)-4-thiazolemethanol dihydrochloride, 1.15 g. of cysteamine hydrochloride and 15 ml. of 48% aqueous hydrobromic acid were stirred at about 100° C. for about 7.5 hours. Water and hydrobromic acid were removed on a rotary evaporator and the resulting residue comprising 2-(2-methylaminomethyl-4-thiazolylmethylthio)ethylamine trihydrobromide formed in the above reaction was dissolved in water and the water removed by evaporation. The residue was again taken up in water and the water removed by evaporation. The residue was then dissolved in a small volume of water and a solution of 5.5 g. of potassium carbonate in 15 ml. of water was added. The resulting alkaline solution was evaporated to dryness. The resulting residue, comprising the free base of 2-(2-methylaminomethyl-4-thiazolylmethylthio)ethylamine, was slurried with ethanol and the ethanol separated and removed by evaporation. The residue was twice slurried with isopropanol. The residue was next extracted with boiling isopropanol several times and the combined isopropanol extracts combined and filtered. Removal of the isopropanol yielded a yellow oil. The yellow oil was dissolved in chloroform and the chloroform solution filtered. Chloroform was evaporated from the filtrate to yield 1.59 g. of a yellow oil comprising 2-(2-methyl-aminomethyl-4-thiazolylmethylthio)ethylamine. The compound had the following physical characteristics:
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:11]3[N:16]4[CH:17]=[N:18][CH:19]=[C:15]4[CH:14]=[CH:13][C:12]=3[C:20](O)=[O:21])=[C:6]([F:23])[CH:5]=2)[CH2:3][CH2:2]1.[CH:24]([O:26][CH2:27][CH2:28][O:29][NH2:30])=[CH2:25].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:24]([O:26][CH2:27][CH2:28][O:29][NH:30][C:20]([C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:17]=[N:18][CH:19]=2)[C:11]=1[NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:5][C:6]=1[F:23])=[O:21])=[CH2:25]
Reactant: C=COCCON
Reactant: O=C(O)c1ccc2cncn2c1Nc1ccc(C2CC2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=COCCONC(=O)c1ccc2cncn2c1Nc1ccc(C2CC2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.8 %

Procedure:
To a mixture of 5-(4-cyclopropyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (400 mg, 1.29 mmol), O-(2-vinyloxyethyl)-hydroxylamine (265 mg, 2.57 mmol) and HOBt (225 mg, 1.67 mmol) in DMF (5 mL) was added EDCI hydrochloride (320 mg, 1.67 mmol), and DIPEA (0.290 mL, 1.67 mmol) before the reaction mixture was stirred at room temperature for 18 hours. The products were partitioned between ethyl acetate and saturated aqueous NaHCO3, the organic layer separated and washed with brine then dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0-35% ethyl acetate in cylcohexane) to give the title compound (270 mg, 53%). LCMS (Method B): RT 2.79 [M+H]+397.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[N:14]=[CH:13][N:12]([C:15]3[S:16][C:17]([C:27]([NH2:29])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=4)[N:19]=3)[C:11]=2[CH:30]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>CN(C)C=O>[Cl:26][C:22]1[CH:21]=[C:20]([C:18]2[N:19]=[C:15]([N:12]3[C:11]4[CH:30]=[C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:43]5[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]5)[CH:8]=[CH:9][C:10]=4[N:14]=[CH:13]3)[S:16][C:17]=2[C:27]([NH2:29])=[O:28])[CH:25]=[CH:24][CH:23]=1
Reactant: NC(=O)c1sc(-n2cnc3ccc(OCCCCCl)cc32)nc1-c1cccc(Cl)c1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(CCCCOc2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(N)=O)s4)c3c2)CC1
Reaction time: 3 h
Yield: 68.6 %

Procedure:
A mixture of 0.023 g (0.05 mmole) of 2-[6-(4-chloro-butoxy)-benzoimidazol-1-yl]-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (I.37a), 0.5 mL of dimethylformamide, 0.035 g (0.25 mmole) of potassium carbonate, 0.001 g of potassium iodide and 0.017 mL (0.15 mmole) of 1-methyl-piperazine was stirred at 100 degrees for 3 hours. The mixture was concentrated under reduced pressure, and diluted with 20 mL of water. The precipitate was collected by filtration and the solid triturated with diethyl ether to give 0.018 g of 4-(3-chloro-phenyl)-2-{6-[4-(4-methyl-piperazin-1-yl)-butoxy]-benzoimidazol-1-yl}-thiazole-5-carboxylic acid amide (I.37) as a white powder. MH+/Z=525
Reaction SMILES: BrC1C=C2C(=CC=1)N(C1C=CC(F)=CC=1)C=C(C(OCC)=O)C2=O.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:41]3[C:36](=[CH:37][C:38]([CH:42]=[O:43])=[CH:39][CH:40]=3)[C:35](=[O:44])[C:34]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:33]2)=[CH:28][CH:27]=1.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:25][C:26]1[CH:27]=[CH:28][C:29]([N:32]2[C:41]3[C:36](=[CH:37][C:38]([CH:42]=[O:43])=[CH:39][CH:40]=3)[C:35](=[O:44])[C:34]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:33]2)=[CH:30][CH:31]=1.[F:25][C:26]1[CH:27]=[CH:28][C:29]([N:32]2[C:41]3[C:36](=[CH:37][C:38]([CH2:42][N:50]4[CH2:55][CH2:54][O:53][CH2:52][CH2:51]4)=[CH:39][CH:40]=3)[C:35](=[O:44])[C:34]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:33]2)=[CH:30][CH:31]=1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(Br)cc2c1=O
Agent: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(C=O)cc2c1=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(CN3CCOCC3)cc2c1=O
Reaction time: 2 h
Yield: 194.9 %

Procedure:
Ethyl 1-(4-fluorophenyl)-6-formyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (H) was prepared from compound D via a method analogous to that described in Example 3. After stirring for two hours, a solution of compound H (10 mg, 0.030 mmol), morpholine (3.1 μL, 0.035 mmol), and acetic acid (4.2 μL, 0.074 mmol) in dichloromethane (1 mL) was treated with sodium triacetoxyborohydride (9.4 mg, 0.044 mmol). After stirring 16 hours, the reaction was concentrated to dryness to give 12 mg (99%) of the title compound that was used without further purification. ES-MS [M+1]+: 411.3.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:15](I)=[CH:14][C:3]=1/[CH:4]=[CH:5]/[C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13].[CH2:19]([OH:22])[CH:20]=[CH2:21]>>[CH3:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH3:12])[C:6]=1/[CH:5]=[CH:4]/[C:3]1[CH:14]=[C:15]([CH2:21][CH2:20][CH:19]=[O:22])[CH:16]=[CH:17][C:2]=1[F:1]
Reactant: C=CCO
Reactant: Cc1cccc(C)c1/C=C/c1cc(I)ccc1F
Product: Cc1cccc(C)c1/C=C/c1cc(CCC=O)ccc1F

Procedure:
(E)-2-(2-Fluoro-5-iodostyryl)-1,3-dimethylbenzene was coupled with allyl alcohol according to the method in Example 42. Purification by flash chromatography (40% CH2Cl2-hexanes) gave (E)-3-(3-(2,6-dimethylstyryl)-4-fluorophenyl)propanal as an oil. Yield (0.115 g, 52%): 1H NMR (400 MHz, DMSO-d6) δ 9.72 (t, J=1.2 Hz, 1H), 7.64 (dd, J=7.2, 2.4 Hz, 1H), 7.27 (d, J=16.8 Hz, 1H), 7.09-7.19 (m, 2H), 7.06 (s, 3H), 6.67 (d, J=16.8 Hz, 1H), 2.78-2.89 (m, 4H), 2.31 (s, 6H).
Reaction SMILES: Br[C:2]1[C:3](=[O:28])[NH:4][C:5](=[O:27])[N:6]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][C@H:15]3[C@:13]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)([CH2:14]3)[CH2:12]2)[N:7]=1.[F:29][C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1>COCCOC.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.O.COCCOC>[F:29][C:30]1[C:35]([C:2]2[C:3](=[O:28])[NH:4][C:5](=[O:27])[N:6]([CH2:8][CH2:9][CH2:10][N:11]3[CH2:16][C@H:15]4[C@:13]([C:17]5[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=5)([CH2:14]4)[CH2:12]3)[N:7]=2)=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)nc1Br
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)nc1-c1cccnc1F
Temperature: 90 °C
Reaction time: 3 h
Yield: 45.4 %

Procedure:
6-bromo-2-(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-1,2,4-triazine-3,5(2H,4H)-dione (P8, 100 mg, 0.218 mmol) was suspended in a degassed mixture of 1,2-Dimethoxyethane (DME) (3.629 ml)/Water (0.726 ml). Then (2-fluoro-3-pyridinyl)boronic acid (92 mg, 0.653 mmol), sodium carbonate (69.2 mg, 0.653 mmol), Tetrakis (50.3 mg, 0.044 mmol) and 2-biphenylyl(dicyclohexyl)phosphane (15.26 mg, 0.044 mmol) were added and the mixture was heated to 90° C. and stirred at that temperature for 3 hours. The mixture was cooled down to room temperature, diluted with 1.3 mL of a mixture of DME/Water (5:1) then 2-biphenylyl(dicyclohexyl)phosphane (15.26 mg, 0.044 mmol), (2-fluoro-3-pyridinyl)boronic acid (92 mg, 0.653 mmol), Tetrakis (50.3 mg, 0.044 mmol) and sodium carbonate (69.2 mg, 0.653 mmol) were added again. The reaction mixture was heated to 90° C. and left stirring at that temperature for 40 minutes. The reaction mixture was cooled down to room temperature and evaporated under reduced pressure. The residue was partitioned between AcOEt and water and extracted. Organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. Crude product was purified by Preparative HPLC affording 6-(2-fluoro-3-pyridinyl)-2-(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-1,2,4-triazine-3,5(2H,4H)-dione (E9, 47 mg, 0.099 mmol, 45.4% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]([CH2:15][CH2:16][N:17]([CH3:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:28]([NH:30][C:31](=[N:39][CH2:40][CH2:41][S:42][CH2:43][C:44]1[N:45]=[C:46]([NH:49][C:50]([NH2:52])=[NH:51])[S:47][CH:48]=1)OC1C=CC=CC=1)#[N:29]>>[C:28]([NH:30][C:31]([NH:39][CH2:40][CH2:41][S:42][CH2:43][C:44]1[N:45]=[C:46]([NH:49][C:50]([NH2:52])=[NH:51])[S:47][CH:48]=1)=[N:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:16][CH2:15][N:8]([CH2:7][C:6]1[CH:26]=[CH:27][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH3:25])#[N:29]
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Reactant: COc1ccc(CN(CCN(C)CCCCCCN)c2ccccn2)cc1
Product: COc1ccc(CN(CCN(C)CCCCCCN=C(NC#N)NCCSCc2csc(NC(=N)N)n2)c2ccccn2)cc1

Procedure:
Preparation is effected analogously to Example 1, using 0.57 g (1.5 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,6-hexanediamine and the equimolar amount of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil that crystallises from ether at -20° C.; MS (+FAB method): m/z (rel. int. [%])=652 ([M+H]+, 12), 121 (100); IR (KBr): 2162 cm-1 (C≡N); m.p.: 52° C. (ether).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:18](O)=[O:19].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:18]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc(C(=O)O)cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of tert-butyl piperazine-1-carboxylate (1.81 g, 9.7 mmol), 3-fluoro-4-methylbenzoic acid (1.50 g, 9.7 mmol), and triethylamine (6.8 mL, 49 mmol) in acetnitrile (30 mL), HBTU (4.06 g, 10.7 mmol) was added. After stirring at rt for 1 h, the mixture was poured onto water (150 mL), and the mixture was extracted with EtOAc (twice). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/EtOAc (4:1-2:1) to give 3.14 g (quant) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[CH:9][C:8]=1[N+:18]([O-:20])=[O:19])[CH3:2].S(=O)(=O)(O)O.[CH3:28]O>>[CH2:21]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([O:17][CH3:28])=[O:16])=[CH:9][C:8]=1[N+:18]([O-:20])=[O:19])[CH3:22]
Reactant: CCN(CC)CCSc1ccc(C=CC(=O)O)cc1[N+](=O)[O-]
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCN(CC)CCSc1ccc(/C=C/C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
3-(4-(2-(Diethylamino)ethylthio)-3-nitrophenyl)acrylic acid (1.74 g, 5.4 mmol) was suspended in methanol (25 mL) under stirring. To this solution, concentrated sulfuric acid (1.0 mL) was added. The resulted solution was heated to reflux for 19 hours. Cooling it to room temperature and the solvent was removed under reduced pressure. 100 ml water was added to dissolve the resulted residue. Cooling it with an ice-bath and adjusting the pH value to 9.0 using ammonia under stirring. (E)-methyl 3-(4-(2-(diethylamino)ethylthio)-3-nitrophenyl)acrylate was obtained as yellow solid. TLC: Rf=0.75 (DCM:MeOH=9:1); MP: 57.4° C.-59.1° C. HPLC: 92.0%; tR=9.74 min (LC/PDA: Diamonsil C18 5μ 150×4.6 mm, flow rate: 1.0 mL/min, grade: 10-100% B, 20 minutes: mobile phase A: water; mobile phase B: acetonitrile; UV254); IR (cm−1): 2967, 2926, 1720, 1639, 1604, 918. 1HNMR (400 MHz, CDCl3) δ: 8.36 (1H, s), 7.70 (1H, d, J=1.6 Hz), 7.69 (1H, d, J=16 Hz), 7.50 (1H, d, J=8 Hz), 7.27 (1H, s), 6.51 (1H, d, J=16 Hz), 3.83 (3H, s), 3.12 (2H, t, J=8 Hz); 2.83 (2H, t, J=8 Hz); 2.64 (4H, q, J=7.2 Hz), 1.07 (6H, t, J=7.2 Hz). MS (m/z): 339 (MH)+.
Reaction SMILES: COC1C=CC([N:9]2[C@H:12]([CH:13]=[C:14]([CH3:16])[CH3:15])[C@H:11]([O:17][C:18](=[O:20])[CH3:19])[C:10]2=[O:21])=CC=1>C(#N)C.O>[C:18]([O:17][C@H:11]1[C@@H:12]([CH:13]=[C:14]([CH3:16])[CH3:15])[NH:9][C:10]1=[O:21])(=[O:20])[CH3:19]
Reactant: COc1ccc(N2C(=O)[C@@H](OC(C)=O)[C@H]2C=C(C)C)cc1
Solvent: CC#N
Solvent: O
Product: CC(=O)O[C@@H]1C(=O)N[C@@H]1C=C(C)C
Temperature: 2.5 °C
Reaction time: 0.17 h
Yield: 91.3 %

Procedure:
A solution of the (±)-cis-N-(4-methoxyphenyl)-3-acetyloxy-4-isobutenylazetidin-2-one (4.88 g, 16.2 mmol) was dissolved in acetonitrile (50 mL) and cooled to 0-5° C. in an ice bath. To this was added a cold solution of ceric ammonium nitrate (26.6 g, 48.6 mmol, 50 mL) in one portion. The deep red reaction was allowed to stir for 10 min and during that time the color gradually lightened to orange. The cold solution was transferred to a separatory funnel, diluted with water, and extracted with ethyl acetate. The organic fraction was washed with several portions of 10% aqueous sodium sulfite, followed by saturated aqueous sodium bicarbonate. The organic fraction was dried (MgSO4) and concentrated to give the desired product (2.71 g, 91%) as a yellow-orange solid that was used directly in the next step; 1H NMR (300 MHz, CDCl3): δ 6.11 (bs, 1H), 5.73 (dd, 1H, J=2.2, 4.7 Hz), 5.12-5.08 (m, 1H), 4.63 (dd, 1H, 4.7, 9.1 Hz), 2.09 (s, 3H), 1.75 (s, 3H), 1.67 (s, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.Cl.CN(C)CCCN=C=NCC.[O:22]=[C:23]([CH3:33])[CH2:24][NH:25][C:26]([CH3:32])([CH3:31])[C:27]([O:29][CH3:30])=[O:28]>ClCCl>[O:22]=[C:23]([CH3:33])[CH2:24][N:25]([C:7](=[O:9])[CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[C:26]([CH3:32])([CH3:31])[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)C(C)(C)NCC(C)=O
Reactant: O=C(O)Cc1ccsc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C(C)(C)N(CC(C)=O)C(=O)Cc1ccsc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.8 %

Procedure:
To a solution of thiophen-3-acetic acid (8.7 g) in dichloromethane (70 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11.7 g), and the mixture was stirred for 10 minutes at room temperature. To the solution was added dropwise a solution of methyl 2-(2-oxopropylamino)isobutyrate (10.6 g) in dichloromethane (10 mL) at room temperature, and the mixture was then stirred for 24 hours at room temperature. After distilling off the solvent, water was added, and then the mixture was extracted with ethyl acetate. The extract was washed with a saturated sodium hydrogencarbonate aqueous solution and dried over anhydrous sodium sulfate. After distilling off ethyl acetate, 7.61 g of methyl 2-[N-(2-oxopropyl)thiophene-3-yl-acetylamino]isobutyrate was obtained.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][C:4](=O)[CH3:5].Cl.[Cl:9][C:10]1[CH:23]=[C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:21]=[C:20]([Cl:30])[C:11]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][NH2:19].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[Cl:9][C:10]1[CH:23]=[C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:21]=[C:20]([Cl:30])[C:11]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][N:19]=[C:4]([CH2:3][CH:2]([CH3:7])[CH3:1])[CH3:5]
Reactant: CC(=O)CC(C)C
Reactant: NOCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: CC(CC(C)C)=NOCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a mixture of 0.10 g of 4-methyl-2-pentanone and 5 ml of pyridine as added 0.40 g of O-(5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyl)hydroxylamine hydrochloride. After stirring at room temperature for 1 hour, the reaction mixture was poured into 5% aqueous citric acid solution, and extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.42 g (yield, 95.4%) of 4-methyl-2-pentanone O-(5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)-pentyl)oxime, nD24.5 1.5230.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](Br)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH:11]1(B(O)O)[CH2:13][CH2:12]1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2].O.C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:11]2[CH2:13][CH2:12]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(N)ccc1Br
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1cc(N)ccc1C1CC1
Temperature: 110 °C

Procedure:
5-amino-2-bromobenzonitrile (5.0 g, 25.4 mmol), cyclopropylboronic acid (4.36 g, 50.8 mmol), Cs2CO3 (49.62 g, 152.3 mmol), and tricyclohexylphosphine (2.85 g, 10.2 mmol) were weighed out and added to a large reaction tube with magnetic stir bar. Toluene (120 mL) and water (40 mL) were added, and the reaction was subjected to vigorous sub-surface nitrogen sparging. Pd(OAc)2 (1.14 g, 5.1 mmol) was weighed out and added, the tube was sealed under nitrogen, and the reaction was heated overnight at 110° C. This was then filtered with water and ethyl acetate washings. The combined washings were treated with saturated aqueous NaHCO3 and the layers were separated. The aqueous was extracted 4 more times with ethyl acetate, and the combined organic layer was washed twice with brine and dried over sodium sulfate. After filtration, concentration, and drying on the high vacuum, 7.65 g was obtained of 5-amino-2-cyclopropylbenzonitrile containing tricyclohexylphosphine derived byproducts. This was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[C:5]([NH2:14])[NH:4][N:3]=1.[CH3:15][C:16]1[CH:17]=[C:18]([C:22](=O)[CH2:23][C:24](OCC)=[O:25])[CH:19]=[CH:20][CH:21]=1>N1C=CC=CC=1>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[C:2]([CH3:1])=[N:3][N:4]3[C:22]([C:18]4[CH:19]=[CH:20][CH:21]=[C:16]([CH3:15])[CH:17]=4)=[CH:23][C:24](=[O:25])[NH:14][C:5]=23)=[CH:8][CH:9]=1
Reactant: Cc1ccc(-c2c(C)n[nH]c2N)cc1
Reactant: CCOC(=O)CC(=O)c1cccc(C)c1
Solvent: c1ccncc1
Product: Cc1ccc(-c2c(C)nn3c(-c4cccc(C)c4)cc(=O)[nH]c23)cc1
Temperature: 25 °C

Procedure:
3-Methyl-4-(4-methylphenyl)-1H-pyrazol-5-amine and ethyl 3-(3-methylphenyl)-3-oxopropanoate are stirred overnight in a pyridine (10 mL) solvent at 95° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and purified by column chromatography to yield the target compound.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([NH2:12])[C:6]=2[CH:5]=[CH:4][N:3]=1.[F:13][C:14]([F:27])([F:26])[O:15][C:16]1[CH:25]=[CH:24][C:19]([CH2:20][N:21]=[C:22]=[O:23])=[CH:18][CH:17]=1>>[CH3:1][C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:22]([NH:21][CH2:20][C:19]3[CH:18]=[CH:17][C:16]([O:15][C:14]([F:13])([F:27])[F:26])=[CH:25][CH:24]=3)=[O:23])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C=NCc1ccc(OC(F)(F)F)cc1
Reactant: Cc1nccc2c(N)cccc12
Product: Cc1nccc2c(NC(=O)NCc3ccc(OC(F)(F)F)cc3)cccc12

Procedure:
Prepared from 1-methylisoquinolin-5-amine (Description 68) and [4-(trifluoromethoxy)benzyl]isocyanate (Description 59) according to the procedure of Description 61. m/z (ES+) 376 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14](OC)=[O:15].C([O-])(=O)C>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][OH:15]
Reactant: COC(=O)Cc1nc(-c2ccccc2)oc1C
Agent: CC(=O)[O-]
Product: Cc1oc(-c2ccccc2)nc1CCO

Procedure:
The title compound is prepared using essentially the same procedure used in Example 11 except using methyl 2-(5-methyl-2-phenyloxazol-4-yl)acetate (example 32) in place of t-butyl (3-([2-methoxyethoxy]-methoxy)-phenoxy])-acetate. MS (ESI) 204 (M+H)+.