Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)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>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([F:28])[CH:34]=2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(Br)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O)CC1
Reactant: OB(O)c1cccc(F)c1
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: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1sc(-c2cccc(F)c2)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O)CC1

Procedure:
A degassed solution of 5-Bromo-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (70 mg, 0.15 mmol) and 3-fluorophenyl boronic acid (32 mg, 0.23 mmol) in a mixture of DME (2.0 mL) and 2M aqueous Na2CO3 (1.0 mL) was treated with Pd(PPh3)4 (17.6 mg, 0.015 mmol). The reaction was heated at reflux for 18 h. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried and concentrated to a residue that was purified by preparative chromatography using EtOAc:hexanes as eluent to provide 5-(3-Fluoro-phenyl)-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester as an oil contaminated with triphenylphosphine oxide that could not be removed (61.7 mg). 1H NMR (CDCl3, 400 MHz): 7.65 (dd, 3H), 7.53 (t, 2H), 7.43 (m, 5H), 7.32 (m, 1H), 7.1 (m, 1H), 7.02 (s, 1H), 4.56 (m, 1H), 3.82 (s, 3H), 3.40 (m, 1H), 2.14 (br s, 1H), 2.05-1.88 (m, 4H), 1.78 (m, 1H), 1.68-1.54 (m, 5H), 1.51-1.26 (m, 4H), 0.98 (m, 1H), 0.75 (d, 3H), 0.72-0.54 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15](SC)[N:14]=3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[NH2:34][C:35]1[CH:36]=[C:37]([OH:42])[CH:38]=[CH:39][C:40]=1[F:41].C([O-])([O-])=O.[K+].[K+]>ClCCl.CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([O:42][C:37]4[CH:38]=[CH:39][C:40]([F:41])=[C:35]([NH2:34])[CH:36]=4)[N:14]=3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2cc(-c3ccnc(SC)n3)cn2)cc1
Reactant: Nc1cc(O)ccc1F
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COc1ccc(Cn2cc(-c3ccnc(Oc4ccc(F)c(N)c4)n3)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To a solution of 4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine (200 mg, 0.64 mmol) in dichloromethane was added m-CPBA (220 mg, 1.28 mmol). The reaction was stirred for 2 hour at RT. Water was added, the organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organics were washed with brine and concentrated in vacuo. The residue was combined with 3-amino-4-fluorophenol (165 mg, 1.28 mmol) and K2CO3 (176 mg, 1.28 mmol) in DMF (5 mL) and the resultant mixture was heated at 90° C. overnight. After filtration and concentration, the residue was purified by silica gel column chromatography to give 5-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluorobenzenamine (210 mg, 84% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.44, (d, J=5.4 Hz, 1H), 8.10 (s, 1H), 7.42 (d, J=5.4 Hz, 1H), 7.25 (d, J=8.4 Hz, 2H), 6.98 (t, J=9.6 Hz, 1H), 6.91 (d, J=8.4 Hz, 2H), 6.52 (dd, J=2.7, 8.7 Hz, 1H), 6.28 (m, 1H), 5.30 (br s, 2H), 5.26 (s, 2H), 3.72 (s, 3H); MS (ESI) m/z: 392.2 (M+H+).
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH2:20][CH2:19]2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CO.C(OCC)C>C(Cl)Cl>[NH:14]1[CH2:15][CH:16]([N:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:29])[C:25]([F:26])([F:27])[F:28])[CH2:22][CH2:23]2)[CH2:17]1
Reactant: O=C(N1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1)C(F)(F)F
Agent: CC(Cl)OC(=O)Cl
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: O=C(N1CCN(C2CNC2)CC1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-[4-(1-benzhydryl-azetidin-3-yl)-piperazin-1-yl]-2,2,2-trifluoro-ethanone (2.11 g, 5.23 mmol) in CH2Cl2 (60 mL) was added 1-chloroethyl chloroformate (2.0 mL, 18.35 mmol) at 0° C. under N2. The resulting mixture was stirred at 0° C. for 90 min and then methanol (4 mL) was added. The resulting mixture was refluxed for 1 h. Upon cooling, diethyl ether (50 mL) was added to the mixture. The resulting solid was collected by filtration and dried to yield the title compound, which was used in the next reaction without further purification. MS m/z (M+H+) 238.1.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](Cl)=[O:13])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]2[C:17]=1[CH:18]=[C:19]([CH3:34])[N:20]2[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[Cl-].[Cl-].C([Al+2])C>C(Cl)Cl>[Cl:15][C:16]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]2[C:17]=1[C:18]([C:12]([C:5]1[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:13])=[C:19]([CH3:34])[N:20]2[CH2:26][CH2:27][N:28]1[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1
Reactant: Cc1ccc(C(=O)Cl)c2ccccc12
Reactant: Cc1cc2c(Cl)cc(Cl)cc2n1CCN1CCOCC1
Agent: CC[Al+2]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2c(C)n(CCN3CCOCC3)c3cc(Cl)cc(Cl)c23)c2ccccc12
Temperature: 25 °C

Procedure:
To a solution of 4-methyl-1-naphthoyl chloride (29 mg, 0.14 mmol) and 4-(2-(4,6-dichloro-2-methyl-1H-indol-1-yl)ethyl)morpholine (44 mg, 0.14 mmol) in 1 mL CH2Cl2 at −70° C. was added dropwise ethyl aluminum dichloride (0.17 mL, 0.31 mmol, 1.8 M in toluene). The reaction mixture was allowed to slowly warm to room temperature overnight. The reaction mixture was then partitioned between ethyl acetate and cold H2O, and the aqueous layer extracted twice with ethyl acetate. The combined organic extract was washed successively with H2O, 10% K2CO3, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography using a gradient from 0 to 3% MeOH in CH2Cl2 to give CBX007 (50 mg, 0.10 mmol). 1H NMR (500 MHz, CDCl3, δ): 2.46 (s, 3H), 2.55 (t, J=4.4 Hz, 4H), 2.74 (t, J=6.9 Hz, 2H), 2.77 (s, 3H), 3.74 (t, J=4.5 Hz, 4H), 4.25 (t, J=6.9 Hz, 2H), 7.10 (d, J=1.7 Hz, 1H), 7.21 (d, J=7.4 Hz, 1H), 7.31 (d, J=1.6 Hz, 1H), 7.42 (d, J=7.3 Hz, 1H), 7.60-7.74 (m, 2H), 8.10 (d, J=7.7 Hz, 1H), 8.94 (d, J=8.2 Hz, 1H). 13C NMR (500 MHz, CDCl3, δ): 12.09, 20.60, 42.21, 54.54, 57.91, 67.28, 108.62, 116.44, 122.84, 123.78, 124.66, 125.62, 126.70, 126.93, 127.12, 128.03, 128.18, 131.09, 131.49, 133.51, 137.34, 137.57, 140.30, 142.76, 194.75. MS m/z 481.6 [M+H]+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[OH:25][C@@H:26]([C@H:28]1[C:49](=[O:50])[N:30]2[CH:31]([C:36]([O:38]CC3C=CC([N+]([O-])=O)=CC=3)=[O:37])[C:32](=O)[C@H:33]([CH3:34])[C@H:29]12)[CH3:27].[C:51]([C@@H:54]1[CH2:58][C@H:57]([SH:59])[CH2:56][N+:55]1([CH3:61])[CH3:60])(=[O:53])[NH2:52]>C(#N)C.O1CCCC1.P([O-])([O-])([O-])=O.[Pd]>[C:51]([C@@H:54]1[CH2:58][C@H:57]([S:59][C:32]2[C@H:33]([CH3:34])[C@@H:29]3[C@@H:28]([C@H:26]([OH:25])[CH3:27])[C:49](=[O:50])[N:30]3[C:31]=2[C:36]([O-:38])=[O:37])[CH2:56][N+:55]1([CH3:61])[CH3:60])(=[O:53])[NH2:52]
Reactant: C[N+]1(C)C[C@@H](S)C[C@H]1C(N)=O
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Agent: [Pd]
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S[C@H]3C[C@@H](C(N)=O)[N+](C)(C)C3)[C@H](C)[C@H]12
Reaction time: 1 h

Procedure:
0.20 ml of diisopropylethylamine and 0.24 ml of diphenylphosphoryl chloride were added dropwise, whilst ice-cooling, to a solution of 400 mg of 4-nitrobenzyl (1R, 5R, 6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 4 ml of dry acetonitrile, and the mixture was stirred at the same temperature for 1 hour. At the end of this time, 0.46 ml of diisopropylethylamine and a solution of the salt prepared in step (1) above in 3 ml of acetonitrile were added to the reaction mixture, whilst ice-cooling, and the mixture was then stirred for 7 hours and then allowed to stand for 2 days at the same temperature. The solvent was then distilled off under reduced pressure, and the residue was washed repeatedly by decantation using diethyl ether and dried under reduced pressure to afford a crude product. This crude product was then dissolved in a mixture of 30 ml of tetrahydrofuran and 30 ml of a 0.1M phosphate buffer (pH 7.0) and hydrogenated at room temperature for 2.5 hours in the presence of 555 mg of 10% w/w palladium-on-charcoal. At the end of this time, an insoluble material was removed by filtration with the help of a Celite (trade mark) filter aid, and the filtrate was washed with diethyl ether. The aqueous layer was then concentrated by evaporation under reduced pressure. The residue was adsorbed on a column of Diaion (trade mark) HP-20AG (Mitsubishi Chemical Industries, Ltd.) and the fractions eluted with a 5% by volume aqueous acetone solution were concentrated by evaporation under reduced pressure, and the residue was lyophilized to afford a crude product as a yellow powder. This crude product was purified by chromatography using a Lobar column (Merck Co., LiChroprep RP-8, size B). The fractions eluted with 5% and 10% by volume aqueous methanolic solutions were collected and concentrated by evaporation under reduced pressure, and the residue was lyophilized to afford 100 mg of the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:11].[NH3:12].[OH-].[Na+]>O>[NH2:12][C:2]1([CH3:1])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:11]
Reactant: CC1Cc2ccccc2C1=O
Reactant: N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(N)Cc2ccccc2C1=O
Temperature: 80 °C
Reaction time: 20 h

Procedure:
According to the procedure of Farnum et. al (Synthesis 1972, 191-192), water (1.35 L) is stirred at 80° C. and de-gassed by periodic evacuating and flushing with nitrogen (3×). K3FeCN6 (202 g, 615 mmol) and 2-methyl-indan-1-one (20 g, 1.37 mmol) are added. The mixture is stirred rapidly under nitrogen at 80° C. while aqueous concentrated ammonia solution (105 mL) is added over 30 minutes. Stirring is continued at 80° C. for 20 hours. When cool, the solution is made alkaline by addition of sodium hydroxide (2 g) and extracted with ethyl acetate (2×200 mL). The organic extract is concentrated to a volume of 200 ml and the product is extracted into aqueous HCl (200 mL, 1M). The acidic aqueous phase is separated, gasified with sodium hydroxide, and extracted with ethyl acetate (2×100 mL). The organic layer is separated, dried (Na2SO4) and the solvent removed to give an orange oil.
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)C=CC=CC=1.CC(C)([O-])C.[K+].[CH3:43][N:44]([CH2:55][CH2:56][CH2:57][CH2:58][CH:59]=O)[C:45](=[O:54])[O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(OC)(C)(C)C>O1CCCC1.O>[CH3:43][N:44]([CH2:55][CH2:56][CH2:57][CH2:58][CH:59]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:45](=[O:54])[O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: c1ccc(CCCCCCCCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CN(CCCCC=O)C(=O)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CN(CCCCC=CCCCCCCCCCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
Compound 12 (6.5 g) was dissolved in tetrahydrofuran (18 mL). Potassium-tert-butoxide (1.2 g) was added thereto at 0° C., followed by stirring at room temperature for 30 minutes. After cooling the reaction solution to 0° C., the solution of Compound 14 (1.7 g) in tetrahydrofran (3 mL) was added drop wise thereto, followed by the stirring at the same temperature for 2 hours. To the reaction solution, tert-butylmethylether (40 mL) and water (30 mL) were added. The organic layer was washed with water and an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethylacetate=1:1→1:2) to obtain the title compound (2.7 g) having the following physical property values.
Reaction SMILES: [C:1]([CH2:6][CH:7]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH2:4][CH3:5])=[O:2].[CH:27](=O)[C:28]1[C:29](=[CH:31][CH:32]=[CH:33][CH:34]=1)[OH:30]>C1(C)C=CC=CC=1>[CH2:4]([O:3][C:1](=[O:2])/[C:6](/[CH3:7])=[CH:27]/[C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[OH:30])[CH3:5]
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(C)=C/c1ccccc1O
Temperature: 25 °C

Procedure:
To a solution of 75.0 g (carbethoxyethylidene)triphenyl phosphorane in 350 ml of toluene, 23.2 g of salicylaldehyde was dropped in at 20° C. while cooling in an ice-bath. After stirring at room temperature for 90 mn., the reaction mixture was diluted with toluene and washed to neutrality with water.
Reaction SMILES: C([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH2:11][CH2:12][NH2:13])(OC(C)(C)C)=O.F[C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21].C(Cl)Cl>C(O)C.[OH-].[Na+]>[NH2:8][C@@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21])[C:14]([OH:16])=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN)C(=O)O
Reactant: N#Cc1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: N#Cc1ccccc1NCCC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 2.4 %

Procedure:
A solution of 928 mg (4 mmoles) of Nα -Boc-L-ornithine and 968 mg (8 mmoles) of 2-fluorobenzonitrile in 4 mL of ethanol and 4 mL of 1N NaOH were heated at reflux for 24 hours. Another 8 mmoles each of 1N NaOH and 2-fluorobenzonitrile were then added and reflux was continued for another 24 hours. The clear solution was cooled to room temperature, and the white paste dumped into 125 mL of CH2Cl2 and extracted with 100 mL of water made basic (pH 12) with NaOH. The aqueous extract was acidified with 5N HCl, and extracted with 125 mL of CH2Cl2. The organic phase was washed with 1M HCl, dried (Na2SO4) and concentrated in vacuo to give an oil. The oil was purified by flash chromatography on silica gel, eluting with 2:1 ethyl acetate:ethanol containing 1% triethylamine. The sole fluorescent product was an oil, 132 mg (10%), with rf of 0.49 in the elution solvent. 125 mg of the oil was dissolved in 22 mL of 5:1:1 acetic acid/water/12M HCl, and stirred for 3 hours at room temperature. The sample was concentrated in vacuo, then ethanol was added and the sample again concentrated in vacuo to give a waxy solid. This was recrystallized from water to give 22.5 mg of white needles. The mother liquor yielded 67 mg of white foam on concentration. Yield (100%).: mp >265°; MS (FAB) m/e calc'd for C12H10N3O2 : 234.1243, found 234.1231; M/Z 223 (M+), 224 (M+H)+. 1H NMR (300 MHz, D2O) δ: 1.74 (m, 2H), 1.96 (m, 2H), 3.33 (t, J=6.0 Hz, 2H), 3.79 (t, J=5.8 Hz, 1H), 6.71 (t, J=7 Hz, 1H), 6.92 (d, J=9 Hz, 1H), 7.55 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:26])[CH2:13][CH2:12][N:11]([C:14](=[O:23])[C@H:15]([NH:19][C:20]([NH2:22])=[S:21])[CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]2([CH3:25])[CH3:24])=[CH:4][CH:3]=1.[Cl:27][CH2:28][C:29](=O)[CH2:30]Cl>CC(C)=O>[Cl:27][CH2:28][C:29]1[N:22]=[C:20]([NH:19][C@H:15]([CH:16]([CH3:17])[CH3:18])[C:14]([N:11]2[CH2:12][CH2:13][C@@:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([OH:26])[C:9]([CH3:24])([CH3:25])[CH2:10]2)=[O:23])[S:21][CH:30]=1
Reactant: O=C(CCl)CCl
Reactant: CC(C)[C@@H](NC(N)=S)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Solvent: CC(C)=O
Product: CC(C)[C@@H](Nc1nc(CCl)cs1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.9 %

Procedure:
To a suspension of 1-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)thiourea (29 mg, 0.073 mmol) in acetone (300 μL) was added 1,3-dichloropropan-2-one (14 mg, 0.105 mmol) and the reaction mixture was stirred overnight at rt. The solvents were removed and the residue purified via column chromatography (SiO2, 25% EtOAc/hep then 50% EtOAc/hep then 10% EtOAc with 0.06% DIPEA). (R)-2-(4-(chloromethyl)thiazol-2-ylamino)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methylbutan-1-one (35 mg, >95% yield) was isolated as a clear glass. HPLC purity: >99%, rt 3.87 min; MS found: 470.22 (M+)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:10]Cl)=[N:4][CH:5]=[C:6]([O:8][CH3:9])[N:7]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[C:13]1[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH2:10][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[C:17]2[N:18]=[CH:19][CH:20]=[CH:21][N:22]=2)=[N:4][CH:5]=[C:6]([O:8][CH3:9])[N:7]=1
Reactant: c1cnc(-c2ncc[nH]2)nc1
Reactant: COc1cnc(CCl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cnc(Cn2ccnc2-c2ncccn2)c(Cl)n1
Temperature: 45 °C
Reaction time: 16 h
Yield: 55.1 %

Procedure:
A mixture of 3-chloro-2-chloromethyl-5-methoxy pyrazine (141 mg, 0.73 mmol), 2-(1H-imidazol-2-yl)-pyrimidine (105 mg, 0.72 mmol) and K2CO3 (307 mg, 2.22 mmol) in DMF (10 mL) is stirred at 45° C. for 16 hours. On cooling, the reaction is quenched with saturated NH4Cl (5 mL) and extracted with DCM (3×15 mL). The combined organic layers are dried and solvent removed. PTLC separation (silica gel; 10% MeOH in DCM) gives 120 mg of 2-[1-(3-chloro-5-methoxy-pyrazin-2-ylmethyl)-1H-imidazol-2-yl]-pyrimidine as an oil. 1H NMR (CDCl3) 8.98 (d, 2H), 7.98 (s, 1H), 7.27 (s, 1H), 7.14–7.18 (m, 2H), 6.05 (s, 2H), 3.97 (s, 3H). H. 2-[1-(3,5-Dimethoxy-pyrazin-2-ylmethyl)-1H-imidazol-2-yl]-pyrimidine (Compound 9)
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=O.[F:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][NH:13][C:12]1[CH:14]=[CH:15][C:9]([F:8])=[CH:10][CH:11]=1)[CH3:7]
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)CNc1ccc(F)cc1
Reaction time: 2 h
Yield: 65.6 %

Procedure:
A solution of ethyl glyoxylate (2.47 g, 0.024 mol) in 1,2-dichloroethane (30 mL) under argon at room temperature was treated succesively with 4-fluoroaniline (1.80 g, 0.016 mol), sodium triacetoxyborohydride (5.12 g, 0.024 mol) and acetic acid (1 mL). After stirring for two hours, the mixture was concentrated, dissolved in ethyl acetate and washed 5% sodium bicarbonate, water and brine. The dried (anhydrous magnesium sulfate) organic solution was concentrated and crystallized from ether/hexanes to give the title product (2.07 g, 65%) as a colorless solid, mp 72°-73° C. Analysis calculated for C10H12 FNO2 ·0.07 H2O: C, 60.54; H, 6.16; N, 7.06; F, 9.58. Found: C, 60.75; H, 6.15; N, 6.96; F, 9.13.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:49])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12](C(OC2C=CC=CC=2)=O)[C:13](=O)[O:14]C2C=CC=CC=2)[CH:7]=1.Cl.Cl.[N:52]1([CH2:57][CH:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[CH2:56][CH2:55][CH2:54][CH2:53]1.C(N(CC)CC)C.O>CN(C)C=O>[F:48][C:45]1[CH:46]=[CH:47][C:42]([NH:41][C:40]([C:37]2([C:35]([NH:34][C:33]3[CH:32]=[CH:31][C:4]([O:5][C:6]4[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]([N:61]5[CH2:62][CH2:63][CH:58]([CH2:57][N:52]6[CH2:56][CH2:55][CH2:54][CH2:53]6)[CH2:59][CH2:60]5)=[O:14])[CH:7]=4)=[CH:3][C:2]=3[F:1])=[O:36])[CH2:39][CH2:38]2)=[O:49])=[CH:43][CH:44]=1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Reactant: C1CCN(CC2CCNCC2)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1)N1CCC(CN2CCCC2)CC1
Temperature: 25 °C
Reaction time: 13 h
Yield: 27.5 %

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (41.0 mg) in N,N-dimethylformamide (2.0 ml) were added 4-(pyrrolidin-1-ylmethyl)piperidine dihydrochloride (74.2 mg), triethylamine (0.0857 ml) and water (0.20 ml), followed by stirring at room temperature for 13 hr. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, heptane:ethyl acetate=1:2, ethyl acetate, then ethyl acetate:methanol=20:1). Fractions containing the target compound were concentrated. To the residue were added diethyl ether and hexane, and the precipitate was collected by filtration. This was washed with hexane and dried under aeration to provide the titled compound as white powder (10.5 mg, 28%).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]1([CH2:18][C:19]([OH:21])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[O:22]1[CH:27]=[CH:26][CH2:25][CH2:24][CH2:23]1.C(N(CC)CC)C>ClCCl>[C:12]1([CH2:18][C:19]([O:21][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][O:22]2)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccccc1)OC1CCCCO1

Procedure:
To a saturated solution of anhydrous p-toluenesulphonic acid in dry dichloromethane (25 ml) successively phenylacetic acid (4a) (0.581 g, 4.26 mmol) and 3,4-dihydro-2H-pyran (3 ml, 32.9 mmol) were added, and the resultant solution was stirred at room temperature until the starting material 4a disappeared (ca. 1 hour). To the reaction mixture triethylamine (1 ml, 7.2 mmol) was added and the volatiles were evaporated. The obtained crude tetrahydro-2H-pyran-2-yl 2-phenylacetate (5a) was immediately utilized in the next step of the synthesis.