Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4](B(O)O)=[CH:3][CH:2]=1.Cl[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+].C(COC)OC>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>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:4]2[C:5]3[O:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[C:9]=3[CH:1]=[CH:2][CH:3]=2)=[N:19][CH:20]=1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Reactant: Clc1ccc(Cl)nc1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: Clc1ccc(-c2cccc3c2oc2ccccc23)nc1
Yield: 75.8 %

Procedure:
Dibenzo[b,d]furan-4-ylboronic acid (9.5 g, 44.8 mmol), 2,5-dichloropyridine (7.0 g, 47.0 mmol), Pd(PPh3)4 (2.6 g, 2.2 mmol) and potassium carbonate (18.6 g, 134 mmol) were added to dimethoxyethane (75 mL) and water (75 mL). The reaction mixture was degassed with nitrogen before being heated to reflux overnight. EtOAc and water were added, the organic layer separated and the aqueous layer was extracted with 3×50 mL dichloromethane and dried over sodium sulfate. After removing the solvent under reduced pressure, the crude product was chromatographed on silica gel with dichloromethane to yield 11.7 g of crude product. The product was crystallized from hexane to give 9.5 g (76%) of 5-chloro-2-(dibenzo[b,d]furan-4-yl)pyridine as white needles. The product was confirmed by GC/MS.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].O>C(O)(=O)C>[C:26]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1)(=[O:28])[CH3:27]
Reactant: Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
196 mg (0.6 mmol) of (Z)-3-[1-(4-aminophenylamino)-1-phenyl-methylidene]-2-indolinone are dissolved in 5 ml of glacial acetic acid and after the addition of 0.1 g (1 mmol) of acetic anhydride stirred for 3 hours at ambient temperature. Then 15 ml of water are added, the product precipitated is suction filtered, washed with water and dried.
Reaction SMILES: [C:1]([NH:4]/[C:5](=[C:11](/[N:13]([CH3:15])C)\[CH3:12])/[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[CH:16]1(N)[CH2:20]C[CH2:18][CH2:17]1>CC(O)=O.O>[C:1]([NH:4]/[C:5](=[C:11](/[NH:13][CH:15]1[CH2:18][CH2:17][CH2:16][CH2:20]1)\[CH3:12])/[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)/C(NC(C)=O)=C(/C)N(C)C
Reactant: NC1CCCC1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)/C(NC(C)=O)=C(/C)NC1CCCC1

Procedure:
(E)-ethyl 2-acetamido-3-(dimethylamino)but-2-enoate (compound 16, 1 g, 4.67 mmol) and cyclopentylamine (0.5 mL) were stirred at room temperature in AcOH (10 mL) for overnight. The reaction mixture was diluted slowly with water (10 mL) and evaporated under reduced pressure to obtain the desired product as a dark brown oil, which could be used without any further purification for the next step.
Reaction SMILES: [CH:1](OC(=O)C)=[O:2].[N:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([O:19][C:20]3[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1>>[N:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([O:19][C:20]3[CH:26]=[CH:25][C:23]([NH:24][CH:1]=[O:2])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1
Reactant: CC(=O)OC=O
Reactant: Nc1ccc(OC2CCN(c3ccncc3)CC2)cc1
Product: O=CNc1ccc(OC2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.2 %

Procedure:
Acetic formic anhydride (1.5 g; pre-formed by heating acetic anhydride and 98% formic acid at 60° C. for 2 hours) was cooled to 5° C. and 4-[1-(4-pyridyl)piperidin-4-yloxy]aniline (1.0 g) was added. The mixture was stirred at ambient temperature for 16 hours and then evaporated. The residue was dissolved in water (50 ml) and the mixture was basified to pH10 by the addition of a 2M aqueous sodium hydroxide solution. The resultant mixture was extracted with methylene chloride, washed with water and with brine, dried (MgSO4) and evaporated to give N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}formamide as a foam (0.72 g);
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][NH:8][C:9](=[O:20])[C:10]1[CH:15]=[C:14]([NH2:16])[C:13]([Cl:17])=[CH:12][C:11]=1[O:18][CH3:19])[CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:1]([N:3]([CH2:6][CH2:7][NH:8][C:9](=[O:20])[C:10]1[CH:15]=[C:14]([N:16]([S:29]([CH3:28])(=[O:31])=[O:30])[S:29]([CH3:28])(=[O:31])=[O:30])[C:13]([Cl:17])=[CH:12][C:11]=1[O:18][CH3:19])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)CCNC(=O)c1cc(N)c(Cl)cc1OC
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)CCNC(=O)c1cc(N(S(C)(=O)=O)S(C)(=O)=O)c(Cl)cc1OC

Procedure:
To a solution of N-(diethylaminoethyl)-5-amino 4-chloro-2-methoxybenzamide (1.1 g) and triethylamine (815 mg) in dry methylene chloride (11 ml) is added dropwise a solution of methanesulfonyl chloride (882 mg) in dry methylene chloride (5ml) under ice-cooling and stirring and the resultant mixture is stirred at room temperature for 30 minutes. The reaction mixture is mixed with aqueous sodium hydrogen-carbonate and the methylene chloride layer is separated. The organic layer is washed with water, dried over anhydrous sodium sulfate and concentrated. The intermediary N-(diethylaminoethyl)-5-bis(methanesulfonyl)amino-4-chloro-2-methoxybenzamide obtained as a residue is mixed with 10 % aqueous sodium hydroxide (18ml) and methanol (2 ml) and heated at 50° C. for 30 minutes. The reaction mixture is acidified with conc. hydrochloric acid, neutralized with aqueous sodium hydrogencarbonate, salted out with brine, and shaken with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, and concentrated. The residue is chromatographed on a column of alumina, which is eluted with methylene chloride. The eluate is concentrated and the residue is washed with ethyl acetate - isoproyl ether to give N-(diethylaminoethyl)-4-chloro-5-methanesulfonamido-2-methoxybenzamide (993 mg) as crystals melting at 123° to 123.5° C.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].C(Cl)(=O)[C:9](Cl)=[O:10].[CH3:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[C:24]([O:26][C:27]3[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=3)[CH:23]=[CH:22][N:21]=2)[CH:17]=[N:16]1.N1C=CC=CC=1>ClCCCl.C1COCC1>[CH3:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[C:24]([O:26][C:27]3[CH:28]=[CH:29][C:30]([NH:33][C:9]([NH:5][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[O:10])=[N:31][CH:32]=3)[CH:23]=[CH:22][N:21]=2)[CH:17]=[N:16]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)C(N)=O
Reactant: Cn1cc(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)NC(=O)C(C)(C)C)nc3)ccn2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
A suspension of 2,2,2-trimethylacetamide (0.045 g, 0.449 mmol) in DCE (4 mL) was treated with oxalyl chloride (0.039 mL, 0.449 mmol), stirred at RT for 1 h, heated to 80° C. for 2.5 h, then cooled to RT and added drop-wise to a solution of Example A2 (0.10 g, 0.374 mmol) in THF (4 mL) and pyridine (0.215 mL, 2.67 mmol). The mixture was stirred at RT for 1 h, treated with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness. The material was treated with MeCN, sonicated, and the resulting solid collected via filtration and dried to afford N-((5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide (106 mg, 72%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 10.44 (s, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.27-8.25 (m, 2H), 8.09 (d, J=9.0 Hz, 1H), 7.96 (s, 1H), 7.74 (dd, J=9.0, 2.9 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H), 6.70 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 1.21 (s, 9H); MS (ESI) m/z: 395.2 (M+H+).
Reaction SMILES: C(C1C=CC(CC[CH:11]([CH:15]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]2[S:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([Cl:39])[CH:33]=2)(=[O:31])=[O:30])[C:12]([NH2:14])=[O:13])=CC=1)#N.C(=O)([O-])[O-].[NH4+:44].[NH4+:45].[CH2:46](O)[CH3:47]>Cl>[C:23]([C:22]1[CH:21]=[CH:20][C:19]([CH2:46][CH2:47][NH:14][C:12](=[O:13])[CH2:11][CH:15]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]2[S:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([Cl:39])[CH:33]=2)(=[O:30])=[O:31])=[CH:18][CH:17]=1)(=[NH:45])[NH2:44]
Reactant: CCO
Reactant: N#Cc1ccc(CCC(C(N)=O)C2c3ccccc3-c3ccccc3N2S(=O)(=O)c2ccc(Cl)c(Cl)c2)cc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Product: N=C(N)c1ccc(CCNC(=O)CC2c3ccccc3-c3ccccc3N2S(=O)(=O)c2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
A solution of N-[2-(4-cyano-phenyl)-ethyl]-2-[5-(3,4-dichloro-benzenesulfonyl)-5,6-dihydro-phenanthridin-6-yl]-acetamide (Example 7) (200 mg, 0.35 mmol) in 9M hydrogen chloride in ethanol (10 mL) was allowed to stand overnight at room temperature, then the mixture was concentrated in vacuo. The residue was dissolved in ethanol (10 mL) and ammonium carbonate (335 mg, 3.5 mmol) was added. The reaction mixture was stirred overnight at room temperature then concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol:NH4OH=5:1:0.1) to yield 113 mg (55%) of the title compound as white crystals. MS (EI) 594.1 (MH+).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[N:11]1[C:15]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=2[N:13]=[CH:12]1)(=[O:3])[CH3:2].[Br:22]N1C(=O)CCC1=O>O1CCCC1.C(Cl)(Cl)Cl>[C:1]([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[N:11]1[C:15]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=2[N:13]=[C:12]1[Br:22])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)O[C@@H]1CCCC[C@H]1n1cnc2cc(Cl)c(Cl)cc21
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(=O)O[C@@H]1CCCC[C@H]1n1c(Br)nc2cc(Cl)c(Cl)cc21
Reaction time: 0.17 h

Procedure:
(±)-Trans-2-(5,6-dichloro-1H-benzimidazol-1-yl)cyclohexyl acetate (part b of this example, 6.62 g, 20.2 mmol) in tetrahydrofuran (120 ml) was refluxed while N-bromosuccinimide (7.20 g, 40.5 mmol) was added in one portion. Reflux was continued for 10 minutes. The solution was cooled and diluted with chloroform (200 ml). The chloroform solution was extracted with aqueous sodium bicarbonate, then water, and dried (sodium sulfate). Evaporation of volatiles in vacuo left white crystals, after trituration from ethyl acetate-hexanes (5.77 g, 70%), m.p. 167-169° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[CH2:9][CH3:10].[CH3:21][O:22][C:23]1[CH:24]=[C:25](/[CH:32]=[CH:33]/[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:26]=[C:27]([O:30][CH3:31])[C:28]=1Br.C(I)C>C1COCC1.O>[CH3:12][O:11][C:7]1[CH:6]=[C:5](/[CH:13]=[CH:14]/[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[CH2:9][CH3:10].[CH3:31][O:30][C:27]1[CH:26]=[C:25](/[CH:32]=[CH:33]/[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=1
Reactant: COc1cc(/C=C/c2ccccc2)cc(OC)c1Br
Agent: CCc1c(OC)cc(/C=C/c2ccccc2)cc1OC
Solvent: O
Solvent: C1CCOC1
Solvent: CCI
Product: COc1cc(/C=C/c2ccccc2)cc(OC)c1
Temperature: -78 °C
Yield: 30 %

Procedure:
3,5-Dimethoxy-4-ethyl-trans-stilbene (compound 15A-a in Scheme 5): t-butyl Li (1.1 mL, 1M in THF) was added at −78° C. to a THF solution (10 mL) containing 3,5-dimethoxy-4-bromo-trans-stilbene (0.53 g). After addition, the solution was slowly heated to reflux for 30 min and then cooled down to −78° C. Ethyl iodide (1.2 eq, 0.265 mL) was added to the solution at −78° C. After reaction finished, water (10 mL) was added dropwise to the mixture, THF was evaporated under reduced pressure. The mixture was extracted with CH2Cl2 (5 mL×3), the combined organic layer was dried over anhydrous magnesium sulfate, and remove under reduced pressure. The product mixture was purified by column chromatography (ether/pet ether=1:8) and gave 3,5-dimethoxy-4-ethyl-trans-stilbene (15A-a) (70%) and 3,5-dimethoxy-trans-stilbene (30%) due to the moisture. Mp: 70-73° C. NMR (400 MHz, CDCl3): δ 1.12 (t, 6H, J=7.2 Hz, CH3), 2.70 (q, 2H, —CH2—), 3.91 (s, 6H, OCH3), 6.74 (s, 2H, H-2, 6), 7.07 (s, 2H), 7.26 (m, 1H, H-4′), 7.36 (m, 2H, H-3′,5′), 7.52 (m, 2H, H-2′,6′).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13](Cl)=[N:12][CH:11]=1.[CH2:18]([NH2:23])[CH2:19][CH2:20][CH2:21][NH2:22]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([NH:22][CH2:21][CH2:20][CH2:19][CH2:18][NH2:23])=[N:12][CH:11]=1
Reactant: NCCCCN
Reactant: Nc1ccccc1NC(=O)c1ccc(Cl)nc1
Product: NCCCCNc1ccc(C(=O)Nc2ccccc2N)cn1
Yield: 53 %

Procedure:
N-(2-Aminophenyl)-6-chloronicotinamide (248 mg, 1 mmol) and 7 ml of 1,4-butanediamine were heated to 80° C. for 3 hours. The excess 1,4-butanediamine was removed under vacuum. To the residue was added 5 ml of 0.20 M NaOH. The mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (158 mg, 53% yield) as a brown solid. LC-MS (m/z) 300 (M+1).
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]([CH:10]([Cl:12])[F:11])([F:9])[F:8])([F:4])([F:3])[F:2].[Br:13]Br.C(=O)=O>>[C:1]([CH:5]([O:6][C:7]([CH:10]([Cl:12])[F:11])([F:8])[F:9])[Br:13])([F:4])([F:3])[F:2]
Reactant: FC(Cl)C(F)(F)OCC(F)(F)F
Reactant: BrBr
Agent: O=C=O
Product: FC(Cl)C(F)(F)OC(Br)C(F)(F)F

Procedure:
CF3CH2OCF2CHFCl (104 g.) and bromine (85 g.) were vaporized in a stream of nitrogen at 15-20 l/hr. The gaseous mixture was then passed through a 1 inch × 12 inch glass tube at 475° C. The crude product (137 g.) was condensed in a "Dry Ice" trap and purified by fractional distillation and preparative gas chromatography. The product CF3CHBrOCF2CHFCl had b.p. 109° C., nD20 1.3525 and analyzed as follows:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:9][CH:8]([O:10]CC2C=CC=CC=2)[CH2:7]1)=[O:5])[CH3:2].C(OCC)(=O)C.[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:7][CH:8]([OH:10])[CH2:9]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)OC(C)(C)C)CC(OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C1(NC(=O)OC(C)(C)C)CC(O)C1
Temperature: 25 °C

Procedure:
The 1-(N-(t-butoxycarbonyl)amino)-3-benzyloxy-cyclobutane-1-carboxylic acid ethyl ester synthesized as above is dissolved in an alcohol solvent such as ethanol or an acetate ester solvent such as ethyl acetate ester, and palladium-on-activated carbon (amount: 10 w/w % or more relative to the substrate) is added to the solution in an atmosphere of hydrogen to allow them to react under stirring at room temperature. The reaction solution is then filtered through Celite, and the filtrate is concentrated and purified to yield 1-(N-(t-butoxycarbonyl)amino)-3-hydroxy-cyclobutane-1-carboxylic acid ethyl ester (Step 4).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]([CH3:27])[CH3:26])=[N:23][N:24]=2)[CH:21]=1.N>CN(C=O)C.CO.C(Cl)Cl>[NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([O:12][C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([N:25]([CH3:27])[CH3:26])=[N:23][N:24]=3)[CH:21]=2)[CH2:4][CH2:3]1
Reactant: CN(C)c1nnc2ccc(F)cn12
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of Intermediate A (75 mg, 0.458 mmol) in DMF (2 mL) was added NaH (60% in oil, 50 mg, 1.25 mmol) and the mixture stirred at RT for 20 min, before Intermediate 59b (75 mg, 0.416 mmol) was added. This mixture was stirred at 60° C. for 1 h. The reaction mixture was applied to an SCX-2 cartridge (10 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM gave the title compound as a yellow gum (82 mg, 61%). LCMS (Method 4): Rt 1.49 min, m/z 324 [MH+].
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]([NH:17][C:18]([C:20]1[N:24]2[CH:25]=[C:26]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:27]=[C:28]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[F:37])[C:23]2=[N:22][C:21]=1[CH3:43])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.O.C(OCC)(=O)C>C1COCC1>[F:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][O:29][C:28]1[C:23]2[N:24]([C:20]([C:18](=[O:19])[NH:17][C@H:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:9][OH:8])=[C:21]([CH3:43])[N:22]=2)[CH:25]=[C:26]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:27]=1
Reactant: CCOC(=O)c1cc(OCc2ccccc2F)c2nc(C)c(C(=O)N[C@@H](CO[Si](C)(C)C(C)(C)C)c3ccccc3)n2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc(OCc2ccccc2F)c2nc(C)c(C(=O)N[C@@H](CO)c3ccccc3)n2c1
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
To a solution of 370 mg of ethyl 3-{[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-phenylethyl]carbamoyl}-8-[(2-fluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-6-carboxylate in 12 ml of THF was added 1.22 ml of a 1 M tetrabutylammonium fluoride/THF solution, followed by stirring for 30 minutes. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 220 mg of ethyl 8-[(2-fluorobenzyl)oxy]-3-{[(1R)-2-hydroxy-1-phenylethyl]carbamoyl}-2-methylimidazo[1,2-a]pyridine-6-carboxylate.
Reaction SMILES: [K].C(OC([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:36])/[CH:23]=[CH:24]/[C:25]3[CH:26]=[N:27][C:28](/[CH:31]=[CH:32]/[C:33]([OH:35])=O)=[CH:29][CH:30]=3)=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.C1C=CC2[N:45]([OH:46])N=NC=2C=1.C(Cl)CCl.NOC1CCCCO1>CN(C=O)C.C(Cl)Cl>[OH:46][NH:45][C:33](=[O:35])/[CH:32]=[CH:31]/[C:28]1[CH:29]=[CH:30][C:25](/[CH:24]=[CH:23]/[C:22](=[O:36])[C:19]2[CH:20]=[CH:21][C:16]([CH2:15][N:12]3[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]3)=[CH:17][CH:18]=2)=[CH:26][N:27]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)nc3)cc2)CC1
Agent: NOC1CCCCO1
Agent: [K]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(/C=C/C(=O)c2ccc(CN3CCNCC3)cc2)cn1)NO
Temperature: 25 °C
Reaction time: 5 h
Yield: 21.2 %

Procedure:
A mixture of 4-(4-{(E)-3-[6-((E)-2-carboxy-vinyl)-pyridin-3-yl]-acryloyl}-benzyl)-piperazine-1-carboxylic acid tert-butyl ester potassium salt (250 mg, 0.48 mmol), HOBT (130 mg, 0.96 mmol), EDC (184 mg, 0.96 mmol), TEA (0.134 ml, 0.96 mmol) and NH2OTHP (84 mg, 0.72 mmol) in DMF (4 ml) and DCM (4 ml) was stirred at room temperature for 5 h. The solution was diluted with DCM and washed with water and brine. The organic phase was dried over Na2SO4 and evaporated in vacuo. The crude mixture was purified by column chromatography (eluent: DCM/MeOH/NH4OH 95:5:0.1) and the resulting product was dissolved in DCM and treated with HCl/Et2O for 4 h. The resulting precipitate was filtered and purified by preparative LC-MS to give 40 mg of (E)-N-hydroxy-3-{5-[(E)-3-oxo-3-(4-piperazin-1-ylmethyl-phenyl)-propenyl]-pyridin-2-yl}-acrylamide as its formate salt.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13](CF)[N:14]=1)=[O:7])(C)(C)C.[F:17][C:18](F)(F)C(O)=O.C(OC(=O)C)(=O)C>C(O)=O>[F:17][CH2:18][N:14]1[CH:13]=[CH:12][S:11][CH:10]1[CH2:9][NH:8][CH:6]=[O:7]
Reactant: CC(C)(C)OC(=O)NCc1nc(CF)cs1
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNCC1SC=CN1CF
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 0.66 g of the above-obtained 2-(tert-butoxycarbonylamino)methyl-4-fluoromethylthiazole was added 2 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure. To the residue was added a saturated aqueous solution of sodium hydrogencarbonate to adjust the pH of the mixture to approximately 8. To this reaction solution was added 20 ml of dichloromethane. To the mixture was added with stirring a solution which had been prepared in advance by reacting 0.33 ml of formic acid with 0.33 ml of acetic anhydride at 50° C. for 10 minutes, and the resulting mixture was stirred at room temperature for an additional one hour. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (10ml×2). The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give 0.27 g of crude 3-fluoromethyl-2-(formylamino)methylthiazole. This compound was dissolved in 6 ml of dichloromethane. 4.2 ml of phosphorus oxychloride was added to the solution at -20° C., and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure. To the residue was added 4.2 ml of phosphorus oxychloride, and the mixture was stirred at 100° C. for 30 minutes. The reaction solution was cooled to room temperature, and then concentrated to dryness under reduced pressure. The residue was dissolved in 10 ml of water, and the solution was washed with 5 ml of dichloromethane. To this was added a saturated aqueous solution of sodium hydrogencarbonate to adjust the pH to approximately 8. The mixture was further extracted with dichloromethane (10ml×2). The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give 0.241 g (yield 58%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:15][C:16]([OH:20])([C:18]#[CH:19])[CH3:17].C(OCC)(=O)C>COCCOC.[Cu]I>[CH3:15][C:16]([OH:20])([C:18]#[C:19][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[CH3:17]
Reactant: Brc1cccnc1
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CC(C)(O)C#Cc1cccnc1
Temperature: 0 °C
Yield: 40 %

Procedure:
3-Bromopyridine (3.0 mL, 31 mmol), triethylamine (22 mL, 160 mmol), CuI (1.2 g, 6.2 mmol), and PdC2(PPh3)2 (1.1 g, 1.5 mmol) were combined in DME (92 mL) and cooled to 0° C. 2-Methyl-3-butyne-2-ol (9.0 mL, 93 mmol) was then added and the reaction was allowed to slowly warm to ambient temperature. The mixture was then heated to 55-60° C. for 16 h. The mixture was filtered through Celite™, and the pad was washed thoroughly with ethyl acetate. The combined filtrates were washed with brine (3×100 mL), dried over MgSO4, and filtered. The solution was concentrated in vacuo, and the residue was purified by column chromatography eluting with 90:10 hexane:ethyl acetate then ethyl acetate to afford 2-methyl-4-(3-pyridinyl)-3-butyn-2-ol (2.0 g; 40% yield) as a brown oil 1H NMR (CDCl3, 300 MHz) δ 8.76 (br s, 1H), 8.52 (br s, 1H), 7.74-7.70 (m, 1H), 4.08 (br s, 1H), 1.63 (s, 3H). MS (EI ionization) 161 (M+).