Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][S:5][C:6]=1[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[NH2:21][C:22]1[S:26][C:25]([C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=2[F:34])=[N:24][C:23]=1[C:35](O)=[O:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[NH2:21][C:22]1[S:26][C:25]([C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=2[F:34])=[N:24][C:23]=1[C:35]([NH:1][C:2]1[CH:3]=[N:4][S:5][C:6]=1[O:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]1)=[O:36]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2sncc2N)CC1
Reactant: Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2sncc2NC(=O)c2nc(-c3c(F)cccc3F)sc2N)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 19.9 %

Procedure:
tert-butyl 4-(4-aminoisothiazol-5-yloxy)piperidine-1-carboxylate (1D4) (47 mg, 0.156 mmol), 5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (1E) (40 mg, 0.156 mmol), HATU (71 mg, 0.187 mmol) and DIEA (84 μL, 0.468 mmol) were mixed in DMF (5 mL), stirred at 50° C. for 1 hour, cooled to room temperature, diluted with ethyl acetate (50 mL), washed with brine, dried over Na2SO4, and concentrated in vacuo at room temperature (25° C.). The residue was purified with flash column (eluent: 10-30% ethyl acetate/petroleum ether) to afford the product tert-butyl 4-(4-(5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxamido)isothiazol-5-yloxy)piperidine-1-carboxylate (1A) (17 mg, 0.031 mmol).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[CH3:16][O:17][NH3+:18]>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[N:18][O:17][CH3:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CO[NH3+]
Agent: [Cl-]
Product: CON=C1CCN(Cc2ccccc2)CC1

Procedure:
The starting material is prepared as follows: The solution of 94.5 g of 1-benzyl-4-piperidone and 46 g of methoxyammonium chloride in 600 ml of ethanol-pyridine (1:1) is refluxed overnight and evaporated. The residue is dissolved in water, the solution made basic with 12.5% aqueous sodium hydroxide and extracted with diethyl ether. The extract is washed with water and saturated aqueous sodium hydroxide, dried and evaporated, to yield the 1-benzyl-4-methoxyiminopiperidine.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].CC[O:8][CH2:9][CH3:10]>[Cl-].[Zn+2].[Cl-]>[CH2:9]([OH:8])[CH2:10][CH2:4][CH2:3]/[CH:2]=[CH:1]/[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: [Li]CCCC
Reactant: CCOCC
Agent: [Cl-]
Agent: [Zn+2]
Product: CCCC/C=C/CCCCO

Procedure:
FIG. 16 shows a synthesis of 5-decenyl acetate which involves the cross-metathesis of vinyl borate pinacol ester (Matheson, D. S J Am Chem Soc (1960) 82, 4228-4233) with 5-hexenol THP ether (or 1,10-diTHP ether of 5-decene) with Catalyst 823 to yield a pinacol ester of 1-borohexen-6-ol THP ether. This product was coupled with butyl lithium and zinc chloride under Suzuki conditions as described by Miycuira (Org Syn VIII p 532) to yield E-5-decenol THP ether in a 91:9 E:Z isomeric ratio. This material was purified by column chromatography and then acetated to yield 5-decenyl acetate in 91:9 E:Z isomeric ratio.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10](=[O:24])[C:11]1[C:16]([O:17][CH2:18][CH3:19])=[CH:15][CH:14]=[C:13]([Br:20])[C:12]=1[O:21]CC)[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10](=[O:24])[C:11]1[C:16]([O:17][CH2:18][CH3:19])=[CH:15][CH:14]=[C:13]([Br:20])[C:12]=1[OH:21])[CH3:2]
Reactant: CCOc1ccc(Br)c(OCC)c1C(=O)NCC1CCCN1CC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOc1ccc(Br)c(O)c1C(=O)NCC1CCCN1CC

Procedure:
10.0 g (0.023 mole) of (-)-N-ethyl-2-(3-bromo-2,6-diethoxybenzamidomethyl)pyrrolidine is dissolved in 250 ml of methylene chloride. 2.4 ml (0.025 mole) of boron tribromide is added. The mixture is left over night at room temperature and is then washed with 2N NH3. The extract is dried with Na2SO4 and evaporated. The oily residue crystallizes after a while. Petroleum ether is added to the product, which is then filtered off. Yield 7.0 g. M.p. 74°-76° C. [α]D20 =-66.7° (1% acetone).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[CH2:31]([O:33][CH2:34][CH2:35]O)[CH3:32].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH2:32][CH2:31][O:33][CH2:34][CH3:35])=[O:27])=[CH:29][CH:30]=2)=[CH:4][CH:3]=1
Reactant: CCOCCO
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOCCOC(=O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Reaction time: 120 h

Procedure:
A solution of 11.8 g. of 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoic acid, 1.00 g. of 2-ethoxyethanol and 5.35 ml. of boron trifluoride etherate in 200 ml. toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords 2-ethoxyethyl 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoate as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:12]([OH:15])[C:13]#[CH:14].C(N(CC)CC)C>C([O-])(O)=O.[Na+].[Cu]I>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([C:14]#[C:13][CH2:12][OH:15])[CH:3]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: C#CCO
Agent: [Cu]I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: OCC#Cc1cnc2ccccc2c1
Yield: 88.3 %

Procedure:
To a dry 2-L three-necked flask previously purged with nitrogen was charged 3-bromoquinoline (118.77 g, 570 mmol), propargyl alcohol (71.9 g, 1.28 mol, 2.25 equiv), triethylamine (1500 mL), copper(I) iodide (3.62, 19 mmol, 0.033 equiv) and dichlorobis(triphenyl-phosphine) palladium(II) (6.67 g, 9.5 mmol). The mixture which resulted was mechanically stirred and heated to reflux for 3 hours. Upon cooling the triethylamine solution was mechanically stirred and heated to reflux for 3 hours. Upon cooling, the triethylamine solution was filtered and washed with triethylamine (300 mL). The filtrate was then concentrated under reduced pressure to provide solids which were suspended in 5% aq. NaHCO3 (600 mL) and extracted with ethyl acetate (1×600 mL). The solids which were left after filtration were treated in the same manner. The combined ethyl acetate extracts were stirred with silica gel (15 g) and decolorizing carbon (3 g) before being filtered through a bed of celite. The filtrate was concentrated under reduced pressure to provide a tan colored solid which was vacuum oven dried at 45° C. overnight. The 3-(3-quinolyl)-2-propyn-1-ol was isolated in 92.14 g (88.3% yield). MS(CI): (M+H)+ at 184; 1H NMR (300 MHz CDCl3) δ4.56 (s, 2H), 4.70 (s, broad, 1H), 7.57 (m, 1H), 7.70 (m, 1H), 7.77 (d, 1H), 8.10 (d, 1H), 8.10 (s, 1H), 9.05 (s, 1H).
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.C(OC([NH:25][C@H:26]1[C@H:29]([CH3:30])[N:28]([S:31]([O-:34])(=[O:33])=[O:32])[C:27]1=[O:35])=O)(C)(C)C>O>[NH2:25][C@H:26]1[C@@H:29]([CH3:30])[N:28]([S:31]([OH:34])(=[O:32])=[O:33])[C:27]1=[O:35]
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1S(=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Product: C[C@@H]1[C@H](N)C(=O)N1S(=O)(=O)O

Procedure:
Following the procedure of example 2D, but substituting (3S-cis)-3-[(t-butoxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, tetrabutylammonium salt for (3S-trans)-3-[(t-butoxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, tetrabutylammonium salt yields the title compound, melting point 200° C., dec., [α]D21 =-61.8°[c=5.1, water].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9].[O-:10][CH2:11][CH3:12].[Na+]>[N+](C1C=CC=CC=1)([O-])=O.[Cu]>[CH2:11]([O:10][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9])[CH3:12]
Reactant: CC[O-]
Reactant: CSc1ccccc1Cl
Agent: [Cu]
Agent: [Na+]
Solvent: O=[N+]([O-])c1ccccc1
Product: CCOc1ccccc1SC

Procedure:
o-Chlorothioanisole (prepared by the procedure of Example 5-A (15.85 g., 0.1 mole) is stirred at reflux in nitrobenzene containing copper powder (100 mg.) and sodium ethoxide (6.8 g., 0.1 mole) for 2 hours. The product is steam distilled and the distillate dried and fractionally distilled under reduced pressure to yield o-ethoxythioanisole.
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]2[C:5]([CH2:6][C:7]3([C:20]2=[O:23])[CH2:18][C:17]2[C:19]4[C:13]([CH:14]=[CH:15][CH:16]=2)=[CH:12][CH:11]=[CH:10][C:9]=4[CH2:8]3)=[CH:4][CH:3]=1.[C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)#[N:25].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[O:23]=[C:20]1[C:7]2([CH2:8][C:9]3[C:19]4[C:13]([CH:12]=[CH:11][CH:10]=3)=[CH:14][CH:15]=[CH:16][C:17]=4[CH2:18]2)[CH2:6][C:5]2[C:21]1=[CH:22][C:2]([C:30]1[CH:31]=[C:26]([CH:27]=[CH:28][CH:29]=1)[C:24]#[N:25])=[CH:3][CH:4]=2
Reactant: O=C1c2cc(Br)ccc2CC12Cc1cccc3cccc(c13)C2
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2ccc3c(c2)C(=O)C2(C3)Cc3cccc4cccc(c34)C2)c1
Temperature: 100 °C
Yield: 59.2 %

Procedure:
6-Bromo-1′,3′-dihydrospiro[indene-2,2′-phenalen]-1(3H)-one (200 mg, 0.57 mmol) and 3-cyanophenylboronic acid (168 mg, 1.17 mmol) was dissolved in 1,4-dioxane (5 mL), Cs2CO3 (0.6 mL, 2 M) was added. Then Pd(PPh3)2Cl2 (10 mg) was added under N2. The mixture was heated at 100° C. for 10 minutes under microwave. The solvent was removed in vacuum. The crude product was purified by preparative TLC to give 3-(1-oxo-1,1′,3,3′-tetrahydrospiro[indene-2,2′-phenalene]-6-yl)benzonitrile (130 mg, 60%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]([F:19])([F:18])[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:22][C:23]1[C:31]([O:32][CH3:33])=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([F:34])[CH:24]=1>Cl.CC(O)C>[CH:13]1([N:10]2[CH2:9][C:8]([F:19])([F:18])[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[C:31]([O:32][CH3:33])=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([F:34])[CH:24]=4)=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)c(F)cc1N
Agent: Cl
Solvent: CC(C)O
Product: COc1cc(C(=O)O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C

Procedure:
2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one (158 mg, 0.5 mmol), 4-amino-2-fluoro-5-methoxy benzoic acid (obtained above), i-PrOH (5 mL) and conc. HCl (10 drops) were heated to 100° C. overnight. The reaction mixture was then cooled to room temperature. The reaction mixture contains desired product plus lots of de-carboxylation byproduct, which were separated by RP-HPLC to give the product as a white solid (12 mg). [M+H] calc'd for C21H22F3N5O4, 466; found 466.
Reaction SMILES: Br[C:2]1[C:3]([Cl:17])=[CH:4][C:5]([NH2:16])=[N:6][C:7]=1[C:8]#[C:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[N:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(#N)C>[Cl:17][C:3]1[C:2]([C:22]2[CH:23]=[N:18][CH:19]=[N:20][CH:21]=2)=[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=[C:5]([NH2:16])[CH:4]=1
Reactant: Nc1cc(Cl)c(Br)c(C#Cc2ccccc2)n1
Reactant: OB(O)c1cncnc1
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: CC#N
Product: Nc1cc(Cl)c(-c2cncnc2)c(C#Cc2ccccc2)n1
Temperature: 120 °C

Procedure:
A mixture of 5-bromo-4-chloro-6-(2-phenylethynyl)pyridin-2-amine C3a (1.0 g, 3.25 mmol), pyrimidin-5-ylboronic acid (604 mg, 4.88 mmol), Tetrakis(triphenylphosphine)palladium(0) (375 mg, 0.33 mmol), sodium carbonate (aqueous solution, 2 mol/l, 4.88 ml, 9.75 mmol) and ACN (15 ml) is stirred in a sealed tube at 120° C. until C3a is almost completely consumed. The mixture is then concentrated in vacuo and the product purified by NP chromatography. Yield: 420 mg (42%). HPLC-MS: M+H=307.
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([O:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[C:25]4[C:21]([C:22]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[CH:23][NH:24]4)=[CH:20][CH:19]=3)[N:14]=2)=[CH:9][C:8]=1[C:34]([F:37])([F:36])[F:35])[CH3:5].Cl>CC(O)C.O>[CH3:5][CH:4]([O:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[C:25]4[C:21]([C:22]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:23][NH:24]4)=[CH:20][CH:19]=3)[N:14]=2)=[CH:9][C:8]=1[C:34]([F:36])([F:37])[F:35])[CH3:3]
Reactant: CCOC(=O)CCc1c[nH]c2cc(-c3noc(-c4cnc(OC(C)C)c(C(F)(F)F)c4)n3)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)Oc1ncc(-c2nc(-c3ccc4c(CCC(=O)O)c[nH]c4c3)no2)cc1C(F)(F)F
Temperature: 70 °C
Yield: 39.3 %

Procedure:
Sodium hydroxide (37 mg) was added to a solution of ethyl 3-(6-{5-[6-[(1-methylethyl)oxy]-5-(trifluoromethyl)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate (D109) (300 mg) in iPrOH (10 mL) and water (10 mL). The resulting mixture was heated at 70° C. for 40 mins. Then 0.5 M HCl solution was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-(6-{5-[6-[(1-methylethyl)oxy]-5-(trifluoromethyl)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoic acid (E83) (111 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.38 (6H, d), 2.61 (2H, t), 2.97 (2H, t), 5.55 (1H, m), 7.34 (1H, d), 7.72 (2H, m), 8.13 (1H, t), 8.63 (1H, d), 9.20 (1H, d), 11.16 (1H, d), 12.05 (1H, br s). MS (ES): C22H19F3N4O4 requires 460; found 461.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([OH:12])=[C:4]([N+:13]([O-])=O)[CH:3]=1.C(OCC)(=O)C.C(O)(=O)C>[Fe].O>[NH2:13][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([C:8]([F:11])([F:9])[F:10])=[CH:6][C:5]=1[OH:12]
Reactant: O=[N+]([O-])c1cc(Cl)c(C(F)(F)F)cc1O
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)c(C(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
A mixture of 2.3 g of 4-chloro-2-nitro 5-trifluoromethylphenol and 10 ml of ethyl acetate was added dropwise to a mixture, which was heated to 80° C., of 2.6 g of electrolytic iron, 10 ml of acetic acid and 20 ml of water, and then the reaction mixture was stirred for one hour. The mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and a saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.7 g of 2-amino-4-chloro-5-trifluoromethylphenol.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH2:10]([NH:12][CH2:13][CH3:14])[CH3:11].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:12]([CH2:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: CCNCC
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCN(CC)c1cc(Cl)nc(Cl)n1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2.0 g (10.90 mmols) of 2,4,6-trichloropyrimidine in 25 mL of anhydrous ethanol at 0° C., was added drop wise a solution 0.79 g (10.90 mmols) of diethylamine in 5 mL of ethanol. This was followed by the addition of 2.3 mL (16.35 mmols) of triethylamine and the mixture was stirred for further 30 min. The mixture was then concentrated and 25 mL of CH2Cl2 and 25 mL of water were added. The organic layer was separated and the aqueous layer was extracted by additional amount of dichloromethane (2×10 mL) and the extracts were combined, dried over anhydrous Na2SO4 and concentrated. Column chromatography on silica gel afforded 1.48 g (62%) of L as colorless solid.
Reaction SMILES: Cl.[CH3:2][Si:3]([CH3:47])([CH3:46])[CH2:4][CH2:5][O:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:12]=[CH:11][C:10]=1[C:24]1[C:25](=[O:45])[O:26][C:27]2[C:32]([C:33]=1[CH2:34]Br)=[CH:31][CH:30]=[C:29]([O:36][CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:28]=2>CCOC(C)=O>[CH3:46][Si:3]([CH3:2])([CH3:47])[CH2:4][CH2:5][O:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:22])[CH3:23])[CH:12]=[CH:11][C:10]=1[C:24]1[C:25](=[O:45])[O:26][C:27]2[C:32]([C:33]=1[CH3:34])=[CH:31][CH:30]=[C:29]([O:36][CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:28]=2
Reactant: C[Si](C)(C)CCOCOc1ccc(-c2c(CBr)c3ccc(OCOCC[Si](C)(C)C)cc3oc2=O)c(OCOCC[Si](C)(C)C)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccc(OCOCC[Si](C)(C)C)cc2OCOCC[Si](C)(C)C)c(=O)oc2cc(OCOCC[Si](C)(C)C)ccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Into 1N HCl (10 mL) (1N HCl solution made using concentrated HCl in 1:1 THF:IPA) was dissolved 3-[2,4-bis-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-4-bromomethyl-7-(2-trimethylsilanyl-ethoxymethoxy)-chromen-2-one (200 mg, 0.544 mmol) and the resulting mixture was stirred for 24 h at room temperature. The reaction mixture was then diluted with EtOAc (100 mL) and the organic layer washed with water (2×20 mL) and brine (30 mL). The organic layer was dried over Na2SO4, filtered and the organic solvent evaporated to yield the title compound, 3-[2,4-Bis-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-4-methyl-7-(2-trimethylsilanyl-ethoxymethoxy)-chromen-2-one as a crude solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5](Cl)=[CH:4][N:3]=1.[CH:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)=[O:10]>[Pd]>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:14]2[CH:15]=[CH:16][C:11]([CH:9]=[O:10])=[CH:12][CH:13]=2)=[CH:4][N:3]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: [Pd]
Product: O=Cc1ccc(-c2cnc(Cl)nc2)cc1

Procedure:
The compound was prepared by palladium-catalyzed arylation of 2,5-dichloropyrimidine and 4-formylphenyl boronic acid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[CH2:14]([NH:21][C:22]([C:24]1[S:28][C:27]([NH2:29])=[N:26][C:25]=1[CH3:30])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([NH:21][C:22]([C:24]1[S:28][C:27]([NH:29][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[N:26][C:25]=1[CH3:30])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Product: Cc1nc(NC(=O)c2ccc(C(F)(F)F)cc2)sc1C(=O)NCc1ccccc1
Yield: 45 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 4-trifluoromethylbenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 45% yield; 1H NMR (CDCl3, 300 MHz) δ 8.05 (d, J=8.2 Hz, 2H), 7.77 (d, J=8.2 Hz, 2H), 7.36-7.29 (m, 5H), 5.97 (s, 1H), 4.60 (d, J=5.6 Hz, 2H), 2.57 (s, 3H); MS (ES+) m/z 420.1 (M+1).
Reaction SMILES: [Cl:1][CH2:2][C:3]#[N:4].[Na].Cl.[C:7]([O:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)(=[O:9])[NH2:8]>CO>[ClH:1].[C:7]([O:10][CH:11]1[CH2:16][CH2:15][N:14]([C:3](=[NH:4])[CH2:2][Cl:1])[CH2:13][CH2:12]1)(=[O:9])[NH2:8]
Reactant: N#CCCl
Reactant: NC(=O)OC1CCNCC1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: N=C(CCl)N1CCC(OC(N)=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.29 ml of chloroacetonitrile were added to a solution of 192 mg of metallic sodium in 80 ml of anhydrous methanol, and the mixture was stirred at room temperature for one hour. 15.10 g of 4-carbamoyloxypiperidine hydrochloride were than added, and the mixture was stirred for a further 2 hours. The reaction mixture was worked up in the same manner as in Example 1(1), giving 21.00 g of 2-(4-carbamoyloxypiperidin-1-yl)-2-iminoethylchloride hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:13]=[O:14])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH3:15][O:16][CH2:17][CH2:18][O:19][CH2:20]Cl>>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:13]=[O:14])[C:11]=1[O:12][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COCCOCCl
Reactant: COC(=O)c1cc(Br)c(O)c(C=O)c1
Product: COCCOCOc1c(Br)cc(C(=O)OC)cc1C=O
Yield: 96 %

Procedure:
Proceeding as in Reference 12, but substituting methyl 3-bromo-5-formyl-4-hydroxybenzoate (12.6 g, 48.6 mmol, 1.0 eq.) and methoxyethoxymethyl chloride (6.8 mL, 7.26 g, 58.3 mmol, 1.2 eq.), gave methyl 3-bromo-5-formyl-4-(2-methoxyethoxymethoxy)-benzoate (16.2 g) as a colorless oil which solidified upon standing.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:32][N:33]1[CH2:39][CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>ClCCl>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:18]=[C:17]4[CH2:29][N:36]3[CH2:37][CH2:38][CH2:39][N:33]([CH3:32])[CH2:34][CH2:35]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: CN1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCCN(C)CC3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of the product of step i) (0.45 g) in dichloromethane (50 mL) was treated with 1-methyl-1,4-diazepane (0.61 g) and sodium triacetoxyborohydride (0.68 g) and then stirred at room temperature overnight. Methanol (5 mL) was added and the solution purified directly by SiO2 chromatography (eluting with 0 to 20% methanol in dichloromethane) followed by HPLC to give the title compound as a solid (150 mg).
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].CC(C)([O-])C.[K+].[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl.C1OCCOCCOCCOCCOCCOC1>C(O)(C)(C)C.O>[O:20]1[CH2:19][CH:18]1[CH2:16][O:3][C:2]1[CH:4]=[CH:5][CH:6]=[CH:7][C:1]=1[O:8][CH3:9]
Reactant: COc1ccccc1O
Reactant: ClCC1CO1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1ccccc1OCC1CO1
Temperature: 50 °C

Procedure:
Guaiacol (8.6 g, 69 mmol), potassium t-butoxide (7.8 g, 69 mmol), epichlorohydrin (19.3 g, 209 mmol), and 18-crown-6 (0.8 g) were mixed in t-butanol (100 ml) and heated to 50° C. for 2 h. Water was added and the product was extracted with two portions of dichlorometane. Washing with water, twice, was followed by drying and evaporation. Quantitative yield.