Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]#[N:9])[CH2:4][CH2:3]1.[OH:10][NH:11][C:12](=N)[CH:13]([CH3:15])[CH3:14]>C(OCC)(=O)C.CCOCC.[Cl-].[Cl-].[Zn+2]>[CH3:14][CH:13]([C:12]1[N:9]=[C:8]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)[O:10][N:11]=1)[CH3:15]
Reactant: N#CN1CCC(O)CC1
Reactant: CC(C)C(=N)NO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)c1noc(N2CCC(O)CC2)n1
Temperature: 100 °C

Procedure:
4-Hydroxypiperidine-1-carbonitrile (3.0 g) and N-hydroxy-2-methylpropanimidamide (2.9 g) are dissolved in ethyl acetate (20 ml) and 1 M ZnCl2 in Et2O (29 ml) is added. A precipitate forms and the solvent is decanted off. Additional Et2O (20 ml) is added to wash the precipitate and again is decanted off. Ethanol (20 ml) is added followed by concentrated aqueous HCl (7.5 ml) and the mixture is heated to 100° C. for 3.5 h.
Reaction SMILES: [CH:1](=[C:8]([C:14]([CH3:16])=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[N:23]=[C:22]([NH2:24])[CH:21]=[C:20]([NH2:25])[N:19]=1>C(O)(=O)C>[NH2:17][C:18]1[N:19]=[C:20]([NH2:25])[C:21]2[CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:14]([CH3:16])[NH:24][C:22]=2[N:23]=1
Reactant: Nc1cc(N)nc(N)n1
Reactant: CCOC(=O)C(=Cc1ccccc1)C(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(C)Nc2nc(N)nc(N)c2C1c1ccccc1
Temperature: 25 °C

Procedure:
2.2 g (10 mmol) of ethyl 2-benzylideneacetoacetate were heated under reflux for 10 hours together with 1.3 g (10 mmol) of 2,4,6-triaminopyrimidine in 25 ml of glacial acetic acid. The reaction mixture was then cooled to room temperature, and the precipitated product was filtered off with suction and recrystallized as the acetate from acetonitrile.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH2:7][C:8]([OH:10])=[O:9])[C:4](=[O:11])[O:3]1.C(O)(=O)[C@H](CC(O)=O)O.N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[O:6][CH:5]([CH2:7][C:8]([O:10][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1(C)OC(=O)[C@H](CC(=O)O)O1
Agent: O=C(O)C[C@H](O)C(=O)O
Agent: c1c[nH]cn1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)C(CC(=O)O[Si](C)(C)C(C)(C)C)O1
Temperature: 22 °C
Reaction time: 18 h
Yield: 95.6 %

Procedure:
A solution of (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid (13.20 g, 75.8 mmol), which was derived from L-malic acid by means known in the art, in N,N-dimethylformamide (25 ml) was treated at 22° C. with imidazole (10.56 g, 0.155 mmol) followed by tert-butyldimethylsilyl chloride (12.0 g, 79.6 mmol) and the resulting mixture was stirred at 22° C. for 18 h. The reaction mixture was then diluted with toluene (500 ml), washed with water (×3), saturated sodium bicarbonate and brine. After drying (magnesium sulfate), the solvent was evaporated under reduced pressure to give an oil. Distillation under vacuum gave 20.9 g (96%) of the title material as a clear oil: Bp 80-90° C./0.1 torr (bulb to bulb distillation, air bath temperature). 1H NMR (400 MHz, CDCl3) δ: 0.33 (s, 3), 0.36 (s, 3), 1.00 (s, 9), 1.11 (s, 3), 1.37 (s, 3), 2.72 (m, 2), 4.35 (dd, 1, J=4, 6).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH:5]([C:10]2[CH:11]=[C:12]([CH:18]=[C:19]([F:21])[CH:20]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]([F:9])([CH3:8])[CH3:7])[CH2:2]1.Br[CH:23]([C:32]1[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=1)[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[C:27]#[N:28]>>[C:38]([C:35]1[CH:34]=[CH:33][C:32]([CH:23]([C:24]2[CH:31]=[CH:30][CH:29]=[C:26]([C:27]#[N:28])[CH:25]=2)[N:1]2[CH2:4][CH:3]([CH:5]([C:10]3[CH:11]=[C:12]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]([F:9])([CH3:8])[CH3:7])[CH2:2]2)=[CH:37][CH:36]=1)#[N:39]
Reactant: CCOC(=O)c1cc(F)cc(C(C2CNC2)C(C)(C)F)c1
Reactant: N#Cc1ccc(C(Br)c2cccc(C#N)c2)cc1
Product: CCOC(=O)c1cc(F)cc(C(C2CN(C(c3ccc(C#N)cc3)c3cccc(C#N)c3)C2)C(C)(C)F)c1

Procedure:
Prepared from ethyl 3-(1-azetidin-3-yl-2-fluoro-2-methylpropyl)-5-fluorobenzoate and 3-[bromo(4-cyanophenyl)methyl]benzonitrile as described in Preparation 17, Part 5; Mass Spectrum: m/e=514.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22]([OH:24])=O)=[CH:18][CH:17]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:49][O:50][C:51]1[CH:56]=[CH:55][C:54]([NH2:57])=[CH:53][CH:52]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.O>[CH3:49][O:50][C:51]1[CH:56]=[CH:55][C:54]([NH:57][C:22](=[O:24])[CH2:21][O:20][C:19]2[CH:25]=[CH:26][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][CH:18]=2)=[CH:53][CH:52]=1
Reactant: COc1ccc(N)cc1
Reactant: COc1cc2nccc(Oc3ccc(OCC(=O)O)cc3)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc(NC(=O)COc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1
Yield: 75.6 %

Procedure:
2-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenoxy}acetic acid (150 mg), WSC.HCl (122 mg), and HOBT.H2O (86 mg) were dissolved in chloroform (5 ml) to prepare a solution. p-Anisidine (63 mg) was then added to the solution, and the mixture was heated under reflux for 4 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with 1 N hydrochloric acid, water, and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development to give the title compound (147 mg, yield 76%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][C:11]2([CH2:16][CH2:15][C:14]([OH:23])([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl[CH2:28][CH2:29][N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.[OH-].[K+].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][C:11]2([CH2:12][CH2:13][C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)([O:23][CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:15][CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCC(O)(c1cccnc1)CC2
Reactant: ClCCN1CCCC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCC(OCCN1CCCC1)(c1cccnc1)CC2
Yield: 34 %

Procedure:
A mixture of 3-hydroxy-3-pyridin-3-yl-9-azaspiro[5.5]undecane-9-carboxylic acid tert-butyl ester (0.867 mmol), 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (1.3 mmol, 1.5 equiv.), dry KOH powder (4.33 mmol, 5 equiv.) and catalytic amounts of 18-Crown-6 in toluene (20 ml) was heated for 16 hours at boiling temperature. The reaction mixture was diluted with ethyl acetate (25 ml) and washed with distilled water (10 ml) and saturated sodium chloride solution (10 ml). The organic phase was dried over sodium sulfate and concentrated. The crude product was then purified by column chromatography (5% MeOH in DCM). Yield: 34%
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([S:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)(=[O:20])=[O:19])[C:9]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:10]=2[F:17])=[CH:6][N:5]=[C:4]([C:31]([NH2:33])=[O:32])[CH:3]=1.C=O.[OH-].[Na+].[C:38](OCC)(=[O:40])C>COCCOC>[OH:40][CH2:38][NH:33][C:31]([C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([CH:8]([S:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)(=[O:20])=[O:19])[C:9]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:10]=2[F:17])=[CH:6][N:5]=1)=[O:32]
Reactant: Cc1cc(C(N)=O)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(C(F)(F)F)nc1
Reactant: CCOC(C)=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: Cc1cc(C(=O)NCO)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(C(F)(F)F)nc1
Reaction time: 16 h
Yield: 73 %

Procedure:
To a solution of 4-methyl-5-[[[6-(trifluoromethyl)pyridin-3-yl]sulfonyl](2,3,6-trifluorophenyl)methyl]pyridine-2-carboxamide (147 mg, 0.300 mmol) in ethylene glycol dimethyl ether (0.8 ml), an aqueous solution of formaldehyde (37%, 0.200 ml) and 1 N aqueous sodium hydroxide (0.200 ml) were added at room temperature, and the mixture was stirred for 16 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=1:1 was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethyl acetate and diethyl ether, and then was collected by filtration to obtain the title compound (113 mg, 0.218 mmol, 73%) as a white solid.
Reaction SMILES: C(C1C=CC([C:11]2[O:15][N:14]=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH:24]=[O:25])=[CH:18][CH:17]=4)=CC=1C(F)(F)F)C(C)C.[CH2:30]([O:32][C:33]1[CH:34]=[C:35](C2ON=C3C4C(CCC=23)=CC(C=C)=CC=4)[CH:36]=[CH:37][C:38]=1[O:39][CH2:40][CH3:41])[CH3:31]>>[CH2:40]([O:39][C:38]1[CH:37]=[C:36]([C:11]2[O:15][N:14]=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH:24]=[O:25])=[CH:18][CH:17]=4)[CH:35]=[CH:34][C:33]=1[O:32][CH2:30][CH3:31])[CH3:41]
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1ccc(OCC)c(OCC)c1
Reactant: CC(C)Cc1ccc(-c2onc3c2CCc2cc(C=O)ccc2-3)cc1C(F)(F)F
Product: CCOc1ccc(-c2onc3c2CCc2cc(C=O)ccc2-3)cc1OCC

Procedure:
This compound was prepared according to the general procedure described for Preparation 23D, employing 67 mgs of 3-(3,4-diethoxyphenyl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (80A). Yield: 67 mgs (99%); LC/MS M+1=364.
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH2:9][OH:10]>[O-2].[O-2].[Mn+4].CCOCC>[CH3:1][CH:2]([CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH:9]=[O:10]
Reactant: CC(C)CCCCC#CCO
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOCC
Product: CC(C)CCCCC#CC=O

Procedure:
Oxidation of 8-methylnon-2yn-1-ol with manganese dioxide in refluxing ether gave 8-methylnon-2yn-1-al. The aldehyde was converted to acetals using appropriate acidic catalysts.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([Cl:20])=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>ClCCl.O1CCOCC1>[ClH:20].[Cl:20][C:15]1[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccnc2Cl)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Clc1ncccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
Dissolve 4-(2-chloro-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (8.300 g, 27.872 mmol) in dichloromethane (200 mL). Slowly add 4N HCl in dioxane (42 mL). Stir at room temperature for 8 hours. Concentrate and wash the resulting solid with diethyl ether to afford the title preparation (7.500 g, 99% yield). MS ES: m/z=198 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O.C(O)C.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>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:23]3[CH:24]=[CH:25][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:21][CH:22]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Brc1ccc2c(ccn2Cc2ccccc2)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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: FC(F)(F)c1ccc(-c2ccc3c(ccn3Cc3ccccc3)c2)cc1
Yield: 11.6 %

Procedure:
Following the procedure described in Step 2 of Example 5 1-benzyl-5-bromo-1H-indole (2.22 g , 7.76 mmol) was coupled to 4-trifluoromethylphenyl boronic acid (1.62 g, 8.54 mmol), using tetrakis(triphenylphosphine)palladium (0.892 g, 0.772 mmol), and potassium carbonate (4.29 g, 31.1 mmol) in water (17 mL), ethanol (4 mL), and toluene (37 mL). Purification by flash chromatography using 0.5-1.0% ethyl acetate in hexane as eluant afforded the title compound as a light yellow solid (0.317 g, 12%). 1HNMR (200 MHz, DMSO-d6): δ 7.7-8.0 (m, 5H), 7.4-7.6 (m, 3H), 7.15-7.4 (m, 5H), 6.6 (d, 1H, J=3.6 Hz), and 5.45 ppm (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[C:3]=1[CH:9]1[O:14][CH2:13][CH2:12][CH2:11][O:10]1.[CH3:15][O:16][C:17](=[O:24])[C:18]([NH:20][C:21](=[O:23])[CH3:22])=[CH2:19].C(=O)(O)[O-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[CH3:15][O:16][C:17](=[O:24])[C:18]([NH:20][C:21](=[O:23])[CH3:22])=[CH:19][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[CH:9]1[O:14][CH2:13][CH2:12][CH2:11][O:10]1
Reactant: C=C(NC(C)=O)C(=O)OC
Reactant: Fc1cccc(I)c1C1OCCCO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: COC(=O)C(=Cc1cccc(F)c1C1OCCCO1)NC(C)=O
Yield: 12.4 %

Procedure:
A DMF (10 ml) solution of 2-(2-fluoro-6-iodo-phenyl)-[1,3]dioxane (1.85 g, 6 mmol), 2-acetylamino-acrylic acid methyl ester (906 mg, 6.33 mmol), sodium bicarbonate (1.26 g, 15 mmol), tetrabutyl ammonium chloride (1.35 g, 4.86 mmol) and palladium (II) acetate (52 mg, 0.23 mmol) is heated at 90° C. for 1.8 hours. The reaction mixture is poured onto water and the aqueous phase is extracted with ethylacetate. The organic layer is washed with brine and dried over MgSO4 and evaporated. The crude product is purified by chromatography (CH2Cl2/MeOH, 95/5) to afford the desired compound (240 mg). MS (ES+): m/e=346.3, (MNa+)
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[CH2:6]1[O:12][CH2:11][C@@H:9]([OH:10])[C@H:7]1[OH:8].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][Si:2]([CH3:4])([CH3:3])[O:8][CH:7]1[CH:9]([O:10][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH2:11][O:12][CH2:6]1
Reactant: C[Si](C)(C)Cl
Reactant: O[C@@H]1COC[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)OC1COCC1O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 107.6 %

Procedure:
TMSCl (8.0 mL, 63.32 mmol) was added dropwise to a solution of 1,4-anhydroerythritol (3.0 g, 28.81 mmol), triethylamine (9.2 mL, 66.0 mmol) and DMAP (few crystals) in dichloromethane (200 mL) at 0° C. The reaction was allowed to slowly warm to room temperature over 1 h and then stirred for an additional 3 h. The solid was filtered and the filtrate concentrated to give a solid. The solid was then filtered through a short silica gel column eluting with 33% hexanes in ethyl ether. Removal of solvents under reduced pressure provided 3,4-bis-trimethylsilanyloxy-tetrahydro-furan (7.7 g, ˜100%) as a colorless liquid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[H-].[Na+].[CH2:11](Br)[CH3:12]>O1CCCC1>[CH2:11]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[CH3:12]
Reactant: CCBr
Reactant: Oc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc(O)cc1

Procedure:
Hydroquinone can be added to a solution of sodium hydride (NaH) dissolved in tetrahydrofuran (THF) and combined with ethyl bromide yielding para-ethoxyphenol. The para-ethoxyphenol can be extracted and added to a solution of tosyl chloride (TsCl) dissolved in pyridine and tetrahydrofuran (THF) at room temperature, yielding para-ethoxytosyloxybenzene. The para-ethoxytosyloxybenzene can be extracted and added to a solution of diatomic iodine (I2) and potassium iodide trioxide (KIO3) dissolved in sulfuric acid (H2SO4) and acetic acid (CH3COOH) yielding 4-ethoxy-3-iodo-1-tosyloxybenzene. The 4-ethoxy-3-iodo-1-tosyloxybenzene is extracted and added to a solution of aqueous sodium hydroxide (NaOH) and tert-butanol, removing the tosylate protecting group and yielding 4-ethoxy-3-iodophenol. The 4-ethoxy-3-iodophenol can be extracted and exposed to resin-bound triphenylphosphine (PPh3) in a solution of azopyridine and methanol (CH3OH) in a salt bath at 0° C., yielding 4-ethoxy-3-iodomethoxybenzene. The 4-ethoxy-3-iodomethoxybenzene can be extracted and added to a solution of titanium tetrachloride (TiCl4) and 1,1-dichlorodimethylether (CHCl2OCH3) dissolved in dichloromethane (CH2Cl2) in a salt bath at −10° C., yielding 2-methoxy-4-iodo-5-ethoxybenzaldehyde. The 2-methoxy-4-iodo-5-ethoxybenzaldehyde can be extracted and half of the yield can be added to tri-iso-propylsilylacetylene (TIPS-acetylene) in an amine solvent such as triethylamine, diethylamine, piperidine, or di-iso-propylethylamine. This mixture can be passed over a palladium (Pd) catalyst bed, yielding 2-methoxy-5-ethoxy-4-((tri-iso-propylsilyl)ethynyebenzaldehyde.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.[OH-].[Na+].O>[N:12]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: c1c[nH]cn1
Reactant: COC(=O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1ccc(-n2ccnc2)cc1
Reaction time: 5 h

Procedure:
Combine methyl 4-fluorobenzoate (1.52 g, 10 mmol), 1H-imidazole (0.82g, 12 mmol) and potassium carbonate (1.40 g, 10 mmol) in dimethylsulfoxide (7 mL) and heat the mixture with stirring at 120°-130° C. for 5 hours, cool, add water and acid, extract with ether. Adjust the pH of the aqueous layer to 8 with sodium carbonate, extract with ether, dry the extract with sodium sulfate and evaporate. 4-(1H-Imidazol -1-yl)benzoic acid is prepared by refluxing this methyl ester (0.61 g, 3 mmol) in 5 mL of 10% aqueous sodium hydroxide for five minutes; cool, neutralize to pH 6-7 with hydrochloric acid, filter and dry the precipitated acid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:9]([NH:11][CH3:12])=[O:10])[CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[S:21][C:22]([C:28]2[C:33]([F:34])=[CH:32][C:31]([C:35]([OH:38])([CH3:37])[CH3:36])=[CH:30][C:29]=2[F:39])=[CH:23][C:24]=1[C:25]([NH2:27])=[O:26]>>[F:39][C:29]1[CH:30]=[C:31]([C:35]([OH:38])([CH3:37])[CH3:36])[CH:32]=[C:33]([F:34])[C:28]=1[C:22]1[S:21][C:20]([NH:19][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:9]([NH:11][CH3:12])=[O:10])[N:7]=2)=[C:24]([C:25]([NH2:27])=[O:26])[CH:23]=1
Reactant: CNC(=O)C(c1cccc(Br)n1)N1CCOCC1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CNC(=O)C(c1cccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1)N1CCOCC1

Procedure:
The title compound was synthesized from 2-(6-bromopyridin-2-yl)-N-methyl-2-morpholin-4-ylacetamide (120 mg, 0.38 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (125 mg, 0.40 mmol) according to the procedure described in Example 1.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.Cl.[F:37][CH2:38][CH2:39][NH2:40].C(N(CC)C(C)C)(C)C>O1CCCC1>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:40][CH2:39][CH2:38][F:37])[N:3]=3)[N:25]=2)=[CH:30][CH:31]=1
Reactant: NCCF
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCCF)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
140 mg (0.260 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A), 52 mg (0.519 mmol) of 2-fluoroethylamine hydrochloride and 67 mg (0.519 mmol) of N,N-diisopropylethylamine were dissolved in 2 ml of tetrahydrofuran and stirred at room temperature overnight. Without further work-up, the reaction mixture was purified by preparative HPLC. 78 mg (yield: 53% of theory) of the target compound were obtained.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][CH:13]=O.[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([CH2:25][N:26]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([CH2:25][N:26]([CH:34]3[CH2:39][CH2:38][N:37]([CH2:13][CH2:12][N:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][N:5]=5)[CH:10]=[CH:11][C:2]4=[O:1])[CH2:36][CH2:35]3)[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: O=CCn1c(=O)ccc2cccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3cccnc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
To a solution of 0.75 g of (2-oxo-1,8-naphthyridin-1(2H)-yl)acetaldehyde in 40 mL of dichloromethane, 1.4 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 0.23 mL of acetic acid and 1.3 g of sodium triacetoxyborohydride were added, and the mixture was stirred at room temperature for 2 hours. Thereto were added water, a saturated aqueous sodium hydrogen carbonate solution and chloroform, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol=200:3 to obtain 1.4 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-oxo-1,8-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white foam.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14]CC)=O)[N:3]=1.[F:17][C:18]1[CH:19]=[C:20]([Mg]Br)[CH:21]=[CH:22][CH:23]=1>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([F:17])[CH:23]=2)=[O:14])[N:3]=1
Reactant: CCOC(=O)c1nc(Cl)c2ccccc2n1
Reactant: Fc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: O=C(c1cccc(F)c1)c1nc(Cl)c2ccccc2n1
Temperature: -20 °C
Reaction time: 4 h

Procedure:
To a suspension of ethyl 4-chloroquinazoline-2-carboxylate (237 mg, 1 mmol) in THF (5 mL) was added dropwise a 1M solution of 3-fluorophenylmagnesium bromide in THF (2 mL, 2 mmol) at −20° C. The reaction mixture was stirred at −20° C. for 4 h. The mixture was quenched by adding 0.5 N HCl solution (5 mL) and the biphasic mixture was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine and dried over MgSO4. (4-chloroquinazolin-2-yl)(3-fluorophenyl)methanone was obtained as a yellow solid (190 mg, 66%). LC-MS (ESI) m/z 287 (M+H)+.