Azzindani/Open_Reaction_Data huggingface dataset:
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:34])([F:33])[C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:22]3[CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=[C:20]([C:19]([F:18])([F:34])[F:33])[CH:21]=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: Brc1ccc2c(ccn2Cc2ccccc2)c1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: FC(F)(F)c1cc(-c2ccc3c(ccn3Cc3ccccc3)c2)cc(C(F)(F)F)c1
Temperature: 85 °C
Yield: 51.2 %

Procedure:
1-Benzyl-5-[3,5-bis(trifluoromethyl)phenyl]-1H-indole was prepared by coupling 1-benzyl-5-bromo-1H-indole (1.44 g, 5.03 mmol), and 3,5-bis-(trifluoromethyl)phenylboronic acid (1.63 g, 6.32 mmol), using [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.211 g, 0.258 mmol), and potassium carbonate (1.38 g, 9.98 mmol) in dioxane (54 mL) and water (5.4 mL) following the procedure described in Step 1 of Example 11. The reaction mixture was heated to 85° C. for 3 hours. Purification by HPLC using 10% methylene chloride in hexane as the mobile phase furnished the title compound as a light yellow solid (1.08 g, 51%), mp: 90-95° C. 1HNMR (200 MHz, DMSO-d6): δ 8.3 (s, 2H), 8.1 (s, 1H), 8.0 (s, 1H), 7.6 (s, 3H), 7.15-7.4 (m, 5H), 6.6 (d, 1H, J=2.6 Hz), and 5.5 ppm (s, 2H).
Reaction SMILES: O.O.O.O.O.O.O.O.O.[N+]([O-])([O-])=O.[Al+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[CH3:23][CH2:24][CH2:25][CH2:26][C:27]#[C:28][CH2:29][CH2:30][CH2:31][CH3:32]>C1COCC1.O.O.O.O.[Rh](Cl)(Cl)Cl.O.[N+]([O-])([O-])=O.[Cu+2].O.O.O.O.[N+]([O-])([O-])=O.[Cu+2].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>[CH3:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCC#CCCCC
Agent: Cl[Rh](Cl)Cl
Agent: [Cu+2]
Agent: O=[N+]([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CCCC/C=C\CCCC
Reaction time: 0.17 h

Procedure:
To a solution of rhodium(III) chloride trihydrate (1.3 mg, 0.005 mmol), copper(II) nitrate hemipentahydrate (2.90 mg, 0.0125 mmol) and aluminum(III) nitrate nonahydrate (0.188 g, 0.50 mmol) in a mixture of THF (2.5 mL) and water (0.5 mL) is added 5-decyne (69 mg, 0.50 mmol). The solution is stirred for 10 minutes and then triethoxysilone (0.21 g, 1.25 mmol) is added. The system is closed and stirred at room temperature for 7 hours. The volatiles are removed in vacuo. A mixture of hexane (5 mL) and ether (1 mL) is added. The solution is dried over magnesium sulfate and filtered through a one inch plug of silica gel. The substrate is eluted with hexane/ether (5:1). The solvent is removed in vacuo to give Z-5-decene.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][NH:5][C:6]1[O:7][CH2:8][C:9](=[O:15])[C:10]=1[C:11]([O:13][CH3:14])=[O:12].C(OC)(=O)CC(OC)=O.ClCC(Cl)=O.FC1C=CC=CC=1CN.[NH:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][N:50]=2)[C:45]([CH:52]=O)=[CH:44]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:43]1[C:51]2=[N:50][CH:49]=[CH:48][CH:47]=[C:46]2[C:45]([CH:52]=[C:8]2[O:7][C:6]([NH:5][CH2:4][C:3]3[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=3[F:1])=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C:9]2=[O:15])=[CH:44]1
Reactant: COC(=O)C1=C(NCc2ccccc2F)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: NCc1ccccc1F
Agent: O=C(Cl)CCl
Agent: O=C(O)[C@@H]1CCCN1
Solvent: COC(=O)CC(=O)OC
Solvent: CCO
Product: COC(=O)C1=C(NCc2ccccc2F)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 22 %

Procedure:
To a solution of methyl 2-[(2-fluorobenzyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.35 g, 1.5 mmol) which similarly prepared according to the procedure described in the Example 4, First step using dimethyl malonate, chloroacetyl chloride and 2-fluorobenzylamine, and 7-azaindole-3-carboxaldehyde (0.22 g, 1.5 mmol) in ethanol (10 mL), L-proline (0.018 g, 0.15 mmol) was added at ambient temperature. The mixture was refluxed for 3 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with methanol then dried to afford the titled compound as solid (0.13 g, y. 24%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]([NH:12][C:13]1[NH:14][C:15]2[C:20]([C:21]=1[C:22]([NH2:24])=[O:23])=[CH:19][CH:18]=[C:17]([O:25][CH3:26])[CH:16]=2)=[O:11]>CN(C)C=O.O>[NH2:9][C:10]([NH:12][C:13]1[NH:14][C:15]2[C:20]([C:21]=1[C:22]([NH2:24])=[O:23])=[CH:19][C:18]([Br:1])=[C:17]([O:25][CH3:26])[CH:16]=2)=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(C(N)=O)c(NC(N)=O)[nH]c2c1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2[nH]c(NC(N)=O)c(C(N)=O)c2cc1Br
Reaction time: 1.5 h
Yield: 30 %

Procedure:
Under ice-cooling, a solution of N-bromosuccinimide (94 mg, 0.53 mmol) in anhydrous N,N-dimethylformamide (1 mL) was added to a solution of 2-aminocarbonylamino-6-methoxyindole-3-carboxamide (Compound No.1-1, 126 mg, 0.51 mmol) in anhydrous N,N-dimethylformamide (1.5 mL) and the mixture was stirred for 1.5 hours. Moreover the whole was stirred for 2 hours at room temperature and stirred for 3 hours at 50° C. After the reaction solution was diluted with water (60 mL) and extracted with ethyl acetate (50 mL), the organic layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, the obtained solid was filtered off and washed with a mixed solvent of diethyl ether-chloroform solution (5:1, 24 mL). The solid was dried at 40° C. under reduced pressure to give the title compound (50 mg) as a gray solid (30%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:32]([C:33]#[N:34])=[C:18]3[N:19]=[CH:20][CH:21]=[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[N+:29]([O-])=O)[N:17]3[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.C(Cl)Cl.[Pd]>[NH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH:22]1[N:17]2[N:16]=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[C:32]([C:33]#[N:34])=[C:18]2[NH:19][CH2:20][CH2:21]1
Reactant: N#Cc1c(-c2ccc(OCc3ccccc3)cc2)nn2c(-c3ccccc3[N+](=O)[O-])ccnc12
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: N#Cc1c(-c2ccc(O)cc2)nn2c1NCCC2c1ccccc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.1 %

Procedure:
To a solution of 2-(4-(benzyloxy)phenyl)-7-(2-nitrophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (2 g, 4.47 mmol) in CH3OH (20 mL) and DCM (20 mL) was added 10% w/w Pd/C (300 mg). The mixture was stirred at RT under H2 for 16 hr. Filtered and purified by chromatography column on silica gel (elution with DCM/CH3OH) to afford 0.92 g (62%) of 7-(2-aminophenyl)-2-(4-hydroxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile as a yellow solid. MS (ESI, m/e) [M+1]+ 331.9.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH3:6][CH:7]1[C:12](=[O:13])[NH:11][C:10](=[S:14])[NH:9][C:8]1=[O:15].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(O)C>O>[OH:15][C:8]1[C:7]([CH3:6])=[C:12]([OH:13])[N:11]=[C:10]([S:14][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:9]=1
Reactant: CCOC(=O)CBr
Reactant: CC1C(=O)NC(=S)NC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CSc1nc(O)c(C)c(O)n1
Yield: 54.3 %

Procedure:
To a solution of 4.0 g (0.0475 mole) of sodium bicarbonate in 40 ml of water was added with stirring 7.5 g (0.0475 mole) of 5-methyl-2-thiobarbituric acid. Ethyl bromoacetate (7.9 g, 0.0475 mole) was then added and 40 ml of ethanol to make a clear solution. After one-half hour a precipitate was formed. Stirring was continued for one-half hour at room temperature. The precipitate was collected and recrystallized from ethanol to give 6.3 g of (4,6-dihydroxy-5-methyl-2-pyrimidinylthio)acetic acid, ethyl ester mp. 211°-214°C.
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH:5]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>C(Cl)Cl>[C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH:5]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH2:21][CH2:22][C:23]([N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)=[O:24])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2SC1c1ccccc1OCCCC(=O)O
Reactant: C1COCCN1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1c2ccccc2SC1c1ccccc1OCCCC(=O)N1CCOCC1
Temperature: -13 °C

Procedure:
To the solution of 1.79 g of 3-acetyl-2-[2-[3-(carboxy)-propoxy]phenyl]benzothiazoline and 0.51 g of triethylamine in 20 ml of anhydrous methylene chloride, 0.68 g of isobutyl chloroformate is added dropwise while stirring at -13° C. and stirred additional 10 minutes at the same temperature. To the solution 0.44 g of morpholine in 5 ml of methylene chloride is added dropwise.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:10]1([C:13](Cl)=O)[CH2:12][CH2:11]1>>[CH:10]1([CH:13]2[C:8]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:2][CH2:1][NH:9]2)[CH2:12][CH2:11]1
Reactant: NCCc1ccccc1
Reactant: O=C(Cl)C1CC1
Product: c1ccc2c(c1)CCNC2C1CC1

Procedure:
In accordance with the same procedures as in Preparation 1-1, except that 12.5 ml of phenethylamine (0.1M) and 10 ml of cyclopropane carbonylchloride(0.11M) were used as starting materials, 2.5 g of the title compound was prepared.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[C:20](=O)[C:19]2[CH:22]=[CH:23][C:24]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:25][C:18]=2[O:17][CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].[Cl-].[NH4+]>O.C1COCC1.C(OCC)C>[CH2:7]([N:14]1[CH2:20][C:19]2[CH:22]=[CH:23][C:24]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:25][C:18]=2[O:17][CH2:16][CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1c2ccc(Oc3ccccc3)nc2OCCN1Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: c1ccc(CN2CCOc3nc(Oc4ccccc4)ccc3C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.5 %

Procedure:
To a mixture of lithium aluminum hydride (0.066 g) and THF-diethyl ether (2 mL-10 mL) was added the compound obtained in step 2 (0.40 g), and the resulting mixture was stirred at room temperature for 3 hr under a nitrogen atmosphere. Lithium aluminum hydride (0.066 g) was added again, and the resulting mixture was stirred at room temperature for 2 hr under a nitrogen atmosphere. 1N Aqueous sodium hydroxide solution (0.13 mL), saturated aqueous ammonium chloride (0.13 mL) and water (0.13 mL) were added, and the resulting mixture was stirred at room temperature for 4 hr. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give 4-benzyl-8-phenoxy-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.19 g, 50%) as a white powder.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[N:9]=[CH:10][C:11]([C:14]([OH:16])=O)=[N:12][CH:13]=1.[NH:17]1[CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[N:17]1([C:14]([C:11]2[CH:10]=[N:9][C:8]([Cl:7])=[CH:13][N:12]=2)=[O:16])[CH2:20][CH2:19][CH2:18]1
Reactant: C1CNC1
Reactant: O=C(O)c1cnc(Cl)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cnc(Cl)cn1)N1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
Oxalyl chloride (1.55 mL, 17.48 mmol), followed by DMF (2 drops), was added to a mixture of 5-chloropyrazine-2-carboxylic acid (2.31 g, 14.57 mmol) in DCM (40 mL). The reaction was stirred at RT for 2 hours after which time the volatiles were removed in vacuo. The residue was taken up DCM (40 mL) and azetidine (1.08 mL, 16.03 mmol) and triethylamine (4.46 mL, 32.06 mmol) added. The mixture was stirred at RT for 72 hours. The volatiles were removed in vacuo and ethyl acetate (100 mL) added to the residue. The organics were washed with water (100 mL), citric acid (50 mL), saturated sodium bicarbonate solution (50 mL), brine (50 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a yellow solid. The residue was chromatographed on silica, eluting with a gradient of 50-100% ethyl acetate in iso-hexane, to give the desired compound as a yellow solid (2.38 g). 1H NMR δ (CDCl3): 2.35-2.42 (2H, m), 4.26 (2H, t), 4.67 (2H, t), 8.52 (1H, d), 9.09 (1H, d); m/z 198 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5](N)=[C:4]([CH3:10])[CH:3]=1.Cl.N([O-])=O.[Na+].C(=O)(O)[O-].[Na+].[C-]#N.[K+].[Cu][C:25]#[N:26]>O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:25]#[N:26])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)cc(C)c1N
Reactant: N#C[Cu]
Agent: Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: O
Product: Cc1cc(Br)cc(C)c1C#N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-bromo-2,6-dimethylbenzenamine (20 g, 100 mmol) and conc. HCl (100 mL) in water (100 mL) was sonicated for 5 min and then cooled to 0° C. A solution of sodium nitrite (6.9 g, 100 mmol) in water (25 mL) was added, and the resulting mixture was stirred at 0° C. for 30 min, then neutralized by the addition of solid sodium bicarbonate. The resulting mixture was slowly poured (in portions) into a solution of potassium cyanide (6.5 g, 100 mmol) and copper(I) cyanide (9.0 g, 100 mmol) in water (50 mL). The resulting mixture was heated at 70° C. for 30 min, then cooled to 25° C. and extracted with EtOAc (3×150 mL). The combined extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to provide 4-bromo-2,6-dimethylbenzonitrile as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.56 (s, 2 H), 2.45 (s, 6 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:13][Si](C=[N+]=[N-])(C)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C1C=CC=CC=1.CO>[CH3:13][O:10][C:9](=[O:11])[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[O:12]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)C(O)c1cccc(Br)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)C(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.7 %

Procedure:
(3-Bromo-phenyl)-hydroxy-acetic acid (526.4 mg, 2.23 mmol) was dissolved in benzene (6 mL) and methanol (3 mL). Trimethylsilyldiazomethane (2 M solution in diethyl ether, 1.23 mL, 2.46 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was concentrated under reduced pressure, and then the residue was dissolved in dichloromethane (11.2 mL). Dess-Martin periodinane (1.95 g, 4.47 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. A saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium thiosulfate solution were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and brine and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 85:15) to give the title compound (502.2 mg, 95% in two steps).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([F:14])=[C:5](/[C:7](=[N:12]/[OH:13])/[C:8]([O:10]C)=[O:9])[N:6]=1.B(Cl)(Cl)Cl.O1CCCC1.C(=O)(O)[O-].[Na+]>ClCCl.[Cl-].[Na+].O>[NH2:1][C:2]1[S:3][C:4]([F:14])=[C:5](/[C:7](=[N:12]/[OH:13])/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: COC(=O)/C(=N\O)c1nc(N)sc1F
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc(/C(=N/O)C(=O)O)c(F)s1
Yield: 35.3 %

Procedure:
To a suspension of methyl 2-(2-amino-5-fluorothiazol-4-yl)-2-(Z)-(hydroxyimino)acetate (1 g) in dichloromethane (20 ml) was added dropwise 1M borontrichloride solution in dichloromethane (22.8 ml) under ice-cooling with stirring, and the mixture was stirred for 3 hours at 50° C. to 10° C. The resulting solution was poured into a mixture of tetrahydrofuran (30 ml) and brine (15 ml), and adjusted to pH 3.0 with saturated aqueous sodium bicarbonate. The separated organic phase was dried with magnesium sulfate and evaporated in vacuo. The residue was subjected to a column chromatography on silica gel and eluted with a mixture of ethyl acetate and methanol (2:1). The fractions containing the object compound were combined and evaporated in vacuo to give 2-(2-amino-5-fluorothiazol-4-yl)-2-(Z)-(hydroxyimino)acetic acid (330.26 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14](/[CH:17]=[CH:18]/[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([Cl:27])[CH:26]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:28][OH:29]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([S:14]([CH2:17][CH:18]([NH:28][OH:29])[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([Cl:27])[CH:26]=3)(=[O:15])=[O:16])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(/C=C/CCc1cncc(Cl)c1)N1CCN(c2ccc(Cl)cc2)CC1
Reactant: NO
Solvent: C1CCOC1
Product: O=S(=O)(CC(CCc1cncc(Cl)c1)NO)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 1-(4-chlorophenyl)-4-{[(1E)-4-(5-chloropyridin-3-yl)but-1-enyl]sulfonyl}piperazine (crude from previous step), in THF (10 mL) at RT was added a solution of hydroxylamine (2 mL, 50% aqueous solution in water). The reaction was stirred for 3 hours at RT before being quenched with saturated aqueous ammonium chloride solution (5 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (3×10 mL). The combined organic extracts were then dried, (MgSO4), filtered and concentrated in vacuo. The residue was then purified by flash chromatography (silica, 100% ethyl acetate) to give the title compound (100 mg, 0.22 mmol).
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:5]=[CH:6][C:7]2[CH2:13][CH2:12][N:11](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:10][C:8]=2[N:9]=1)[CH3:2].[ClH:33]>CO.O1CCOCC1>[ClH:33].[CH2:1]([S:3][C:4]1[N:5]=[CH:6][C:7]2[CH2:13][CH2:12][NH:11][CH2:10][C:8]=2[N:9]=1)[CH3:2]
Reactant: CCSc1ncc2c(n1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCSc1ncc2c(n1)CNCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A suspension of 81 mg (0.185 mmol) of trityl compound from Step D in 0.5 mL of methanol was treated with 4 N hydrogen chloride solution in dioxane. The reaction mixture was stirred at ambient temperature for 2 h, then concentrated under nitrogen and then in vacuo. Trituration with ether gave 47 mg (˜100%) of the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]#[C:11][C:12]2[C:13]([CH3:24])=[N:14][CH:15]=[N:16][C:17]=2[N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:5][N:4]=1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[S:30](Cl)(=[O:32])=[O:31].N1C=CC=CC=1.O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([NH:9][S:30]([C:26]2[S:25][CH:29]=[CH:28][CH:27]=2)(=[O:32])=[O:31])=[CH:7][C:6]([C:10]#[C:11][C:12]2[C:13]([CH3:24])=[N:14][CH:15]=[N:16][C:17]=2[N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[CH:5][N:4]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COc1ncc(C#Cc2c(C)ncnc2N2CCOCC2)cc1N
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COc1ncc(C#Cc2c(C)ncnc2N2CCOCC2)cc1NS(=O)(=O)c1cccs1
Temperature: 25 °C

Procedure:
To 100 mg (0.31 mmol) 2-Methoxy-5-(4-methyl-6-morpholin-4-yl-pyrimidin-5-ylethynyl)-pyridin-3-ylamine (E-9) in 5 mL DCM is added 112 mg (0.61 mmol) thiophen-2-sulfonyl chloride and 72 μL (0.97 mmol) pyridine and the reaction mixture is stirred over night at RT. Water (2 mL) is added, the mixture is shaken for five minutes, the aqueous phase is separated and is extracted three times with 4 mL DCM. The combined organic phases are dried over MgSO4 and concentrated under reduced pressure. The crude product is purified by RP chromatography (C18, 20-80% ACN in water containing 1% formic acid). Yield: 95 mg (65%). HPLC-MS: M+H=472; tR=0.82 min.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[CH3:21]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].CI>O>[CH3:21][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:13])[F:14])[CH:7]=2)[C:2](=[O:1])[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4]1
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: CCOC(=O)c1cn(C)c2cc(C(F)(F)F)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 105 %

Procedure:
A slurry of ethyl 4-hydroxy-7-(trifluoromethyl)quinoline-3-carboxylate (10.0 g, 35.1 mmol), DMF (50 mL), potassium carbonate (12.11 g, 88.00 mmol), and methyl iodide (11.00 ml, 175.0 mmol) was heated to 90° C. After 20 minutes, the dark solution was cooled to room temperature and water (25 mL) was added slowly, keeping the temperature <40° C. The reaction mixture was cooled to ambient temperature, and the brown slurry was filtered and washed with 2:1 DMF/water (20 mL×2) and water (20 mL×2). The solids were partially dried on the frit giving the title compound (11.0 g, 36.8 mmol, 105% yield), which was used without further purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:24](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:13]([O:15][CH3:24])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(=Cc2ccc(OC)c(OC)c2)C(=O)O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C(=Cc1ccc(OC)c(OC)c1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
3-(3,4-dimethoxyphenyl)-2-(4-methoxyphenyl)prop-2-enoic acid (2 g, 6.37 mmol) was dissolved in dimethyl formamide (DMF) (4 mL) and added potassium carbonate (K2CO3) (2.28 g, 16.6 mmol) followed by methyl iodide (CH3I) (0.48 mL, 7.64 mmol) drop wise. The reaction mixture was stirred for 2 hours at room temperature (RT) and the reaction was monitored by TLC. Upon the completion of reaction, K2CO3 was filtered and cold water (100 mL) was added to the filtrate. The resulting precipitate was filtered to get pale yellow solid (2 g, 100%).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].C(=O)([O-])[O-].[Ca+2].ClCCl.[CH:13]([C:17]1[CH:23]=[C:22]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[C:20]([CH:31]([CH2:33][CH3:34])[CH3:32])[C:18]=1[NH2:19])([CH2:15][CH3:16])[CH3:14]>ClC(Cl)C.O>[CH:31]([C:20]1[CH:21]=[C:22]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[C:17]([CH:13]([CH2:15][CH3:16])[CH3:14])[C:18]=1[N:19]=[C:1]=[S:2])([CH2:33][CH3:34])[CH3:32]
Reactant: S=C(Cl)Cl
Reactant: CCC(C)c1cc(Cc2ccccc2)cc(C(C)CC)c1N
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCC(C)c1cc(Cc2ccccc2)cc(C(C)CC)c1N=C=S
Reaction time: 2 h

Procedure:
14.3 g of thiophosgene, 23.0 g of calcium carbonate and 460 ml of dichloromethane are stirred with 230 ml of water. A solution of 30.8 g of 2,6-di-sec-butyl-4-benzylaniline in 200 ml of dichloroethane is stirred dropwise into this mixture at room temperature. The reaction mixture is stirred for two hours under reflux and, after cooling, is filtered over diatomaceous earth. The organic phase is separated from the filtrate, dried over sodium sulfate and freed of the solvent to give the title compound of formula ##STR15## in the form of a yellow oil which is used without further purification for the next reaction.