Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH:3]1[CH2:8][CH:7]([CH:9]([CH3:11])[CH3:10])[CH2:6][CH2:5][C:4]1([OH:13])[CH3:12].[CH2:15]([Br:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]C.[CH3:23]N(C)C=O>O>[Br-:22].[CH3:14][N+:2]([CH3:23])([CH2:1][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:3]1[CH2:8][CH:7]([CH:9]([CH3:11])[CH3:10])[CH2:6][CH2:5][C:4]1([OH:13])[CH3:12]
Reactant: CC(C)C1CCC(C)(O)C(N(C)C)C1
Reactant: CCCCCCCBr
Reactant: CN(C)C=O
Solvent: O
Product: CCCCCCC[N+](C)(C)C1CC(C(C)C)CCC1(C)O
Product: [Br-]
Temperature: 90 °C

Procedure:
Five grams of 2-dimethylamino-1-p-menthanol and 10 g. of heptyl bromide were dissolved in 5 ml. of dimethylformamide. The solution was warmed at 90°C (under nitrogen) for 16 hours, cooled to room temperature and diluted with water (approximately 100 ml.). The mixture was transferred to a separatory funnel and washed three times with ethyl ether (20-25 ml.). The neutral, aqueous phase was concentrated to dryness on a film evaporator (at 50°C). Ninety-five percent ethanol was added to the flask contents to assist the azeotropic removal of water. Last traces of DMF were removed at high vacuum (1 mm.). Yield of dimethyl heptyl (1-hydroxy-p-menthan-2-yl) ammonium bromide was 10.2 g. (100T of theory).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.[Li]CCCC.[C:17](=[O:19])=[O:18]>C1COCC1.O>[Cl:11][C:9]1[C:10]2[C:2]([C:17]([OH:19])=[O:18])=[CH:3][NH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Clc1ncnc2[nH]cc(Br)c12
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1c[nH]c2ncnc(Cl)c12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (G-1) (6.24 g, 26.8 mmol, 1.0 eq) in anhydrous THF (100 mL) at −78° C. under argon, n-BuLi solution (2.5 M in THF, 23.6 mL, 59.0 mmol, 2.2 eq) is added dropwise over 30 min. The reaction mixture is stirred at −78° C. for 1 h and then dry ice (300 g) is added in portions under an argon atmosphere. The resulting mixture is allowed to warm to RT and then stirred at RT overnight. The reaction mixture is diluted with H2O (200 mL) and extracted with ethyl acetate (50 mL×4). The aqueous layer is acidified with conc. HCl to adjust the pH to 3-4. The precipitate is collected by filtration, rinsed with H2O (30 mL) and dried in vacuo to afford the product, 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (H-1).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[CH:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.[NH3:21].[CH2:22]([OH:24])[CH3:23]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:6]([CH2:5][OH:4])=[C:7]([CH:8]([NH:21][C:22](=[O:24])[CH3:23])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:16]=1
Reactant: CC(=O)OCc1ccc(Cl)cc1C(Br)c1ccccc1
Reactant: N
Reactant: CCO
Product: CC(=O)NC(c1ccccc1)c1cc(Cl)ccc1CO
Temperature: 100 °C

Procedure:
In a Parr bomb containing 47 g. of the compound of Example 5 in 200 ml. of ethanol, dry ammonia is introduced to a pressure of 5 atmospheres. After heating for 4 hours at 100° C., the resulting solution is evaporated. The oily residue is successively washed with light petroleum and diisopropyl ether, then it is taken up in a mixture of water and ethyl ether to give a solid which is used as such for the subsequent hydrolysis. Yield 16 g. A sample of the titular product crystallized from a mixture of ethyl ether and light petroleum melts at 131°-135° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH2:22][N:23](C)[C:24](=O)OC(C)(C)C)=[CH:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:32].NN.[C:35](=[O:38])([O-:37])O.[Na+].[C:40]([O:43]CC)(=[O:42])[CH3:41].Cl>O1CCCC1.C(O)C>[C:40]([OH:43])(=[O:42])/[CH:41]=[CH:2]/[C:35]([OH:37])=[O:38].[CH3:24][NH:23][CH2:22][C:13]1[CH:14]=[C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:11]([S:8]([C:5]2[CH:6]=[N:7][CH:2]=[C:3]([CH3:32])[CH:4]=2)(=[O:10])=[O:9])[CH:12]=1
Reactant: Cc1cc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2)cnc1Cl
Reactant: O=C([O-])O
Reactant: CCOC(C)=O
Agent: Cl
Agent: NN
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2cncc(C)c2)c1
Product: O=C(O)/C=C/C(=O)O
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a solution (5 mL) of tert-butyl {[1-(6-chloro-5-methyl-3-pyridinesulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}methylcarbamate (237 mg) in tetrahydrofuran was added hydrazine (160 mg) at room temperature with stirring. After stirring at the same temperature for 3 hr, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 mL), manganese dioxide (75% chemically treated product, 1.0 g) was added, and the mixture was stirred at room temperature for 10 min. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→1:1) to give an oil. The obtained oil was dissolved in ethanol (2 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added. After stirring at room temperature for 2 hr, the solvent was evaporated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue (93 mg) was dissolved in ethanol (3 mL), and fumaric acid (29 mg) was added. After allowing to stand at room temperature for 30 min, the precipitated crystals were collected by filtration and washed with methanol to give the title compound as a colorless solid (yield 91 mg, 40%).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[S:11](=O)(=[O:14])([OH:13])[OH:12].C(=O)([O-])[O-].[Na+:20].[Na+:21]>>[Na:20][Na:21].[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([S:11]([OH:14])(=[O:13])=[O:12])=[CH:8][C:2]=1[C:1]([OH:10])=[O:9]
Reactant: [Na+]
Reactant: Nc1ccccc1C(=O)O
Reactant: O=S(=O)(O)O
Agent: O=C([O-])[O-]
Product: Nc1ccc(S(=O)(=O)O)cc1C(=O)O
Product: [Na][Na]

Procedure:
Anthranilic acid is heated with concentrated sulfuric acid to 180° C. for 1 hour, after which the acid is neutralized with sodium carbonate solution. Evaporation of the water yields the disodium salt of the title compound. Structural verification was obtained by carbon magnetic resonance, proton magnetic resonance and infra-red analysis.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH2:20]N(C)C)=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CC[O:35]CC1.[C:39](#N)[CH3:40]>>[C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH:20]=[O:35])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:7]([O:9][CH2:39][CH3:40])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC#N
Reactant: C[N+]1([O-])CCOCC1
Reactant: CN(C)Cc1cc2ccccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C=O)cc2ccccc2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a solution of (S)-ethyl 2-(3-(bromomethyl)-1-(4-chlorophenyl)naphthalen-2-yl)-2-tert-butoxyacetate from Example 22 (200 mg, 0.408 mmol) in acetonitrile (4 mL) was added N-methylmorpholine N-oxide (478 mg, 4.08 mmol) and 4 Å molecular sieves (200 mg). The reaction mixture was stirred at room temperature for 2 h. Additional N-methylmorpholine N-oxide (500 mg, 4.27 mmol) was added and the reaction mixture was stirred at room temperature for another 2 h. The reaction mixture was then filtered and the organics washed with sat. NaHCO3, extracted by DCM, dried over MgSO4. The organic layer was then filtered, concentrated down and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to provide 110 mg (64%) of the desired product. 1H-MNR 400 MHz (CDCl3) δ: 10.82 (s, 1H), 8.55 (s, 1H), 8.01 (d, J=4 Hz, 1H), 7.55-7.23 (m, 7H), 5.19 (s, 1H), 4.17-4.13 (m, 2H), 1.22 (t, J=7 Hz, 3H), 1.04 (s, 9H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[F:14][C:15]([F:49])([F:48])[C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:19]=[C:18]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38]3[CH:39]=[C:40]([S:44](Cl)(=[O:46])=[O:45])[CH:41]=[CH:42][CH:43]=3)[CH:33]=2)[N:17]=1>C1COCC1>[N:1]1([S:44]([C:40]2[CH:39]=[C:38]([C:34]3[CH:33]=[C:32]([C:18]4[N:17]=[C:16]([C:15]([F:14])([F:48])[F:49])[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=5)[N:19]=4)[CH:37]=[CH:36][N:35]=3)[CH:43]=[CH:42][CH:41]=2)(=[O:45])=[O:46])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Reactant: C1CCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1)N1CCCC1
Temperature: 0 °C
Yield: 86.4 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of pyrrolidine (0.065 g, 0.91 mmol), triethylamine (0.09 ml, 0.63 mmol) and THF (2 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.20 g, 0.34 mmol) in THF (3 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/hexane) and crystallization (dichloromethane/hexane) yielded the title compound as a white solid (0.17 g, 85%). MS (ISP) 578.6 [(M+H)+]; mp 184° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[F:12].[Li][CH:14]([CH2:16]C)[CH3:15].C1C[O:21]CC1.C1CCCCC1.B(F)(F)F.C(OCC)C>C1COCC1>[F:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[C:7]=1[CH2:15][C@H:14]([OH:21])[CH3:16]
Reactant: [Li]C(C)CC
Reactant: C1CCOC1
Reactant: COc1cc(F)c(F)cc1OC
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCCCC1
Product: COc1cc(F)c(F)c(C[C@@H](C)O)c1OC
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 19 %

Procedure:
A solution of 1,2-difluoro-4,5-dimethoxybenzene (3.48 g, 20 mmol) in 10 mL of anhydrous THF was slowly added to a cooled at −78° C. solution of sec-BuLi in THF/cyclohexane (1.4M in cyclohexane, 15 mL, 21 mmol mixed with 80 mL of THF). The mixture was stirred at −70° C. for 10 min, then a solution of R-(+)-propylene oxide (1.51 g, 1.8 mL, 26 mmol) in 15 mL of THF was added dropwise at −100° C. to −90° C., then the mixture was cooled to −105° C. and a 46.5% solution of BF3 in diethyl ether (4.18 mL, 30 mmol) was added dropwise. The mixture was stirred at −100° C. to −90° C. for 2 h, then the reaction was quenched with 20 mL of sat. aq. NH4Cl at −90° C. The mixture was stirred and warmed to 0° C. overnight. Then 20 mL of water was added and mixture was extracted with EtOAc (2×60 mL), the extract was dried over Na2SO4 and evaporated to give crude oil, which was purified by column (silicagel, EtOAc/hexane 1:9, Rf=0.29 in EtOAc/hexane 3:7) to give (2R)-1-(2,3-difluoro-5,6-dimethoxyphenyl)propan-2-ol (883 mg, 19%) as pale oil. 1H NMR (300 MHz, CDCl3): 6.65 (m, 1H), 4.06 (m, 1H), 3.83 (s, 3H), 3.82 (s, 3H), 2.87 (m, 2H), 2.05 (d, J=4.71 Hz, 1H), 1.25 (d, J=6.24 Hz, 3H).
Reaction SMILES: C([Li])CCC.[C:6]1([CH2:12][C:13]([OH:15])=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[CH2:17][CH2:18][CH2:19][CH:20]1[O:24][CH2:23][CH2:22][O:21]1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31]Cl>C1COCC1.CCCCCC.CN(C)P(N(C)C)(N(C)C)=O>[C:6]1([C:12]([CH2:17][CH2:18][CH2:19][CH:20]2[O:24][CH2:23][CH2:22][O:21]2)([CH2:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=2)[C:13]([OH:15])=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ClCc1ccccn1
Reactant: ClCCCC1OCCO1
Reactant: O=C(O)Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(O)C(CCCC1OCCO1)(Cc1ccccn1)c1ccccc1
Temperature: 25 °C

Procedure:
A 2.5M hexane solution of butyl lithium (180 ml) was added to an ice-cooled solution of phenylacetic acid (20 g), hexamethylphosphoramide (25.6 ml) and tetrahydrofuran (260 ml). The reaction mixture was stirred to room temperature, then cooled back to 0° C. A solution of 2-(3-chloropropyl)-1,3-dioxolane in THF (20 ml) was added dropwise and the mixture was stirred to room temperature overnight. The reaction was cooled back down to 0° C. then butyl lithium (60 ml of a 2.5M hexane solution) was added dropwise followed by picolyl chloride (0.147 mol) in THF (40 ml). The ice-bath was removed and the reaction was stirred at room temperature for 3 days. The reaction mixture was quenched with half-saturated aqueous NH4Cl. Ethyl acetate and chloroform were added to dissolve the solids. The aqueous layer was neutralized with 1N HCl and extracted with chloroform. The combined organic layers were dried (MgSO4) and concentrated to give a solid which was washed with ether to give the subtitle compound (28.1 g).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[O:5][N:4]=[C:3]1/[C:8](=[N:15]\[O:16][CH2:17][C:18]1[N:23]=[C:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:21]=[CH:20][CH:19]=1)/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[H-].[Na+].Br[CH2:35][CH2:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>CN(C)C=O>[CH:37]1([CH2:36][CH2:35][N:24]([C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:17][O:16]/[N:15]=[C:8](\[C:3]3[N:2]([CH3:1])[C:6](=[O:7])[O:5][N:4]=3)/[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:23]=2)[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: Cn1c(/C(=N\OCc2cccc(NC(=O)OC(C)(C)C)n2)c2ccccc2)noc1=O
Reactant: BrCCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(/C(=N\OCc2cccc(N(CCC3CCCCC3)C(=O)OC(C)(C)C)n2)c2ccccc2)noc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
A solution of tert-butyl {6-[({[(Z)-(4-methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}carbamate (100 mg, 0.235 mmol, 1 eq.) in N,N-dimethylformamide (2 ml) was treated with sodium hydride (10 mg, 0.259 mmol, 1.1 eq.) and stirred at room temperature for 30 minutes. (2-Bromoethyl)cyclohexane (67 mg, 0.353 mmol, 1.5 eq.) was than added and stirring was allowed overnight. The reaction was quenched by addition of water and extracted with EtOAc (3×20 ml). The organics were combined, washed with aq. sat. NaCl, dried over MgSO4 and concentrated to afford tert-butyl (2-cyclohexylethyl){6-[({[(Z)-(4-methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}carbamate (108 mg, 86% yield) which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=[O:5].N1C=CC=C(C2C=C3C=CNC3=NC=2)C=1.[CH3:27][S:28]([C:31]1[CH:32]=[C:33]([C:37]2[CH:38]=[C:39]3[CH:45]=[CH:44][NH:43][C:40]3=[N:41][CH:42]=2)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29]>>[CH3:27][S:28]([C:31]1[CH:32]=[C:33]([C:37]2[CH:38]=[C:39]3[C:45]([C:4]([C:3]4[C:6]([F:11])=[CH:7][CH:8]=[C:9]([F:10])[C:2]=4[F:1])=[O:5])=[CH:44][NH:43][C:40]3=[N:41][CH:42]=2)[CH:34]=[CH:35][CH:36]=1)(=[O:29])=[O:30]
Reactant: CS(=O)(=O)c1cccc(-c2cnc3[nH]ccc3c2)c1
Reactant: O=Cc1c(F)ccc(F)c1F
Agent: c1cncc(-c2cnc3[nH]ccc3c2)c1
Product: CS(=O)(=O)c1cccc(-c2cnc3[nH]cc(C(=O)c4c(F)ccc(F)c4F)c3c2)c1

Procedure:
was prepared using the protocol of Steps 3 and 4 of Scheme 17, substituting propane-2-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide with 2,3,6-Trifluoro-benzaldehyde and 5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine 89 with 5-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridine in Step 3. MS(ESI) [M−H+]−=429.0.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](/C=C/C3C=CC=CC=3)=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.O[C:21]1C2C(=CC(CCC3C=CC=CC=3)=CC=2)[N:24]=[CH:23][CH:22]=1>C(O)C.[Pd]>[OH:1][C:2]1[C:11]2[C:6](=[C:7]3[C:8](=[CH:9][CH:10]=2)[N:24]=[CH:23][CH:22]=[CH:21]3)[N:5]=[CH:4][CH:3]=1
Reactant: Oc1ccnc2cc(/C=C/c3ccccc3)ccc12
Reactant: Oc1ccnc2cc(CCc3ccccc3)ccc12
Agent: [Pd]
Solvent: CCO
Product: Oc1ccnc2c1ccc1ncccc12
Yield: 99.2 %

Procedure:
Preparation 3: Preparation of 4-hydroxy-7-phenethylquinoline trans-4-Hydroxy-7-styrylquinoline (280 mg, 1.13 mmol) obtained in the Preparation 2 was dissolved in ethanol (200 ml), hydrogenated in the presence of 10% palladium on activated carbon (100 mg) and purified through silica gel column chromatography (Wako Gel™ C-200, methylene chloride : methanol=9 : 1) to obtain the titled compound (220mg, 78%).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.[NH2:9][C@@H:10]([CH3:26])[CH2:11][N:12]1[CH:16]=[CH:15][C:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([Cl:25])[CH:18]=2)=[N:13]1>>[Cl:25][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][N:12]([CH2:11][C@H:10]([NH:9][C:6]([C:4]3[N:3]=[CH:2][S:1][CH:5]=3)=[O:8])[CH3:26])[N:13]=2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cscn1
Product: C[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cscn1
Yield: 15 %

Procedure:
The title compound was prepared using the method of Example 54 but starting from 1,3-thiazole-4-carboxylic acid (149 mg; 1.51 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (300 mg; 1.51 mmol). Crude product was purified by EtOH trituration to obtain 84 mg (20%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.12 (d, 3H), 4.30-4.53 (m, 3H), 6.95 (d, 1H), 7.86 (d, 1H), 7.95-8.04 (m, 2H), 8.15 (s, 1H), 8.28 (d, 1H), 8.77 (d, 1H), 9.23 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16](F)=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-:24].[Na+].[CH3:26]O>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:24][CH3:26])=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [OH-]
Reactant: CO
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1F
Agent: [Na+]
Solvent: O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
(3-Chloro-4-fluoro-phenyl)-(7-fluoro-6-nitro-quinazolin-4-yl)-amine was suspended in 100 ml methanol and 2 ml 50% NaOH in water was added and the mixture was heated at 70° C. for 2 hours. The mixture was then poured into water and stirred vigorously for 30 minutes, then filtered and washed with water and dried under vacuum at 60° C. overnight to give 7.2 g of (3-Chloro-4-fluoro-phenyl)-(7-methoxy-6-nitro-quinazolin-4-yl)-amine.
Reaction SMILES: [Br:1][CH:2]([CH:5]=[O:6])[CH:3]=[O:4].O.[C:8]1(C)[CH:13]=CC(S(O)(=O)=O)=C[CH:9]=1.CC(O)C>C1CCCCC1>[Br:1][C:2](=[CH:5][O:6][CH:8]([CH3:13])[CH3:9])[CH:3]=[O:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=CC(Br)C=O
Solvent: C1CCCCC1
Solvent: CC(C)O
Solvent: O
Product: CC(C)OC=C(Br)C=O
Temperature: 86 °C

Procedure:
A mixture of 2-bromomalonaldehyde, para-toluenesulfonic acid monohydrate, 2-propanol and cyclohexane were stirred at 86° C. in flask with a dean-stark trap under azeotropic conditions. Further distillation removed another 40% of the original solvent volume. The mixture was cooled to 0° C., then concentrated in-vacuo, to isolate the title compound (13.2 g). 1H-NMR: 9.16 (s, 1H), 7.65 (s, 1H), 4.51 (m, 1H), 1.47 (d, 6H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.CC1C=C(C)N2N=C(C=O)N=C2N=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][C:32]2([CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[O:37][C:36](=[O:38])[CH2:35][C:34](=[O:39])[CH2:33]2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].ClC1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=CC=1OC(C)C>>[Cl:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][C:32]2([CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[O:37][C:36](=[O:38])[CH:35]([CH2:6][C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[C:34](=[O:39])[CH2:33]2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: O=Cc1nccs1
Agent: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: Cc1cc(C)n2nc(C=O)nc2n1
Product: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cc3nccs3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared analogously to Example B(31), where 1,3-thiazole-2-carbaldehyde was substituted in place of 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was substituted in place of 6-[2-(3-chloro-4-isopropoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione in final Step of that example.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:33]([NH:36][CH2:37][CH2:38][CH3:39])[CH2:34][CH3:35].C(N(CC)CC)C>ClCCl>[CH2:33]([N:36]([CH2:37][CH2:38][CH3:39])[C:8]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1)=[O:10])[CH2:34][CH3:35]
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: CCCNCCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CCC)C(=O)c1cc(Cl)ccn1
Yield: 67.3 %

Procedure:
Stir a solution of 4-chloro-2-pyridine carboxylic acid (1.0 g, 6.3 mmol), 1-hydroxybenzotriazole (850 mg, 6.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (1.21 g, 6.3 mmol), dipropyl amine (862 μL, 6.3 mmol), and triethylamine (1.75 mL, 12.6 mmol) in dichloromethane (63 mL) at room temperature over the weekend. Wash the solution with 0.1 N citric acid (2×50 mL), saturated aqueous sodium bicarbonate (50 mL), saturated aqueous sodium chloride (50 mL), dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 10:90 to 20:80 ethyl acetate:hexanes)to give the title compound (1.02 g, 67%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:24]=[C:23]([N:25]([CH3:27])[CH3:26])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.[Br:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[C:40]([O:48][C:49]([F:52])([F:51])[F:50])[CH:39]=1>CO.C(Cl)Cl.[OH-].[OH-].[Pd+2]>[Br:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([N:8]2[CH2:9][CH2:10][CH:11]([NH:14][C:15]3[N:24]=[C:23]([N:25]([CH3:26])[CH3:27])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[CH2:12][CH2:13]2)(=[O:46])=[O:45])=[C:40]([O:48][C:49]([F:51])([F:50])[F:52])[CH:39]=1
Reactant: CN(C)c1nc(NC2CCN(Cc3ccccc3)CC2)nc2ccccc12
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1nc(NC2CCN(S(=O)(=O)c3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Temperature: 50 °C
Reaction time: 16.5 h
Yield: 42.8 %

Procedure:
To a solution of N2-(1-benzyl-piperidin-4-yl)-N4,N4-dimethyl-quinazoline-2,4-diamine (500 mg, 1.38 mmol) in MeOH (5 mL) was added 20% Pd(OH)2 (100 mg). The mixture was stirred at ambient temperature under hydrogen atmosphere for 1.5 hr, at 50° C. for 8 hr, at ambient temperature for 16.5 hr, filtered through a pad of celite, and concentrated. To a solution of the residue in CH2Cl2 (5 mL) was added diisopropylethylamine (510 μL, 2.93 mmol). The mixture was cooled to 4° C. and a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (493 mg, 1.45 mmol) in CH2Cl2 (2 mL) was added below 5° C. The reaction mixture was stirred at 4° C. for 2 hr. The reaction was quenched with saturated aqueous NaHCO3 The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 33% EtOAc in hexane) to give N2-[1-(4-bromo-2-trifluoromethoxy-benzenesulfonyl)-piperidin-4-yl]-N4,N4-dimethyl-quinazoline-2,4-diamine (339 mg, 43%) as a pale yellow solid.