Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Si:6]([O:13][C@@H:14]1[C@H:18]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C@@H:17]([CH2:27][O:28][CH3:29])[O:16][C@H:15]1[N:30]1[CH:38]=[N:37][C:36]2[C:31]1=[N:32][C:33]([CH2:54][OH:55])=[N:34][C:35]=2[NH:39][CH2:40][CH:41]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:55][CH2:54][C:33]1[N:32]=[C:31]2[C:36]([N:37]=[CH:38][N:30]2[C@H:15]2[C@H:14]([O:13][Si:6]([C:9]([CH3:11])([CH3:12])[CH3:10])([CH3:7])[CH3:8])[C@H:18]([O:19][Si:20]([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:22])[CH3:21])[C@@H:17]([CH2:27][O:28][CH3:29])[O:16]2)=[C:35]([NH:39][CH2:40][CH:41]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:34]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CO)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COS(C)(=O)=O)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
Methanesulfonyl chloride (0.6 ml, 7.7 mmol) was slowly added to a stirred solution of {9-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methanol (4.22 g, 5.87 mmol) (preparation 15) and triethylamine (1.2 ml, 8.62 mmol) in dichloromethane (50 ml) and the mixture stirred at room temperature for 30 minutes. Triethylamine (1 ml, 7.2 mmol) and methanesulfonyl chloride (0.5 ml, 6.4 mmol) were then added and stirring continued for a further 15 minutes. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with a gradient system of ethyl acetate:pentane (1:3) changing to ethyl acetate:pentane (1:1) to afford the title compound as a gum (4.52 g). MS: 820 (MNa+).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=2)[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([N:10]2[CH2:11][CH2:12][C@@H:8]([NH2:7])[CH2:9]2)=[N:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(Br)cn2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CCN(c2ccc(Br)cn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
Dissolve [(R)-1-(5-bromo-pyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (9.17 g, 26.9 mmol) in CH2Cl2 (45 mL), add TFA (10 mL) and stir at RT overnight. Remove the excess reagent in vacuo. Dilute the residue with CH2Cl2 (100 mL) and wash with 1.0 M NaOH (100 mL). Extract the aqueous layer with CH2Cl2 (3×100 mL). Combine the organic layers, dry with Na2SO4, filter and concentrate to give 6.03 g (93%) of the title compound. MS/ES m/z (79Br) 242 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2].C[Si](C)(C)N[Si](C)(C)C.[Li].Cl[C:22]1[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=1>C1COCC1>[C:1]([C:3](=[C:22]1[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][NH:23]1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2]
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)CC#N
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C#N)=C1N=C(C(F)(F)F)C=CN1
Temperature: 50 °C
Yield: 79.7 %

Procedure:
tert-Butyl 2-cyanoacetate (97.45 g, 690 mmol) was dissolved in anhydrous THF (1 L), and cooled on an ice-bath for 90 min with stirring under nitrogen. A 1M solution of lithium hexamethyldisilazane in THF (690 mL, 690 mmol) was added dropwise. The mixture was stirred for an additional 1 hr, then 2-chloro-4-trifluoromethylpyrimidin (105 g, 590 mmol) was added dropwise. The mixture was then heated to 50° C. for 3 hr with stirring under nitrogen, allowed to cool, and the solvent removed under reduced pressure. Hydrochloric acid (1N) was added to the residue to achieve a pH of 1-2. The precipitated solids were collected by filtration and dried under vacuum to give tert-butyl 2-cyano-2-[4-trifluoromethylpyrimidin-2(1H)-ylidene]acetate (135 g, 82% yield) as a bright yellow solid, >98% pure by LC/MS. tert-Butyl 2-cyano-2-[4-trifluoromethylpyrimidin-2(1H)-ylidene]acetate (48 g; 166 mmol) was suspended in 4M hydrogen chloride in dioxane (415 mL, 1.66 mol) and the mixture stirred at room temperature for 6 hr, then concentrated under reduced pressure to give 2-(4-trifluoromethylpyrimidin-2-yl)acetonitrile (31 g, 100% yield) as an orange oil, >98% pure by LC/MS. To a stirred solution of 2-(4-trifluoromethylpyrimidin-2-yl)acetonitrile (31.0 g; 166 mmol) in absolute ethanol (800 mL) was added potassium O-ethylxanthate (26.6 g; 166 mmol) followed by potassium carbonate (45.8 g; 332 mmol). The mixture was heated to 100° C. for 3 hr, cooled to room temperature, iodomethane (47.1 g; 332 mmol) added dropwise, and 1N hydrochloric acid (2 L) added. The resulting mixture was extracted with DCM (1.5 L), and the DCM layer was washed twice with brine (1 L each). The solvent was removed under reduced pressure to give 3,3-bis(methylthio)-2-(4-trifluoromethylpyrimidin-2-yl)acrylonitrile (36 g, 75% yield) as a light brown solid, >95% pure by LC/MS.
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[CH2:7][CH:6]=[C:5]([C:8]2[S:9][C:10]([C:13]3[CH:14]=[C:15]([NH:20][C:21]4[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=4)[CH:16]=[C:17]([CH3:19])[CH:18]=3)=[CH:11][N:12]=2)[CH2:4][CH2:3]1>CO.CCO.[Pd]>[O:31]=[S:2]1(=[O:1])[CH2:7][CH2:6][CH:5]([C:8]2[S:9][C:10]([C:13]3[CH:14]=[C:15]([NH:20][C:21]4[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=4)[CH:16]=[C:17]([CH3:19])[CH:18]=3)=[CH:11][N:12]=2)[CH2:4][CH2:3]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3=CCS(=O)(=O)CC3)s2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3CCS(=O)(=O)CC3)s2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.9 %

Procedure:
N-{3-[2-(1,1-Dioxido-3,6-dihydro-2H-thiopyran-4-yl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (Example 135, 100 mg, 0.214 mmol) was dissolved in a 1:2 v/v mixture MeOH/EtOH (15 mL). Palladium on carbon (57.0 mg, 0.054 mmol) was added, and the reaction was flushed with hydrogen (3×). The reaction was stirred under hydrogen atmosphere at room temperature for 72 hrs. The reaction was filtered through a pad of Celite and concentrated under reduced pressure. Column chromatography on silica (gradient elution, 0 to 75% EtOAc in hexanes) afforded the title compound (0.073 g, 0.156 mmol, 72% yield) as a colorless foam. MS ESI: [M+H]+ m/z 469.0. 1H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.83 (d, J=4.9, 1H), 7.99 (m, 2H), 7.45 (bs, 1H), 7.28 (d, J=4.9, 1H), 7.16 (bs, 1H), 3.43 (m, 1H), 3.34 (m, 2H), 3.18 (m, 2H), 2.39 (m, 2H), 2.26 (s, 3H), 2.31 (m, 2H). rhSYK activity=+++.
Reaction SMILES: C([O-])(O)=[O:2].[Na+].[Cl:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:9][C:8]=1[C:20]1[C:29]([F:30])=[CH:28][C:27]2[N:26]=[CH:25][C:24]3[N:31]=[C:32]([CH3:48])[N:33]([C@H:34]4[CH2:39][CH2:38][N:37]([CH:40](CC=O)[C:41]([O-:43])=O)[CH2:36][C@@H:35]4[F:47])[C:23]=3[C:22]=2[CH:21]=1.CO.C(Cl)Cl>CO>[Cl:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:9][C:8]=1[C:20]1[C:29]([F:30])=[CH:28][C:27]2[N:26]=[CH:25][C:24]3[N:31]=[C:32]([CH3:48])[N:33]([C@H:34]4[CH2:39][CH2:38][N:37]([C:40](=[O:2])[CH2:41][OH:43])[CH2:36][C@@H:35]4[F:47])[C:23]=3[C:22]=2[CH:21]=1
Reactant: Cc1nc2cnc3cc(F)c(-c4ccc(Oc5ncccn5)cc4Cl)cc3c2n1[C@H]1CCN(C(CC=O)C(=O)[O-])C[C@@H]1F
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1nc2cnc3cc(F)c(-c4ccc(Oc5ncccn5)cc4Cl)cc3c2n1[C@H]1CCN(C(=O)CO)C[C@@H]1F
Reaction time: 24 h
Yield: 81.7 %

Procedure:
NaHCO3 (11 g, 0.1309 mol) was added to a stirred solution of 2-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-oxoethylacetate (8 g, 0.013 mol) in MeOH (300 mL) at RT and stirred for 24 h. The reaction was monitored by TLC (5% MeOH/DCM), after completion of reaction, the reaction mixture was filtered and wand washed with MeOH (100 mL). The filtrate was concentrated to remove methanol and the residue was dissolved in DCM (200 mL) and washed with water, brine solution, dried over sodium sulphate and evaporated under vacuum. The residue was purified by column chromatography on silica gel (0-4% MeOH/DCM) to afford the 1-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-hydroxyethanone (6.0 g, 81% yield). Obtained solid was recrystallized in EtOH (alternatively in MeOH) 1HNMR (CDCl3, 400 MHz): δ 9.33 (s, 1H), 8.65-8.64 (d, 2H), 8.08-8.05 (d, 1H), 8.00-7.85 (m, 1H), 7.51-7.30 (m, 2H), 7.30-7.28 (dd, 1H), 7.15-7.13 (m, 1H), 5.65-5.25 (m, 1H), 4.96-4.75 (m, 1H), 4.35-4.15 (m, 2H), 3.92-3.74 (m, 2H), 3.35-3.15 (m, 1H), 3.05-2.85 (m, 2H), 2.80 (s, 3H), 2.45-2.15 (m, 2H); LCMS: 100%, m/z=565.1 (M+1); HPLC (Method-3): 99.80%, Chiral HPLC: 99.48%, rt=20.38 min., Column. AG/CHIRALPAK AD-H/03. Free Form
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[Br:9][C:10]1[C:25]([F:26])=[CH:24][C:13]2[O:14][C:15]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=3[CH:17]=[N:18][C:12]=2[CH:11]=1.C(OCC)C>C1(C)C(C)=CC=CC=1>[Br:9][C:10]1[C:25]([F:26])=[CH:24][C:13]2[O:14][C:15]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=3[C@H:17]3[C@H:2]([C:1]([OH:7])=[O:8])[CH2:3][CH2:4][C:5](=[O:6])[N:18]3[C:12]=2[CH:11]=1
Reactant: Fc1ccc2c(c1)Oc1cc(F)c(Br)cc1N=C2
Reactant: O=C1CCCC(=O)O1
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: O=C(O)[C@@H]1CCC(=O)N2c3cc(Br)c(F)cc3Oc3cc(F)ccc3[C@@H]12
Temperature: 150 °C

Procedure:
Glutaric anhydride (7.93 g, 69.5 mmol) was added to a stirred solution of 8-bromo-3,7-difluoro-dibenz[b,f][1,4]oxazepine (14.4 g, 46.4 mmol) in xylene (30 mL) and the mixture was heated to 150° C. for 72 h. The reaction mixture was allowed to cool to ambient temperature, and diethyl ether was added. The product was collected by filtration and dried to yield the title compound which was used without further purification (16.2, 82%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[Cl:12])=[O:4].[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K].O>CN(C)C=O>[Cl:12][C:6]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][N:17]1[C:13](=[O:23])[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16]1=[O:18]
Reactant: O=C(CBr)c1cc(Cl)ccc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)c2ccccc2C1=O)c1cc(Cl)ccc1Cl
Temperature: 25 °C
Yield: 88 %

Procedure:
To an ice-cooled solution of 2-bromo-1-(2,5-dichlorophenyl)ethanone (0.10 g, 0.37 mmol) in N,N-dimethylformamide (8 mL) was added potassium phthalimide (76 mg, 0.41 mmol). The mixture was warmed to room temperature for 2 hours. The resultant mixture was then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. Recrystallization with diethyl ether afforded 2-(2-(2,5-dichlorophenyl)-2-oxoethyl)isoindoline-1,3-dione as a white solid. (110 mg, 88% yield). 1H NMR (400 MHz, CDCl3): 7.92-7.94 (m, 2H), 7.78-7.80 (m, 2H), 7.72 (m, 1H), 7.45-7.46 (m, 2H), 5.08 (s, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:12][CH3:13])=[C:9]([NH2:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C[O:15][C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([N:24]2[CH:28]=[C:27]([C:29]3[CH:30]=[N:31][N:32]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:33]=3[CH2:34][CH3:35])[N:26]=[CH:25]2)[CH:18]=1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:12][CH3:13])=[C:9]([NH:11][C:16](=[O:15])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([N:24]3[CH:28]=[C:27]([C:29]4[CH:30]=[N:31][N:32]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:33]=4[CH2:34][CH3:35])[N:26]=[CH:25]3)[CH:18]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCc1c(-c2cn(-c3cc(C(=O)OC)ccc3C)cn2)cnn1-c1ccccc1
Reactant: COc1ccc(C(C)(C)C)cc1N
Product: CCc1c(-c2cn(-c3cc(C(=O)Nc4cc(C(C)(C)C)ccc4OC)ccc3C)cn2)cnn1-c1ccccc1

Procedure:
Example 153 was prepared from 5-tert-butyl-2-methoxy-phenylamine and 3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoic acid methyl ester (Example 151) in the same manner as Example 151. ESI MS m/z 534 [C33H35N5O2+H]1.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[C:12]([CH3:37])[C:13]3[N:17]=[C:16]([C:18]4[C:19](=[O:35])[NH:20][CH:21]=[CH:22][C:23]=4[NH:24][C@H:25]([CH2:33][OH:34])[CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[NH:15][C:14]=3[CH:36]=2)[CH2:6][CH2:5]1)(=O)C.O>Cl.O1CCOCC1>[OH:34][CH2:33][C@@H:25]([NH:24][C:23]1[CH:22]=[CH:21][NH:20][C:19](=[O:35])[C:18]=1[C:16]1[NH:15][C:14]2[CH:36]=[C:10]([N:7]3[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]3)[CH:11]=[C:12]([CH3:37])[C:13]=2[N:17]=1)[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(=O)N1CCN(c2cc(C)c3nc(-c4c(N[C@H](CO)Cc5ccccc5)cc[nH]c4=O)[nH]c3c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(N2CCNCC2)cc2[nH]c(-c3c(N[C@H](CO)Cc4ccccc4)cc[nH]c3=O)nc12
Temperature: 80 °C
Yield: 10.1 %

Procedure:
To a solution of (S)-3-[6-(4-acetyl-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-4-(1-hydroxymethyl-2-phenyl-ethylamino)-1H-pyridin-2-one (900 mg, 18 mmol) in 4 M HCl in dioxane (10 mL) was added water (1 mL). The reaction mixture was heated to 80° C. for 14 h and cooled to room temperature. Concentration with high vacuum gave the title compound (0.83 g, 100%) which was used for the next step without purification. LCMS (M+H)+ m/z 459 (t=1.13 min.).
Reaction SMILES: [F:1][CH:2]([F:16])[C@@H:3]1[C@@H:13]([OH:14])[C@H:12]([OH:15])[C@H:6]2[N:7]=[C:8](SC)[O:9][C@H:5]2[CH2:4]1.Cl.[NH:18]1[CH2:21][CH2:20][CH2:19]1.C([O-])(O)=O.[Na+]>CCO>[N:18]1([C:8]2[O:9][C@H:5]3[CH2:4][C@H:3]([CH:2]([F:16])[F:1])[C@@H:13]([OH:14])[C@H:12]([OH:15])[C@H:6]3[N:7]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: CSC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](C(F)F)C[C@@H]2O1
Reactant: C1CNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O[C@H]1[C@H](O)[C@@H](C(F)F)C[C@@H]2OC(N3CCC3)=N[C@H]12
Reaction time: 0.17 h
Yield: 84.7 %

Procedure:
To a solution of (3 aR,4R,5R,6S,7aS)-6-(difluoromethyl)-2-(methylthio)-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazole-4,5-diol (52.6 mg, 0.208 mmol) in EtOH (5 mL) was added azetidine hydrochloride (97 mg, 1.04 mmol). The mixture was heated at reflux for 5 h. After cooling, solid NaHCO3 (200 mg, 2.38 mmol) was added and stirred for 10 min Solvent was evaporated and the residue was purified by silica gel column chromatography, eluted with 5% 2 M NH3 MeOH solution in DCM to give the product (3aR,4R,5R,6S,7aS)-2-(azetidin-1-yl)-6-(difluoromethyl)-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazole-4,5-diol (46.2 mg, 85%) as a white solid. MS m/z 263.1 (M+1, 100%); 1H NMR (400 MHz, MeOD) δ 6.14 (td, J=56.8 Hz, 1.8 Hz, 1H), 4.66-4.69 (m, 1H), 4.00 (t, J=7.6 Hz, 4H), 3.62 (t, J=7.2 Hz, 1H), 3.34 (t, J=9.2 Hz, 1H), 3.24 (t, J=7.9 Hz, 1H), 2.29-2.36 (m, 2H), 2.21 (dt, J=15.1 Hz, 3.6 Hz, 1H), 1.95-2.10 (m, 1H), 1.82-1.90 (m, 1H); 13C NMR (100 MHz, MeOD) δ 164.62, 117.96 (t, J=238.5 Hz), 81.20, 79.89 (d, J=1.6 Hz), 71.36 (dd, J=7.2 Hz, 1.0 Hz), 68.72, 51.91, 42.25 (t, J=19.8 Hz), 22.61 (t, J=4.7 Hz), 17.75.
Reaction SMILES: [NH:1]([C:4]1[CH:5]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:8][CH:9]=1)[C:2]#[N:3].Cl.[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:18]=1[NH2:19]>C(#N)C>[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][C:18]=1[NH:19][C:2]([NH:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=1)=[NH:3]
Reactant: COc1ccc(C(F)(F)F)cc1N
Reactant: N#CNc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CC#N
Product: COc1ccc(C(F)(F)F)cc1NC(=N)Nc1cccc(C(F)(F)F)c1

Procedure:
A mixture of 3-cyanamidobenzotrifluoride (0.40 g, 2.15 mmol), 2-methoxy-5-triflouromethylaniline hydrochloric acid salt (0.53 g, 2.33 mmol) and acetonitrile (20 ml) was stirred at reflux for 40 h. The solvent was evaporated. Dichloromethane (50 ml) was added and the mixture was washed with saturated aqueous sodium hydrogen carbonate (50 ml). The organic phase was purified by chromatography using silica gel and a mixture of methanol (10%) and dichloromethane as eluent. The product was isolated as the free base. Yield 0.40 g, 49%. M.p. 45-47° C.
Reaction SMILES: [F:1][CH2:2][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=1)([CH3:6])[CH2:4][F:5].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH2:41][CH2:42][O:43][CH3:44])[N:36]=[CH:35][N:34]=[C:33]2[O:45][C:46]1[CH:47]=[C:48]([CH:50]=[CH:51][CH:52]=1)[NH2:49].C(N(CC)C(C)C)(C)C>C1COCC1>[F:1][CH2:2][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:13]([NH:49][C:48]2[CH:50]=[CH:51][CH:52]=[C:46]([O:45][C:33]3[C:32]4[C:37](=[CH:38][C:39]([O:40][CH2:41][CH2:42][O:43][CH3:44])=[C:30]([O:29][CH3:28])[CH:31]=4)[N:36]=[CH:35][N:34]=3)[CH:47]=2)=[O:21])[N:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:8]=1)([CH3:6])[CH2:4][F:5]
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(CF)CF)nn4-c4ccccc4)c3)c2cc1OC
Yield: 43 %

Procedure:
Using the procedure described in Example 159B, phenyl 3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate as described in Example 167B (0.186 g, 0.5 mmol), 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (0.137 g, 0.4 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6 mL) at 50° C. for 6 hours, to afford 1-[3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}urea as solid (0.106 g, 43%). 1H NMR (300 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.57 (s, 1H), 8.55 (s, 1H), 7.56 (m, 6H), 7.40 (m, 3H), 7.18 (d, 1H), 6.94 (d, 1H), 6.50 (s, 1H), 4.70 (m, 2H), 4.54 (m, 2H), 4.33 (m, 2H), 3.98 (s, 3H), 3.78 (m, 2H), 3.35 (s, 3H), 1.30 (s, 3H); LC-MS (ESI) m/z 619 (M+H)+.
Reaction SMILES: C[CH:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=C[CH:4]=1.C=O.C(O)(=O)C.[CH2:16]([N:23]1CCC(=O)CC1)C1C=CC=CC=1>CO>[CH2:8]1[CH:7]2[CH2:6][NH:9][CH2:2][CH:3]1[CH2:4][NH:23][CH2:16]2
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CC(N)c1ccccc1
Agent: C=O
Solvent: CC(=O)O
Solvent: CO
Product: C1NCC2CNCC1C2
Temperature: 25 °C

Procedure:
A mixture of α-methylbenzylamine (10.7 g, 0.088 mol), paraformaldehyde (21.1 g, 0.703 mol), acetic acid (10.2 mL, 0.179 mol) and 1-benzyl-4-piperidone (16.7 g, 0.088 mol) in MeOH (418 mL) was heated at reflux overnight. Upon cooling to room temperature the solvents were removed in vacuo. Water (700 mL) and KOH pellets (11.7 g, 0.209 mol) were added and the mixture was extracted with 3×150 mL CH2Cl2. The organic layer was dried (K2CO3), filtered and the solvent was removed in vacuo. The yellow residues were triturated with hexane and the combined organic solvents were concentrated to provide bispidine (1) as a crude yellow oil (26.7 g, 90%).
Reaction SMILES: C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.[CH3:9][N:10]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])=[C:11]1[CH2:25][OH:26]>O=[Mn]=O>[CH3:9][N:10]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])=[C:11]1[CH:25]=[O:26]
Reactant: Cc1cn(C)c(CO)c1-c1ccccc1[N+](=O)[O-]
Agent: O=[Mn]=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1cn(C)c(C=O)c1-c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.4 %

Procedure:
100 mg of MnO2, prepared according to Attenburrow's method, are suspended in a carbon tetrachloride/methylene chloride (4:1) mixture containing 500 mg of alcohol (12). The reaction medium is stirred at room temperature for 11/2 hours. The oxidizing agent is then filtered on celite. 230 mg of compound (13) are obtained (Yld:46%). This compound is purified by chromatography on a silica column (eluent:ethyl acetate/hexane, 1:1). It has the appearance of a yellow oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[Cl:5][C:6]1[CH:7]=[C:8]([NH:13][C:14](=[O:28])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[Cl:27])[CH:9]=[CH:10][C:11]=1[OH:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:12][C:11]1[CH:10]=[CH:9][C:8]([NH:13][C:14](=[O:28])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][C:18]=2[Cl:27])=[CH:7][C:6]=1[Cl:5]
Reactant: BrCCBr
Reactant: O=C(COc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(COc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(OCCBr)c(Cl)c1
Reaction time: 2.5 h

Procedure:
A solution of 3.66 mL (41.56 mmol) 1,2-dibromoethane in 5 mL DMF was slowly added at RT to a suspension of 1.580 g (4.156 mmol) N-(3-chloro-4-hydroxy-phenyl)-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide and 2.880 g (8.310 mmol) potassium carbonate in 20 mL DMF and the mixture was stirred for 2.5 h. The reaction mixture was evaporated down i. vac. and diluted with EtOAc . The org. phase was washed with water and saturated aqueous NaCl, dried over magnesium sulphate and evaporated down i. vac. Column chromatography (silica gel, petroleum ether→dichloromethane) yielded the product.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([O:9]CC)=[O:8])[C:4](=[O:12])[N:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].O1CCCC1.[OH-].[Na+]>CO>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[C:4](=[O:12])[N:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19]
Reactant: CCOC(=O)c1cn(C)n(-c2ccccc2C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1-n1c(=O)c(C(=O)O)cn1C
Yield: 39.4 %

Procedure:
In the same manner as in Reference Example 65 and using ethyl 1-methyl-2-(2-methylphenyl)-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (2.1 g, 8.2 mmol), tetrahydrofuran (6 mL), methanol (4 mL) and 4N aqueous sodium hydroxide solution (9 mL) as starting materials, the title compound (750 mg, 40%) was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:15]([O-])([OH:17])=[O:16].O>OS(O)(=O)=O>[CH3:1][C:2]1[C:10]([N+:15]([O-:17])=[O:16])=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C(F)(F)F)cc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(C(=O)O)cc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 76 %

Procedure:
To a stirred solution of 2-methyl-5-(trifluoromethyl)benzoic acid (2.00 g, 9.80 mmol) in H2SO4 (20 mL, 12 N) was added HNO3 (2 mL, 12N) at 0° C. After stirring for 3 hours, water was added and resulting precipitate was collected. The solid was washed with water and dried to give the titled compound as a white solid (1.90 g, 76% yield). 1H-NMR (400 MHz, CDCl3) δppm; 8.43 (s, 1H), 8.15 (s, 1H), 2.77 (s, 3H); MS (ES) [M−H] 247.8.