Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:35]([O:37][CH3:38])=[O:36])[CH:13]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[S:14][CH2:15][CH2:16][NH:17]C(OC(C)(C)C)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:39]>C(OCC)(=O)C>[ClH:39].[NH2:17][CH2:16][CH2:15][S:14][CH:13]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[C@@H:12]([C:35]([O:37][CH3:38])=[O:36])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(SCCNC(=O)OC(C)(C)C)c1cccc2ccccc12
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(SCCN)c1cccc2ccccc12
Temperature: -30 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of methyl N-[(benzyloxy)carbonyl]-S-{2-[(tert-butoxycarbonyl)amino]ethyl}-3-(1-naphthyl)cysteinate (25b) (3.3 g, 6.13 mmol) in ethyl acetate (80 mL) at −30° C., was bubbled over HCl gas for 10 min, stirred at −30° C. for 15 min and then allowed to RT for 3 h. Evaporation to near dryness and precipitation from ether afforded pure title compound (25c) (2.6 g, 89%) as a white solid. MS APCI m/z=439 (M+1), 2.34 min.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4]2([C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:13][C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:3][C:2]1=O.[CH3:21][NH2:22]>>[CH3:21][N:22]1[CH2:6][CH2:5][C:4]2([C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:13][C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:3][C:2]1=[O:1]
Reactant: CN
Reactant: O=C1CC2(CCO1)c1ccccc1Oc1ccccc12
Product: CN1CCC2(CC1=O)c1ccccc1Oc1ccccc12

Procedure:
A mixture of xanthene-9-spiro-4'-tetrahydropyran-2'-one (0.5 g.) and methylamine (5 ml.) is heated at 250° C. for 4 hours in a steel bomb. The gummy residue (0.52 g.) is chromatographed on silica gel, eluting with increasing concentrations of chloroform in light petroleum (b.p. 60°-80° C.). Elution with 25% chloroform in light petroleum gives, on evaporation of the solvent, a solid residue which is recrystallised from ethanol to give 1'-methylxanthene-9-spiro-4'-piperidin-2'-one, m.p. 158°-159° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:22].Br[C:24]1[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:15])[F:16])[N:11]3[N:17]=[CH:18][C:19]([C:20]#[C:21][C:24]4[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:25]=4)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:22]
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(Cl)c(C)c3)nc12
Product: Cc1cc(-c2cc(C(F)F)n3ncc(C#Cc4ccc(S(N)(=O)=O)s4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-7-difluoromethyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.16) (159 mg, 0.5 mmol) and commercially available 5-bromo-thiophene-2-sulfonamide (121 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (190 mg, 79%). MS (ISN) 477.0 [(M−H)−]; mp 216° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[C:14]([O:20][CH3:21])[CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[C:14]([O:20][CH3:21])[CH:13]=2)[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: COc1cc(O)ccc1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Oc2cc(Cl)ccc2C#N)ccc1C=O
Yield: 82.9 %

Procedure:
4-Chloro-2-fluorobenzonitrile (0.60 g, 3.9 mmol), 4-hydroxy-2-methoxybenzaldehyde (0.59 g, 3.9 mmol) and cesium carbonate (1.26 g, 3.9 mmol) were heated with stirring in dry DMF (4 ml) at 50° C. for 21 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water, 10% aqueous sodium carbonate (2×), water (2×), brine, and dried over magnesium sulphate. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-(4-formyl-3-methoxy-phenoxy)-benzonitrile (0.93 g, 83%) as an orange solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]3)=[C:22]([O:32][CH3:33])[CH:21]=2)[CH:16]=[C:15]([C:34]([F:37])([F:36])[F:35])[CH:14]=1>>[CH3:33][O:32][C:22]1[CH:21]=[C:20]([NH:19][C:17]2[CH:16]=[C:15]([C:34]([F:36])([F:37])[F:35])[CH:14]=[C:13]([NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=3)[N:18]=2)[CH:25]=[CH:24][C:23]=1[N:26]1[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]1
Reactant: COc1cc(Nc2cc(C(F)(F)F)cc(Cl)n2)ccc1-n1cnc(C)c1
Reactant: Nc1cccc(C(F)(F)F)c1
Product: COc1cc(Nc2cc(C(F)(F)F)cc(Nc3cccc(C(F)(F)F)c3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 62 from 3-trifluoromethylaniline and (6-chloro-4-trifluoromethyl-pyridin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. The title compound was obtained as a yellowish solid (Yield=60%). MS ISP (m/e): 508.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.74 (s, 1H), 7.65 (d, 1H), 7.60 (d, 1H), 7.43 (t, 1H), 7.30 (d, 1H), 7.18 (d, 1H), 7.11 (d, 1H), 7.00 (dxd, 1H), 6.89 (s, 1H), 6.87 (s, 1H), 6.82 (s, 1H), 6.51 (s, 1H), 6.44 (s, 1H9, 3.70 (s, 3H), 3.31 (s, 3H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C:13]([CH3:16])([CH3:15])[N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:11]1[CH2:24][C:25]1[N:26]=[CH:27][S:28][CH:29]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.[Si:35](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]>C1COCC1>[Si:35]([C:27]1[S:28][CH:29]=[C:25]([CH2:24][C@H:11]2[C@@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[O:14][C:13]([CH3:15])([CH3:16])[N:12]2[C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[N:26]=1)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2cscn2)[C@@H](CO[Si](C)(C)C(C)(C)C)OC1(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2csc([Si](C)(C)C(C)(C)C)n2)[C@@H](CO[Si](C)(C)C(C)(C)C)OC1(C)C
Temperature: -50 °C

Procedure:
(4S,5S)-Tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-(thiazol-4-ylmethyl)oxazolidine-3-carboxylate (0.148 g, 0.334 mmol) in THF (3 mL) was cooled to −78° C. when n-butyllithium (2.5 M in hexanes) (0.160 ml, 0.401 mmol) was added dropwise. The solution was warmed to −50° C. for 40 minutes and then cooled to −78° C. TBS-Cl (0.0605 g, 0.401 mmol) in THF (2 mL) was added dropwise and the solution was allowed to slowly warm to 0° C. when it was quenched with saturated ammonium chloride. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, brine and dried over sodium sulfate to afford the title compound, which was used without further purification.
Reaction SMILES: [Si](O[CH2:9][C:10]1[CH:27]=[CH:26][C:13]([O:14][CH:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]([O:18][CH3:19])=[O:17])=[C:12]([CH2:28][CH:29]=[CH2:30])[CH:11]=1)(C(C)(C)C)(C)C.C(Br)(Br)(Br)[Br:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)=O>CC#N>[Br:32][CH2:9][C:10]1[CH:27]=[CH:26][C:13]([O:14][CH:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]([O:18][CH3:19])=[O:17])=[C:12]([CH2:28][CH:29]=[CH2:30])[CH:11]=1
Reactant: BrC(Br)(Br)Br
Reactant: C=CCc1cc(CO[Si](C)(C)C(C)(C)C)ccc1OC(C(=O)OC)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CC(C)=O
Product: C=CCc1cc(CBr)ccc1OC(C(=O)OC)c1ccccc1
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
To a cooled (0° C.) solution of the product of Step D (156 mg, 0.366 mmol) in CH3CN (2 mL), were added carbon tetrabromide (182 mg, 0.55 mmol) and triphenylphosphine (144 mg, 0.55 mmol). After 30 minutes at 0° C., the reaction mixture was allowed to warm to room temperature, at which point acetone (40 mL, 0.55 mmol) was added. After 16 hours at room temperature, the reaction mixture was filtered, the filtrate was concentrated in vacuo, and the residue was purified on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexanes to afford 86 mg (63 %) of the title compound (Rf =0.13, 5% ethyl acetate/hexanes).
Reaction SMILES: [F:1][C:2]1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]4[CH:38]=[C:37]5[C:32]([CH2:33][CH2:34][N:35](C(=O)C(F)(F)F)[CH2:36]5)=[CH:31][CH:30]=4)[N:23]=3)=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)[CH:10]=[CH:9][C:8]=1[O:45][CH3:46])=[O:5].C1COCC1.[Li+].[OH-]>O>[F:51][C:47]1[CH:48]=[CH:49][CH:50]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]4[CH:38]=[C:37]5[C:32]([CH2:33][CH2:34][NH:35][CH2:36]5)=[CH:31][CH:30]=4)[N:23]=3)=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)[CH:10]=[CH:9][C:8]=1[O:45][CH3:46])=[O:5]
Reactant: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CN(C(=O)C(F)(F)F)CC4)n2)cc1NC(=O)c1c(F)cccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)cc1NC(=O)c1c(F)cccc1F
Temperature: 50 °C
Yield: 73.6 %

Procedure:
To a solution of 2,6-difluoro-N-{2-(methyloxy)-5-[3-(2-{[2-(trifluoroacetyl)-1,2,3,4-tetrahydro-7-isoquinolinyl]amino}-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}benzamide (50 mg, 0.072 mmol) in 10:1 THF:H2O (10 mL) was added 1M LiOH (0.43 ml, 0.43 mmol) and the reaction mixture was heated at 50° C. overnight. The reaction was washed with brine (10 mL), organic layer removed, adsorbed to silica gel and purified by column chromatography (0-10% MeOH/DCM+1% NH4OH) to afford the title compound (32 mg, 74%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 2.75 (t, 2H, J=5.86 Hz), 3.13 (t, 2H, J=5.86 Hz), 3.93 (s, 3H), 3.97 (s, 2H), 6.64 (d, 1H, J=5.31 Hz), 6.86-6.89 (m, 1H), 6.94-7.03 (m, 4H), 7.24-7.44 (m, 5H), 8.16 (d, 1H, J=5.31 Hz), 8.32-8.38 (m, 2H), 8.50 (d, 1H, J=6.96 Hz), 8.98 (m, 1H); ESIMS (M+H)+=604.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11].O>[Cl-].[Zn+2].[Cl-].ClCCl>[C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2c(c1)CCO2
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCO2
Temperature: 100 °C
Yield: 24.1 %

Procedure:
A mixture of 44.4 g (0.37 moles) of 2,3-dihydrobenzofuran and 37.8 g (0.37 moles) of acetic anhydride were added with 5.0 g (37 mmoles) of anhydrous zinc chloride. The mixture was heated to 95-105° C. for 10 hrs; after cooling to room temperature the mixture is added with 50 ml of water and 50 ml of dichloromethane. The organic phase was separated and the aqueous phase was extracted twice with dichloromethane (2× 30 ml). The organic phases were collected together, and washed with 50 ml of a saturated aqueous solution of sodium carbonate. The organic phase was separated and evaporated u.v. (20° C./21 mbar). The residue was then distilled at 99-100° C./0.08 mbar obtaining 14.5 g (0.089 moles) of 5-acetyl-2,3-dihydrobenzofuran.
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[C:22]3[C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:24])[C:13]=3[CH:12]=[CH:11][C:10]=2[NH:25][C:26](=[O:29])[CH2:27]Cl)=[O:7])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[N:41]1([CH2:47][CH2:48][OH:49])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>O1CCCC1>[CH3:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[C:22]3[C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:24])[C:13]=3[CH:12]=[CH:11][C:10]=2[NH:25][C:26](=[O:29])[CH2:27][N:44]2[CH2:45][CH2:46][N:41]([CH2:47][CH2:48][OH:49])[CH2:42][CH2:43]2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)Nc2c(NC(=O)CCl)ccc3c2C(=O)c2ccccc2C3=O)cc1
Reactant: OCCN1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2c(NC(=O)CN3CCN(CCO)CC3)ccc3c2C(=O)c2ccccc2C3=O)cc1
Reaction time: 0.12 h
Yield: 48 %

Procedure:
Compound CC-12 (0.86 g, 2 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and to the solution was added successively with DIPEA (1 ml, 6 mmole) and 2-(piperazin-1-yl)ethanol (0.97 ml, 8 mmole) under stirring for 5 to 10 minutes. This mixture was heated under reflux for 16 hours. After the completion of the reaction, the mixture was filtered, and the filtrate was concentrated by reduced pressure concentrator (such as Vacuum Evaporator). The residue was extracted with ethyl acetate for several times. The extract was dried on magnesium sulfate, and concentrated under reduced pressure. The crude product was washed with ethyl acetate/hexane. Finally, the crude product was recrystallized in hot ethanol to obtain a kelly green compound CC-44. Mol. Wt.: 526.5830 (C30H30N4O5); Rf: 0.41 (ethyl acetate:n-hexane=1:2); Yield: 48%; Mp.: 210-211° C. (EtOH); HRMS (EI) m/z: calcd [M]+, 526.2216 (C30H30N4O5+). Found, 526.2219. 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 1.92 (t, J=6.0 Hz, 2H, —NCH2—), 2.03 (br, 4H, —CH2—), 2.39 (br, 4H, —CH2—), 2.43 (s, 3H, —CH3), 3.01 (s, 2H, —CH2N—), 3.26-3.30 (m, 2H, —CH2OH), 4.29 (t, J=5.4 Hz, 1H, —CH2OH), 7.43 (d, J=8.1 Hz, 2H, Ar—H), 7.87-7.91 (m, 2H, Ar—H), 8.07-8.19 (m, 4H, Ar—H), 8.27 (d, J=8.7 Hz, 1H, Ar—H), 8.79 (d, J=8.7 Hz, 1H, Ar—H), 10.00 (s, 1H, Ar—NH—), 10.50 (s, 1H, Ar—NH—); 13C-NMR (75 MHz, DMSO-d6) δ (ppm): 20.93, 52.32, 52.93, 58.21, 59.1, 61.69, 125.11, 126.37, 126.72, 126.98, 127.81, 128.04, 128.33, 129.24, 130.53, 130.53, 140.68, 142.70, 166.37 (NCO), 169.28 (NCO), 181.50 (CO), 183.67 (CO).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([O:18][CH3:19])[CH:17]=2)[CH:13]=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[NH2:20][C:21]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[C:22]=1[C:23]([NH2:25])=[O:24].OS([O-])=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[C:12]([C:13]3[NH:25][C:23](=[O:24])[C:22]4[C:21](=[CH:29][C:28]([O:30][CH3:31])=[CH:27][C:26]=4[O:32][CH3:33])[N:20]=3)[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COc1cc(C=O)cc(N2CCN(C(C)C)CC2)c1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)cc(N2CCN(C(C)C)CC2)c1
Temperature: 120 °C
Reaction time: 20 h
Yield: 79.1 %

Procedure:
To a solution of 3-(4-isopropylpiperazin-1-yl)-5-methoxybenzaldehyde (1.23 g, 4.68 mmol) in N,N-dimethylacetamide (20 mL) was added 2-amino-4,6-dimethoxybenzamide (0.59 g, 3.00 mmol), NaHSO3 (58.5 wt %, 0.87 g, 4.80 mmol) and p-toluenesulfonic acid monohydrate (1.82 g, 9.60 mmol). The reaction mixture was stirred at 120° C. for 20 h under nitrogen. After that time the reaction was cooled to rt and concentrated under reduced pressure. The residue was diluted with saturated Na2CO3 solution to adjust the pH to 12. The precipitated solids were collected by filtration, washed with water and dried under vacuum. The product was purified by flash column chromatography (silica gel, 86:10:4 dichloromethane/ethyl acetate/methanol followed by 86:10:4 dichloromethane/ethyl acetate/7 N NH3 in methanol) and prep. HPLC to give 2-(3-(4-isopropylpiperazin-1-yl)-5-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (1.04 g, 50%) as a white solid: mp 212-213° C.; 1H NMR (400 MHz, DMSO-d6): δ 11.99 (s, 1H), 7.36 (s, 1H), 7.20 (s, 1H), 6.76 (d, J=2.34 Hz, 1H), 6.60 (t, J=1.95 Hz, 1H), 6.53 (d, J=1.95 Hz, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.81 (s, 3H), 3.22 (t, J=4.29 Hz, 4H), 2.68 (quin, J=6.54 Hz, 1H), 2.58 (t, J=4.68 Hz, 4H), 1.01 (d, J=6.63 Hz, 6H); ESI MS m/z 437 [M−H]−.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22]>>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: Oc1ccccc1F
Product: Nc1nnc(Oc2ccccc2F)c(-c2ccccc2)n1
Yield: 9.8 %

Procedure:
6-(2-Fluorophenoxy)-5-phenyl-1,2,4-triazin-3-amine (44 mg, 10%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.40 g, 1.59 mmol) and 2-fluorophenol (0.36 g, 3.18 mmol) according to the general procedure of Example 3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].C([O-])([O-])=O.[K+].[K+].[C:16]([C:18]1[CH:19]=[C:20]([S:25]([NH:28][C:29]2[S:33][N:32]=[CH:31][N:30]=2)(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=1F)#[N:17].Cl>CN(C=O)C>[C:16]([C:18]1[CH:19]=[C:20]([S:25]([NH:28][C:29]2[S:33][N:32]=[CH:31][N:30]=2)(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=1[O:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])#[N:17]
Reactant: Cc1cccc(Br)c1O
Reactant: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(Br)c1Oc1ccc(S(=O)(=O)Nc2ncns2)cc1C#N
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 2-bromo-6-methylphenol (6.0 mmol, 1120 mg) and K2CO3 (10.5 mmol, 1450 mg) in DMF (15.0 mL) was added 3-cyano-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (Preparation 65, 4.5 mmol, 1280 mg). The reaction mixture was heated at 80° C. After stirring for overnight at 80° C., the reaction was cooled to room temperature and poured into 1 N aqueous HCl (100 mL) to precipitate which was filtered to obtain solid. The solid was washed with water (100 mL) and heptane (100 mL) and the solid was dried under vacuum to furnish the title compound. LCMS Rt=3.05 minutes MS m/z 451 [M(79Br)H]+, 453 [M(81Br)H]+ 1HNMR (d6-DMSO): δ 2.17 (s, 3H), 6.70 (d, 1H), 7.25-7.31 (m, 1H), 7.44-7.48 (m, 1H), 7.64-7.69 (m, 1H), 8.01 (dd, 1H), 8.34 (d, 1H), 8.52 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.[Cl:11]N1C(=O)CCC1=O>CN(C)C=O.C(OC)(C)(C)C>[OH:8][N:7]=[C:6]([Cl:11])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(C=NO)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(Cl)=NO)cc1
Yield: 79.7 %

Procedure:
A solution of 4-methylbenzaldehyde oxime (2 g) and N-chlorosuccinimide (2.17 g) in dimethylformamide (20 mL) was stirred for one hour at 55° C. After the reaction solution was diluted with t-butylmethylether, the solution was washed with water and saturated brine. The organic layer was dried over-anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain N-hydroxy-4-methylbenzene carboximidoyl chloride (2 g). A solution of resultant N-hydroxy-4-methylbenzene carboximidoyl chloride and 1,3-dichloro-5-[1-(trifluoromethyl)-vinyl]benzene (5.3 g) in toluene (50 mL) was heated to reflux for 8 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain [5-(3,5-dichlorophenyl) 3-(4-methylphenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (5.0 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:16]=[CH:15][C:12](C#N)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.C[Mg]Br.C([O:22][CH2:23][CH3:24])C.Cl>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:16]=[CH:15][C:12]([C:23](=[O:22])[CH3:24])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: CCOCC
Reactant: CN1CCN(Cc2ccc(C#N)cc2)CC1
Agent: C[Mg]Br
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(CN2CCN(C)CC2)cc1
Temperature: 0 °C
Yield: 89.9 %

Procedure:
0.73 g of 4-(4-methyl-piperazin-1-yl-methyl)-benzonitrile (3.40 mmol) were dissolved in toluene (13 ml) and added to a solution of 3 M methyl magnesium bromide in diethyl ether (3.4 ml, 10.2 mmol) under nitrogen atmosphere. The resulting suspension was heated under reflux for 4 hours. The reaction was cooled down to 0° C., acidified with 10% HCl and then heated under reflux for 1 hour. The two phases were separated and the aqueous phase rinsed with AcOEt, then brought to basic conditions with NH4OH and extracted with DCM. The organic phase was dried over Na2SO4 and concentrated in vacuo to dryness to obtain 0.71 g of 1-[4-(4-methyl-piperazin-1-yl-methyl)-phenyl]-ethanone as a yellow oil.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:16][CH2:17][N:18]3[CH:23]4[CH2:24][CH2:25][CH:19]3[CH2:20][CH:21]([N:26]3[C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=5[N:28]=[C:27]3[CH3:35])[CH2:22]4)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[F:36].C(N(CC)CC)C.[CH3:44][C:45]([CH3:50])([CH3:49])[C:46](Cl)=[O:47]>ClCCl>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:16][CH2:17][N:18]3[C@H:23]4[CH2:24][CH2:25][C@@H:19]3[CH2:20][CH:21]([N:26]3[C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=5[N:28]=[C:27]3[CH3:35])[CH2:22]4)[CH2:15][CH2:14][N:13]([C:46](=[O:47])[C:45]([CH3:50])([CH3:49])[CH3:44])[CH2:12][CH2:11]2)=[CH:6][C:5]=1[F:36]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccc(Cl)c(F)c2)CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccc(Cl)c(F)c2)CCN(C(=O)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
A mixture of 1-(8-{2-[4-(4-chloro-3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (0.20 g, 0.39 mmol), triethylamine (0.11 mL, 0.78 mmol) and trimethylacetyl chloride (0.053 mL, 0.43 mmol) in dichloromethane (4 mL) was stirred at rt for 1 h before the reaction mixture was quenched with saturated sodium bicarbonate solution. The organic layer was separated, dried, concentrated and purified by chromatography on silica gel eluting with a dichloromethane to 1:9 methanol:dichloromethane gradient to give 1-((1R,5S)-8-{2-[4-(4-chloro-3-fluorophenyl)-1-(2,2-dimethylpropanoyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole as a white foam (0.11 g, 51%). 1H NMR (400 MHz, CDCl3) δ 7.67 (m, 1H), 7.40 (m, 1H), 7.29 (m, 1H), 7.03-7.19 (m, 4H), 4.72 (m, 1H), 3.90 (m, 2H), 3.33 (m, 4H), 2.59 (s, 3H), 2.42 (m, 2H), 1.78-2.13 (m, 14H), 1.27 (s, 9H). HRMS C33H42ClFN4O m/z 565.3109 (M+H)Cal., 565.3134 (M+H)Obs..
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[N-:7]=[N+:8]=[N-:9].[Li+].O>CN(C)C=O>[N:7]([CH:2]1[CH2:3][CH2:4][O:5][C:1]1=[O:6])=[N+:8]=[N-:9]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCCO1
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CCOC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.56 g (10 mmol) of 2-bromo-,γ-butyrolactone are dissolved in 2 ml of dimethylformamide, and 612 mg (12.5 mmol) of lithium azide are added at 0° C. The mixture is stirred at room temperature for 2 hours, water is added and the mixture is extracted three times with methylene chloride. The combined organic phases are washed three times with water, dried over sodium sulphate and concentrated. 1.10 g (86.6% of theory) of the title compound are obtained.