Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.[CH3:33][N:34]([CH3:43])[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:40]3[CH2:41][CH2:42][N:37]([CH2:36][CH2:35][N:34]([CH3:43])[CH3:33])[CH2:38][CH2:39]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: CN(C)CCN1CCNCC1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CCN1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]-pyrimidine-3-amido]-1H-pyrazol-1-yl]acetic acid (100 mg, 0.22 mmol) in DMF (10 mL) was added dimethyl[2-(piperazin-1-yl)ethyl]amine (68 mg, 0.43 mmol), DIEA (125 mg, 0.97 mmol) and HATU (123 mg, 0.32 mmol). The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (2#-Analyse HPLC-SHIMADZU(HPLC-10)): Column, XBridge BEH130 Prep C18 OBD Column, 19&#65533; 100 mm 5 um 13 nm; mobile phase, Water with 10 mM NH4CO3 and ACN (15% ACN up to 40% in 6 min); Detector, UV 254/220 nm. This resulted in 79.1 mg (61%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[2-(dimethylamino)ethyl]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow solid. LCMS (Method 25) [M+H]+=602.2, RT=0.89 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.7, 7.1 Hz), 8.69-8.67 (m, 2H), 8.30 (s, 1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz), 7.55 (d, 1H, J=2.7 Hz), 7.45 (d, 1H, J=9.0 Hz), 7.28 (dd, 1H, J=4.2, 6.9 Hz), 7.02 (t, 1H, J=73.2 Hz), 5.23 (s, 2H), 3.48-3.42 (m, 4H), 2.45-2.32 (m, 8H), 2.13 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].CC(C)=O.C(=O)=O.[Li]CCCC.[C:22]([N:26]1[C:30]2[NH:31][C:32](=[O:44])[CH2:33][CH:34]([C:35]3[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=3[F:43])[C:29]=2[C:28]([CH:45]2[CH2:48][C:47](=[O:49])[CH2:46]2)=[N:27]1)([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([N:26]1[C:30]2[NH:31][C:32](=[O:44])[CH2:33][CH:34]([C:35]3[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=3[F:43])[C:29]=2[C:28]([CH:45]2[CH2:48][C:47]([C:2]3[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=3)[C:5]#[N:6])([OH:49])[CH2:46]2)=[N:27]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: N#Cc1cccc(Br)c1
Reactant: CC(C)(C)n1nc(C2CC(=O)C2)c2c1NC(=O)CC2c1cc(F)c(F)cc1F
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)n1nc(C2CC(O)(c3cccc(C#N)c3)C2)c2c1NC(=O)CC2c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.9 %

Procedure:
To a stirring solution of 3-bromobenzonitrile (3.7 g, 20.4 mmol) in 50 mL of THF at −78° C. (acetone/CO2 bath) was added a solution of n-BuLi (8.2 mL, 20.4 mmol, 2.5 M in hexanes). After 15 min, a solution of 1-tert-butyl-3-(3-oxo-cyclobutyl)-4-(2,4,5-trifluoro-phenyl)-1,4,5,7-tetrahydro-pyrazolo[3,4-b]pyridin-6-one (2.0 g, 5.1 mmol in 10 mL of THF) was added. After one hr, the reaction mixture was quenched cold by the addition of a saturated NH4Cl solution, and was then allowed to warm to room temperature. The reaction mixture was diluted with CH2Cl2, and the layers were separated. The organic layer was dried over MgSO4, filtered through a pad of diatomaceous earth, and concentrated under reduced pressure to give a tan solid. Purification of this material was accomplished by MPLC using a 35 g ISCO cartridge on a Biotage® system eluting with a gradient of 25-50% EtOAc/hexanes. The product-containing fractions were collected and concentrated to yield the title compound (0.98 g, 40% yield) as a tan solid. Rf=0.29 (50% EtOAc/hexanes).
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:9]2[C@@:5]([C:12]([O:14][CH3:15])=[O:13])([O:6][C:7]([CH3:11])([CH3:10])[O:8]2)[O:4][C@@H:3]1[CH2:16]OS(C1C=CC(C)=CC=1)(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C=O)C>[N:28]([CH2:16][C@@H:3]1[O:4][C@@:5]2([C:12]([O:14][CH3:15])=[O:13])[O:6][C:7]([CH3:11])([CH3:10])[O:8][CH:9]2[C@@H:2]1[OH:1])=[N+:29]=[N-:30]
Reactant: COC(=O)[C@]12O[C@H](COS(=O)(=O)c3ccc(C)cc3)[C@H](O)[C@H]1OC(C)(C)O2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@]12O[C@@H](CN=[N+]=[N-])[C@@H](O)C1OC(C)(C)O2
Temperature: 100 °C
Yield: 52 %

Procedure:
To a solution of 17 (400 mg, 1.0 mmol) in DMF (2 mL) was added NaN3 (97 mg, 1.5 mmol). The reaction mixture was heated at 100° C. (oil bath) for 20 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc/H2O. The EtOAc layer was washed with H2O (2×20 mL), brine (1×20 mL) and dried over MgSO4. EtOAc was evaporated and the crude material was purified by silica gel chromatography using EtOAc/Hexane. Product 15 was obtained as a white solid (140 mg; yield 52%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH3:8])[C:4](=[O:7])[CH2:5][Cl:6].[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:9]([NH:2][C@@H:3]([CH3:8])[C:4](=[O:7])[CH2:5][Cl:6])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@H](N)C(=O)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)c1ccccc1)C(=O)CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a vigorously stirred suspension of (S)-3-amino-1-chloro-2-butanone, monohydrochloride (3.0 g., 19.0 mmole) in 150 ml. of tetrahydrofuran at 0°-5° is added, sequentially, benzoyl chloride (2.2 ml., 19.0 mmole), triethylamine (2.65 ml., 19.0 mmole), and sodium bicarbonate (1.6 g., 19.0 mmole). The reaction mixture is stirred for 15 minutes in the cold and then for 2 hours at room temperature. The solvent is evaporated and the residue is partitioned between ethyl acetate (400 ml.) and ice-water (40 ml.). The organic layer is washed with 5% potassium bisulfate (2×30 ml.) and water (3×30 ml.), then dried and evaporated. The resulting crystalline residue is recrystallized from benzene-petroleum ether giving three crops of comparable purity totaling 3.67 g.; m.p. 119.5°-121.5° (first crop), 118°-119.5° (third crop). A portion is recrystallized once more giving an analytically pure sample of (S)-3-(benzoylamino)-1-chloro-2-butanone; m.p. 119.5°-121°.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)O[C:2]2=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(=O)C.[C:28]([NH:31][NH2:32])(=[O:30])[CH3:29]>C1(C)C=CC=CC=1>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]1[O:30][C:28]([CH3:29])=[N:31][N:32]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CC(=O)NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1nnc(-c2ccccc2N)o1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of isatoic anhydride (16.3 g, 0.1 mol), p-toluenesulfonic acid (0.2 g, 1.1 mmol), glacial acetic acid (10 ml), acethydrazide (7.4 g, 0.1 mol) and dry toluene (90 ml) was stirred at 120° C. for 4 h, cooledto room temperature and poured into ice water. Toluene (500 ml) was added, and the phases were separated. The aqueous phase was extracted with CH2Cl2 (2×100 ml).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N-:5]=[N+:6]=[N-:7].[Na+].[C:9]([C:11](=[CH:17][NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH3:28])=[CH:21][N:20]=1)[C:12](OCC)=[O:13])#[N:10]>O1CCCC1>[CH2:25]([C:22]1[CH:23]=[CH:24][C:19]2[N:20]([CH:21]=1)[C:12](=[O:13])[C:11]([C:9]1[NH:10][N:7]=[N:6][N:5]=1)=[CH:17][N:18]=2)[CH2:26][CH2:27][CH3:28]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1ccc(NC=C(C#N)C(=O)OCC)nc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCc1ccc2ncc(-c3nnn[nH]3)c(=O)n2c1
Yield: 30.4 %

Procedure:
Aluminum chloride (0.89 g., 6.67 mmoles was carefully added to cold (-30°) tetrahydrofuran (42 ml.). Sodium azide (1.3 g., 20.0 mmoles was then added and the mixture heated at reflux for 40 minutes. Ethyl 2-cyano-3-(5-n-butyl-2-pyridylamino)acrylate (1.50 g., 5.49 mmoles) was added and the mixture heated under reflux for 18 hours. The cooled mixture was concentrated and the residue treated with ice water (50 ml.). The mixture was acidified to pH 3 with 6N hydrochloric acid. The mixture was filtered and the collected solid treated with boiling 3% aqueous sodium bicarbonate for 10 minutes. The mixture was filtered and the filtrate acidified to pH 4 with 6N hydrochloric acid. The precipitate was recrystallized from N,N-dimethylformamide to give the title compound (0.45 g., 30.4%), m.p. 284°-285° (decomp).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][CH2:13][CH2:14][O:15][CH3:16])[CH2:2]1.[CH3:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[NH:19]1>O.CO>[CH3:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[N:19]1[CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][O:15][CH3:16]
Reactant: COCCOc1ccccc1OCC1CO1
Reactant: CC1CCCC(C)N1
Solvent: CO
Solvent: O
Product: COCCOc1ccccc1OCC(O)CN1C(C)CCCC1C
Yield: 76.8 %

Procedure:
A mixture of 4.5 g of 1,2-epoxy-3-[2-(2-methoxyethoxy)phenoxy]-propane, 2.4 g of 2,6-dimethylpiperidine, 30 ml of methanol and 1 drop of water is refluxed for 8 hours. The methanol is then removed, and the residue is cooled. The precipitated colorless crystals are collected by filtration, and washed with petroleum benzine to give 5.2 g of 1-(2,6-dimethylpiperidino)-3-[2-(2-methoxyethoxy)phenoxy]-2-propanol, melting at 92°-94°C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[N+:27]([C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=1[C@:37]1([O:55][C@H:54]([C:56]([O:58][CH3:59])=[O:57])[C@@H:49]([O:50][C:51](=[O:53])[CH3:52])[C@H:44]([O:45][C:46](=[O:48])[CH3:47])[C@H:39]1[O:40][C:41](=[O:43])[CH3:42])[OH:38])([O-:29])=[O:28]>C(Cl)(Cl)(Cl)Cl>[N+:27]([C:30]1[CH2:35][C:34](=[CH:36][Br:1])[CH:33]=[CH:32][C:31]=1[C@:37]1([O:55][C@H:54]([C:56]([O:58][CH3:59])=[O:57])[C@@H:49]([O:50][C:51](=[O:53])[CH3:52])[C@H:44]([O:45][C:46](=[O:48])[CH3:47])[C@H:39]1[O:40][C:41](=[O:43])[CH3:42])[OH:38])([O-:29])=[O:28]
Reactant: COC(=O)[C@H]1O[C@](O)(c2ccc(C)cc2[N+](=O)[O-])[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)[C@H]1O[C@](O)(C2=C([N+](=O)[O-])CC(=CBr)C=C2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 19.5 %

Procedure:
N-bromosuccinimide (117.2 mg, 0.66 mmol) and benzoyl peroxide (159 mg, 0.66 mmol) were added to a solution of methyl 1-(2-nitro-4-methylphenyl)-2,3,4-tri-O-acetyl-β-D-glucopyranuronate (206 mg, 0.44 mmol) in carbon tetrachloride (20 ml). The mixture was refluxed for 5 hours and stirred at room temperature for 12 hours. The reaction mixture was evaporated under reduced pressure, and purified by column chromatography on silica gel (ethyl acetate-hexane, 2:3) to give 47 mg of methyl 1-(2-nitro-4-bromomethylene-phenyl)-2,3,4-tri-O-acetyl-β-D-glucopyranuronate in 20% yield. 1H NMR (300 MHz, DMSO-d6) δ1.98-2.02 (m, 9H, CH3), 3.64 (s, 3H, OCH3), 4.73 (s, 2H, CH2), 4.77 (s, 1H, sugar-H), 5.09-5.13 (m, 2H, sugar-H), 5.47 (t, J=9 Hz, 1H, sugar-H), 5.76 (d, J=7.7 Hz, 1H, sugar-H), 7.43 (d, J=8.7 Hz, 1H, ArH), 7.76 (d, J=8.7 Hz, 1H, ArH), 8.02 (s, 1H, ArH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[N:10]=[N:9]1>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[N:10]=[N:9]1
Reactant: CCOC(=O)c1cn(-c2ccccc2F)nn1
Solvent: CCO
Solvent: O
Product: O=C(O)c1cn(-c2ccccc2F)nn1
Temperature: 60 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
Ethyl 1-(2-fluorophenyl)-1H-1,2,3-triazole-4-carboxylate (110 mg) was dissolved in ethanol (3 ml)-water (2 ml)-1M aqueous sodium hydroxide solution (1 ml) and the mixture was stirred at 60° C. for 12 hr. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water, neutralized (pH: 2) with 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (92 mg).
Reaction SMILES: [CH:1]([CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)=O.[CH3:15][NH2:16]>CO.C(Cl)Cl>[CH3:15][NH:16][CH2:1][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)C1
Reactant: CN
Solvent: ClCCl
Solvent: CO
Product: CNCC1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 12 h
Yield: 95.2 %

Procedure:
To a solution of 1,1-dimethylethyl 3-formyl-1-pyrrolidinecarboxylate (500 mg, 2.51 mmol) in MeOH/DCM (6 mL, 1:1) were added NaHCO (1.05 g, 12.6 mmol) followed by methylamine (2.51 mL, 5.02 mmol, 2.0 M in MeOH). After 12 h at 25° C., NaBH (1.05 g, 12.6 mmol) was added. After 1 h, the reaction was concentrated and the residue was partitioned between DCM and H O. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried over MgSO4, concentrated and purified via column chromatography (silica, 4% MeOH in DCM (1% NH OH)) yielding the title compound (512 mg, 95%) as a brown oil: LC/MS (ES) m/e 215 (M+H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C1C(=O)N([Br:17])C(=O)C1.[O-]S([O-])(=S)=O.[Na+].[Na+]>CC#N>[Br:17][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([CH3:9])[C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(N)cccc1F
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: Cc1c(N)ccc(Br)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-fluoro-2-methylaniline (20 g, 0.16 mol) in CH3CN (500 mL) was added NBS (31.3 g, 0.176 mol) in portions at 10° C. The resulting mixture was stirred at room temperature for 30 minutes. Upon completion, saturated Na2S2O3 (500 mL) was added slowly into the reaction mixture at 10° C. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was washed with petroleum ether affording the title compound (20 g), which was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6): δ 7.08 (t, 1H), 6.40 (dd, 1H), 5.35 (br, 2H), 1.98 (d, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:30][CH:31]([CH2:34][CH2:35][CH3:36])[CH:32]=O.[H-].[Na+]>C(#N)C.O>[CH3:30][CH:31]([CH2:34][CH2:35][CH3:36])[CH:32]=[CH:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCCC(C)C=O
Reactant: CCOC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: CCCC(C)C=CCCCC(=O)OCC
Yield: 54 %

Procedure:
104.54 g (0.5 mol) of ethyl 5-bromovalerate and 137.5 g (0.525 mol) of triphenyl phosphine were refluxed for 36 hours in 1 l of acetonitrile. After the reaction terminated, 500 ml of acetonitrile was distilled off, then the reaction mixture was dried. Under nitrogen atmosphere, 50.1 g (0.5 mol) of 2-methyl valeraldehyde was added, then the reaction mixture was stirred. Controlling the reaction temperature to within the range of 25°-35° C., 20.0 g (0.5 mol) of oily (60%) sodium hydride was added little by little. After the addition, the reaction mixture was stirred over night at room temperature. After the reaction ended, 250 g of water was added into the reaction mixture, then oil layer was separated and the water layer was extracted three times with 150 ml of hexane. The organic layers were combined and washed with 150 ml of water. After the hexane solution was dried sufficiently with anhydrous Magnesium sulfate, solvent was removed under reduced pressure, and distilled to obtain 57.3 g of ethyl 7-methyl-5-decenoate (Yield: 54%, based upon starting material). The product was gradually added dropwise into 500 ml of dried ethylether solution including 5.12 g (0.135 mol) of aluminum lithium hydride under nitrogen stream. The dropwise addition was done while a reaction vessel was cooled sufficiently by ice water. After the addition was completed, the reaction temperature was returned to room temperature and stirred for 2 hours. Then, 300 ml of water was added gradually into the reaction mixture, and the organic layer was separated. The water layer was returned to pH7 and extracted three times with 100 ml of diethylether. The organic layers were combined and washed with 100 ml of water, and solvent was removed from the reaction mixture under reduced pressure to obtain 44.2g of 7-methyl-5-decen-1-ol (Yield: 52", based upon starting material).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:15]([CH3:18])[C:16]#[N:17].[I-].[K+]>CC(CC)=O.O>[O:7]([CH:15]([CH3:18])[C:16]#[N:17])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: CC(Cl)C#N
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CC(C#N)Oc1ccccc1
Reaction time: 0.33 h

Procedure:
A mixture of phenol (18.8 g.) and anhydrous potassium carbonate (25 g.) in dry ethyl methyl ketone (35 ml.) was stirred and heated to reflux, during the dropwise addition of a solution of 2-chloropropionitrile (19.7 g.) in dry ethyl methyl ketone (15 ml.) containing finely-powdered potassium iodide (0.5 g.). The addition took 20 minutes. Stirring and heating were continued for a total of 2 hours after which the mixture was cooled, poured into water (200 ml.) and extracted with ether (200, 75 and 75 ml.). The combined ether extract was washed several times with 2N-sodium hydroxide to remove phenol, dried over anhydrous sodium sulphate, and evaporated. The residue was distilled under water-pump vacuum to give pure 2-phenoxypropionitrile, b.p. 117°-118°/13 mm.
Reaction SMILES: [CH3:1][S:2][CH:3]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:5]2([CH2:10][CH2:9][N:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][CH:15]=3)=[O:12])[CH2:7][CH2:6]2)[CH2:4]1.[Na].C[OH:34]>C1COCC1.O>[CH3:1][S:2]([CH:3]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:5]2([CH2:10][CH2:9][N:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[O:12])[CH2:7][CH2:6]2)[CH2:4]1)=[O:34]
Reactant: CO
Reactant: CSC1CC2(CCN(C(=O)Nc3ccc(-c4ccccc4)cc3)CC2)c2ccccc21
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)C1CC2(CCN(C(=O)Nc3ccc(-c4ccccc4)cc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 35 h

Procedure:
To a solution of 2,3-dihydro-1-methylthio-N-4-biphenylylspiro[1H-indene-3,4′-piperidine]-1′-carboxamide (1100, 55.4 mg, 0.129 mmol) in methanol (3.0 mL), THF (2.0 mL) and H2O (1.0 mL) was added sodium meta periodade (34.6 mg, 0.161 mmol). After being stirred for 35 h at room temperature, the resulting mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried (Na2SO4), and concentrated in vacuo. The residue was triturated with ethyl acetate and isopropyl ether to give 2,3-dihydro-1-methylsulfinyl-N-4-biphenylylspiro[1H-indene-3,4′-piperidine]-1′-carboxamide 45.4 mg; 79%) as an amorphous solid, 1200.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[O:13])[N:3]=1.CCN(C(C)C)C(C)C.[NH:30]1[CH:34]=[CH:33][C:32]([NH2:35])=[N:31]1>CN(C=O)C>[NH:30]1[CH:34]=[CH:33][C:32]([NH:35][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)=[O:13])[N:3]=2)=[N:31]1
Reactant: O=C(c1cccc(F)c1)c1nc(Cl)c2ccccc2n1
Reactant: Nc1cc[nH]n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cccc(F)c1)c1nc(Nc2cc[nH]n2)c2ccccc2n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
To a solution of (4-chloroquinazolin-2-yl)(3-fluorophenyl)methanone from Example 1 (57 mg, 0.20 mmol) in DMF (3 mL), DIEA (0.069 mL, 0.4 mmol) and 1H-pyrazol-3-amine (83 mg, 1 mmol) were added. The mixture was stirred at 50° C. for 2 h. The reaction was quenched by adding water and the precipitate was filtered. The crude solid was purified on preparative TLC using DCM/MeOH as mobile phase to afford (4-(1H-pyrazol-3-ylamino)quinazolin-2-yl)(3-fluorophenyl)methanone (18 mg, 27%). 1H NMR (300 MHz, DMSO-d6) δ 6.80 (s, 1H), 7.67-7.61 (m, 4H), 7.92-7.84 (m, 4H), 8.78 (m, 1H), 10.82 (s, 1H), 12.54 (s, 1H); LC-MS (ESI) m/z 334 (M+H)+.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([NH:20][CH:21]([CH3:23])[CH3:22])([C:18]#[N:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:24]S(O)(=O)=O>C(Cl)Cl>[CH:1]([N:14]1[CH2:17][C:16]([NH:20][CH:21]([CH3:23])[CH3:22])([C:18]([NH2:19])=[O:24])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: CC(C)NC1(C#N)CN(C(c2ccccc2)c2ccccc2)C1
Solvent: ClCCl
Product: CC(C)NC1(C(N)=O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-benzhydryl-3-isopropylaminoazetidine-3-carbonitrile (I-(7A-106)a; 3.40 g, 11.1 mmol) in methylene chloride (25 ml) cooled in an ice bath was treated with H2SO4 (5.95 ml, 111 mmol), dropwise. After the reaction mixture was allowed to warm to room temperature and stir overnight, it was cooled in an ice bath and then carefully quenched with concentrated NH4OH to pH 11. The mixture was extracted with methylene chloride, the combined organic layers were dried (Na2SO4) and then concentrated, in vacuo, to afford a crude foam (3.3 g) that was then purified on a Biotage™ Flash 40M column using 0–2% methanol in methylene chloride as eluant to afford the title compound I-(7A-106)b (2.32 g, 64%) as a brown solid: +ESI MS (M+1) 324.4; 1H NMR (400 MHz, CD3OD) δ 7.40 (d, J=7.5 Hz, 4H), 7.24 (t, J=7.5 Hz, 4H), 7.15 (t, J=7.1 Hz, 2H), 4.46 (s, 1H), 3.53 (d, J=8.7 Hz, 2H), 3.06 (d, J=8.7 Hz, 2H), 2.90 (septuplet, J=6.4 Hz, 1H), 0.97 (d, J=6.6 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([CH3:17])[N:9]=2)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH3:28])[N:23]=[CH:22]2>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH3:28])[N:23]=[CH:22]4)=[O:14])=[C:10]([CH3:17])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1nc(-c2ccc(F)cc2)ccc1C(=O)O
Reactant: Cn1ncc2cc(N)ccc21
Product: Cc1nc(-c2ccc(F)cc2)ccc1C(=O)Nc1ccc2c(cnn2C)c1

Procedure:
Using the procedure outlined in Example 15, the title compound was prepared from 6-(4-fluorophenyl)nicotinic acid (D3) (100 mg, 0.43 mmol) and 5-amino-1-methylindazole (58 mg, 0.39 mmol) as a white solid (21 mg). MS (ES): MH+ 361, (M−H)− 359.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8].[Cl:18][C:19]1[CH:20]=[C:21]([N:26]=[C:27]=[S:28])[CH:22]=[C:23]([Cl:25])[CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27](=[S:28])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:17])=[C:6]([CH:16]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:22]=[C:23]([Cl:25])[CH:24]=1
Reactant: Nc1ccc(F)c(C(=O)Nc2ccccc2)c1
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Product: O=C(Nc1ccccc1)c1cc(NC(=S)Nc2cc(Cl)cc(Cl)c2)ccc1F
Yield: 87.5 %

Procedure:
Prepared according to the procedure described for Example 60 using 5-amino-2-fluoro-N-phenyl-benzamide (0.920 g, 4.00 mmol) and 3,5-dichlorophenyl isothiocyanate (0.817 g, 4.00 mmol) to afford the product (1.52 g); m.p. 195-196° C.