Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31](F)=[CH:32][CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:33]=[CH:32][C:31]([N:35]6[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]6)=[N:30][CH:29]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: C1CCNCC1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(F)nc4)ccc2OCC3)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(N5CCCCC5)nc4)ccc2OCC3)c(F)c1
Temperature: 150 °C
Yield: 8.5 %

Procedure:
2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene, from the procedure for 249, (470 mg, 1.0 mmol), Piperidine (102 mg, 1.2 mmol), DIPEA (340 mg, 3 mmol) and NMP (4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 150° C. for 120 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to give 232 (46.2 mg, yield: 8.5%). 1HNMR (DMSO-d6, 400 MHz): δ8.74 (s, 1H), 8.31 (s, 1H), 8.10 (d, J=4.8 Hz, 1H), 7.91-7.87 (m, 1H), 7.78-7.77 (m, 2H), 7.50-7.40 (m, 1H), 7.18 (d, J=4.4 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 6.93 (d, J=8.8 Hz, 1H), 4.31 (s, 2H), 3.64 (s, 4H), 3.16 (s, 2H), 1.63-1.57 (m, 4H) ESI-MS: m/z=543 [M+H+]
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Cl:9][C:10]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]2)=[CH:26][C:11]=1[C:12]([NH:14][CH2:15][C:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2)=[O:13]>CS(C)=O>[Cl:9][C:10]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[CH2:32][CH2:33][C:34]3([O:37][CH2:4]3)[CH2:35][CH2:36]2)=[CH:26][C:11]=1[C:12]([NH:14][CH2:15][C:16]12[CH2:23][CH:22]3[CH2:24][CH:18]([CH2:19][CH:20]([CH2:21]3)[CH2:25]1)[CH2:17]2)=[O:13]
Reactant: C[S+](C)(C)=O
Reactant: O=C1CCN(Cc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CN2CCC3(CC2)CO3)ccc1Cl
Reaction time: 0.08 h
Yield: 86.4 %

Procedure:
To dimethylsulfoxide (2 ml) was added sodium hydride (0.033 g, 60 % in oil) at room temperature. The mixture was stirred for 5min. at this temperature and a solution of trimethylsulfoxonium iodide (0.178 g) in dimethylsulfoxide (2 ml) was added. After 30 min., 2-chloro-5-[(4-oxo-1-piperidinyl)methyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.28 g, Example 83a) in dimethylsulfoxide (2 ml) was added and the reaction stirred at room temperature for 3 h before being quenched with ice/water (20 ml). The mixture was extracted three times with ethyl acetate, the combined organic layers washed with brine and dried over magnesium sulfate. The crude material was purified on silica gel, eluting with ethyl acetate to afford the subtitle compound as a white foam (0.25 g).
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl[C:9]([C:19]([F:22])([F:21])[F:20])=[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:11]=O>C1COCC1.O.[OH-].[Na+]>[CH2:6]([O:5][C:3]([C:2]1[S:1][C:9]([C:19]([F:20])([F:22])[F:21])=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1)=[O:4])[CH3:7]
Reactant: CCOC(=O)CS
Reactant: O=CC(=C(Cl)C(F)(F)F)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Reaction time: 0.75 h
Yield: 56.2 %

Procedure:
To a solution of ethyl 2-mercaptoacetate (0.88 g, 6.75 mmol) in THF (45 mL) NaH (271 mg, 6.75 mmol, 60% in mineral oil) is added at −10° C. The mixture is stirred at 0° C. for 30 min before a solution of 3-chloro-4,4,4-trifluoro-2-phenyl-but-2-enal 1.32 g (4.5 mmol) in THF (5 mL) is added. The reaction mixture is stirred at it for 45 min, then treated with 2 N aq. NaOH (2 mL). Stirring is continued for 15 min and the mixture is diluted with water (100 mL) and 1 N aq. NaOH (15 mL). The mixture is extracted with diethyl ether (70 mL). The organic extract is dried over Na2SO4 and evaporated. The crude product is purified by prep. HPLC (Waters Xterra MS18, 75×30 mm, 10 μm, 10 to 95% acetonitrile in water containing 0.5% formic acid) to give 4-phenyl-5-trifluoromethyl-thiophene-2-carboxylic acid ethyl ester (760 mg) as a brownish oil, LC-MS: tR=1.12 min; 1H NMR (CDCl3): δ 7.75-7.72 (m, 1H), 7.42 (s, 5H), 4.39 (q, J=7.0 Hz, 2H), 1.40 (t, J=7.0 Hz, 3H).
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:21][CH2:22][C:23]4([OH:37])[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24]4)[CH:14]=[C:15]([F:20])[CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[H-].[Na+].I[CH3:41]>CN(C=O)C>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:21][CH2:22][C:23]4([O:37][CH3:41])[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:25][CH2:24]4)[CH:14]=[C:15]([F:20])[CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCCC(O)(COc2cc(F)cc3ccc(-c4nnc5ccccn45)nc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(COc2cc(F)cc3ccc(-c4nnc5ccccn45)nc23)CCCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.9 %

Procedure:
tert-butyl 4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-yloxy)methyl)-4-hydroxyazepane-1-carboxylate (0.060 g, 0.106 mmol) and sodium hydride (0.00468 g, 0.117 mmol) were added to 1 mL of DMF, then iodomethane (0.00732 mL, 0.117 mmol) was added and the reaction stirred for 1 hour at ambient temperature. The reaction mixture was concentrated, and DCM was added to the residue. Solids were removed by filtration and the filtrate was purified on Silica gel using 6% NH4OH in MeOH and DCM to yield 32 mg of the desired product as a clear oil. MS ESI (+) m/z 522 (M+1) detected.
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([NH:24][C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[NH:26])[CH:22]=2)[CH2:17][CH2:16][CH2:15]1)C(=O)OC1C=CC=CC=1.O.[OH-].[Na+]>C(O)C.C(Cl)Cl>[CH3:1][NH:2][CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([NH:24][C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[NH:26])[CH:22]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: CN(CCN1CCCc2ccc(NC(=N)c3cccs3)cc21)C(=O)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CNCCN1CCCc2ccc(NC(=N)c3cccs3)cc21
Yield: 63.8 %

Procedure:
A solution of compound 5 (1.30 g, 2.991 mmol) in ethanol:H2O (30 mL, 3:1) was treated with NaOH (1.19 g, 29.916 mmol) at room temperature and the resulting solution was refluxed for 6 h. The reaction was brought to room temperature, diluted with CH2Cl2 (25 mL) and washed with brine (15 mL). The aqueous layer was extracted with more CH2Cl2 (2×20 mL) and combined CH2Cl2 layer was dried (Na2SO4). The solvent was evaporated and crude product was purified by column chromatography on silica gel (2 M NH3 in MeOH:CH2Cl2, 5:95 to 1:9) to obtain compound 44 (0.6 g, 64%) as a solid. 1H NMR (DMSO-d6) δ 7.69 (d, 1H, J=3.0 Hz), 7.57 (dd, 1H, J=0.9, 5.1 Hz), 7.07 (dd, 1H, J=3.6, 5.1 Hz), 6.78 (d, 1H, J=7.5 Hz), 6.22 (brs, 2H), 6.08 (d, 1H, J=1.2 Hz), 5.99 (dd, 1H, J=1.5, 7.6 Hz), 3.27-3.23 (m, 4H), 2.68-2.61 (m, 4H), 2.31 (s, 3H), 1.87-1.80 (m, 2H); ESI-MS (m/z, %): 315 (MH+, 100); ESI-HRMS calculated for C17H23N4S (MH+), calculated: 315.1637; observed: 315.1652; HPLC purity 98.67% by area.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl.[O:8]=[C:9]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH2:10][NH:11][C:12](=[O:26])[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1.Br[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([F:44])([F:43])[F:42].O>CN(C=O)C>[O:8]=[C:9]([N:27]1[CH2:28][CH2:29][N:30]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:41]([F:42])([F:43])[F:44])[CH2:31][CH2:32]1)[CH2:10][NH:11][C:12](=[O:26])[C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:18]=1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(Cc2ccccc2C(F)(F)F)CC1)c1ccc(Oc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 39 %

Procedure:
K2CO3 (130 mg, 0.95 mmol) was added to N-(2-Oxo-2-piperazin-1-yl-ethyl)-4-phenoxy-benzamide hydrochloride (141 mg, 0.38 mmol) in 5 mL of DMF. After 10 minutes atr room temperature, 1-Bromomethyl-2-trifluoromethyl-benzene (75 mg, 0.32 mmol) was added and the resulting mixture was stirred at 60° C. for 4 hours. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulphate and concentrated. Purification by column chromatography (60-120 mesh silica gel using 6:4 EtOAc and Hexane as the eluent) afforded N-{2-Oxo-2-[4-(2-trifluoromethyl-benzyl)-piperazin-1-yl]-ethyl}-4-phenoxy-benzamide in 39% yield. LC-MS purity: 86%. 1H NMR (DMSO-D6): δ 8.5 (t, 1H), 7.9 (d, 2H), 7.8 (d, 1H), 7.7 (q, 2H), 7.4 (m, 3H), 7.2 (t, 1H), 7.1 (m, 2H), 7 (m, 2H), 4.1 (d, 2H), 3.7 (s, 2H), 3.5 (m, 4H), 2.4 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[N:10]=[C:11]([O:17][CH3:18])[C:12]([C:15]#[N:16])=[N:13][CH:14]=2)[CH:3]=1.[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.C(N(CC)CC)C>C(#N)C>[C:15]([C:12]1[N:13]=[CH:14][C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)[CH:3]=2)=[N:10][C:11]=1[O:17][CH3:18])#[N:16]
Reactant: COc1nc(Nc2cc(Cl)ncn2)cnc1C#N
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1nc(Nc2cc(NCC3CCN(C(=O)OC(C)(C)C)CC3)ncn2)cnc1C#N
Yield: 40.1 %

Procedure:
A solution of 5-(6-chloropyrimidin-4-ylamino)-3-methoxypyrazine-2-carbonitrile (4.5 mg, 0.017 mmol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (4 mg, 0.034 mmol) and triethylamine (12 uL, 0.085 mmol) in acetonitrile (1.5 mL) was heated at 145° C. for 90 min using microwave irradiation. The solvent was removed in vacuo and the crude mixture was purified by preparative thin layer chromatography, eluting with dichloromethane/MeOH (10/1), to give the title compound as a yellow oil (3 mg, 40%).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[O:3][C:4]1[CH:33]=[CH:32][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][NH:16][CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[O:11])=[CH:6][CH:5]=1.Br[C:37]1[S:47][C:40]2=[N:41][C:42](=[O:46])[CH:43]=[C:44]([CH3:45])[N:39]2[N:38]=1.C(N(CC)C(C)C)(C)C>C(O)C>[F:35][C:2]([F:1])([F:34])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:37]3[S:47][C:40]4=[N:41][C:42](=[O:46])[CH:43]=[C:44]([CH3:45])[N:39]4[N:38]=3)[CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:23][CH:22]=2)(=[O:19])=[O:20])=[O:11])=[CH:32][CH:33]=1
Reactant: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CNCCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1cc(=O)nc2sc(Br)nn12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(=O)nc2sc(N3CCN(S(=O)(=O)c4ccc(OC(F)(F)F)cc4)[C@@H](C(=O)NCc4ccc(OC(F)(F)F)cc4)C3)nn12
Temperature: 100 °C
Reaction time: 3 h
Yield: 64.1 %

Procedure:
To a mixed solution of the compound (0.038 g) obtained in Example 783, the compound (0.023 g) obtained in Step 3 and ethanol (1.0 ml) was added N,N-diisopropylethylamine (0.019 ml) at room temperature. After stirring at 100° C. for 3 hr, the reaction mixture was concentrated under reduced pressure, and the residue was purified by thin layer silica gel chromatography (methanol:chloroform=1:9) to give the title compound (0.032 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:14][CH2:13][O:12][CH2:11]2)[CH:5]=[C:4]([CH3:15])[C:3]=1[C:16]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]2[C:17]=1[CH2:18][CH2:19][C@H:20]2[O:26][C:27]1[CH:40]=[CH:39][C:30]2[C@H:31]([CH2:34][C:35]([O:37]C)=[O:36])[CH2:32][O:33][C:29]=2[CH:28]=1>C(O)(C)C>[CH3:15][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH:10]2[CH2:14][CH2:13][O:12][CH2:11]2)[CH:7]=[C:2]([CH3:1])[C:3]=1[C:16]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]2[C:17]=1[CH2:18][CH2:19][C@H:20]2[O:26][C:27]1[CH:40]=[CH:39][C:30]2[C@H:31]([CH2:34][C:35]([OH:37])=[O:36])[CH2:32][O:33][C:29]=2[CH:28]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCC6CCOC6)cc5C)ccc(F)c43)ccc21
Solvent: CC(C)O
Product: Cc1cc(OCC2CCOC2)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O

Procedure:
The title compound is prepared from methyl 2-((3S)-6-((1R)-4-(2,6-dimethyl-4-((tetrahydrofuran-3-yl)methoxy)phenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate following a procedure analogous to that described in example 1. Isopropanol is used instead of methanol. LC (method 1): tR=1.42 min; Mass spectrum (ESI+): m/z=533 [M+H]+.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH3:15][N:16]1[C:20]([CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][N:33]([C:36]4[CH2:37][CH2:38][C:39]5[N:40]([C:42]([C:45]([F:48])([F:47])[F:46])=[N:43][N:44]=5)[N:41]=4)[CH2:32][CH2:31]3)=[CH:26][CH:25]=2)=CC=N1.OCCCN1C[CH2:57][N:56]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:55][CH2:54]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:48][C:45]([F:47])([F:46])[C:42]1[N:40]2[N:41]=[C:36]([N:33]3[CH2:34][CH2:35][N:30]([C:27]4[CH:26]=[CH:25][C:24]([O:23][CH2:22][CH2:21][CH2:20][N:16]5[CH2:15][CH2:57][N:56]([C:59]([O:61][C:62]([CH3:63])([CH3:65])[CH3:64])=[O:60])[CH2:55][CH2:54]5)=[CH:29][CH:28]=4)[CH2:31][CH2:32]3)[CH:37]=[CH:38][C:39]2=[N:44][N:43]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Reactant: Cn1nccc1CCOc1ccc(N2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(N3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.2 %

Procedure:
DIAD (3.24 mL, 16.47 mmol) was added dropwise to 4-{4-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl}phenol (obtained as described in Example 16, preparation of starting materials) (5 g, 13.72 mmol), tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate (CAS 132710-90-8, 5.03 g, 20.59 mmol) and triphenylphosphine (5.40 g, 20.59 mmol) in THF (50 mL) at 0° C. under nitrogen. The resulting solution was stirred at ambient temperature for 16 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (100 mL), and washed sequentially with 2M NaOH (100 mL) and saturated brine (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, eluting with EtOAc. Pure fractions were evaporated to dryness to give tert-butyl 4-[3-(4-{4-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl}phenoxy)propyl]piperazine-1-carboxylate (3.66 g, 45%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)([C:8]#[N:9])[CH2:4][CH2:3]1.[CH2:16](O)[CH2:17][OH:18].O>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N:15]1[CH:14]=[CH:13][CH:12]=[N:11][C:10]=1[C:5]1([C:8]#[N:9])[CH2:6][CH2:7][C:2]2([O:18][CH2:17][CH2:16][O:1]2)[CH2:3][CH2:4]1
Reactant: OCCO
Reactant: N#CC1(c2ncccn2)CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: N#CC1(c2ncccn2)CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 80.1 %

Procedure:
A solution of 4-oxo-1-(pyrimidin-2-yl)cyclohexanecarbonitrile (333 mg, 1.66 mmol), ethylene glycol (96.9 μl, 1.74 mmol), and p-toluenesulfonic acid monohydrate (15.7 mg, 82.7 μmol) in benzene (10 mL) was refluxed for 1.5 h while the water formed during the reaction was removed azeotropically using a Dean-Stark apparatus. After being cooled down to room temperature, the reaction was diluted (Et2O) and washed (2×H2O, 2×sat aqueous NaHCO3, and 2× brine). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by flash chromatography (SiO2, 40-50% EtOAc/Hexanes, gradient elution) gave 8-pyrimidin-2-yl-1,4-dioxa-spiro[4,5]decane-8-carbonitrile (325 mg, 1.33 mmol, 80%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[CH2:18][C@@H:17]([NH:21]C(=O)OCC2C=CC=CC=2)[CH2:16]1.[H][H]>CO.[Pd]>[NH2:21][C@H:17]1[CH2:16][N:15]([C:3]2[CH:4]=[CH:5][C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][C:9]3=[O:14])=[CH:7][C:2]=2[F:1])[C:19](=[O:20])[CH2:18]1
Reactant: [H][H]
Reactant: O=C(N[C@@H]1CC(=O)N(c2ccc(N3CCOCC3=O)cc2F)C1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: N[C@@H]1CC(=O)N(c2ccc(N3CCOCC3=O)cc2F)C1

Procedure:
260 mg (0.6 mmol) benzyl (R)-{1-[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenyl]-5-oxo-pyrrolidin-3-yl}-carbamate are dissolved in 10 ml of methanol, combined with 180 mg palladium on charcoal and hydrogenated for 3.75 hours in a Parr apparatus at 3 bar hydrogen pressure at ambient temperature.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[CH:4]=1.[CH2:10]([O:12][C:13](=[O:18])[C:14](Br)([F:16])[F:15])[CH3:11]>C(OCC)C>[CH2:10]([O:12][C:13](=[O:18])[C:14]([F:16])([F:15])[O:9][C:5]1[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=1)[CH3:11]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C(F)(F)Oc1cccnc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 35.1 %

Procedure:
A suspension of 60% of NaH in oil (2.52 g, 126 mmol) was washed three times with hexanes and the solid was suspended in dry DMF (100 ml). Pyridine-3-ol (10 g, 105 mmol) was slowly added over a period of 5 min and the reaction mixture was stirred at room temperature for about 10 min. The reaction mixture was cooled at 0° C. and 2-bromo-2,2-difluoroacetic acid ethyl ester (21.32 g, 105 mmol) was slowly added. The reaction mixture was heated at 90° C. for 20 h. After cooling the reaction to reach room temperature, ethyl ether was added and the suspension was washed with water and brine. The organic layer was dried over sodium sulfate for 15 min, the solvent was evaporated and the crude was purified by flash chromatography, using 100% methylene chloride to obtain 2,2-difluoro-2-(pyridin-3-yloxy)acetic acid ethyl ester as a brown oil (8 g). 2,2-Difluoro-2-(pyridin-3-yloxy)acetic acid ethyl ester was converted to 2,2-difluoro-2-(pyridin-3-yloxy)acetaldehyde (7 g) by following the procedure described in Example 9, Step 7 above and then converted to the title compound by following Example 1, Steps 8-12 above.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][C:34]([F:38])=[CH:33][CH:32]=4)=[C:4]2[N:3]=1.[CH:39](B1OC(C)(C)C(C)(C)O1)=[CH2:40]>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:38][C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][C:28]([C:27]1[CH:26]=[N:25][N:5]3[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][C:2]([CH:39]=[CH2:40])=[N:3][C:4]=13)=[CH:37]2
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3cnc4ccc(F)cc4c3)cnn12
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=Cc1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Temperature: 100 °C
Yield: 88.4 %

Procedure:
To 5-chloro-3-(6-fluoroquinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (2.5 g, 4.4 mmol) in 1,4-Dioxane (50 mL) and 2M Na2CO3 (25 mL) was added vinylboronic acid pinacol ester (0.9 ml, 5.2 mmol), and Pd(PPh3)4 (0.5 g, 0.4 mmol). The reaction mixture was heated at 100° C. for 16 hours, at which time LC/MS analysis confirmed full consumption of starting material. Following removal of dioxane under reduced pressure, organics were extracted with CH2Cl2 (4×40 mL, dried (Na2SO4) and concentrated in vacuo. Gradient column chromatography on silica eluting with 20 to 50% EtOAc/hexanes gave 3-(6-fluoroquinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)-5-vinylpyrazolo[1,5-a]pyrimidin-7-amine as a yellow solid (2.2 g, 3.89 mmol, 88%). LC/MS: 3.05 mins, m/z=566.3 (MH+).
Reaction SMILES: [Na].[F:2][C:3]([F:14])([F:13])[C:4]1[CH:8]=[C:7]([NH:9][C:10](=O)C)[O:6][N:5]=1.C1C=CC=CC=1.S(OC)(OC)(=O)=O>CO>[F:14][C:3]([F:2])([F:13])[C:4]1[CH:8]=[C:7]([NH:9][CH3:10])[O:6][N:5]=1
Reactant: CC(=O)Nc1cc(C(F)(F)F)no1
Agent: [Na]
Solvent: c1ccccc1
Solvent: CO
Solvent: COS(=O)(=O)OC
Product: CNc1cc(C(F)(F)F)no1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium metal (0.28 g, 12.3 mmole) was dissolved in dry methanol (12.3 ml) and to this solution was added 3-trifluoromethyl-5-acetylaminoisoxazole (2.38 g, 12.26 mmole). After stirring at room temperature for 15 minutes, the mixture was concentrated in vacuo and dry benzene (12.3 ml) was added to the residue. The mixture was concentrated in vacuo and dry benzene (18.4 ml) and dimethyl sulfate (1.55 g, 12.3 mmole) were added to the residue, followed by refluxing for 2 hours. After cooling, the precipitated crystals were filtered off. The filtrate was washed with a 8% solution of sodium bicarbonate and concentrated in vacuo. A 5% solution of sodium hydroxide (11.8 g) was added to the residue and the mixture was sitrred at room temperature for 2 hours. It was extracted with methylene chloride and the methylene chloride layer was dried with anhydrous sodium sulfate. The extract was concentrated in vacuo and the resulting residue was recrystallized from cyclohexane to give the title compound as colorless columns. Yield: 1.41 g (65.4%). m.p. 48.5°-50.0° C.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][OH:18])[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[CH:21]1[O:25]CCO1.Cl.[CH2:27]1COCC1>>[Br:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[N:14]=[C:13]([N:15]([CH2:16][CH2:17][OH:18])[CH3:27])[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[CH:21]=[O:25]
Reactant: C1CCOC1
Reactant: N#Cc1ccc(NCCO)nc1Oc1ccc(Br)c(C2OCCO2)c1
Agent: Cl
Product: CN(CCO)c1ccc(C#N)c(Oc2ccc(Br)c(C=O)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of 6 (2-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-6-(2-hydroxy-ethylamino)-nicotinonitrile, 1.1 g, 2.7 mmol) in THF (200 mL) was added a HCl solution (1 M, 100 mL). The reaction was stirred at room temperature overnight. The THF was evaporated in vacuo. The white solid that formed was filtered and air-dried to afford 0.94 g (55% yield for two steps) of the title compound.