Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[OH:10].[Br:11][CH2:12][CH2:13]Br>>[Br:11][CH2:12][CH2:13][O:10][C:3]1[C:2]([Cl:1])=[C:7]([F:8])[CH:6]=[CH:5][C:4]=1[F:9]
Reactant: BrCCBr
Reactant: Oc1c(F)ccc(F)c1Cl
Product: Fc1ccc(F)c(OCCBr)c1Cl
Yield: 31 %

Procedure:
2-Chloro-3,6-difluorophenol was reacted with 1,2-dibromoethane according to the procedure described in Step 2A to yield 2C (2.1 g, 31%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.65 (t, J=6.57 Hz, 2H), 4.43 (t, J=6.57 Hz, 2H) 6.89 (m, 1H) 7.01 (m, 1H).
Reaction SMILES: ClC1C(F)=CC=C(Cl)C=1[C@H](OC1C(N)=NC=C(B2OC(C)(C)C(C)(C)O2)C=1)C.[NH2:29][C:30]1[N:35]=[CH:34][C:33]([C:36]2[CH:37]=[N:38][N:39]([CH:41]3[CH2:46][CH2:45][N:44](C(=O)CO)[CH2:43][CH2:42]3)[CH:40]=2)=[CH:32][C:31]=1[O:51][C@@H:52]([C:54]1[C:59]([Cl:60])=[CH:58][CH:57]=[C:56]([F:61])[C:55]=1[Cl:62])[CH3:53]>>[Cl:62][C:55]1[C:56]([F:61])=[CH:57][CH:58]=[C:59]([Cl:60])[C:54]=1[C@H:52]([O:51][C:31]1[C:30]([NH2:29])=[N:35][CH:34]=[C:33]([C:36]2[CH:37]=[N:38][N:39]([CH:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[CH:40]=2)[CH:32]=1)[CH3:53]
Reactant: C[C@@H](Oc1cc(-c2cnn(C3CCN(C(=O)CO)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N)c1c(Cl)ccc(F)c1Cl
Product: C[C@@H](Oc1cc(-c2cnn(C3CCNCC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared according to procedure 62 using 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine and 4-(4-bromo-pyrazol-1-yl)-1-cyclopentyl-piperidine (prepared according to general procedure 11 using bromocyclopentane as alkylation reagent). 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.55 (s, 1H), 7.48 (s, 1H), 7.31 (m, 1H), 7.07 (m, 1H), 6.88 (s, 1H), 6.08 (m, 1H), 4.64 (m, 1H), 2.04 (m, 2H), 1.98 (m, 2H), 1.86 (d, J=8 Hz, 3H), 1.73 (m, 2H); LCMS: 435 [M+1]; c-Met Ki: 0.02 μM.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([O:11]CC)=O.[C:14](#[N:16])[CH3:15].Cl>C1COCC1.C(OCC)(=O)C>[O:11]=[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1)[CH2:15][C:14]#[N:16]
Reactant: CC#N
Reactant: CCOC(=O)c1ccccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#CCC(=O)c1ccccn1
Temperature: 65 °C
Yield: 100 %

Procedure:
To a mixture of sodium hydride (15 g, 60% in oil, 375 mmol) and ethyl 2-picolinate (50 g. 331 mmol) in anhydrous THF (250 mL) was added dropwise a solution of anhydrous acetonitrile (20 g, 487 mmol) in anhydrous THF (200 mL), at about 65° C. After complete addition the reaction mixture was heated at about 65° C., for about 5 h. After cooling to rt, ethyl acetate (500 mL) was added, followed by 1 M aqueous HCl (360 mL). The resulting layers were separated, and the aqueous layer was extracted with ethyl acetate (250 mL). The combined organic layers were washed with water (2×100 mL), dried (MgSO4), filtered, and concentrated in vacuo to give crude 3-oxo-3-(2-pyridyl)propanenitrile (48.6 g, 331 mmol, 100%), which was used as such in the next step. 1H-NMR (CDCl3, Bruker 400 MHz) 4.39 (2H, s); 7.58 (1H, m); 7.91 (1H, dt, J=2 Hz, 10 Hz); 8.11 (1H, dt, J=2 Hz, 10 Hz); 8.70 (1H, s).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[N:3]1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Cl:20]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:20][C:6]1[N:2]([CH3:1])[N:3]=[CH:4][C:5]=1[N+:7]([O-:9])=[O:8]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: Cn1cc([N+](=O)[O-])cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1ncc([N+](=O)[O-])c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
Following WO 2007/99326, to a 500 mL 3-neck-round bottom flask was added 1-methyl-4-nitro-1H-pyrazole (4.30 g, 33.8 mmol) and THF (12 mL). The mixture was cooled to −78° C. and lithium hexamethyldisilazide in THF (1M, 88.4 mL, 90 mmol) was added dropwise via an addition funnel over 20 min. The brown mixture was stirred for 30 min and warmed to −45° C. over 30 min. The mixture was cooled back down to −78° C. and hexachloroethane (10.5 g, 44.2 mmol) dissolved in THF (20 mL) was added via an addition funnel over 15 min. The mixture was stirred for 2.5 h, warmed from −78° C. to −40° C. and the reaction was monitored by LCMS. Upon completion of the reaction, the reaction was quenched with a solution of saturated NH4Cl (150 mL), and ethyl acetate (100 mL) was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layer was washed with water (150 mL), dried over Na2SO4 and the organic solvent was distilled off. The crude product was purified via flash chromatography (CH2Cl2/7% MeOH) to yield 5-chloro-1-methyl-4-nitro-1H-pyrazole as a white solid (1.40 g, 20%). 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 3.92 (s, 3H); ESIMS m/z=162.0 (M+1)
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH2:5].[F:6][C:7]([F:14])([F:13])[C:8]([O:10]CC)=O.O>C(#N)C>[F:14][C:7]([F:6])([F:13])[C:8]([NH:5][CH2:4][CH2:3][NH:2][CH3:1])=[O:10]
Reactant: CNCCN
Reactant: CCOC(=O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: CNCCNC(=O)C(F)(F)F
Reaction time: 8 h
Yield: 142.6 %

Procedure:
A solution of N-methylethylenediamine (27.0 g, 364 mmol) and ethyl trifluoroacetate (96.6 mL, 812 mmol) in a mixture of ACN (350 mL) and water (7.8 mL, 436 mmol) was refluxed with stirring overnight. Solvents were evaporated in vacuo. The residue was re-evaporated with i-PrOH (3×100 mL), followed by heat-cool crystallization from DCM (500 mL). Formed crystals were filtered, washed with DCM and dried in vacuo to provide compound A (88.3 g, 85%) as white solid powder.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=3[O:13][N:12]=2)=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[2H][C:28]1([2H])[C:33]([2H])([2H])[C:32]([2H])([2H])[N:31]([2H])[C:30]([2H])([2H])[C:29]1([2H])[2H].C(#N)C>O>[F:20][C:18]1[CH:17]=[CH:16][C:15]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:31]4[CH2:32][CH2:33][CH2:28][CH2:29][CH2:30]4)=[CH:6][CH:7]=3)=[N:12][O:13][C:14]=2[CH:19]=1
Reactant: Fc1ccc2c(-c3ccc(OCCBr)cc3)noc2c1
Reactant: [2H]N1C([2H])([2H])C([2H])([2H])C([2H])([2H])C([2H])([2H])C1([2H])[2H]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Fc1ccc2c(-c3ccc(OCCN4CCCCC4)cc3)noc2c1
Temperature: 25 °C
Yield: 73.9 %

Procedure:
Combine 3-[4-(2-bromo-ethoxy)-phenyl]-6-fluoro-benzo[d]isoxazole (550 mg, 1.63 mmol), potassium carbonate (500 mg, 3.62 mmol), piperidine- d11 (630 mg, 6.55 mmol) and 5% aqueous acetonitrile. Under a nitrogen atmosphere, heat to reflux overnight. Cool to room temperature and pour the reaction mixture into water resulting in white solid precipitation. Collect the solid and dry in vacuo. Dissolve the solid in ethyl acetate and filter to remove the insoluble materials and concentrate in vacuo. Take the solid up in diethyl ether, filter and precipitate the hydrochloride salt out of solution by addition of hydrogen chloride in diethyl ether. Collect the desired salt and dry in vacuo to give the title compound as a solid (410 mg, 67% Yield).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1([CH3:24])[C:11]([CH3:13])([CH3:12])[O:10][B:9]([C:14]2[CH:23]=[CH:22][C:17]([O:18][CH2:19][CH2:20][OH:21])=[CH:16][CH:15]=2)[O:8]1.C(N(CC)CC)C.Cl>C(Cl)Cl>[CH3:1][S:2]([O:21][CH2:20][CH2:19][O:18][C:17]1[CH:22]=[CH:23][C:14]([B:9]2[O:8][C:7]([CH3:24])([CH3:6])[C:11]([CH3:12])([CH3:13])[O:10]2)=[CH:15][CH:16]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OB(c2ccc(OCCO)cc2)OC1(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2ccc(OCCOS(C)(=O)=O)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.33 mL) was added to a mixture of 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethanol (0.92 g) and triethylamine (0.73 mL) in methylene chloride (18 mL), and the mixture was stirred at room temperature for 1 hr. 1 mol/L hydrochloric acid was added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford the title compound (1.28 g).
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([O:7][C:8]2[C:13]([CH2:14][NH2:15])=[CH:12][N:11]=[CH:10][N:9]=2)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.Cl[C:27]1[N:32]=[C:31]([Cl:33])[C:30]([C:34]([F:37])([F:36])[F:35])=[CH:29][N:28]=1>CN(C=O)C>[Cl:33][C:31]1[C:30]([C:34]([F:36])([F:35])[F:37])=[CH:29][N:28]=[C:27]([NH:15][CH2:14][C:13]2[C:8]([O:7][C:4]3[CH:3]=[CH:2][C:1]([CH3:16])=[CH:6][CH:5]=3)=[N:9][CH:10]=[N:11][CH:12]=2)[N:32]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: Cc1ccc(Oc2ncncc2CN)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Oc2ncncc2CNc2ncc(C(F)(F)F)c(Cl)n2)cc1
Temperature: -10 °C
Yield: 27 %

Procedure:
(4-(p-Tolyloxy)pyrimidin-5-yl)methanamine (1.0 equiv.) was placed in a round bottom flask with DIEA (1.0 equiv.), and DMF (0.4 M). The flask was placed in a cooling bath and cooled to −10° C. To the flask was added 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.0 equiv.) and stirring continued at −10° C. The reaction mixture was allowed to warm to room temperature over 3 h. The reaction mixture was loaded directly onto a silica gel column (100 g) and purified using 5-27% ethyl acetate in hexanes, followed by 27% ethyl acetate in hexanes. Fractions containing desired product (lower Rf spot by thin layer chromatography) were combined and the solvent was were removed under reduced pressure to give 4-chloro-N-((4-(p-tolyloxy)pyrimidin-5-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-amine (27.0% yield) as a light yellow solid. MS (ESI) m/z 396.2 [M+1]+.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Cl)=[CH:35][CH:34]=1>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:37][C:36]3[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[CH:34][CH:35]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Product: COc1ccc(Cn2ccc3c(-c4ccc5c(c4)CCCO5)c(C(OC(C)(C)C)C(=O)O)c(C)nc32)cc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 4-methoxybenzyl chloride. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.50-7.42 (m, 1 H), 7.27-7.16 (m, 3 H), 7.03 (t, J=3.2 Hz, 1 H), 6.93 (dd, J=6.1, 8.3 Hz, 1 H), 6.88 (d, J=8.6 Hz, 2 H), 6.25 (dd, J=3.5, 11.3 Hz, 1 H), 5.60-5.49 (m, 2 H), 5.47-5.38 (m, 1 H), 4.28 (t, J=4.9 Hz, 2 H), 3.80 (s, 3 H), 2.95-2.79 (m, 2 H), 2.78 (s, 3 H), 2.10-2.04 (m, 2 H), 1.01-0.91 (s, 9 H); LC/MS (m/z) ES+=515.38 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]#[N:15])=[N:12][CH:13]=2)=[CH:5][CH:4]=1)=[O:2].C([O-])([O-])=[O:19].[K+].[K+].OO>CS(C)=O.C(Cl)Cl>[CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:15])=[O:19])=[N:12][CH:13]=2)=[CH:5][CH:4]=1)=[O:2]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cnc(Oc2ccc(C=O)cc2)cn1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: NC(=O)c1cnc(Oc2ccc(C=O)cc2)cn1
Temperature: 25 °C
Reaction time: 22 h
Yield: 47.4 %

Procedure:
Dissolve 5-(4-formylphenoxy)pyrazine-2-carbonitrile (1.87 g, 8.30 mmol) and K2CO3 (0.573 g, 4.15 mmol) in DMSO (21 mL). Add 30% H2O2 (2.4 mL, 20.8 mmol) and stir at room temperature for 22 hours. Add additional K2CO3 (0.573 g, 4.15 mmol) and heat at 55° C for about 2.5 hours. Cool the reaction mixture and dilute with CH2Cl2, (200 mL). Wash with water (1×100 (mL) and saturated aqueous NaHCO3 (1×100 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography, eluting with 0-50% ethyl acetate in dichloromethane to give the title compound (0.478 g, 23.7%): TOF MS ES+ 244.1 (M+H)+, HRMS calcd for C12H10N33 244.0722 (M+H)+, found 244.0709, time 0.38 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=7.2 min, 100% purity.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[Br-].C1(C([PH3+])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1(C)[CH2:38][C:37](=O)[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:40]([O:42][CH3:43])=[O:41])[CH:35]=2)O1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:1][C:2]1([CH3:5])[CH2:3][C:37](=[CH2:38])[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:40]([O:42][CH3:43])=[O:41])[CH:35]=2)[O:4]1
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1ccc2c(c1)C(=O)CC(C)(C)O2
Agent: [Br-]
Agent: [K+]
Agent: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=C1CC(C)(C)Oc2ccc(C(=O)OC)cc21
Temperature: -30 °C

Procedure:
Potassium tert-butoxide (96.0 mg, 0.85 mmol) was added to a suspension of triphenylmethylphosphonium bromide (305 mg, 0.85 mmol) in toluene (3.00 mL) while stirring at −30° C. under N2 atmosphere. After stirring for 1 hour at −30° C., a solution of methyl 2,2-dimethyl-4-oxo-3,4-dihydro-2H-chromene-6-carboxylate (100 mg, 0.43 mmol) in toluene (2.00 mL) was added slowly via a syringe. The suspension was stirred for a further 30 minutes at −30° C. and then heated to reflux overnight. The mixture was allowed to cool to room temperature, diluted with EtOAc (50.0 mL) and washed with water (10.0 mL). The organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified by silica gel chromatography eluting with 0-25% EtOAc/hexanes to give the desired product as a pale-yellow oil.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.[NH2:10][C:11]([NH2:13])=[S:12]>C(O)C>[ClH:2].[ClH:1].[N:7]1[CH:8]=[CH:9][C:4]([CH2:3][S:12][C:11](=[NH:10])[NH2:13])=[CH:5][CH:6]=1
Reactant: NC(N)=S
Reactant: ClCc1ccncc1
Agent: Cl
Solvent: CCO
Product: N=C(N)SCc1ccncc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
A suspension of 4-chloromethylpyridine hydrochloride (82 g) in gently boiling ethanol (260 cc) is added dropwise and in the course of 30 minutes to a suspension of thiourea (45.5 g) in boiling ethanol (260 cc). The reaction mixture is stirred for 1 hour 30 minutes at the boil and then cooled to 5° C. The resulting crystals are filtered off, washed twice with ethanol (60 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. 2-(Pyrid-4-yl-methyl)-isothiourea dihydrochloride (116 g), melting at 260° C., is thus obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].O[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([OH:28])[CH2:25][CH2:26][CH3:27])=[CH:20][CH:19]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]([OH:28])[CH2:25][CH2:26][CH3:27])=[CH:20][CH:19]=2)[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCCC(O)c1ccc(CO)cc1
Reactant: CCOC(=O)CCc1ccc(O)cc1F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCCC(O)c1ccc(COc2ccc(CCC(=O)OCC)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 51.5 %

Procedure:
A solution of ethyl 3-(2-fluoro-4-hydroxyphenyl)propanoate (2.12 g, 10.0 mmol), 1-[4-(hydroxymethyl)phenyl]-butane-1-ol (1.80 g, 10.0 mmol) and tributylphosphine (4.04 mL, 20.0 mmol) in toluene (150 mL) was stirred under ice-cooling and 1,1′-(azodicarbonyl)dipiperidine (5.04 g, 20.0 mmol) was added by small portions. The mixture was warmed to room temperature and stirred for 22 hr. Hexane (75 mL) was added to the reaction mixture, and precipitated insoluble material was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-30:70) to give the title compound as a colorless oil (1.93 g, yield 52%).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=O)[C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]([NH2:32])=[O:31])[CH:25]=2)=[C:21]([F:35])[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([NH:18][C:19]2[CH:34]=[CH:33][C:22]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([C:30]([NH2:32])=[O:31])[CH:25]=3)=[C:21]([F:35])[CH:20]=2)=[O:16])[C:9]1=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cc(Oc2ccc(N)cc2F)ccn1
Reactant: O=C(O)c1cccn(Cc2ccccc2)c1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cc(Oc2ccc(NC(=O)c3cccn(Cc4ccccc4)c3=O)cc2F)ccn1
Reaction time: 12 h
Yield: 69.2 %

Procedure:
A homogeneous solution of 1-benzyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (0.10 g, 0.41 mmol, 1.0 eq), 4-(4-amino-2-fluorophenoxy)picolinamide (0.10 g, 0.41 mmol, 1.0 eq) and TBTU (0.17 g, 0.45 mmol, 1.1 eq) in DMF (2 mL) was treated with DIPEA (0.18 mL, 1.0 mmol, 2.5 eq) at room temperature and the reaction mixture was stirred for 12 h. The reaction mixture was quenched with 10% aqueous LiCl (15 mL) and the resulting solution was extracted with ethyl acetate (4×40 mL). The combined organic extracts were washed with 10% aqueous LiCl (4×50 mL), dried (Na2SO4), filtered and the filtrate concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, eluting with ethyl acetate) to afford the product (0.13 g, 67%) as a solid. 1H NMR (DMSO-d6) δ 12.26 (s, 1H), 8.49-8.56 (m, 2H), 8.33-8.36 (m, 1H), 8.15 (br m, 1H), 8.03-8.07 (m, 1H), 7.74-7.75 (m, 1H), 7.51-7.54 (m, 1H), 7.41-7.46 (m, 4H), 7.20-7.24 (m, 3H), 6.71 (dd, 1H, J=6.89 Hz), 5.32 (s, 2H) HRMS (ESI+), Calcd.: 477.1374. found: 477.1378.
Reaction SMILES: [C:1]([C:3]1([NH:23][C:24](=[O:26])[CH3:25])[CH2:8][CH2:7][CH:6]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16](OCC)=[C:15](C)[CH:14]=2)(=[O:12])=[O:11])[CH2:5][CH2:4]1)#[N:2].NC1(C#N)CCC(NS(C2C=CC([C:44]([F:47])([F:46])[F:45])=CC=2)(=O)=O)CC1>>[C:1]([C:3]1([NH:23][C:24](=[O:26])[CH3:25])[CH2:4][CH2:5][CH:6]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([C:44]([F:47])([F:46])[F:45])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:7][CH2:8]1)#[N:2]
Reactant: N#CC1(N)CCC(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Reactant: CCOc1ccc(S(=O)(=O)NC2CCC(C#N)(NC(C)=O)CC2)cc1C
Product: CC(=O)NC1(C#N)CCC(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
Intermediate 127 was prepared by a method analogous to the method of preparing Intermediate 126 using N-(4-amino-4-cyanocyclohexyl)-4-trifluoromethyl benzenesulfonamide (Intermediate 125) as the starting material.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[C:8]([C:25]#[N:26])=[N:7]1.[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][C@@H:45]1[CH2:50][OH:51])=[O:43])([CH3:40])([CH3:39])[CH3:38]>>[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][N:47]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:27]=[CH:28][C:29]([C:31]([F:33])([F:34])[F:32])=[CH:30][C:3]=3[C:2]([F:1])([F:35])[F:36])[N:7]=[C:8]4[C:25]#[N:26])[C:17](=[O:24])[N:18]=2)[CH2:46][C@@H:45]1[CH2:50][OH:51])=[O:43])([CH3:40])([CH3:39])[CH3:38]
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(c2)c(C#N)nn3Cc2ccc(C(F)(F)F)cc2C(F)(F)F)S1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1CO
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(c3)c(C#N)nn4Cc3ccc(C(F)(F)F)cc3C(F)(F)F)S2)C[C@@H]1CO

Procedure:
4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-cyano-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 1-(2,4-Bis-trifluoromethyl-benzyl)-5-(2-ethylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-1H-indazole-3-carbonitrile and 2-(R)-Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:20])=[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)[N:6]=[N:7][CH:8]=1.[H-].[Na+].Br[CH2:24][CH:25]1[CH2:27][CH2:26]1.CO>CN(C)C=O>[CH:25]1([CH2:24][N:7]2[CH:8]=[C:3]([O:2][CH3:1])[C:4](=[O:20])[C:5]([C:9]3[N:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:12]=[CH:11][CH:10]=3)=[N:6]2)[CH2:27][CH2:26]1
Reactant: BrCC1CC1
Reactant: COc1cnnc(-c2ccnn2-c2ccccc2)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cn(CC2CC2)nc(-c2ccnn2-c2ccccc2)c1=O

Procedure:
Under an argon atmosphere, to a solution of 5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4-ol (2.0 g) in dimethylformamide (40 mL) was added 60% sodium hydride (596 mg) with stirring under ice-cooling, and the mixture was stirred at the same temperature for 1.5 hr. Then, (bromomethyl)cyclopropane (1.085 mL) was added, and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added methanol, and the mixture was concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) and crystallized from methanol/ethyl acetate to give the title compound (2.12 g) as white prisms.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=O)=[CH:8][CH:7]=1.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>CO.O>[OH:17][N:16]=[CH:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([O:2][CH3:1])=[O:14])=[CH:7][CH:8]=1
Reactant: COC(=O)COc1ccc(C=O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)COc1ccc(C=NO)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.3 %

Procedure:
A solution of methyl-(4-formylphenoxy)acetate (100 g, 0.515 mol) in methanol (500 mL) was cooled to 0-5° C. To this was added a solution of hydroxylamine hydrochloride (54 g) and sodium acetate (64 g) in water (500 mL) drop-wise and stirred at rt for 6 h. The reaction mixture diluted with water and filtered off the solid. The solid was washed with water and dried under vacuum to give the title compound (80 g, 74%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Li+].[Cl-].[I:14]I>C1COCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([F:1])[C:7]=1[I:14]
Reactant: II
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(I)c1F
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
2,4-Difluoro-1-nitrobenzene 15 (159 mg, 1.0 mmol) in THF (2 mL) was added to a solution of TMPZnCl.LiCl (2) (1.3 M in THF, 0.85 mL, 1.1 mmol) at 25° C. and the reaction mixture was then stirred at this temperature for 45 min according to TP 2. I2 (381 mg, 1.5 mmol) dissolved in dry THF (2 mL) was then dropwise added and the resulting mixture was stirred for 0.5 h. The reaction mixture was quenched with a sat. aq. Na2S2O3 solution (10 mL) and with a sat. aq. NH4Cl solution (20 mL), extracted with diethyl ether (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo. Purification by flash-chromatography (CH2Cl2/n-pentane, 1:1) furnished compound 17c (256 mg, 90%) as a colourless solid.