Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=2)[NH2:43])[CH2:36][CH2:35]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:43][C:42]5[CH:44]=[CH:45][CH:46]=[C:40]([N:37]6[CH2:36][CH2:35][N:34]([CH3:33])[CH2:39][CH2:38]6)[CH:41]=5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Product: COc1cc(C(=O)Nc2cccc(N3CCN(C)CC3)c2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was prepared in a manner analogous to compound 149 from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid and 3-(4-methylpiperazin-1-yl)aniline with yield 35 mg (28%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43-1.72 (m, 6H) 1.98 (br. s., 2H) 2.22 (s, 2H) 2.35-2.50 (m, 4H) 2.97-3.23 (m, 4H) 3.98 (s, 3H) 4.06 (t, J=12 Hz, 2H) 4.79 (m, 1H) 6.55-6.79 (m, 1H) 7.12-7.26 (m, 2H) 7.40 (s, 1H) 7.52-7.72 (m, 2H) 8.03 (s, 1H) 8.28 (s, 1H) 8.35 (d, J=8.34 Hz, 1H) 9.94 (s, 1H). [M+H] calc'd for C32H38F2N8O3, 621. found 621.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:13][C@@H:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[N+:22]([O-:24])=[O:23])[CH2:11][C@H:10]1[CH2:25][OH:26])=O)(C)(C)C>O1CCOCC1.ClCCl>[ClH:1].[Br:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C@@H:12]2[CH2:13][NH:9][C@H:10]([CH2:25][OH:26])[CH2:11]2)=[C:16]([N+:22]([O-:24])=[O:23])[CH:17]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Nc2ccc(Br)cc2[N+](=O)[O-])C[C@H]1CO
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Br)ccc1N[C@@H]1CN[C@H](CO)C1
Reaction time: 2 h
Yield: 87 %

Procedure:
Add 4.0 M hydrogen chloride in dioxane (950 mL) slowly to a solution of (2S,4S)-4-(4-bromo-2-nitro-phenylamino)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.22 mol, 95 g) in dry dichloromethane (475 mL) at room temperature and stir for 2 h. Filter the precipitated solid and dry under vacuum to obtain the title compound (70 g, 87%) as an orange solid. 1H NMR (400 MHz, CD3OD) δ 1.98-2.05 (m, 1H), 2.71-2.79 (m, 1H), 3.36 (dd, 1H), 3.58-3.63 (m, 1H), 3.76 (dd, 1H), 3.88-3.95 (m, 2H), 4.55-4.58 (m, 1H), 7.03 (d, 1H), 7.66 (dd, 1H), 8.30 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C.C(O)CO>O>[Cl:1][C:2]1[CH:11]=[C:10]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)cc(Cl)c2c1
Reactant: C1COCCN1
Solvent: OCCO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2nc(Cl)cc(N3CCOCC3)c2c1
Temperature: 145 °C

Procedure:
A mixture of 2,4-dichloro-6-methoxyquinoline (0.228 g), morpholine (262 μL), N,N-diisopropylethylamine (348 μL), and ethylene glycol (4 mL) was heated with microwave (145° C.) for 75 min with stirring. The reaction mixture was cooled to room temperature, followed by addition of water, the mixture was extracted with chloroform and washed with saturated brine, and the organic layer was dried with anhydrous sodium sulfate. The desiccant was removed by filtration, the residue concentrated under reduced pressure was purified by silica gel column chromatography (chloroform/hexane=1/1) to obtain 2-chloro-6-methoxy-4-morpholinoquinoline (0.182 g). (2) To a mixture of 2-chloro-6-methoxy-4-morpholinoquinoline (0.160 g), Pd2(dba)3 (0.026 g), (±)-BINAP (0.054 g), (S)-1-(3-aminopyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone mono hydrochloride (0.210 g), and 1,4-dioxane (3 mL) was added sodium t-butoxide (0.111 g) under nitrogen atmosphere, and the mixture was stirred at 70° C. for 1.5 h. After cooled to room temperature, the reaction mixture was diluted with ethyl acetate and water, the interlayer was removed by Celite filtration, and the organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform/methanol, and NH silica gel, ethyl acetate/hexane) to obtain light yellow amorphous (S)-1-(3-(6-methoxy-4-morpholinoquinolin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.081 g).
Reaction SMILES: C([Mg]Cl)CCC.C([Li])CCC.CCCCCC.Br[C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][C:27]=1[F:28])[N:24]([CH3:29])[N:23]=[CH:22]2.CN([CH:33]=[O:34])C>C1COCC1.C1(C)C=CC=CC=1>[F:28][C:27]1[CH:26]=[C:25]2[C:21]([CH:22]=[N:23][N:24]2[CH3:29])=[CH:20][C:19]=1[CH:33]=[O:34]
Reactant: CN(C)C=O
Reactant: Cn1ncc2cc(Br)c(F)cc21
Agent: CCCC[Mg]Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cn1ncc2cc(C=O)c(F)cc21
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A 2 M solution of n-butyl magnesium chloride in THF (4.8 mL, 9.57 mmol) was added to toluene (34 mL) under nitrogen and cooled to −10° C. To this was added a 1.3 M solution of n-butyl lithium in hexane (12.2 mL, 19.5 mmol) and after 1 h, the RM was cooled to −30° C. To the RM was then added a solution of 5-bromo-6-fluoro-1-methyl-1H-indazole (vii) (4 g, 17.73 mmol) in THF (17 mL) and the reaction was warmed up to −10° C. After 1 h, DMF (8.23 mL, 106 mmol) was added and the RM was stirred at −10° C. for another 1 h. The reaction was quenched using 2 N HCl and was allowed to warm up to room temperature. After 30 min, the RM was basified with saturated aqueous NaHCO3 solution and then extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4 and evaporated under vacuo. The residue was triturated with Et2O. The precipitate formed was filtered off to give a yellow solid identified as the desired aldehyde (tR 0.79 min (conditions 2), MH+=179).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[NH:12][C:11]2=O.[OH-].[NH4+]>>[Cl:3][C:11]1[C:10]2[C:15](=[CH:16][CH:17]=[C:8]([O:7][CH3:6])[CH:9]=2)[N:14]=[C:13]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:12]=1
Reactant: COc1ccc2nc(-c3cccnc3)[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: COc1ccc2nc(-c3cccnc3)nc(Cl)c2c1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
In a sealed tube, phosphorus oxychloride (11 mL, 120 mmol) was added to 6-methoxy-2-(pyridin-3-yl)quinazolin-4(3H)-one (2.70 g, 10.66 mmol). The mixture was refluxed at 120° C. for 12 h. After cooling, the remaining phosphorus oxychloride was removed in vacuo to leave a tan solid. This residue was added to an ice-water mixture (100 mL) with cooling and allowed to stir. The pH of the suspension was adjusted to about pH 9 via dropwise addition of 28% ammonium hydroxide, and stirring was continued for 30 mins. The resulting solid was filtered to give the desired product as a tan solid (2.55 g, 9.39 mmol, 88%). LC-MS m/z=272.0 (M+1) (retention time=2.05) 1H NMR (300 MHz, DMSO) δ 9.55 (s, 1H), 8.81-8.64 (m, 2H), 8.09 (d, J=9.2 Hz, 1H), 7.78 (dd, J=9.2, 2.8 Hz, 1H), 7.61 (dd, J=7.9, 4.8 Hz, 1H), 7.49 (d, J=2.5 Hz, 1H), 4.00 (s, 3H).
Reaction SMILES: C(OC([N:8]([CH2:15][CH3:16])[C@@H:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:15]([NH:8][C@@H:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])[CH3:16]
Reactant: CCN(C(=O)OC(C)(C)C)[C@@H](C)C(=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN[C@@H](C)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-methyl 2-(tert-butoxycarbonyl(ethyl)amino)propanoate (4.40 g, 19.0 mmol) was dissolved in dichloromethane and treated with TFA (10 mL). The reaction mixture was stirred for 2 h at room temperature and concentrated in vacuo. The residue was diluted with brine and NaOH (aq. 50%) was added dropwise until pH=12.5. This was extracted with EtOAc (3×30 mL). The combined organic extracts were dried (MgSO4), flitered and concentrated in vacuo to afford the title compound as an opaque liquid (1.85 g, 74%). [M+H] calc'd for C6H13NO2, 132; found, 132.
Reaction SMILES: O=P(Cl)(Cl)Cl.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14]1[N:15]2[N:22]=[C:21]([CH3:23])[CH:20]=[C:16]2[O:17][C:18]=1[CH3:19].CN([CH:27]=[O:28])C>>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14]1[N:15]2[N:22]=[C:21]([CH3:23])[C:20]([CH:27]=[O:28])=[C:16]2[O:17][C:18]=1[CH3:19]
Reactant: CN(C)C=O
Reactant: Cc1cc2oc(C)c(-c3ccc(Cl)cc3Cl)n2n1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nn2c(-c3ccc(Cl)cc3Cl)c(C)oc2c1C=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To DMF (12 ml) is added POCl3 (1.326 ml, 14.23 mmol) dropwise at RT. After 10 mins 3-(2,4-dichloro-phenyl)-2,6-dimethyl-pyrazolo[5,1-b]oxazole (Intermediate HE) (2.00 g, 7.11 mmol) is added. The reaction is stirred at RT for 16 hours. On cooling to 0° C. the reaction mixture is quenched with 1M HCl and added in portions to sat. Na2CO3 (100 ml). The product is extracted with EtOAc (2×100 ml) and the combined organics are washed with brine, dried over MgSO4 and concentrated in vacuo. The resulting solid is recrystallised from EtOAc/iso-hexane to afford the title compound as a pale yellow solid. MS: m/z 309.10 [M+H]+
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[S:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.C([O-])(=O)C.[K+]>CC(N(C)C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: c1ccsc1
Reactant: O=Cc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=Cc1ccc(-c2cccs2)cc1
Temperature: 150 °C
Reaction time: 16 h

Procedure:
3.7 g (20 mmol) of 4-bromobenzaldehyde, 9.5 ml (120 mmol) of thiophene, 2.94 g (30 mmol) of potassium acetate and 1.16 g (1 mmol) of tetrakis(triphenylphosphine)-palladium (Fluka, Buchs, Switzerland) in 50 ml of dimethylacetamide are placed in a pressure reactor and stirred at 150° C. under nitrogen for 16 hours. The reaction mixture is concentrated by evaporation; the residue is taken up in water and extracted three times with methylene chloride. After removal of the solvent, the residue is chromatographed on silica gel (hexanelethyl acetate 4:1). The title compound is obtained in the form of a yellow solid. TLC: Rf=0.36 (hexane/ethyl acetate 4:1). HPLC20-100: tRet=15.26. 1H-NMR (CD3OD; 200 MHz): 9.98/s (1H); 7.93 and 7.85/each d, J=9.5 (2×2H); 7.60/d, J=2.5 (1H); (1H); 7.17/d×d, J=2.5 and 5 (1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O>[C:10]1([C:2]2[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: CSc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CSc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
A 100 mL of reactor equipped with magnetic stir bar was charged with 140 mg (0.15 mmol) of {[(t-Bu)2P(OH)]2PdCl}2 (from Experiment 7), 2.03 g (10.0 mmol) of 4-bromothioanisole, 1.83 g (15.0 mmol) of PhB(OH)2 and 4.16 g (30.0 mmol) of K2CO3 in 13 mL of DME and 7 mL of H2O. The reaction mixture was refluxed for 12 h until the starting material was completely consumed as judged by TLC. The reaction was cooled to room temperature, transferred to a separatory funnel, and diluted with 300 mL of hexane and 100 mL of H2O. The layers were separated, and organic layer was washed with H2O (2×100 mL), brine (100 mL), and dried over mgSO4, filtered, and solvents removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel using hexane as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to give 1.90 g (95% yield) of 4-phenylthioanisole. It was >95% pure by 1H NMR and GC/MS. 1H NMR (300 MHz, CDCl3): δ7.47-7.39 (m, 5H), 7.31 (m, 2H), 7.22 (m, 2H), 2.39 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3): δ140.5, 138.0, 137.6, 128.8, 127.4, 127.1, 126.9, 126.8 ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH:18](Br)([CH3:20])[CH3:19]>>[CH:18]([N:15]1[CH2:16][CH2:17][N:12]([C:4]2[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:13][CH2:14]1)([CH3:20])[CH3:19]
Reactant: Fc1cc(N2CCNCC2)cc(C(F)(F)F)c1
Reactant: CC(C)Br
Product: CC(C)N1CCN(c2cc(F)cc(C(F)(F)F)c2)CC1

Procedure:
Beginning with 1-(3-fluoro-5-trifluoromethyl-phenyl)-piperazine and isopropylbromide, the title compound was recovered by the procedure described in Example 2; MS m/z (rel. intensity, 70 eV) 290 (M+, 30), 275 (bp), 190 (20), 84 (23), 56 (64).
Reaction SMILES: B(Cl)([C@H]1[C@H](C)C2C(C)(C)C(CC2)C1)[C@H]1[C@H](C)C2C(C)(C)C(CC2)C1.[NH2:25][C:26]1[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][C:29](/[CH:36]=[C:37](/[OH:41])\[C:38]([OH:40])=[O:39])=[CH:28][C:27]=1[Cl:42].C(N(CC)CC)C>C1COCC1>[NH2:25][C:26]1[C:31]([C:32]([F:33])([F:34])[F:35])=[CH:30][C:29]([CH2:36][C@@H:37]([OH:41])[C:38]([OH:40])=[O:39])=[CH:28][C:27]=1[Cl:42]
Reactant: Nc1c(Cl)cc(/C=C(/O)C(=O)O)cc1C(F)(F)F
Agent: C[C@@H]1C2CCC(C[C@H]1B(Cl)[C@@H]1CC3CCC([C@H]1C)C3(C)C)C2(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1c(Cl)cc(C[C@@H](O)C(=O)O)cc1C(F)(F)F
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
33.5 g (104.3 mmol) (−)-DIP-chloride dissolved in 195 ml THF was added under protective nitrogen gas to a mixture of 24.5 g (86.9 mmol) (E)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-hydroxy-acrylic acid, 12.1 ml (86.9 mmol) triethylamine and 98 ml THF cooled to −20° C. The reaction mixture was stirred for 1.5 hours at −20° C., brought to ambient temperature and evaporated down under reduced pressure. The residue was combined with 200 ml aqueous 1-molar sodium hydroxide solution and 150 ml TBME and stirred thoroughly. The aqueous phase was separated off, acidified with 2-molar hydrochloric acid solution with stirring and extracted twice with 250 ml TBME. The combined organic phases were filtered through activated charcoal and evaporated down under reduced pressure. The residue was heated to boiling with 500 ml of water and the hot solution was filtered clear through Celite. The precipitate formed at ambient temperature was suction filtered and dried at 65° C. in the circulating air dryer.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][N:18]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=[N:19]1>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:17][N:18]1[C:22]([C:2]2[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=2)=[CH:21][CH:20]=[N:19]1
Reactant: COC(=O)c1cc(Br)cs1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2ccnn2C)cs1
Reaction time: 1 h
Yield: 99.5 %

Procedure:
A solution of methyl 4-bromo-2-thiophenecarboxylate (2.5 g, 11.31 mmol), potassium carbonate (7.81 g, 56.5 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.59 g, 12.44 mmol)[prepared according to Preparation 7] and bis(tri-t-butylphosphine)palladium(0) (0.289 g, 0.56 mmol) in 1,4-dioxane (47 ml) and water (9 ml) was stirred at 80° C. in a sealed tube for 1 h. 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.59 g, 12.44 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.289 g, 0.56 mmol) were added and the reaction stirred an additional 1 h. The mixture was partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (10-40% EtOAc in hexanes) affording methyl 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (2.5 g, 11.25 mmol, 99% yield) as a yellow solid: LCMS (ES) m/e 223 (M+H)+.
Reaction SMILES: O[CH2:2][CH:3]([C:7]1[S:8][C:9]([C:12]2[C:13]3[CH:20]=[CH:19][N:18](COCC[Si](C)(C)C)[C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:10][N:11]=1)[CH2:4][C:5]#[N:6].CS(Cl)(=O)=O.[C-:34]#[N:35].[Na+]>C(Cl)Cl.O>[N:15]1[C:14]2[NH:18][CH:19]=[CH:20][C:13]=2[C:12]([C:9]2[S:8][C:7]([CH:3]([CH2:2][C:34]#[N:35])[CH2:4][C:5]#[N:6])=[N:11][CH:10]=2)=[N:17][CH:16]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnc(C(CO)CC#N)s3)ncnc21
Reactant: [C-]#N
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#CCC(CC#N)c1ncc(-c2ncnc3[nH]ccc23)s1
Reaction time: 0.5 h
Yield: 7 %

Procedure:
A solution of the above prepared 4-hydroxy-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]butanenitrile in DCM (12 mL) at 0° C. was treated sequentially with TEA (130 μL, 0.94 mmol) and methanesulfonyl chloride (73 μL, 0.94 mmol). After 1 hour reaction time, the mixture was diluted with water and extracted with ethyl acetate three times. The extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was then dissolved in DMSO (5 mL) and sodium cyanide (110 mg, 2.3 mmol) was added. After 30 minutes, the mixture was diluted with water, extracted with ether, washed with water, brine and dried over sodium sulfate. Concentration and purification by flash column chromatography (ethyl acetate/hexanes) afforded the desired product (14 mg, 7%). MS(ES): 425 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:11](COCC[Si](C)(C)C)[C:10]([O:20][C@H:21]3[C@H:25]4[O:26][CH2:27][C@@H:28]([OH:29])[C@H:24]4[O:23][CH2:22]3)=[N:9][C:5]2=[N:6][C:7]=1I.[F:30][C:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[CH:33][C:32]=1[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CS(C)=O.CC([P+](Cl)(C(C)(C)C)C(C)(C)C)(C)C.C1C=CC(C2C(N)=CC=CC=2)=CC=1.[Pd+2]>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C:10]([O:20][C@H:21]3[C@H:25]4[O:26][CH2:27][C@@H:28]([OH:29])[C@H:24]4[O:23][CH2:22]3)=[N:9][C:5]2=[N:6][C:7]=1[C:35]1[CH:34]=[CH:33][C:32]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[C:31]([F:30])[CH:36]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(I)c(Cl)cc21
Reactant: OB(O)c1ccc(-c2ccccc2)c(F)c1
Agent: [Pd+2]
Agent: CC(C)(C)[P+](Cl)(C(C)(C)C)C(C)(C)C
Agent: Nc1ccccc1-c1ccccc1
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)c(F)c3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (3R,3aR,6R,6aR)-6-((6-chloro-5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol (40 mg, 0.072 mmol) and (2-fluoro-[1,1′-biphenyl]-4-yl)boronic acid (18.72 mg, 0.087 mmol) in anhydrous dioxane (0.4 ml) was purged with N2 and then chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (7.4 mg, 0.014 mmol) and tripotassium phosphate (0.217 ml, 0.217 mmol) were added under N2 flow. The mixture was stirred at 25° C. overnight. The crude mixture was extracted with DCM and the combined organic extracts were washed with water and evaporated under reduced pressure. 1 ml of 1:1 CH2Cl2 and TFA was added to the resulting residue and the reaction mixture was stirred for 2 hours. Then the solvent was evaporated under reduced pressure to give an amber residue. The residue was diluted with 1.5 ml DMSO, filtered and purified by mass directed reverse phase column chromatography eluting with acetonitrile/water+0.1% TFA to give the title product. LC-MS: calculated for C24H19ClFN3O4, 467.10, observed m/e: 468.11 (M+H)+ (RT 0.76/2.00 min).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.C[N:17](C=O)C.N>C1COCC1>[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([NH2:17])=[O:6]
Reactant: CN(C)C=O
Reactant: O=C(O)CCC(F)(F)F
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)CCC(F)(F)F
Reaction time: 4 h

Procedure:
To a solution of 4,4,4-trifluorobutanoic acid (19.9 g) in THF (200 mL) were added oxalyl chloride (30.5 mL) and DMF (0.54 mL) at 0° C., and the mixture was stirred for 4 hr. The obtained reaction mixture was added to 28% aqueous ammonia (150 mL) at 0° C., and the mixture was stirred for 1 hr. The reaction mixture was filtration, and the filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained solid was suspended in diisopropyl ether. The precipitate was collected by filtration, washed with diisopropyl ether, and dried to give the title compound (17.9 g) as a solid.
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([F:15])[C:5]=1[CH3:16])=[N+]=[N-]>C(O)C.[C].[Pd]>[NH2:1][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([F:15])[C:5]=1[CH3:16]
Reactant: CCOC(=O)c1ccc(N=[N+]=[N-])c(C)c1F
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc(N)c(C)c1F
Yield: 42.4 %

Procedure:
In 40 ml of ethanol was dissolved 2.00 g of ethyl 4-azido-2-fluoro-3-methylbenzoate, followed by adding thereto 0.40 g of 5% palladium-carbon, and the resulting mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a column chromatography (eluent; toluene:ethyl acetate=10:1) to obtain 0.75 g of ethyl 4-amino-2-fluoro-3-methylbenzoate as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.[C:31](Cl)(=[O:35])[O:32][CH2:33][CH3:34].C(N(CC)CC)C>O1CCCC1>[F:26][C:25]([F:28])([F:27])[C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:7]1[CH:8]=[CH:9][C:4]2[N:5]([CH:30]=[C:2]([NH:1][C:31](=[O:35])[O:32][CH2:33][CH3:34])[N:3]=2)[N:6]=1)=[O:29]
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Yield: 62 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (150 mg, 0.362 mmol), ethyl chlorocarbonate (41 μL, 0.435 mmol), triethylamine (75 μL, 0.544 mmol) and tetrahydrofuran (3 mL) as starting materials and in the same manner as in Example 388, the title compound (109 mg, 62%) was obtained as a white powder.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([F:20])[C:12]=2[F:21])[CH2:3][CH2:2]1.[CH:22]1(N=C=NC2CCCCC2)CCCC[CH2:23]1.CN(C1C=CC=CN=1)C.C(C1C=NC(C2C=CC(O)=CC=2)=NC=1)CCCCCCC>C(Cl)Cl>[CH:2]1([CH2:3][CH2:1][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([F:20])[C:12]=2[F:21])[CH2:23][CH2:22]1
Reactant: O=C(O)c1ccc(OCCCCCCC2CC2)c(F)c1F
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: O=C(O)c1ccc(OCCCCCCCCC2CC2)c(F)c1F

Procedure:
1.2 g of 4-(6-cyclopropylhexyloxy)-2,3-difluorobenzoic acid were added to a solution of 0.84 g of dicyclohexyl-carbodiimide, 50 mg of dimethylaminopyridine and 1.15 g of 4-(5-octylpyrimidin-2-yl)phenol in 50 ml of methylene chloride. After a reaction time of 24 hours, the precipitate (dicyclohexylurea) was filtered off with suction. The filtrate was freed from solvent and chromatographed (SiO2, CH2Cl2).