Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[C:6]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:8])[CH3:7].[CH:14]12[CH2:26][CH2:25][CH:21]([C:22](=[O:24])[CH2:23]1)[C:20]1[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=1>C1COCC1.C1(C)C=CC=CC=1>[C:10]([O:9][C:6](=[O:8])[CH2:7][C:22]1([OH:24])[CH2:23][CH:14]2[CH2:26][CH2:25][CH:21]1[C:20]1[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(=O)OC(C)(C)C
Reactant: O=C1CC2CCC1c1ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CC1(O)CC2CCC1c1ccccc12
Temperature: -50 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3.5 mL of DIPA in 6 mL THF were added dropwise 9.9 mL of n-butyllithium (2.5M in Hept) at −20° C. After 20 min, 12 mL of toluene were added and the solution was stirred for 30 min. The mixture was cooled to −50° C., 4.5 mL of tert.-butyl acetate were added and stirring was continued for 1 h at −50° C. Then, 2.5 g of rac-(1R*,8R*)-tricyclo[6.2.2.02,7]dodeca-2,4,6-trien-9-one dissolved in 6 mL of toluol were added and the solution was stirred at −50 to −20° C. over 2.5 h. The reaction mixture was poured on ice/aq. HCl, the organic phase was separated, washed with sat. aq. NaHCO3, dried over Na2SO4 and concentrated in vacuo. The crude reaction product was purified by CC with Hept/EtOAc (4:1) to yield 2.6 g of the major racemate, rac-(1R*,8R*,9R*)-(9-hydroxy-tricyclo[6.2.2.02,7]dodeca-2,4,6-trien-9-yl)-acetic acid tert-butyl ester as beige solid and 0.4 g of the minor racemate, rac-(1R*,8R*,9S*)-(9-hydroxy-tricyclo[6.2.2.02,7]dodeca-2,4,6-trien-9-yl)-acetic acid tert-butyl ester as yellow oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.C([Mg]Cl)(C)C.[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[N:24]([CH:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23](=[O:39])[C:22]2=[O:40]>O1CCCC1>[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[N:24]([CH:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:23](=[O:39])[C:22]2([OH:40])[C:8]1[C:7]([OH:10])=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1
Reactant: Oc1ccc2c(c1)OCC2
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2c(Cl)cccc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2c(Cl)cccc2C1(O)c1cc2c(cc1O)OCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 387.2 %

Procedure:
To a cooled (0° C.) solution of 2,3-dihydrobenzofuran-6-ol (0.52 g, 3.8 mmol) in anhydrous tetrahydrofuran (25 mL) was added isopropylmagnesium chloride (2.1 mL, 2 M solution in tetrahydrofuran, 4.2 mmol). The resultant suspension was stirred at 0° C. for 0.5 h and followed by the addition of 7-chloro-1-(diphenylmethyl)-1H-indole-2,3-dione (2.11 g, 15.5 mmol) in one portion. The reaction mixture was stirred at ambient temperature for 3 h and concentrated in vacuo. The crude product was purified by column chromatography with ethyl acetate in hexanes (0% to 50% gradient) to afford 7-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one (7.12 g, 95%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ9.43 (s, 1H), 7.56-7.18 (m, 13H), 6.99-6.86 (m, 2H), 6.60 (s, 1H), 6.08 (s, 1H), 4.56 (t, J=8.6 Hz, 2H), 3.10 (t, J=8.6 Hz, 2H).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][N:14]2[CH2:17][C:18](=[O:35])[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:23][CH:22]=2)=[CH:10][CH:9]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:27]([C:24]1[CH:23]=[CH:22][C:21]([O:20][CH2:19][C:18](=[O:35])[CH2:17][N:14]2[C:15]3[C:11](=[CH:10][CH:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:16]=3)[CH:12]=[CH:13]2)=[CH:26][CH:25]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCc1ccc(OCC(=O)Cn2ccc3ccc(C(=O)OC(C)(C)C)cc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCc1ccc(OCC(=O)Cn2ccc3ccc(C(=O)O)cc32)cc1
Temperature: 25 °C

Procedure:
59 mg (0.12 mmol) tert-butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-6-carboxylate are dissolved in 15 ml absolute dichloromethane and mixed with 1.05 g (9.20 mmol) trifluoroacetic acid. After stirring at room temperature for 2½ hours, concentration to dryness is carried out on the rotary evaporator. Three admixtures with 10 ml of a mixture of petroleum ether and ethyl acetate (1:2) each and respective concentration to dryness on the rotary evaporator leave as a crude product a solid which is purified on an RP-HPLC column (stationary phase: cromasil, mobile phase: acetonitrile/water 9:1) by means of chromatography.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[C:3]=1[NH2:18].[CH:19]1([CH2:24][C:25](Cl)=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(#N)C.C(OCC)(=O)C>[CH:19]1([CH2:24][C:25]([NH:18][C:3]2[C:4]([C:14]([F:17])([F:16])[F:15])=[CH:5][C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:7][C:2]=2[CH3:1])=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cc1cc(N2CCOCC2)cc(C(F)(F)F)c1N
Reactant: O=C(Cl)CC1CCCC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cc(N2CCOCC2)cc(C(F)(F)F)c1NC(=O)CC1CCCC1
Temperature: 150 °C
Yield: 51.5 %

Procedure:
2-Methyl-4-morpholin-4-yl-6-trifluoromethyl-phenylamine (0.18 g) and cyclopentylacetyl chloride (112 mg) were dissolved in acetonitrile (4 mL) and heated to 150° C. for 10 minutes in a sealed microwave process vial. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (2×20 mL) and brine (1×20 mL). The organic phase was dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography to furnish 132 mg (52%) of the title compound as a white solid. LC-MS (m/z) 371 (MH+); tR=2.87, (UV, ELSD) 99%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.20 (m, 2H), 1.51 (m, 2H), 1.60 (m, 2H), 1.76 (m, 2H), 2.11 (s, 3H), 2.24 (m, 1H), 2.26 (d, 2H), 3.16 (t, 4H), 3.73 (t, 4H), 7.00 (d, 1H), 7.12 (d, 1H), 9.16 (s, 1H).
Reaction SMILES: [CH:1]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:20])C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH:3]12[O:20][CH:4]1[CH2:5][CH2:6][CH:1]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]2
Reactant: CCOC(=O)C1CC=CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1CCC2OC2C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of ethyl cyclohex-3-ene-1-carboxylate (14.0 g, 90 mmol) in CH2Cl2 (350 mL) was added meta-chloroperbenzoic acid (18.9 g, 110 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2.5 hours. After cooling to 0° C., the reaction was neutralized with aqueous Na2CO3 solution. The organic layer was collected and washed with water and brine, then was dried over MgSO4 and concentrated in vacuo to a light oil (17.8 g), which was used in the next reaction with further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20]([OH:22])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][C:24]1[O:28][N:27]=[C:26]([CH2:29][NH2:30])[CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:12][N:11]=[C:10]([C:20]([NH:30][CH2:29][C:26]3[CH:25]=[C:24]([CH3:23])[O:28][N:27]=3)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(CN)no1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Product: Cc1cc(CNC(=O)c2cc(-c3ccc(Cl)cc3)c(OCC(F)(F)F)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example D) and 5-methyl-3-isoxazolemethanamine (CAS registry No. 154016-48-5) as starting materials; LC-MS (UV peak area/ESI) 100%, 426.0822 (M+H)+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[CH2:27]([NH2:29])[CH3:28]>C(#N)C>[CH3:26][S:23]([C:17]1[CH:16]=[C:15]2[C:20]([CH2:21][CH2:22][CH:13]([CH2:12][NH:29][CH2:27][CH3:28])[O:14]2)=[CH:19][CH:18]=1)(=[O:24])=[O:25]
Reactant: CCN
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CCNCC1CCc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 25: [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), ethanamine (2.0 M in MeOH, 0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 269 (M+, 5), 131 (6), 77 (6), 58 (bp), 56 (4).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[F:17][CH:18]([F:28])[O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][OH:25])=[CH:22][CH:21]=1>>[CH2:1]([N:5]1[C:9]2=[C:10]([O:25][CH2:24][C:23]3[CH:22]=[CH:21][C:20]([O:19][CH:18]([F:17])[F:28])=[CH:27][CH:26]=3)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4]
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Reactant: OCc1ccc(OC(F)F)cc1
Product: CC=CCn1c(C)c(C)c2cnnc(OCc3ccc(OC(F)F)cc3)c21
Yield: 37.8 %

Procedure:
The title compound (cis/trans=21/79) was prepared as a white powder in 37.8% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=20/80) and 4-difluoromethoxybenzyl alcohol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:5]=[C:6]([C:8]2[S:12][CH:11]=[N:10][CH:9]=2)[CH:7]=1.[Li+].CC([N-]C(C)C)C.[CH3:32][C:33]1([CH3:44])[C:42](=[O:43])[CH2:41][CH2:40][CH2:39][C:34]21[O:38][CH2:37][CH2:36][O:35]2>C1COCC1.[Cl-].[NH4+]>[CH3:32][C:33]1([CH3:44])[C:42]([C:11]2[S:12][C:8]([C:6]3[CH:5]=[C:4]([NH:13][C:14]4[N:19]=[C:18]([C:20]([F:21])([F:23])[F:22])[CH:17]=[CH:16][N:15]=4)[CH:3]=[C:2]([CH3:1])[CH:7]=3)=[CH:9][N:10]=2)([OH:43])[CH2:41][CH2:40][CH2:39][C:34]21[O:35][CH2:36][CH2:37][O:38]2
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Reactant: CC1(C)C(=O)CCCC12OCCO2
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCCC4(OCCO4)C3(C)C)s2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
To a stirred solution of INTERMEDIATE 4 (1.09 g, 3.24 mmol) in THF (17 mL) was added LDA (2M, 4.86 mL, 9.72 mmol) dropwise at −78° C. The orange solution was left to stir for 30 min at that temperature, treated with 6,6-dimethyl-1,4-dioxaspiro[4.5]decan-7-one (0.72 g, 3.9 mmol) in THF (4.5 mL) dropwise, and allowed to warm to room temperature as the bath did. The reaction mixture was diluted with saturated ammonium chloride solution, and extracted with EtOAc (3×). The combined organics were washed with brine, dried (sodium sulfate), filtered concentrated, and purified by column chromatography on silica to afford 6,6-dimethyl-7-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-dioxaspiro[4.5]decan-7-ol (964 mg, 1.85 mmol) as a light yellow foam. MS ESI: [M+H]+ m/z 521.1.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1B1OC(C)(C)C(C)(C)O1.CCN(C(C)C)C(C)C>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>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1csc(Br)n1
Reactant: CC1(C)OB(c2c(F)cccc2F)OC1(C)C
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
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1csc(-c2c(F)cccc2F)n1
Temperature: 120 °C
Reaction time: 3 h
Yield: 75.3 %

Procedure:
To a screw-cap vial equipped with a magnetic stir bar, ethyl 2-bromo-1,3-thiazole-4-carboxylate (Ark Pharm, 2.026 g, 8.582 mmol) was added followed by 2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Combi-Blocks, 2.47 g, 10.3 mmol) and bis(tri-tert-butylphosphine)palladium (781.8 mg, 1.530 mmol). The vial was sealed with a PTFE-lined septum, and was then evacuated and backfilled with nitrogen three times. 1,4-Dioxane (10.0 mL) was added via syringe, followed by DIPEA (2.41 g, 18.6 mmol) and deoxygenated water (0.60 mL). The reaction mixture was stirred at 120° C. for 3 h. After cooling to room temperature, the mixture was filtered through a silica gel plug (eluted with EtOAc). The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the title compound as a pale yellow oil (1.739 g, 75%). LCMS calc. for C12H10F2NO2S (M+H)+: m/z=270.0. found 270.0.
Reaction SMILES: [Br:1][C:2]1[N:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].Cl>[OH-].[Na+]>[Br:1][C:2]1[N:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1cc(C)cnc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cnc(Br)c(C(=O)O)c1
Reaction time: 3 h
Yield: 89.1 %

Procedure:
A mixture of ethyl 2-bromo-5-methylnicotinate (7.1 g, 0.03 m) and 10% NaOH solution (500 ml) was heated on a stream bath with stirring. After 3 hours, the solution was cooled and neutralized with 12 N HCl. After cooling in an ice bath, the mixture was filtered to yield 5.6 g (39% yield) of 2-bromo-5-methylnicotinic acid.
Reaction SMILES: [C:1](Cl)([C:3]([O:5][CH3:6])=[O:4])=[O:2].[F:8][C:9]1[CH:30]=[CH:29][C:12]([O:13][C:14]2[CH:28]=[CH:27][C:17]([O:18][CH2:19][CH2:20][NH:21][C:22](=[O:26])[O:23][CH2:24][CH3:25])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1>ClCCCl.CN(C)C1C=CN=CC=1>[C:1]([N:21]([CH2:20][CH2:19][O:18][C:17]1[CH:27]=[CH:28][C:14]([O:13][C:12]2[CH:11]=[CH:10][C:9]([F:8])=[CH:30][CH:29]=2)=[CH:15][CH:16]=1)[C:22](=[O:26])[O:23][CH2:24][CH3:25])([C:3]([O:5][CH3:6])=[O:4])=[O:2]
Reactant: CCOC(=O)NCCOc1ccc(Oc2ccc(F)cc2)cc1
Reactant: COC(=O)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: CCOC(=O)N(CCOc1ccc(Oc2ccc(F)cc2)cc1)C(=O)C(=O)OC
Temperature: 25 °C

Procedure:
With stirring and under nitrogen, a solution of methoxalyl chloride in 10 ml of 1,2-dichloroethane is added dropwise at +80° C. over 20 minutes to a solution of 10.0 g of ethyl 2-[4-(4-fluorophenoxy)phenoxy]ethylcarbamate and 0.3 g of 4-dimethylaminopyridine in 70 ml of 1,2-dichloroethane. The mixture is then stirred for 16 hours at +80° C. After cooling to room temperature, the reaction mixture is washed in succession with a cold 5% solution of sodium hydrogencarbonate, with 0.1N hydrochloric acid and, finally, with water, and dried over sodium sulfate. The 1,2-dichloroethane is completely removed by vacuum distillation. If desired, the crude ethyl N-methoxalyl-2-[4-(4-fluorophenoxy)phenoxy]ethylcarbamate can be purified by chromatography (eluant: 5:1 mixture of n-hexane/diethyl ether); nD20 : 1.5295.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[C:28](O)=[O:29].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:28](=[O:29])[C:27]5[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=[C:25]([F:24])[CH:26]=5)[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: O=C(O)c1cc(F)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1cc(F)cc(C(F)(F)F)c1
Yield: 87.5 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (309 mg, 1.00 mmol), 3-fluoro-5-(trifluoromethyl)benzoic acid (312 mg, 1.50 mmol), 1-hydroxybenzotriazole (203 mg, 1.50 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (288 mg, 1.50 mmol) and N,N-dimethylformamide (5.0 mL) as starting materials and in the same manner as in Example 106, the title compound (437 mg, 88%) was obtained as a white powder.
Reaction SMILES: [F:1][C:2]([F:62])([F:61])[C:3]1[CH:4]=[C:5]([CH:58]=[CH:59][CH:60]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[N:36]=[C:35]([CH2:37][N:38]([CH3:57])[CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][C:50]([O:52]C(C)(C)C)=[O:51])[CH:34]=[CH:33][CH:32]=2)=[O:30])[CH:11]=1)=[O:9].FC(F)(F)C(O)=O>ClCCl>[F:61][C:2]([F:1])([F:62])[C:3]1[CH:4]=[C:5]([CH:58]=[CH:59][CH:60]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[N:36]=[C:35]([CH2:37][N:38]([CH3:57])[CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][C:50]([OH:52])=[O:51])[CH:34]=[CH:33][CH:32]=2)=[O:30])[CH:11]=1)=[O:9]
Reactant: CN(CCOCCOCCOCCC(=O)OC(C)(C)C)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CCOCCOCCOCCC(=O)O)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.7 %

Procedure:
Into a 50-mL vial, was placed a solution of tert-butyl 3-(2-(2(2-(((6-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)pyridin-2-yl)methyl)(methyl)amino)ethoxy)ethoxy)ethoxy)-propanoate (200 mg, 0.23 mmol, 1.00 equiv) in dichloromethane (10 mL), and 2,2,2-trifluoroacetic acid (2 mL). The resulting solution was stirred for 3 h at 25° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was dissolved in 50 mL of ethyl acetate. The resulting mixture was washed with 4×30 mL of brine, dried over sodium sulfate, and concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 84.9 mg (31%) of a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.34 (s, 1H), 9.89 (s, 1H), 9.54 (m, 1H), 9.02 (m, 1H), 8.19 (m, 4H), 7.84 (m, 2H), 7.57 (m, 5H), 7.29 (s, 1H), 4.60 (t, J=5.7 Hz, 6H), 3.77 (t, J=4.8 Hz, 2H), 3.48 (m, 16H), 2.84 (s, 3H), 2.51 (m, 2H), 1.9 (s, 4H), 1.7 (s, 2H). MS (ES, m/z): 807 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11]C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]([CH2:23][CH2:24][OH:25])[CH:20]([CH3:22])[CH3:21].CC(C)([O-])C.[K+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[CH:20]([N:19]([CH3:18])[CH2:23][CH2:24][O:25][C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=[CH:4][N:3]=1)([CH3:22])[CH3:21]
Reactant: Clc1ncccc1OCCOC1CCCCO1
Reactant: CC(C)N(C)CCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CC(C)N(C)CCOc1ncccc1OCCO
Temperature: 50 °C
Reaction time: 48 h
Yield: 76.9 %

Procedure:
A solution of 2-chloro-3-[2-(tetrahydro-2H-pyran-2-yloxy]ethoxy]pyridine (from Example 4; 100 mg, 0.39 mmol), 2-(N-methyl-N-isopropylamino)ethanol (68 μl, 0.58 mmol) and 1.0 M potassium tert-butoxide in tert-butanol (0.8 mL, 0.80 mmol) in 4 mL of toluene was heated at 100° C. for 1 day. The organic phase was washed with 3×2 mL of water and 2 mL of brine. The organic phase was shaken at 50° C. with 4 mL of 2.0 M acetic acid for 2 days. The aqueous phase was washed with 3×3 mL of ethyl acetate, made basic by addition of potassium hydroxide, saturated with sodium chloride and extracted with 3×2 mL of ethyl acetate. The organic phase was dried (MgSO4) and concentrated under reduced pressure to give 75 mg (0.30 mmol, 76%) of the title compound as a colorless oil. LC-UV purity 95%. MS m/z 255 (M+1)+, calc. 255 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:74][C:75]1[CH:81]=[CH:80][C:78]([NH2:79])=[CH:77][CH:76]=1>CN(C=O)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:36][CH2:37][CH:38]([CH3:41])[CH2:39][CH2:40]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:79][C:78]3[CH:80]=[CH:81][C:75]([F:74])=[CH:76][CH:77]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42]
Reactant: Nc1ccc(F)cc1
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and 4-fluoroaniline (7.92 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (26.4 mg, 72%). LC-MS m/z 667 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([NH:10]C(=O)CN2C(=O)C3=CC=CC=C3C2=O)[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.NN>C(O)C>[NH2:10][CH:8]([CH3:9])[CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(CC1CCCCC1)NC(=O)CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(N)CC1CCCCC1
Reaction time: 24 h

Procedure:
To a suspension of (±)-N-(2-cyclohexyl-1-methylethyl)-2-phthalimidoacetamide (12.0 g, 36.7mmol) in ethanol (180 ml) was added hydrazine hydrate (2.05 g, 40.3 mmol) and the mixture heated under reflux for 1.5 hours. After cooling and standing at 0° for 24 hours, the slurry was filtered and the residue washed with petrol (40°-60°). The combined filtrateswere evaporated to dryness and the oily residue triturated with petrol (3×100 ml). The combined extracts were evaporated to dryness to givea colourless oil. The oil was dissolved in ether (50 ml) and the solution added to a warm solution of fumaric acid (2.7 g) in ethanol (50 ml). On standing, a colourless solid was deposited, m.p. 132°-134° C.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:22])[CH2:15][CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH2:32]([O:39][CH2:40]Cl)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH:17]1([CH2:16][C@H:15]([CH2:40][O:39][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:14]([N:9]2[C@@H:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:12][O:11][C:10]2=[O:13])=[O:22])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: ClCOCc1ccccc1
Reactant: O=C(CCC1CCCC1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H](COCc1ccccc1)CC1CCCC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 71.8 %

Procedure:
To a solution of (4S)-benzyl-3-(3-cyclopentylpropanoyl)oxazolidin-2-one (42.4 g, 141 mmol) in dichloromethane (500 mL) at 0° C. under nitrogen was added titanium (IV) chloride (1 M in DCM, 155 mL, 155 mmol) in a slow steady stream. After 5 min, diisopropylethylamine (27 mL, 155 mmol) was added dropwise. After stirring at 0° C. for 1 h, benzyloxymethylchloride (TCI-America) (39 mL, 280 mmol) was added in a slow steady stream to the resulting titanium enolate, and the mixture was maintained at 0° C. for 3.5 h. The reaction mixture was then quenched with water (400 mL). The aqueous layer was extracted with dichloromethane (150 mL×2). The organic extracts were washed with saturated NaHCO3, were dried (MgSO4) and were evaporated. The residue was washed with ether (2×), and then was triturated with hexanes/ether to provide 2 crops of (4S)-3-((2R)-3-cyclopentyl-2-{[(phenylmethyl)oxy]methyl}propanoyl)-4-(phenylmethyl)-1,3-oxazolidin-2-one as a pale yellow solid (42.7 g, 72%). LCMS: (M+H)+: 422.2.