Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[CH3:28][C:29]1([CH3:35])[O:33][C:32](=[O:34])[N:31]=[CH:30]1>>[CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([N:31]5[CH2:30][C:29]([CH3:35])([CH3:28])[O:33][C:32]5=[O:34])=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C(c1ccc(I)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: CC1(C)C=NC(=O)O1
Product: CC1(C)CN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C4CC4)CC3)cc2)C(=O)O1
Yield: 28.5 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (473 mg) described in Preparation Example 95 and 5,5-dimethyloxazolin-2-one (138 mg) described in Preparation Example 43, the title compound (131 mg) was obtained.
Reaction SMILES: [C:1](N1C2C(=NC=CC=2)N=N1)(=[O:3])[CH3:2].[CH2:13]([OH:24])[CH2:14][C:15]1[CH:23]=[CH:22][C:20]([OH:21])=[C:17]([O:18][CH3:19])[CH:16]=1.[OH-].[Na+]>C1COCC1.Cl>[C:1]([O:21][C:20]1[CH:22]=[CH:23][C:15]([CH2:14][CH2:13][OH:24])=[CH:16][C:17]=1[O:18][CH3:19])(=[O:3])[CH3:2]
Reactant: COc1cc(CCO)ccc1O
Reactant: CC(=O)n1nnc2ncccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(CCO)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-acetyl-1H-1,2,3-triazolo[4,5-b]pyridine (0.964 g, 5.95 mmol) in dry THF (24 mL) was added to a solution of homovanillyl alcohol (1.00 g, 5.95 mmol) in 1N aq. NaOH (5.95 mL, 5.95 mmol) at 25° C. The reaction was stirred at 25° C. for 60 min. The reaction was diluted with 1N HCl (40 mL) and extracted with Et2O (3×50 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Biotage Horizon, 40M, Si, ˜30 mL/min, 100% hexanes for 144 mL, gradient to 50% EtOAc in hexanes over 360 mL, gradient to 100% EtOAc over 1944 mL) to afford 4-(2-hydroxyethyl)-2-methoxyphenyl acetate, as a colorless oil. Rf=0.71 (EtOAc). LCMS calc.=233.1; found=233.1 (M+Na)+. 1H NMR (500 MHz, CDCl3): δ 6.95 (d, J=8.0 Hz, 1 H); 6.83 (d, J=1.8 Hz, 1 H); 6.79 (dd, J=1.8, 8.0 Hz, 1 H); 3.88 (t, J=6.6 Hz, 2 H), 3.84 (s, 3 H); 2.82 (t, J=6.5 Hz, 2 H); 2.30 (s, 3 H); 1.76 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:11](=[O:31])[CH2:12][C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=3[C:21]([O:23]C)=[O:22])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[OH-].[K+]>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:11](=[O:31])[CH2:12][C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=3[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CCCCCCCN(CCc1ccc(Cl)cc1)C(=O)Cc1ccc(OCc2ccccc2C(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCN(CCc1ccc(Cl)cc1)C(=O)Cc1ccc(OCc2ccccc2C(=O)O)cc1
Yield: 5.5 %

Procedure:
Methyl 2-[(4-{2-[[2-(4-chlorophenyl)ethyl](heptyl)amino]-2-oxoethyl}phenoxy)methyl]benzoate (0.112 g, 0.209 mmol) was dissolved in EtOH (5 ml, 95%) and potassium hydroxide (0.018 g, 0.313 mmol) was added. The reaction was performed in an single node microwave oven (7 min, 150 deg). Workup was by removing the solvent by evaporation and addition of HCl (2 ml, 1 M). The water-phase was extracted with two portions of EtOAc (20 ml) and the organic phase was dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). The solvent was removed by evaporation to give 0.006 g of 2-[(4-{2-[[2-(4-chlorophenyl)ethyl](heptyl)amino]-2-oxoethyl}phenoxy)methyl]benzoic acid (yield 5.5%). 1HNMR (Rotamers, 300 MHz, CDCl3): δ 0.85 (t, 3H), 1.22 (m, 8H), 1.39 (m, 2H), 2.62-3.7 (bm, 8H), 5.45-5.55 (m, 2H), 6.89-7.43 (bm, 9H), 7.52 (m, 1H), 7.78 (t, 1H), 8.13 (t, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][C:7]2[N:8]=[C:9]([O:33][CH2:34][CH2:35][CH3:36])[C:10]3[N:15]=[C:14]([C:16]4[CH:21]=[C:20]([CH3:22])[C:19]([O:23][CH2:24][CH:25]5[CH2:29][O:28]C(C)(C)[O:26]5)=[C:18]([CH3:32])[CH:17]=4)[O:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1>ClCCl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]=[C:9]([O:33][CH2:34][CH2:35][CH3:36])[C:10]3[N:15]=[C:14]([C:16]4[CH:17]=[C:18]([CH3:32])[C:19]([O:23][CH2:24][CH:25]([OH:26])[CH2:29][OH:28])=[C:20]([CH3:22])[CH:21]=4)[O:13][C:11]=3[N:12]=2)=[CH:37][CH:38]=1
Reactant: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCC4COC(C)(C)O4)c(C)c3)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCC(O)CO)c(C)c3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The 5-(4-chloro-benzyl)-2-[4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,5-dimethyl-phenyl]-7-propoxy-oxazolo[5,4-d]pyrimidine obtained in step (a) was dissolved in 6 ml of dichloromethane and 2 ml of trifluoroacetic acid. The reaction mixture was stirred for 2 h at room temperature. Then the solvents were removed in vacuo and the residue was purified by preparative HPLC (method HPLC1). 4.1 mg of the title compound were obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])[CH2:17][CH2:16]1)=[O:14].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[N:54]1([C:60]2[CH:68]=[CH:67][C:63]([C:64](O)=[O:65])=[CH:62][CH:61]=2)[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1>CN(C=O)C.O>[O:14]=[C:13]([N:15]1[CH2:16][CH2:17][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:29])[F:30])[CH2:19][CH2:20]1)[CH2:12][NH:11][C:64](=[O:65])[C:63]1[CH:67]=[CH:68][C:60]([N:54]2[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]2)=[CH:61][CH:62]=1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1ccc(N2CCCCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 21.8 %

Procedure:
DIPEA (188.6 mg, 0.25 mL, 1.45 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (282.2 mg, 0.8 mmol) in DMF (4 mL). HOBT (108 mg, 0.8 mmol) and EDCI (279.7 mg, 1.45 mmol) were then added at room temperature. After 2 minutes, 4-piperidin-1-yl-benzoic acid (150 mg, 0.729 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 50% EtOAc in Hexane as eluent) to afford 80 mg (21.7% yield) N-{2-Oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-4-piperidin-1-yl-benzamide. LCMS Purity: 94.74%. 1H NMR (DMSO-d6): δ 8.2 (s, 1H), 7.9-7.5 (m, 6H), 7.0-6.9 (d, 2H), 4.2-4.0 (d, 2H), 3.8-3.5 (m, 4H), 3.35-3.2 (m, 4H), 3.2-3.0 (m, 4H), 1.7-1.5 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15]C(OC(C)(C)C)=O)=[CH:8][CH:7]=[CH:6][C:5]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3](=[O:31])[C:4]1[C:5]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:6][CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]
Reactant: COC(=O)c1c(OCCCCNC(=O)OC(C)(C)C)cccc1OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(OCCCCN)cccc1OCc1ccccc1

Procedure:
A solution of 2-benzyloxy-6-(4-tert-butoxycarbonylaminobutoxy)-benzoic acid methyl ester (1.6 g, 3.7 mmol) in 30 mL of methylene chloride/TFA (2:1) is stirred at RT for 20 min. The solvent is removed under reduced pressure and the residue is re-dissolved in methylene chloride, washed with sat. NaHCO31 water and brine, and dried over sodium sulfate. The solvent is removed under reduced pressure to afford the title compound as a colorless liquid: (M+1)+=330.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([OH:27])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:7].C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][S:36]([CH3:35])(=[O:38])=[O:37])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([CH2:13][CH2:14][O:15][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCO)(c3ccccc3)C2)cc(O)c1OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OS(C)(=O)=O)c1OC
Temperature: -5 °C
Reaction time: 18 h

Procedure:
Combine 1-(3,4-dimethoxy-5-hydroxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (0.95 g, 2.6 mmol) and triethylamine (1.0 mL, 7.7 mmol) in dichloromethane (15 mL). Cool the reaction mixture to −5° C. with an salt-ice bath. Slowly, add methanesulfonyl chloride (0.45 mL, 5.8 mmol). Warm to ambient temperature. After 18 hours, quench the reaction by the addition of ice. Separate the organic layer and extract with aqueous 1M hydrochloric acid solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain the title compound.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:14]=[C:13]([CH2:15]B2OCC(C)(C)CO2)[O:12][C:11]=1[CH3:24])(C)C)(C)(C)C.BrC1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[N:27]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH3:33][O:32][C:28]1[N:27]=[C:15]([C:13]2[O:12][C:11]([CH3:24])=[C:10]([CH2:9][OH:8])[CH:14]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: Cc1oc(CB2OCC(C)(C)CO2)cc1CO[Si](C)(C)C(C)(C)C
Reactant: COc1cccc(Br)n1
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: COCCOC
Solvent: O
Product: COc1cccc(-c2cc(CO)c(C)o2)n1
Reaction time: 8 h
Yield: 100.4 %

Procedure:
A mixture of tert-butyl({5-[(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)methyl]-2-methylfuran-3-yl}methoxy)dimethylsilane (2.4 g), 2-bromo-6-methoxypyridine (1.9 g), tetrakis(triphenylphosphine)palladium(0) (0.4 g), 2N aqueous sodium carbonate solution (7 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), 1N tetrabutylammonium fluoride in tetrahydrofuran (10 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (10% ethyl acetate/hexane to 100% ethyl acetate/hexane) to give the title compound (1.5 g, 95%) as an oil.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([N:18]2[C:22]([SH:23])=[N:21][N:20]=[N:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O.C(OCC)(=O)C>[O:1]([CH2:8][CH2:9][CH2:10][S:23][C:22]1[N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:19]=[N:20][N:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccccc1
Reactant: Sc1nnnn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: c1ccc(OCCCSc2nnnn2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.4 %

Procedure:
3-phenoxypropyl bromide (1.53 g) was dissolved in acetone (9 mL), 1-phenyl-5-mercapto-1H-tetrazole (1.27 g) and potassium carbonate (985 mg) were added, and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added water, and the extract obtained by extraction with ethyl acetate was washed with water and a saturated saline, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a titled compound (2.23 g) having the following physical property values.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([C:17]2[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[NH:10][S@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])=[CH:5][CH:4]=1)=[O:2].[CH3:27][Mg]Br>C1COCC1>[OH:2][CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]([C:17]2[C:22]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[NH:10][S@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])=[CH:7][CH:8]=1)[CH3:27]
Reactant: C[Mg]Br
Reactant: CC(C)(C)[S@](=O)N[C@@H](c1ccc(C=O)cc1)c1ncccc1C(F)(F)F
Solvent: C1CCOC1
Product: CC(O)c1ccc([C@H](N[S@@](=O)C(C)(C)C)c2ncccc2C(F)(F)F)cc1

Procedure:
(S)—N—((S)-(4-Formylphenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (0.200 g, 0.520 mmol) was dissolved in dry THF (30 mL) and cooled in an ice bath. Methylmagnesium bromide (3M in Et2O, 0.50 mL, 1.50 mmol) was added dropwise and the reaction stirred. The resulting mixture was stirred for 1 h and then quenched by addition of saturated aqueous NH4Cl (10 mL). H2O (100 mL) and EtOAc (100 mL) were added, and the phases were mixed and separated. The organic layer was dried with MgSO4 and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to EtOAc gradient) gave impure material which was further purified using reverse phase HPLC to give the desired (S)—N-((1S)-(4-(1-hydroxyethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:9]=2)[C:4]=1[C:21]([OH:23])=O.[CH3:24][NH2:25]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:9]=2)[C:4]=1[C:21]([NH:25][CH3:24])=[O:23]
Reactant: CN
Reactant: COc1cccc(-c2ccc3c(C(=O)O)c(OC)ccc3c2)c1
Product: CNC(=O)c1c(OC)ccc2cc(-c3cccc(OC)c3)ccc12

Procedure:
The compound was prepared by reaction of 2-methoxy-6-(3-methoxyphenyl)-1-naphthoic acid (300 mg, 0.97 mmol, 1 eq) with 33% methylamine (1 eq) according to method D. Purification by column chromatography was not necessary. The desired compound was obtained in quantitative yield (311 mg).
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.[O:12]([CH2:19][CH2:20][CH2:21][N:22]1[CH2:32][CH2:31][CH:25]([C:26]([O:28]CC)=O)[CH2:24][CH2:23]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+].[C:35]([OH:40])(=[O:39])[C:36]([OH:38])=[O:37]>O1CCCC1.CO>[C:35]([OH:40])(=[O:39])[C:36]([OH:38])=[O:37].[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:26]([C:36]2[CH:35]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)([CH:25]2[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][CH2:19][O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:32][CH2:31]2)[OH:28])=[CH:6][CH:7]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CCOC(=O)C1CCN(CCCOc2ccccc2)CC1
Agent: II
Agent: O=C(O)C(=O)O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Product: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCN(CCCOc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
To a mixture of 5.10 g (0.21 mole) of magnesium turnings and a crystal of iodine in 800 ml of dry tetrahydrofuran (distilled from lithium aluminum hydride) was added a solution of 36.75 g (0.21 mole) of p-bromofluorobenzene in 100 ml of tetrahydrofuran. The reaction flask was cooled in an ice bath during this addition, and the reaction mixture was under an atmosphere of nitrogen. The mixture was stirred at ambient temperature for 1 hr. A solution of 20.17 g (0.0693 mole) of ethyl N-(3-phenoxypropyl)isonipecotate in 100 ml of tetrahydrofuran was added and the solution was stirred at room temperature for 16 hr. The mixture was poured into an icy solution of ammonium chloride and the aqueous mixture was extracted with methylene chloride. The methylene chloride solution was extracted with dilute sodium hydroxide and was dried over magnesium sulfate. The solvent was removed in vacuo to give a gummy residue. The residue was treated with a solution of oxalic acid in methanol and the salt was recrystallized from methanol-ether to give 24.17 g (66.2%) of white crystalline solid, m.p. 153°-155° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]3[C:32](=[O:33])[C:31]4[C:30](=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:29]3=[O:38])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCN2C(=O)c3ccccc3C2=O)CC1
Yield: 40.6 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (17.0 g) and N-(4-bromobutyl)phthalimide (15.8 g) were reacted and treated in the same manner as in Preparation Example 150 to give 9.3 g of 4-amino-5-chloro-N-(1-(4-(2,3-dihydro-1,3-dioxo-1 H-isoindol-2-yl)butyl)piperidin-4-ylmethyl)-2-methoxybenzamide.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][CH2:23][CH2:24][CH:25]([F:46])[CH2:26][C@@H:27]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)(=[O:31])=[O:30])=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[CH3:47][CH:48](O)[CH3:49].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][CH2:23][CH2:24][CH:25]([F:46])[CH2:26][C@@H:27]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[N:28]([S:29]([C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH:48]([CH3:49])[CH3:47])=[O:21])[CH:7]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: CCOC(=O)[C@H](CC(F)CCNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](CC(F)CCNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1)N(C(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
To a solution of the material from Step 5 (50 mg, 0.076 mmol), 2-propanol (0.023 mL, 0.304 mmol) and Ph3P (80 mg, 0.304 mmol) in THF (1 mL) at 0° C. was slowly added diisopropyl azodicarboxylate (0.059 mL, 0.304 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness and the residue was purified by column chromatography on silica gel using ethyl acetate-hexanes (0:100 to 90:10) to afford 31 mg of the title compound as a colorless foam. LCMS (M+1)=701.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([F:13])([F:12])[CH2:10][OH:11])=[C:4]([CH3:14])[CH:3]=1.N1C=CN=C1.[C:20]([Si:24]([CH3:27])([CH3:26])Cl)([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]([C:9]([F:12])([F:13])[CH2:10][O:11][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:27])[CH3:26])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Br)cc(C)c1C(F)(F)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(C)c1C(F)(F)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
To a solution of Intermediate 7B (2.68 g, 10.11 mmol) and imidazole (1.376 g, 20.22 mmol) in DMF (30 ml) was added tert-butyl dimethylchlorosilane (1.828 g, 12.13 mmol). The mixture was stirred at rt overnight, diluted with EtOAc and sat. NaHCO3. The organic layer was extracted by EtOAc (3×20 ml). The combined organic layer was washed with water and brine, dried (MgSO4) and concentrated. The crude product was purified by flash chromatography to give Intermediate 7C (2.56 g, 66.8% yield) as a colorless oil. 1H NMR (400 MHz, chloroform-d) δ ppm −0.01 (s, 6H) 0.84 (s, 9H) 2.42 (t, J=4.61 Hz, 6H) 4.00 (t, J=13.18 Hz, 2H) 7.20 (s, 2H). 19F NMR (376 MHz, chloroform-d) δ ppm −95.94 (br. s., 2F).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH3:18][O:19][C:20](=[O:38])[CH2:21][C:22]1[C:23]([CH3:37])=[N:24][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35]Cl)=[CH:31][CH:30]=2)[C:26]=1[CH3:27].C(OCC)(=O)C>CN(C)C=O.O>[CH3:18][O:19][C:20](=[O:38])[CH2:21][C:22]1[C:23]([CH3:37])=[N:24][N:25]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([CH2:35][S:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:8][CH:7]=3)=[CH:33][CH:34]=2)[C:26]=1[CH3:27]
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(CCl)cc2)c1C
Reactant: FC(F)(F)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nn(Cc2ccc(CSc3ccc(C(F)(F)F)cc3)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(Trifluoromethyl)thiophenol (0.25 ml, 1.8 mmol) was dissolved in 5 ml dimethylformamide, and K2CO3 (337 mg, 2.4 mmol) was added to the solution. A solution of [1-(4-chloromethyl-benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-acetic acid methyl ester (intermediate 16.1.2, 1 g, 1.6 mmol) in dimethylformamide was added to the mixture within 5 min, and the mixture was stirred for 1 h at room temperature. Ethyl acetate and water were added, the mixture was washed with aqueous NaOH solution (1 M) and with water. The organic layer was dried over MgSO4 and the solvent was evaporated under reduced pressure. The residue was purified by MPLC (silica gel, CH2Cl2/methanol 99:1) and preparative reversed phase HPLC (gradient of methanol in water+0.1% NH3).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[OH:4].[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C>[Cl:19][C:20]1[CH:25]=[C:24]([O:4][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[C:2]([F:1])([F:17])[F:18])[N:23]=[CH:22][N:21]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OC(c1ccccc1-c1ccncc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: FC(F)(F)C(Oc1cc(Cl)ncn1)c1ccccc1-c1ccncc1
Temperature: 110 °C
Yield: 79.1 %

Procedure:
The mixture of 2,2,2-trifluoro-1-(2-pyridin-4-yl-phenyl)ethanol (100 mg, 0.40 mmol), 4,6-dichloro-pyrimidine (54 mg, 0.38 mmol), cesium carbonate (468 mg, 1.44 mmol) and 1,4-dioxane (1 ml). The mixture was heated at 110° C. overnight. The reaction mixture was cooled to room temperature. 10 ml of ethyl acetate was added, and then the mixture was filtered through Celite. The filtrate was concentrated to give 110 mg of 4-chloro-6-[2,2,2-trifluoro-1-(2-pyridin-4-yl-phenyl)-ethoxy]-pyrimidine, yield: 76%.