Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[O:15][CH3:16].C(N(CC)CC)C.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>C(Cl)Cl>[CH3:16][O:15][CH:3]1[CH:2]([NH:1][C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:31])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4]1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC1CN(C(=O)OC(C)(C)C)CCC1N
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC1CN(C(=O)OC(C)(C)C)CCC1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1,1-dimethylethyl 4-amino-3-(methyloxy)-1-piperidinecarboxylate D19 (2.85 g) in DCM (100 ml) was added triethylamine (5.2 ml, 37.2 mmol), and benzoyl chloride (2.2 ml, 18.6 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The resulting mixture was poured into water and extracted with DCM. The organic layer was dried over anhydrous MgSO4, concentrated in vacuo to get the desired product D20 as an oil in 4.0 g. LCMS [MH+] 335@1.56 and 1.61 min (isomers seen) (5 min run)
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:34])[NH:14][C:15]=23)[CH2:32][CH2:33]1
Reactant: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f12) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: FC(F)(F)C(O)=O.C[O:9][C:10](=[O:44])/[C:11](/[NH:22][C:23](=[O:43])[C:24]1[C:29]([CH3:30])=[CH:28][C:27]([C:31]([NH:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([OH:41])[CH:36]=2)=[O:32])=[CH:26][C:25]=1[Cl:42])=[CH:12]/[C:13]1[CH:21]=[CH:20][C:16]2[NH:17][N:18]=[N:19][C:15]=2[CH:14]=1.O.[OH-].[Li+]>CO.O1CCCC1.O>[NH:17]1[C:16]2[CH:20]=[CH:21][C:13](/[CH:12]=[C:11](\[NH:22][C:23](=[O:43])[C:24]3[C:29]([CH3:30])=[CH:28][C:27]([C:31]([NH:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([OH:41])[CH:36]=4)=[O:32])=[CH:26][C:25]=3[Cl:42])/[C:10]([OH:44])=[O:9])=[CH:14][C:15]=2[N:19]=[N:18]1
Reactant: COC(=O)/C(=C/c1ccc2[nH]nnc2c1)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(C(=O)NCc2cccc(O)c2)cc(Cl)c1C(=O)N/C(=C\c1ccc2[nH]nnc2c1)C(=O)O
Temperature: 25 °C
Reaction time: 125 h
Yield: 61.4 %

Procedure:
A mixture of (Z)-3-(1H-benzotriazol-5-yl)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]-6-methylbenzoyl]amino]propenoic acid methyl ester trifluoroacetate salt (Example 210; 18 mg, 0.028 mmol) and lithium hydroxide monohydrate (6 mg, 0.144 mmol) in methanol/tetrahydrofuran/water (2:2:1; 0.5 mL) was stirred at room temperature for 125 h. After the volatiles were removed under reduced pressure, the residue was taken up in a mixture of chloroform/methanol/water/acetic acid (150:30:10:6) (10 mL) and evaporated to dryness. The crude product was re-suspended in the same solvent mixture (1 mL) and applied to a column of two piggy-backed SepPak Plus® silica gel cartridges that had been pre-washed with chloroform. The column was eluted with in turn with chloroform, chloroform/methanol/water/acetic acid (600:30:10:6), chloroform/methanol/water/acetic acid (300:30:10:6 and chloroform/methanol/water/acetic acid (150:30:10:6). The appropriate fractions were combined, evaporated and lyophilized to furnish (Z)-3-(1H-benzotriazol-5-yl)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]-6-methylbenzoyl]amino]propenoic acid (8.7 mg, 61% yield) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14](Cl)=[O:15].[Cl:17][C:18]1[CH:31]=[C:30]([NH2:32])[CH:29]=[CH:28][C:19]=1[O:20][CH2:21][CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25].ClCCl.CO.N>>[Cl:17][C:18]1[CH:31]=[C:30]([NH:32][C:14](=[O:15])[C:13]#[C:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=2[Cl:1])[CH:29]=[CH:28][C:19]=1[O:20][CH2:21][CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25]
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Reactant: O=C(Cl)C#Cc1ccc(C(F)(F)F)cc1Cl
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)CCOc1ccc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)cc1Cl

Procedure:
Prepared analogously to Example 4.1.d. from (2-chloro-4-trifluoromethylphenyl)propynoic acid chloride and [2-(2-chloro-4-aminophenoxy)ethyl]diethylamine. Yield: 0.26 g (27.5% of theory); C22H21Cl2F3N2O2 (M=473.32); calc.: molecular ion peak (M+H)+: 473/475; found: molecular ion peak (M+H)+: 473/475; Rf value: 0.5 (silica gel, dichloromethane/methanol/ammonia (9:1:0.1)).
Reaction SMILES: C([O:5][C:6]1[CH2:11][CH:10]([C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)[CH2:9][C:8](=[O:18])[CH:7]=1)(=O)CC>O1CCCC1>[CH3:17][N:15]1[CH:16]=[C:12]([CH:10]2[CH2:9][C:8](=[O:18])[CH:7]([C:6](=[O:5])[CH2:7][CH3:8])[C:6](=[O:5])[CH2:11]2)[CH:13]=[N:14]1
Reactant: CCC(=O)OC1=CC(=O)CC(c2cnn(C)c2)C1
Solvent: C1CCOC1
Product: CCC(=O)C1C(=O)CC(c2cnn(C)c2)CC1=O
Yield: 166.4 %

Procedure:
A mixture of 30.0 g (121 mmols) of 5-(1-methyl-1H-pyrazol-4-yl)-3-oxo-1-cyclohexenyl propionate and 7.4 g (61 mmols) of 4-N,N-dimethylaminopyridine was dissolved in 300 ml of tetrahydrofuran. The solution was heated to reflux for 5 hours to perform the reaction. After completion of the reaction, the reaction mixture was allowed to cool. The reaction solution was concentrated and the product was extracted with chloroform. Water was added to the extract and the aqueous phase was adjusted to pH of 4 to 5. The 4-N,N-dimethylaminopyridine was removed. After washing the chloroform phase with water and drying, the solvent was distilled off under reduced pressure to give 25.0 g of the product.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:20][CH3:21])[C:5](=[O:19])[N:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[CH:10][CH:9]=2)[CH:7]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].[C:41]1(B(O)O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:21][O:20][C:4]1[C:5](=[O:19])[N:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[CH:10][CH:9]=2)[CH:7]=[C:2]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1nc(Cl)cn(-c2ccnn2-c2ccccc2)c1=O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1nc(-c2ccccc2)cn(-c2ccnn2-c2ccccc2)c1=O
Yield: 6.5 %

Procedure:
To a mixture of 5-chloro-3-methoxy-1-(1-phenyl-1H-pyrazol-5-yl)pyrazin-2(1H)-one (245 mg), tri-tert-butylphosphine (25.0 mg), Pd2(dba)3 (37.0 mg), cesium carbonate (791 mg) and 1,4-dioxane (10.0 ml) was added phenylboronic acid (120 mg) at room temperature. The reaction mixture was heated using a microwave reactor at 95° C. for 1.5 hr. The reaction mixture was concentrated, dichloromethane was added, and the mixture was washed with saturated brine. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the title compound (18.0 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:14][C:15]([C:17]2([NH:32]C(=O)OC(C)(C)C)[CH2:22][CH2:21][N:20]([C:23]3[C:24]4[CH:31]=[CH:30][NH:29][C:25]=4[N:26]=[CH:27][N:28]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:10][CH2:11][NH:12][CH3:13])=[CH:5][CH:4]=1>C(Cl)Cl.CO>[NH2:32][C:17]1([C:15]([NH:14][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=2)[CH2:10][CH2:11][NH:12][CH3:13])=[O:16])[CH2:18][CH2:19][N:20]([C:23]2[C:24]3[CH:31]=[CH:30][NH:29][C:25]=3[N:26]=[CH:27][N:28]=2)[CH2:21][CH2:22]1
Reactant: CNCCC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CNCCC(NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
Hydrogen chloride (4M in dioxane, 0.461 mL, 1.84 mmol) was added to tert-butyl 4-(1-(4-chlorophenyl)-3-(methylamino)propylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 68) (10 mg, 0.02 mmol) in a mixture of DCM (3 mL) and methanol (1 mL) at 22° C. The resulting solution was stirred at 22° C. for 2 hours. The mixture was evaporated and the residue was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 30% (2M NH3 in MeOH) in DCM and pure fractions were evaporated to dryness to afford 4-amino-N-(1-(4-chlorophenyl)-3-(methylamino)propyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (7 mg, 86%) as a colourless gum.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]1[C@@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]([C:32]3([CH3:35])[CH2:34][CH2:33]3)=[O:31])[CH2:26][CH2:25]2)=[O:23])[CH2:10]1)C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:21][C:16]1[CH:15]=[C:14]([C@@H:13]2[C@@H:9]([NH:7][CH3:6])[CH2:10][N:11]([C:22]([CH:24]3[CH2:29][CH2:28][N:27]([C:30]([C:32]4([CH3:35])[CH2:33][CH2:34]4)=[O:31])[CH2:26][CH2:25]3)=[O:23])[CH2:12]2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Reaction time: 20 h
Yield: 72.8 %

Procedure:
Under an atmosphere of nitrogen to a solution of rac-{(3R,4S)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid tert-butyl ester (3.02 g, 5.61 mmol) in dichloromethane (30 mL) was added at ambient temperature trifluoroacetic acid (4.3 mL, 56 mmol) and stirred for 20 h at this temperature. The reaction mixture was added slowly onto an aqueous solution of sodium carbonate (1M, 60 mL). The organic layer was separated and washed with brine (50 mL). The aqueous layers were extracted with dichloromethane (30 mL), dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate:methanol=50:50:0 to 0:90:10) afforded the title compound (1.79 g, 73%) as a light brown oil. MS m/e: 338.3 [M+H]+.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[C:7]([OH:11])([CH3:10])([CH3:9])[CH3:8]>CN(C)C1C=CN=CC=1>[O:6]=[C:2]([CH3:1])[CH2:3][C:4]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)(C)O
Reactant: C=C1CC(=O)O1
Agent: CN(C)c1ccncc1
Product: CC(=O)CC(=O)OC(C)(C)C
Yield: 98.6 %

Procedure:
To a mixture of tert-butyl alcohol [74.1 g] and 4-(dimethylamino)pyridine [0.61 g] was added dropwise diketene [84.1 g] at 50° to 60° C. in the course of one hour while stirring. The stirring was continued for one further hour at 30° to 50° C. to obtain a colorless and clear reaction mixture, which was subjected to distillation under reduced pressure (b.p. 85° C./20 mmHg) to yield tert-butyl 3-oxobutyrate [156 g] as an oily product. The yield was 98.6%.
Reaction SMILES: CS(C)=O.[NH:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13](Br)[CH:12]=1.[OH-].[K+]>C(OC(=O)C)C>[F:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([N:5]2[CH:9]=[CH:8][N:7]=[CH:6]2)[CH:12]=1
Reactant: COc1ccc(F)cc1Br
Reactant: c1c[nH]cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(F)cc1-n1ccnc1
Temperature: 140 °C
Reaction time: 24 h
Yield: 47 %

Procedure:
To a degassed DMSO (20 mL) solution of imidazole (1.0 g, 15 mmol) was added 4-fluoro-2-bromoanisole (1.25 mL, 10 mmol), KOH (1.12 g, 20 mmol) and Cu2O (280 mg, 2 mmol) under nitrogen. The resulting mixture was stirred at 140° C. for 24 hrs under N2. After cooling to room temperature, the mixture was poured into ethylacetate (EA) (50 mL) and filtered. The filtrate was washed with water (50 mL×3) and dried over anhydrous magnesium sulfate. After rotary evaporation, the crude oil was purified via column chromatography on silica gel with eluent of EA/MeOH (9/1, v/v), affording a light yellow liquid (47%). 1H-NMR (400 MHz, CDCl3) δ(ppm) 7.82 (s, 1H), 7.21 (m, 1H), 7.17 (m, 1H), 7.07 (m, 2H), 7.00 (m, 1H), 3.84 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[CH:30]=[C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:47])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][N:21]4[C:30]([Br:47])=[C:31]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:32]=[C:20]4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nc(-c5ccccc5)cn4cc3-c3ccccc3)cc2)CCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nc(-c5ccccc5)c(Br)n4cc3-c3ccccc3)cc2)CCC1
Yield: 59.6 %

Procedure:
To a solution of compound 5-2 (110 mg, 0.2 mmol) in CHCl3 (5 mL) was added NBS (40 mg 0.22 mmol.) and the mixture was heated to reflux for 1 hrs. After cooling, the mixture was diluted with 15 mL of DCM, the combined organic phase was washed with 0.1N HClaq and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep.TLC to give 71 mg of 5-4.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:19]([O:26][C:27]([C:29]1[S:30][C:31]([CH:35]=O)=[C:32]([CH3:34])[CH:33]=1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[C:1]([O:5][C:6](=[O:16])/[CH:7]=[CH:35]/[C:31]1[S:30][C:29]([C:27]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:28])=[CH:33][C:32]=1[CH3:34])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(C(=O)OCc2ccccc2)sc1C=O
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)OCc2ccccc2)sc1/C=C/C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 84.9 %

Procedure:
A solution of diethylphosphonoacetic acid tert-butyl ester (0.44 g, 1.74 mmol) in tetrahydrofuran (3 mL) was added dropwise to a suspension of 60% sodium hydride (0.055 g, 1.38 mmol) in tetrahydrofuran (15 mL) with stirring at 0° C. After stirring at room temperature for 30 minutes, a solution of 5-formyl-4-methylthiophene-2-carboxylic acid benzyl ester (0.3 g, 1.15 mmol) obtained in step 2 in tetrahydrofuran (3 mL) was added dropwise at 0° C. After stirring at room temperature for 2 hours, the mixture was worked up according to a conventional method, and purified by silica gel column chromatography to give the title compound (0.35 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[O:21][N:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:69])[C:58]2[CH:63]=[C:62]([F:64])[CH:61]=[CH:60][C:59]=2[C:65]([F:68])([F:67])[F:66])[CH2:53][CH2:52]1)=[O:50]>CN(C=O)C.O>[F:64][C:62]1[CH:61]=[CH:60][C:59]([C:65]([F:67])([F:66])[F:68])=[C:58]([CH:63]=1)[C:57]([N:54]1[CH2:55][CH2:56][N:51]([C:49](=[O:50])[CH2:48][NH:47][C:22]([C:19]2[CH:18]=[C:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[F:10])[O:21][N:20]=2)=[O:24])[CH2:52][CH2:53]1)=[O:69]
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Reactant: O=C(O)c1cc(-c2ccccc2F)on1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)c1cc(-c2ccccc2F)on1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 32.7 %

Procedure:
DIPEA (219 mg, 0.29 mL, 1.68 mmol) was added to a stirred solution of 5-(2-fluoro-phenyl)-isoxazole-3-carboxylic acid (100 mg, 0.48 mmol) in DMF (2 mL). HOBT (68.5 mg, 0.5 mmol) and EDCI (97.2 mg, 0.5 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (100 mg, 0.48 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid precipitated. The obtained solid was purified by column chromatography (using silica gel of 60-120 mesh and 50% EtOAc in hexane as eluent) to afford 82 mg (32.5% yield) of 5-(2-fluoro-phenyl)-isoxazole-3-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 98.05%. 1H NMR (DMSO-d6): δ 8.8 (t, 1H), 7.9 (m, 2H), 7.4 (m, 5H), 7.2 (d, 1H), 7.2 (d, 1H), 4.2 (m, 2H), 3.9 (m, 1H), 3.5 (m, 3H), 3.4 (m, 1H), 3.1 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[CH3:23])[N:3]=1.ClCC(Cl)(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:34][C:35]1[CH:41]=[CH:40][C:38]([OH:39])=[CH:37][C:36]=1[OH:42].Cl>O>[Cl:34][C:35]1[C:36]([OH:42])=[CH:37][C:38]([OH:39])=[C:40]([C:2]2[N:3]=[C:4]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[N:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=3[CH3:15])[N:7]=2)[CH:41]=1
Reactant: Cc1ccc(-c2nc(Cl)nc(-c3ccc(C)cc3C)n2)c(C)c1
Reactant: Oc1ccc(Cl)c(O)c1
Agent: Cl
Agent: ClCC(Cl)(Cl)Cl
Agent: [Al+3]
Solvent: O
Product: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3cc(Cl)c(O)cc3O)n2)c(C)c1
Temperature: 120 °C
Reaction time: 4 h
Yield: 32.4 %

Procedure:
To a 1 L three-necked, round-bottomed flask equipped with a magnetic stirrer, thermometer, condenser, and a nitrogen atmosphere are charged 20.0 g (61.9 mmol) of 2-chloro-4,6-bis-(2,4-dimethylphenyl)-s-triazine and 50 mL of tetrachloroethane. The mixture is warmed to dissolve the solids and 8.24 g (62.0 mmol) of aluminum chloride are added in small portions all at once followed by 9.00 g (62.1 mmol) of 4-chlororesorcinol. The mixture is stirred at 120° C. for four hours. After cooling to room temperature 50 mL of water and 10 mL of concentrated hydrochloric acid are added and the mixture is refluxed for two hours. After cooling, the mixture is extracted thrice with ethyl acetate and the combined organic layers are dried over anhydrous magnesium sulfate and filtered. The solvent is removed under reduced pressure to yield a yellow solid. Recrystallization from ethyl acetate/heptane affords 8.65 g of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[Br:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=1>>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:28])=[CH:22][CH:21]=1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc(Br)cc1
Product: O=C(Cc1ccc(Br)cc1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(4-bromophenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.30 (dd, J=7.9, 1.3 Hz, 1H), 8.03 (dd, J=8.1, 1.3 Hz, 1H), 7.97-8.01 (m, 1H), 7.91 (td, J=7.5, 1.3 Hz, 1H), 7.54-7.56 (m, 2H), 7.33-7.36 (m, 2H), 3.78-3.83 (m, 4H), 3.65 (s, 2H), 3.08-3.13 (m, 4H); MS (ESI−) M/Z 441 (M−H)−.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][CH3:22])=[CH:16][CH:17]=4)[C:12](OS(F)(=O)=O)=[C:11]3[C:28]([O:30][CH3:31])=[O:29])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[C:36]([O:43][CH2:44][CH2:45][O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:35]=1.C([O-])([O-])=O.[K+].[K+].C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCO.C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][CH3:22])=[CH:16][CH:17]=4)[C:12]([C:37]4[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][C:36]=4[O:43][CH2:44][CH2:45][O:46][CH2:47][C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)=[C:11]3[C:28]([O:30][CH3:31])=[O:29])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccc(B(O)O)c(OCCOCc2ccccc2)c1
Reactant: CCCOc1ccc2c(c1)C(OS(=O)(=O)F)=C(C(=O)OC)[C@H]2c1ccc2c(c1)OCO2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCCOCc1ccccc1)=C(C(=O)OC)[C@H]2c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
A 50 mL three-necked flask under nitrogen was charged with (S)-methyl 1-(1,3-benzodioxol-5-yl)-3-[(fluorosulfonyl)oxy]-5-propoxy-1H-indene-2-carboxylate (prepared as described in Example 1 (vii)) (500 mg, 1.07 mmol), (4-methoxy-2-[2-(phenylmethoxy)ethoxy]phenyl]boronic acid (Compound (v)) (330 mg, 1.09 mmol), toluene (15 mL), EtOH (1 mL), and Pd(dppf)Cl2 catalyst (24 mg, 0.033 mmol). The mixture was stirred for 0.5 h at room temperature followed by the addition of 1.3 M K2CO3 solution (1.0 mL, 1.3 mmol) and heated to 70° C. for 45 min. The mixture was cooled to room temperature, charged with Norit A charcoal (5 g) and filtered through celite. The filtrate was then concentrated in vacuo affording (S)-methyl 1-(1,3-benzodioxol-5-yl)-3-[4-methoxy-2-[2-(phenylmethoxy)ethoxy]phenyl]-5-propoxy-1H-indene-2-carboxylate as a yellow gum (640 mg, 98% yield).
Reaction SMILES: I[C:2]1[C:3](=[O:28])[NH:4][C:5](=[O:27])[N:6]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][C@H:15]3[C@:13]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)([CH2:14]3)[CH2:12]2)[CH:7]=1.[CH3:29][O:30][C:31]1[C:36](B(O)O)=[CH:35][CH:34]=[CH:33][N:32]=1.[F-].[K+]>CO.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:29][O:30][C:31]1[C:36]([C:2]2[C:3](=[O:28])[NH:4][C:5](=[O:27])[N:6]([CH2:8][CH2:9][CH2:10][N:11]3[CH2:16][C@H:15]4[C@:13]([C:17]5[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=5)([CH2:14]4)[CH2:12]3)[CH:7]=2)=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)cc1I
Reactant: COc1ncccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: CO
Product: COc1ncccc1-c1cn(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)c(=O)[nH]c1=O

Procedure:
5-Iodo-1-{3-[(1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hex-3-yl]-propyl}-1H-pyrimidine-2,4-dione (Prep40, 150 mg, 0.3 mmol) was dissolved in degassed MeOH (4 mL). 2-Methoxy-pyridine-3-boronic acid (136 mg, 0.9 mmol), KF (155 mg, 2.7 mmol), and Pd(OAc)2 (15 mg, 10% weight) were added and the mixture was heated to vigorous reflux for 2.5 hours. The mixture was diluted with MeOH, loaded on SCX cartridge washing with MeOH and MeOH/NH3 95:5. The solvent was evaporated under vacuum and the residue was purified by flash chromatography with ethyl acetate to give the title compound as free base (70 mg, 48% yield).