Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)Cl.Cl[Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].[OH:12][CH2:13][CH2:14]/[C:15](=[CH:25]\[S:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)/[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17].N1C=CN=C1>O>[Si:5]([O:12][CH2:13][CH2:14]/[C:15](=[CH:25]\[S:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)/[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17])([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(Nc1ccccc1)/C(=C/Sc1ccccc1)CCO
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC/C(=C\Sc1ccccc1)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
2 ml of methylene chloride solution including 0.79 g of chloro t-butyl dimethylsilane was dropped into 6 ml of methylene chloride solution including 1.20 g of (E)-4-hydroxy-N-phenyl-2-(phenylthiomethylene)butanamide and 0.63 g of imidazole at room temperature. The resulting solution was stirred at room temperature for 2 hours and added with water, then filtered using ethyl acetate. The organic layer was washed with water 3 times, then washed with brine, and dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.63 g of the title compound.
Reaction SMILES: [CH3:1][O:2][CH:3]=[CH:4][C:5]1[N:9]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[O:12][C:11]2([CH3:22])[CH3:21])[CH:8]=[N:7][CH:6]=1>CO.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:9]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[O:12][C:11]2([CH3:22])[CH3:21])[CH:8]=[N:7][CH:6]=1
Reactant: COC=Cc1cncn1C1c2ccccc2C(=O)OC1(C)C
Agent: [Pd]
Solvent: CO
Product: COCCc1cncn1C1c2ccccc2C(=O)OC1(C)C
Reaction time: 72 h

Procedure:
To a solution of 4-[5-(2-methoxy-vinyl)-imidazole-1-yl]-3,3-dimethyl-isochroman-1-one (0.110 g, 0.37 mmol) in methanol (5 mL) is added Pd/C (0.020 g). The reaction vessel is flushed with hydrogen gas and stirred under balloon pressure for 72 h. The mixture is filtered, and the filtrate concentrated in vacuo to give a residue which is purified by silica gel chromatography (dichloromethane-methanol, 19:1) to give 4-[5-(2-methoxy-ethyl)-imidazol-1-yl]-3,3-dimethyl-isochroman-1-one as a white solid; HRMS (ESI) m/z 301.1555 [(M+H)+: Calcd for C17H20N2O3: 301.1552]; 1H NMR (400 MHz, MeOD) δ ppm 1.25 (s, 3 H), 1.56 (s, 3H), 3.13 (br. s, 2 H), 3.45 (br. s, 3 H), 3.70-3.79 (m, 2 H), 5.71 (s, 1 H), 6.90 (s, 1 H), 7.15 (br. s, 1 H), 7.52 (d, J=7.6 Hz, 1 H), 7.60-7.72 (m, 1 H), 7.74-7.86 (m, 1 H), 8.24 (dd, J=7.8, 1.5 Hz, 1 H)
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([N:15]=[CH:16][N:17]=2)[C:5]([NH2:14])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[CH3:1][C:2]1[C:3]2[N:4]([N:15]=[CH:16][N:17]=2)[C:5]([NH:14][C:18](=[O:20])[CH3:19])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1c(-c2ccccc2)nc(N)n2ncnc12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(-c2ccccc2)c(C)c2ncnn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6.6 Parts of 8-methyl-7-phenyl-1,2,4-triazolo[2,3-c]pyrimidin-5-amine (Example 1) is suspended in 50 parts by volume pyridine and 10 parts by volume acetic anhydride. The solution is stirred at room temperature for approximately 18 hours until a clear solution is formed. After approximately 21 hours turbidity develops and a solid gradually forms. After standing for approximately 40 hours most of the solvent is removed in vacuo. The residue is stirred in water, filtered, washed with water and dried. The product is recrystallized from methanol to give N-[8-methyl-7-phenyl-1,2,4-triazolo[2,3-c]pyrimidin-5-yl]acetamide having the formula: ##STR8##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+].CCOCC.CCCCCC>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([C:12](=[O:14])[CH2:11][CH2:10][S:9]2)=[CH:7][CH:8]=1
Reactant: COc1cccc(SCCC(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)SCCC2=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.6 %

Procedure:
The acid from Step 1 (2.55 g, 12 mmol) was dissolved in trifluoroacetic acid (10 mL), treated with trifluoroacetic anhydride (5 mL) and stirred at room temperature (10 minutes). The reaction was poured into 10% Na2CO3 (60 mL), extracted with ether, washed with brine, dried over MgSO4, and concentrated in vacuo to give a red oil which was passed through a column of silica gel with 50% ether/hexane to give 7-methoxythiochroman-4-one as an orange solid (1.18 g, 51%): mp 49°-51° C.; 1H NMR (CDCl3) 300 MHz 8.06 (d, J=8.9 Hz, 1H) 6.72 (m, 2H) 3.83 (s, 3H) 3.20 (m, 2H) 2.95 (m, 2H). Mass spectrum: M+H=195.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH3:10])[N:5]([CH2:7][CH2:8][NH2:9])[CH:6]=1.[CH3:11][C:12]1[CH:13]=[C:14]([CH2:19][CH2:20][CH:21]=O)[CH:15]=[CH:16][C:17]=1[CH3:18]>>[CH3:11][C:12]1[CH:13]=[C:14]([CH2:19][CH2:20][CH:21]2[NH:9][CH2:8][CH2:7][N:5]3[C:4]([CH3:10])=[N:3][C:2]([I:1])=[C:6]23)[CH:15]=[CH:16][C:17]=1[CH3:18]
Reactant: Cc1ccc(CCC=O)cc1C
Reactant: Cc1nc(I)cn1CCN
Product: Cc1ccc(CCC2NCCn3c(C)nc(I)c32)cc1C

Procedure:
According to the general procedure (GP10), the microwave-assisted Pictet-Spengler reaction (60 W; 110° C.; 6 bars; 10 min.) between 2-(4-iodo-2-methyl-imidazol-1-yl)-ethylamine (758 mg; 3.020 mmol) and 3-(3,4-dimethyl-phenyl)-propionaldehyde (490 mg; 3.020 mmol) afforded 8-[2-(3,4-dimethyl-phenyl)-ethyl]-1-iodo-3-methyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine which was Boc-protected and finally purified by FC (DCM/MeOH=25/1).
Reaction SMILES: C(N(CC)CC)C.[C:8]([OH:27])(=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(Cl)(=O)OCC.[C:34]([OH:43])(=[O:42])[C:35]1[C:36](=[CH:38][CH:39]=[CH:40][CH:41]=1)[NH2:37]>C(Cl)Cl.C(Cl)(Cl)Cl>[C:8]([NH:37][C:36]1[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=1[C:34]([OH:43])=[O:42])(=[O:27])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: Nc1ccccc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)Nc1ccccc1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
Triethylamine (0.46 ml) was added to a suspension of stearic acid (853 mg) in methylene chloride (8.5 ml). Then, ethyl chlorocarbonate (0.32 ml) was dropwise added to the mixture while being cooled with ice. After being stirred for 1 hour at 0° C., the mixture, with a solution of anthranilic acid (411 mg) and triethylamine (0.42 ml) in methylene chloride (2 ml) dropwise added thereto, was stirred for 16 hours at 45° C. The reaction mixture was then diluted with chloroform, washed with water and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue was recrystallized from hexane-ethyl acetate mixed solution, thereby yielding 1.107 g of the aimed compound as colorless crystals. According to the comparison by using TLC and 1H-NMR, this product was identified as the aimed compound obtained by Example 1-1 (2).
Reaction SMILES: Br[CH2:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:25][C:26]1[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=1>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:23]=[CH:24][C:3]([CH2:2][N:27]3[C:26]([CH3:25])=[CH:30][C:29]([CH3:31])=[N:28]3)=[CH:4][CH:5]=2)=[CH:11][C:12]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CBr)cc1
Reactant: Cc1cc(C)[nH]n1
Product: Cc1cc(C)n(Cc2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)n1

Procedure:
70 mg of 4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was coupled to 50 mg of 3,5-dimethyl-1H-pyrazole via Procedure P. The reaction was evaporated to dryness and purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide. MS (Q1) 417.3 (M)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:17]([NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[O:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.Cl[C:27]([O:29][C:30]([CH3:32])=[CH2:31])=[O:28].O.C(Cl)Cl>N1C=CC=CC=1>[CH3:15][C:14]1[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:27](=[O:28])[O:29][C:30]([CH3:32])=[CH2:31])[CH:7]=2)=[CH:10][CH:11]=[C:12]([NH:16][C:17]([NH:19][C:20](=[O:25])[C:21]([CH3:22])([CH3:24])[CH3:23])=[O:18])[N:13]=1
Reactant: C=C(C)OC(=O)Cl
Reactant: Cc1nc(NC(=O)NC(=O)C(C)(C)C)ccc1Oc1ccnc(N)c1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: C=C(C)OC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C(C)(C)C)nc2C)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
A solution of N-((5-((2-aminopyridin-4-yl)oxy)-6-methylpyridin-2-yl)carbamoyl)pivalamide (0.280 g, 0.815 mmol) in pyridine (6 mL) was treated with isopropenyl chloroformate (0.100 mL, 0.913 mmol) and stirred at RT overnight. The mixture was treated with water and DCM, stirred for 0.5 h, the layers separated and the aqueous layer extracted with additional DCM (3×). The combined organics were dried over Na2SO4 and concentrated to dryness to afford prop-1-en-2-yl (4-((2-methyl-6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)carbamate (328 mg, 94%). MS (ESI) m/z: 428.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:18]([N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)=[CH:17][C:3]=1[C:4]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][C:7]=1[CH3:16])=[O:5].[OH-].[Na+].[BH4-].[Na+]>O>[CH3:12][C:11]1[CH:10]=[C:9]([C:13]([OH:15])=[O:14])[CH:8]=[C:7]([CH3:16])[C:6]=1[CH:4]([C:3]1[CH:17]=[C:18]([N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH:19]=[CH:20][C:2]=1[CH3:1])[OH:5]
Reactant: Cc1ccc(-n2ccnc2)cc1C(=O)c1c(C)cc(C(=O)O)cc1C
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(-n2ccnc2)cc1C(O)c1c(C)cc(C(=O)O)cc1C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
To a solution of 16.2 g of 2-methyl-5-(1-imidazolyl)-2',6'-dimethyl-4'-carboxybenzophenone and 2.1 g of sodium hydroxide in 113 ml of water is added 2.8 g of sodium borohydride, and the mixture is stirred at 70°-75° C. for 3 hours. After completion of the reaction, a small amount of an isoluble substance is filtered off from the warm mixture and the filtrate is adjusted to pH 4 with concentrated hydrochloric acid under stirring at 80°-90° C. The precipitated crystals are collected by filtration under reduced pressure and washed with water well. After drying, recrystallization from dimethylformamide gives 14.0 g of α-(2,6-dimethyl-4-carboxyphenyl)-2-methyl-5-(1-imidazolyl)benzenemethanol, melting at 310°-312° C. with decomposition.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]([CH3:25])[CH2:14][CH2:15][CH:16]([N:17]([CH3:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]([CH3:25])[CH2:14][CH:15]=[C:16]([N:17]([CH3:24])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2n(c1=O)C(C)CCC2N(C)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnc2n(c1=O)C(C)CC=C2N(C)c1ccccc1
Yield: 58.4 %

Procedure:
5.0 g. (14.64 mmoles) of 6-methyl-9-(N-methylanilino)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid ethyl ester are dissolved in 100 ml. of chloroform. The solution is heated for 9 hours under reflux and air is bubbled into the reaction mixture. The solvent is distilled off in vacuo. The residue is crystallized from ethanol. 2.9 g. (58.4%) of 6-methyl-9-(N-methyl-anilino)-4-oxo-6,7-dihydro-4H-pyrido[I,2-a]pyrimidine-3-carboxylic acid ethyl ester is obtained which does not give a melting point depression when admixed with the product of Example 7. Melting point: 140°-142° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH:5]=[C:4]([CH3:9])[O:3]1.[Cl:11]Cl>C(Cl)Cl>[Cl:11][C:5]1[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]=1[CH3:9]
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: ClCl
Solvent: ClCCl
Product: CC1=C(Cl)C(=O)OC(C)(C)O1
Temperature: 20 °C
Yield: 100 %

Procedure:
A solution of 2,2,6-trimethyl-4H-1,3-dioxin-4-one (0.2 mol, 28.4 g) in 100 ml of CH2Cl2 was cooled to -50° C. and liquid chlorine (0.25 mol) was added dropwise over five minutes. The solution was allowed to warm to 20° C. over 30 minutes, and the solvent was then removed in vacuo, leaving 35.8 g (100% yield, 92% assay) of a pale yellow oil. A portion of this mixture was purified by flash chromatography (10% Et2O/hexanes on silica) to provide the title compound as white crystals.
Reaction SMILES: [CH3:1][C:2]1[C:3](Cl)=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.O.[NH2:14][NH2:15]>>[NH:14]([C:3]1[C:2]([CH3:1])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:15]
Reactant: Cc1cc2ccccc2nc1Cl
Reactant: NN
Solvent: O
Product: Cc1cc2ccccc2nc1NN

Procedure:
73.5 g of 3-methyl-2-chloroquinoline in 102 ml of hydrazine hydrate are heated under reflux for 3 hours. The reaction mixture is cooled and the solid is filtered off, washed and dried. The crystalline mass obtained is recrystallized from isopropanol to give 50.5 g of 2-hydrazino-3-methylquinoline melting at 128° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([CH2:17][O:18][CH2:19][CH:20]=[CH2:21])([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C:4](=[O:22])[N:3]1[C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=1.[C:35](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[O:1]=[C:2]1[N:6]([CH3:35])[C:5]([CH2:17][O:18][CH2:19][CH:20]=[CH2:21])([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:15])([F:16])[F:14])[CH:8]=2)[C:4](=[O:22])[N:3]1[C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([C:31]([F:34])([F:32])[F:33])[CH:24]=1
Reactant: O=C([O-])[O-]
Reactant: C=CCOCC1(c2cccc(C(F)(F)F)c2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCOCC1(c2cccc(C(F)(F)F)c2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 814 mg of 4-[2,5-dioxo-4-[(2-propenyloxy)methyl]-4-(3-trifluoromethylphenyl)imidazolidin-1-yl]-2-trifluoromethylbenzonitrile in DMF (1.5 mL) is added potassium carbonate (279 mg) and methyliodide (420 μL). The mixture is stirred 5 hours at room temperature, evaporated, washed with brine, extracted with ethyl acetate, dried over magnesium sulfate and concentrated to give the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)Cl.C(OCC)(=O)C.[CH:21]([NH2:23])=O>>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:23][CH:21]=[N:1]2)=[CH:7][CH:8]=1
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: NC=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=c1[nH]cnc2cc(F)ccc12
Temperature: 0 °C
Yield: 82 %

Procedure:
A solution of 2-amino-4-fluorobenzoic acid (3 g, 19.3 mmol) in formamide (30 ml) was heated at 150° C. for 6 hours. The reaction mixture was poured onto ice/water (1/1) (250 ml). The precipitated solid was collected by filtration, washed with water and dried to give 7-fluoro-3,4-dihydroquinazolin-4-one (2.6 g, 82%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:26]4[CH:39]=[CH:38][C:29]5[C@H:30]([CH2:33][C:34]([O:36]C)=[O:35])[CH2:31][O:32][C:28]=5[CH:27]=4)[CH:19]=3)=[C:13]([CH3:40])[CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH-].[Li+]>O1CCCC1.CO>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([O:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:26]4[CH:39]=[CH:38][C:29]5[C@H:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:31][O:32][C:28]=5[CH:27]=4)[CH:19]=3)=[C:13]([CH3:40])[CH:12]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CCN(C(C)=O)CC5)cc4C)c3)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)N1CCC(Oc2cc(C)c(-c3cccc(COc4ccc5c(c4)OC[C@H]5CC(=O)O)c3)c(C)c2)CC1
Reaction time: 2 h
Yield: 75.5 %

Procedure:
(S)-Methyl 2-(6-((4′-((1-acetylpiperidin-4-yl)oxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 6a (10 mg, 0.02 mmol) was dissolved in 2 mL of a mixture of the solvents tetrahydrofuran and methanol (V/V=1:1), followed by addition of 1M aqueous lithium hydroxide solution (0.2 mL, 0.20 mmol). The reaction solution was stirred for 2 hours. The resulting solution was concentrated under reduced pressure, 1M hydrochloric acid was added dropwise to adjust the pH to 5, and extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (S)-2-(6-((4′-((1-acetylpiperidin-4-yl)oxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid 6 (8 mg, yield 84.2%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([C:12]2[O:13][C:14]([CH2:17][N:18]3[CH2:23][C@H:22]([CH3:24])[O:21][C@H:20]([CH3:25])[CH2:19]3)=[N:15][N:16]=2)[CH:3]=1.[CH3:26][O:27][C:28]1[C:33]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH3:25][C@H:20]1[O:21][C@@H:22]([CH3:24])[CH2:23][N:18]([CH2:17][C:14]2[O:13][C:12]([C:4]3[CH:3]=[C:2]([C:31]4[CH:32]=[C:33]([NH:34][S:35]([CH3:38])(=[O:36])=[O:37])[C:28]([O:27][CH3:26])=[N:29][CH:30]=4)[CH:10]=[C:9]4[C:5]=3[CH:6]=[N:7][N:8]4[CH3:11])=[N:16][N:15]=2)[CH2:19]1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Reactant: C[C@@H]1CN(Cc2nnc(-c3cc(Br)cc4c3cnn4C)o2)C[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ncc(-c2cc(-c3nnc(CN4C[C@@H](C)O[C@@H](C)C4)o3)c3cnn(C)c3c2)cc1NS(C)(=O)=O
Temperature: 110 °C
Yield: 17.1 %

Procedure:
6-Bromo-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3,4-oxadiazol-2-yl)-1-methyl-1H-indazole (45 mg, 0.111 mmol), N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide (36.4 mg, 0.111 mmol), sodium carbonate (35.2 mg, 0.332 mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (8.10 mg, 0.011 mmol) were added to a microwave vial and dissolved in 1,4-dioxane (0.5 ml) and water (0.5 ml). The reaction mixture was heated under microwave irradiation at 110° C. for 15 mins. The reaction mixture was passed through a 2 g silica cartridge that was then washed with methanol. The solvent was evaporated under a stream of nitrogen and the residual solid was purified by Mass Directed Automated Preparative HPLC (Method B) and the solvent was evaporated under a stream of nitrogen to give the title compound as a white solid (10 mg).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][C:4]1([CH3:10])[CH3:9].[Cl:11][C:12]1[N:13]=[C:14](Cl)[C:15]2[CH2:21][N:20]([C@H:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:23])[CH2:19][CH2:18][C:16]=2[N:17]=1.CCN(C(C)C)C(C)C.C(O)(C)C>O.CCOC(C)=O>[Cl:11][C:12]1[N:13]=[C:14]([N:6]2[CH2:7][CH2:8][CH:3]([O:2][CH3:1])[C:4]([CH3:10])([CH3:9])[CH2:5]2)[C:15]2[CH2:21][N:20]([C@H:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:23])[CH2:19][CH2:18][C:16]=2[N:17]=1
Reactant: C[C@@H](c1ccccc1)N1CCc2nc(Cl)nc(Cl)c2C1
Reactant: COC1CCNCC1(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(C)O
Product: COC1CCN(c2nc(Cl)nc3c2CN([C@@H](C)c2ccccc2)CC3)CC1(C)C
Temperature: 60 °C

Procedure:
A mixture of racemic 4-methoxy-3,3-dimethylpiperidine (0.30 g, 1.95 mmol), (S)-2,4-dichloro-6-(1-phenylethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (0.40 g, 1.30 mmol), DIEA (0.50 g, 3.90 mmol), and isopropanol (10 mL) was heated at 60° C. for 24 h. The mixture was diluted with water and EtOAc and the organic layer was then separated, dried (Na2SO4), filtered and concentrated. The residue was taken to the next step without further purification. MS (ESI+) m/z 415.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[N:19]=[N:20][C:21](Cl)=[CH:22][CH:23]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[N:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccc(Cl)nn3)cc(C)c21
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cccnn3)cc(C)c21
Reaction time: 2 h
Yield: 77.9 %

Procedure:
A mixture of [6-(6-Chloro-pyridazin-3-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.5 g, 1.37 mmol), 10% Pd/C (0.45 g) and K2CO3 (0.38 g, 2.75 mmol) in EtOAc (20 mL) was hydrogenated at 30 psi for 2 hours. The mixture was filtered through a pad of celite and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (DCM:MeOH 95:5) to give [1-hydroxy-4-methyl-6-(pyridazin-3-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.35 g, 77%). 1H NMR (400 MHz, DMSO): δ 9.26 (s, 1H), 8.98 (dd, J=1.6, 4.8 Hz, 1H), 7.76-7.73 (m, 1H), 7.44 (dd, J=1.2, 8.8 Hz, 1H), 7.26 (d, J=2.4 Hz, 1H), 7.12 (d, J=1.6 Hz, 1H), 5.53 (dd, J=2.4, 9.2 Hz, 1H), 4.03 (q, J=7.2 Hz, 2H), 3.14 (dd, J=2.8, 15.6 Hz, 1H), 2.33-2.24 (m, 1H), 2.30 (s, 3H), 1.13 (t, J=7.2 Hz, 3H). MS (ESI) m/z=329 [M+H]+.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[C:39]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][C:22]3[C:23]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)[O:25][C:21]=3[CH:20]=2)=[CH:14][C:13]=1[Cl:43].[CH3:44][S:45](Cl)(=[O:47])=[O:46].O>C1COCC1.CCOC(C)=O>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([C:19]2[C:39]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][C:22]3[C:23]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)[O:25][C:21]=3[CH:20]=2)[S:45]([CH3:44])(=[O:47])=[O:46])=[CH:14][C:13]=1[Cl:43]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(Nc3ccc(Br)c(Cl)c3)c(C3CC3)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc(Br)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 48.9 %

Procedure:
A 1M solution of LiHMDS in THF (1.049 mL, 1.049 mmol) was added dropwise to a solution of ethyl 6-((4-bromo-3-chlorophenyl)amino)-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylate (440 mg, 0.807 mmol) in THF (15 mL) at −78° C. After stirring for 45 min, the red solution was added dropwise via cannula to a solution of MsCl (0.252 mL, 3.23 mmol) in THF (1 mL) at −78° C. Upon complete addition the yellow solution was allowed to warm to RT and stirred overnight. Water (150 mL) and EtOAc (150 mL) were added. The organic layer was separated and washed with water, brine, dried over MgSO4, filtered and concentrated. The crude product was purified on silica gel (hex/EtOAc) to give ethyl 6-(N-(4-bromo-3-chlorophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylate (259 mg, 0.395 mmol, 49% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.22 (s, 1H), 8.05 (d, 2H), 7.78 (d, 1H), 7.64-7.71 (m, 3H), 7.62 (s, 1H), 7.31 (dd, 1H), 4.35 (q, 2H), 3.46 (s, 3H), 2.10-2.22 (m, 1H), 1.34 (t, 3H), 0.69-1.13 (m, 3H), 0.42 (br. s., 1H).