Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:25]=[CH:24][C:10]3[S:11][C:12]4[CH:17]=[CH:16][C:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[CH:14][C:13]=4[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.C[O:32][B:33](OC)[O:34]C>O1CCCC1>[C:18]1([C:15]2[CH:16]=[C:17]([B:33]([OH:34])[OH:32])[C:12]3[S:11][C:10]4[CH:24]=[CH:25][C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[CH:8][C:9]=4[C:13]=3[CH:14]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc(-c2ccc3sc4ccc(-c5ccccc5)cc4c3c2)cc1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cc(-c2ccccc2)cc2c1sc1ccc(-c3ccccc3)cc12
Temperature: -78 °C

Procedure:
2,8-diphenyldibenzo[b,d]thiophene (6.0) was dissolved in anhydrous tetrahydrofuran (80 mL) under nitrogen atmosphere and the solution was then cooled to −78° C. 20.0 mL of n-butyl lithium (1.6 M solution) was added dropwise into the reaction mixture and continuously stirred to equilibrate to room temperature. The reaction mixture was then cool to −60° C. and trimethyborate (5.67 mL) was added and the reaction was allowed to stir overnight. The reaction was then quenched with 20% aqueous hydrochloric acid, and extracted the organic layer with ethyl acetate; ethyl acetate layer was then washed thoroughly with water and dried over anhydrous sodium sulfate, and was evaporated to dryness to yield 4.5 g of 2,8-diphenyldibenzo[b,d]thiophene-4-boronic acid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])(C)(C)C.C(O[C:28](=[O:54])[CH2:29][C:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[N:38]=[C:39]([CH2:45][O:46]C3CCCCO3)[S:40][C:41]=2[CH2:42][CH2:43][CH3:44])[CH:32]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:28](=[O:54])[CH2:29][C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]4[N:38]=[C:39]([CH2:45][OH:46])[S:40][C:41]=4[CH2:42][CH2:43][CH3:44])[CH:32]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CCCc1sc(COC2CCCCO2)nc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1sc(CO)nc1-c1cccc(C2=Nc3cc(N(C)C)c(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (79 mg) (Example J6) and 3-oxo-3-{3-[-5-propyl-2-(tetrahydro-pyran-2-yloxymethyl)-thiazol-4-yl]-phenyl}-propionic acid tert-butyl ester (138 mg) (Example K41) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as yellow solid (45 mg).
Reaction SMILES: [C:1]1([CH:11]=[N:12][OH:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.ClN1C(=O)CCC1=O.[CH:22]([P:24](=[O:29])([O:27][CH3:28])[O:25][CH3:26])=[CH2:23].C(N(CC)CC)C>>[C:1]1([C:11]2[CH2:23][CH:22]([P:24](=[O:29])([O:27][CH3:28])[O:25][CH3:26])[O:13][N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C=CP(=O)(OC)OC
Reactant: ON=Cc1cccc2ccccc12
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Product: COP(=O)(OC)C1CC(c2cccc3ccccc23)=NO1

Procedure:
Preparation is carried out in analogy to Example 1 from 31.2 g (0.2 mol) of 1-naphthaldoxime, 29.4 g (0.22 mol) of N-chlorosuccinimide, 29.2 ml (0.22 mol) of dimethyl vinylphosphonate and 30.6 ml (0.22 mol) of triethylamine, with 56 g of oily compound being obtained.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10]1)C)(C)(C)C.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[NH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[C:16]1[C:14]([N:11]1[CH2:12][CH2:13][CH:9]([NH:7][CH3:6])[CH2:10]1)=[O:15]
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(C(=O)c2cc3ccccc3[nH]2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC1CCN(C(=O)c2cc3ccccc3[nH]2)C1
Reaction time: 18 h
Yield: 99 %

Procedure:
A solution of [1-(1H-indole-2-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (0.500 g, 1.46 mmol) in CH2Cl2 (20 mL) was treated with TFA (8 mL). After 18 h at rt, the mixture was concentrated to give the title compound (520 mg, 99%). MS (ESI): mass calcd. for C16H17N3O, 243.14; m/z found, 244.4 [M+H]+. MS (ESI): mass calcd. for C14H16N3O, 243.43; m/z found, 244.3 [M+H]+. 1H NMR (MeOD): 7.68-7.63 (m, 1H), 7.48-7.43 (m, 1H), 7.28-7.21 (m, 1H), 7.11-7.05 (m, 1H), 7.05-7.00 (m, 1H), 4.44-3.76 (m, 5H), 2.85-2.74 (m, 3H), 2.67-2.08 (m, 2H).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[C:11](Cl)(=[O:13])[CH3:12].[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[C:1]([NH:4][CH2:5][C:6]1[S:7][C:8]([C:11](=[O:13])[CH3:12])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(=O)NCc1cccs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)NCc1ccc(C(C)=O)s1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
To a solution of 40 g of 2-acetylaminomethylthiophene and 30.3 g of acetylchloride in 600 ml of dichloroethane is added a small portion of 76.3 g of anhydrous aluminum chloride under cooling at 5°-10° C. After the mixture is stirred at 10° C. for 30 minutes and poured into ice-cold water, the precipitated crystals are collected by filtration to give 2-acetylaminomethyl-5-acetylthiophene, melting F- at 129°-130° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].S(Cl)(Cl)=O.[CH3:23]N(C=O)C.C(N(CC)CC)C>ClCCCl.CO>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([O:18][CH3:23])=[O:17])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn2c(O)c(C(=O)O)cnc12
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCOC(=O)c1cnn2c(O)c(C(=O)OC)cnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
3-Ethoxycarbonyl-7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylic acid (27.0 g, 0.11 mol) obtained in Example 19, step 2 was suspended in 1,2-dichloroethane (320 mL), and thionyl chloride (39 mL, 0.54 mol) was added. DMF (22 mL) was added, and the mixture was heated under reflux for 6 hr. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was suspended in methylene chloride (300 mL), and triethylamine (75 mL, 0.54 mol) was added in an ice bath. Methanol (50 mL) was added dropwise over 30 min, and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, and the residue was added to 2 mol/L hydrochloric acid containing ice (about 500 mL). The precipitated solid was collected by filtration, and washed with water (50 mL) to give the title compound (27.5 g, 95%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:11][C:10]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:24][N:25](C=O)C>O1CCOCC1.[C-]#N.[Zn+2].[C-]#N.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>[C:24]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:11][C:10]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:9]2)=[CH:4][CH:3]=1)#[N:25]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(Br)cc2)CC2(C1)OCCO2
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [C-]#N
Agent: [Zn+2]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(C#N)cc2)CC2(C1)OCCO2
Temperature: 120 °C

Procedure:
To a solution of tert-butyl [2-(4-bromophenyl)-5,8-dioxaspiro[3.4]oct-2-yl]carbamate (1-5) (21.3 g, 55.5 mmol) in dioxane (100 mL) and DMF (100 mL) was added zinc cyanide (6.52 g, 55.5 mmol) and bis(tri-t-butylphosphine)palladium(0) (2.84 g, 5.55 mmol) and the reaction was heated to 120° C. under N2 for 1 hour. The reaction mixture was cooled to rt, filtered, and concentrated. The crude residue was purified by column chromatography eluting with 1-60% EtOAc/Hexane. The appropriate fractions were combined and the solvent removed in vacuo to give tert-butyl [2-(4-cyanophenyl)-5,8-dioxaspiro[3.4]oct-2-yl]carbamate (1-6). MS (M+H)+: 331.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.ON1C2C=CC=CC=2N=N1.[NH:28]1[CH2:34][CH2:33][CH2:32][C@H:29]1[CH2:30][OH:31].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.C(Cl)Cl>[C:1]1([NH:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([N:28]2[CH2:34][CH2:33][CH2:32][C@H:29]2[CH2:30][OH:31])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccccc1Nc1ccccc1
Reactant: OC[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccccc1Nc1ccccc1)N1CCC[C@H]1CO

Procedure:
2.13 g (10 mmol) of N-phenylanthranilic acid, 1.35 g (10 mmol) of 1-hydroxybenzotriazole hydrate, 1.0 ml (10 mmol) of L-prolinol and 2.06 g (10 mmol) of DCC in 50 ml 1:1/methylene chloride:DMF. The coupling was carried out as described in Example 25 for the coupling of the acid and S(+)-2-pyrrolidinemethanol. Clean product of the title compound was obtained in virtually quantitative yield as a brownish gum without chromatographic purification. TLC (90:10/CH2Cl2 :MeOH): Rf =0.75. 1H NMR (CDCl3) δ: 7.50(bs,1H); 6.75-7.36 (m,9H); 4.65-4.80(m,1H); 4.25-4.40 (m,1H); 3.38-3.85(m,4H); 1.55-2.15(m,4H).
Reaction SMILES: [I:1]I.N(OCCC(C)C)=O.[C:11]([O:15][C:16]([N:18]1[C:22]([CH3:23])=[CH:21][C:20](N)=[N:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[C:22]([CH3:23])=[CH:21][C:20]([I:1])=[N:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: Cc1cc(N)nn1C(=O)OC(C)(C)C
Reactant: II
Agent: CC(C)CCON=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(I)nn1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 16.6 %

Procedure:
Iodine (0.774 g, 3.0 mmol) was dissolved in DCM (5 mL) then isoamyl nitrite (0.682 mL, 5.1 mmol) was added followed by the slow addition of 3-amino-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester (0.50 g, 2.54 mmol) as a solution in DCM (4 mL). The reaction mixture was stirred at room temperature for 1.5 hours and then poured onto saturated sodium thiosulfate solution. The phases were separated and the aqueous layer was extracted with DCM (×3). The organics were washed with brine then dried over sodium sulfate, filtered and evaporated. The crude material was purified by chromatography on a silica II cartridge, eluting with 2-6% ethyl acetate in pentane to give 3-iodo-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester as a solid (0.13 g).
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[N:5]=[C:4]([S:13][CH:14]([CH3:16])[CH3:15])[N:3]=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>C(#N)C>[N:17]1([C:2]2[C:7]([I:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[N:5]=[C:4]([S:13][CH:14]([CH3:16])[CH3:15])[N:3]=2)[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: CC(C)Sc1nc(Cl)c(I)c(C(F)(F)F)n1
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: CC(C)Sc1nc(-n2ccnc2)c(I)c(C(F)(F)F)n1

Procedure:
4-Chloro-5-iodo-2-isopropylthio-6-trifluoromethylpyrimidine (3.0 g) was dissolved in acetonitrile (30 ml) and imidazole (1.6 g) was added at room temperature with stirring. The mixture was refluxed fbr 3 hr and then the solvent was removed under reduced pressure. The residue was added water and precipitates was filtered off to give crude 4-imidazol-1-yl-5-iodo-2-isopropylthio-6-trifluoromethyl-pyrimidine. It was recryslized from methanol-water mixture as colorless needles (2.61 g), mp 118-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]1[NH:13][C:14]2[CH:20]=[C:19]([C:21](Cl)=[O:22])[CH:18]=[CH:17][C:15]=2[N:16]=1.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[NH2:34].CCN(C(C)C)C(C)C>C1COCC1>[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[NH:34][C:21]([C:19]1[CH:18]=[CH:17][C:15]2[N:16]=[C:12]([C:3]3[C:4]([C:8]([F:10])([F:11])[F:9])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[NH:13][C:14]=2[CH:20]=1)=[O:22]
Reactant: Nc1ccc2ccccc2n1
Reactant: O=C(Cl)c1ccc2nc(-c3c(Cl)cccc3C(F)(F)F)[nH]c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccc2ccccc2n1)c1ccc2nc(-c3c(Cl)cccc3C(F)(F)F)[nH]c2c1
Temperature: 60 °C

Procedure:
To a stirred suspension of 2-(2-chloro-6-trifluoromethylphenyl)-3H-benzoimidazole-5-carbonyl chloride (394 mg, 1.0 mmol) and quinolin-2-ylamine (144 mg, 1.0 mmol) in THF (6 mL) was added DIPEA (0.53 ml, 3.0 mmol). The solution was heated at 60° C. for 2 days and the reaction was quenched with water and aqueous layer was extracted with EtOAc. The organic layer was washed with water, brine, dried with MgSO4, and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using heptane/EtOAc (1:4) as eluent to give 2-(2-chloro-6-trifluoromethylphenyl)-3H-benzoimidazole-5-carboxylic acid quinolin-2-ylamide as a white solid. 1H NMR (Methanol-d4, 400 MHz): δ 8.45 (d, 1H), 8.37 (d, 1H), 8.08 (d, 1H), 7.94 (m, 4H), 7.83 (m, 1H), 7.74 (m, 1H), 7.54 (m, 1H). MS (m/z) 467.1 (M+1); Retention time: 1.45 min (Method 10).
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[C:29]([CH3:30])=[C:28]([CH3:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)[N:20]=1>>[N:22]1[CH:23]=[CH:24][N:25]=[CH:26][C:21]=1[C:19]1[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[C:29]([CH3:30])=[C:28]([CH3:31])[S:27][C:17]=2[N:18]=1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: Cc1sc2nc(-c3cnccn3)nc(Cl)c2c1C
Product: Cc1sc2nc(-c3cnccn3)nc(NCCc3ccc4c(c3)OCCO4)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyrazin-2-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-ethylenedioxyphenethylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([O:14][CH3:15])=[C:8]([F:16])[C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([O:14][CH3:15])=[C:8]([F:16])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1c(F)c(OC)cc(OC)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(OC)c(Cl)c(C(=O)O)c1F
Temperature: 25 °C
Yield: 76.7 %

Procedure:
A suspension of methyl 2-chloro-6-fluoro-3,5-dimethoxybenzoate (2.7 g, 0.010 mol) and sodium hydroxide (1.088 g, 0.0272) in anhydrous ethanol (30 mL) was refluxed for 24 h. The resulting reaction mixture was cooled to room temperature and concentrated under vacuum to get a crude residue. The crude residue was dissolved in water and extracted with ether (3×30 mL). The aqueous layer was acidified with conc.HCl and the precipitated solid was filtered, washed with cold water and dried in vacuo to afford the title compound (1.8 g, yield: 71%) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2].[H-].[Na+].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28]Br.[Cl-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:28][CH2:27][CH2:26][CH2:25][Br:24])[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2]
Reactant: BrCCCCBr
Reactant: CCOC(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCCCBr
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A solution of 12.0 g. of 5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester in 240 ml. of dimethylformamide is treated under nitrogen at -10° C. with 0.08 mol. of sodium hydride (3.5 g. of a 55% dispersion in mineral oil) and stirred in an ice-bath for 30 minutes. Then, there are added thereto at -10° C. 26.0 g. of 1,4-dibromobutane in one batch; the mixture is thereafter stirred at room temperature for 1 hour and subsequently heated at 60° C. for 18 hours. After cooling, the mixture is poured into 2 liters of ice-water, 100 g. of sodium chloride are added and the separated oily product is immediately extracted with methylene chloride. The organic phase, shielded from daylight, is washed with a solution of sodium chloride, dried over sodium sulfate and evaporated to dryness under reduced pressure. The resulting oil is taken up in chloroform and chromatographed on 500 g. of silica gel with chloroform/n-heptane/ethanol (10:10:1) as the eluant, care is taken that the eluate remains shielded from daylight. The uniform fractions are combined and evaporated, and there is obtained 2-(4-bromobutyl)-5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester as an oil, which has to be employed in the next stage as quickly as possible.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[N:8][O:9][CH:10]=[C:6]2[C:5](=[O:11])[NH:4][C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](I)[CH3:20]>CN(C)C=O>[CH2:19]([N:4]1[C:5](=[O:11])[C:6]2=[CH:10][O:9][N:8]=[C:7]2[N:2]([CH3:1])[C:3]1=[O:12])[CH3:20]
Reactant: Cn1c(=O)[nH]c(=O)c2conc21
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(=O)c2conc2n(C)c1=O

Procedure:
In 50 ml of dimethylformamide is dissolved 2 g of the 7-methyl-5H,7H-isoxazolo[3,4-d]pyrimidine-4,6-dione obtained in Example 19, followed by addition of 1.6 g of potassium carbonate and 2 ml of ethyl iodide. Then, the reaction and after-treatment are carried out in the same manner as Example 23 to obtain 0.9 g of the captioned compound as colorless crystals. melting point: 87°-88° C.
Reaction SMILES: O1CCOCC1.[OH-].[Li+].[CH:9]1([C:14]([N:16]2[CH2:21][CH:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)[CH2:19][CH:18]([C:33]([O:35]CC)=[O:34])[CH2:17]2)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1>O>[CH:9]1([C:14]([N:16]2[CH2:21][CH:20]([C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:26][CH:27]=3)[CH2:19][CH:18]([C:33]([OH:35])=[O:34])[CH2:17]2)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCOC(=O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)C2CCCC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)C2CCCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
37 ml of dioxane, 18.5 ml of water and 0.51 g (21.4 mmol) of lithium hydroxide were added to 2.30 g (5.34 mmol) of ethyl 1-(cyclopentylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylate. The mixture was stirred overnight at RT. For work-up, the dioxane was removed under reduced pressure, water was added to the reaction mixture and the mixture was acidified using aqueous 1 N hydrochloric acid solution. The mixture was extracted with dichloromethane. The organic phase was dried with sodium sulphate and concentrated under reduced pressure. Yield: 2.17 g (99% of theory)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([CH3:21])[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:29][C:30]4[CH:43]=[CH:42][C:33]5[C@H:34]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH2:35][O:36][C:32]=5[CH:31]=4)[CH:23]=3)=[C:17]([CH3:44])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[CH3:21][C:19]1[CH:20]=[C:15]([O:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:16]=[C:17]([CH3:44])[C:18]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:29][C:30]2[CH:43]=[CH:42][C:33]3[C@H:34]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH2:35][O:36][C:32]=3[CH:31]=2)[CH:23]=1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CCN(C(=O)OC(C)(C)C)CC5)cc4C)c3)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CCNCC5)cc4C)c3)ccc21
Yield: 115 %

Procedure:
Methyl (S)-2-(6-((4′-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-2′,6′-dimethyl-biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 3j (75 mg, 0.13 mmol) was dissolved in 15 mL hydrochloric acid in dioxane. The reaction solution was reacted for 1 hour. The resulting solution was concentrated under reduced pressure to obtain the crude title compound (S)-methyl 2-(6-((2′,6′-dimethyl-4′-(piperidin-4-yloxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 4a (75 mg), as a white solid which was directly used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:9](O)[CH2:10][N:11]2[C:19]3[CH:18]=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[C:13]3[CH2:21][N:22]([CH3:25])[CH2:23][CH2:24][C:12]2=3)[CH:6]=[N:7][CH:8]=1.S(=O)(=O)(O)O.[OH-].[K+]>>[F:27][C:2]([F:1])([F:28])[C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[N:11]2[C:19]3[CH:18]=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[C:13]3[CH2:21][N:22]([CH3:25])[CH2:23][CH2:24][C:12]2=3)[CH:6]=[N:7][CH:8]=1
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2cncc(C(F)(F)F)c2)CCN(C)C1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc2c(c1)c1c(n2/C=C/c2cncc(C(F)(F)F)c2)CCN(C)C1
Temperature: 5 °C

Procedure:
1-(5-(Trifluoromethyl)pyridin-3-yl)-2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethanol (1 equiv.) is refluxed with 25% sulfuric acid for 2 h. The reaction mixture is cooled to 5° C. with an ice-water bath. KOH (15% aq. solution) is added dropwise to the reaction mixture until pH 9-10 is achieved. The reaction mixture is extracted with EtOAc. The combined organic layers are washed with water followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product is purified by column chromatography over silica gel (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%).
Reaction SMILES: [CH:1]1([C:5]2[C:14](I)=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH3:16])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH:17]([O:19]CCCC)=[CH2:18].C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl>CS(C)=O.O.C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:17]([C:14]1[C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:6][C:7]([CH3:16])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:19])[CH3:18]
Reactant: C=COCCCC
Reactant: COC(=O)c1cc(I)c(C2CCC2)cc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cc(C(C)=O)c(C2CCC2)cc1C
Temperature: 120 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To a solution of methyl 4-cyclobutyl-5-iodo-2-methylbenzoate (152.3, 5.00 g, 15.1 mmol, 1.00 equiv) in DMSO (50 mL) under nitrogen were added 1-(ethenyloxy)butane (3.03 g, 30.3 mmol, 2.00 equiv), DPPP (624 mg, 1.51 mmol, 0.10 equiv), Pd(OAc)2 (324 mg, 1.51 mmol, 0.10 equiv), and TEA (3.06 g, 30.2 mmol, 2.00 equiv). The resulting mixture was stirred overnight at 120° C. under nitrogen, then cooled to ambient temperature and diluted with water. The pH was adjusted to 1 with hydrogen chloride (aq., 6 M). The resulting mixture was diluted with 200 mL of ethyl acetate, washed with brine (3×200 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:30) as eluent to furnish 2.28 g (61%) of the title compound as a yellow oil.