Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[C:26]([C:30]1[CH:31]=[C:32]([CH:38]=[C:39]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:40]=1[OH:41])[CH:33]=[CH:34][C:35](O)=[O:36])([CH3:29])([CH3:28])[CH3:27].[NH2:46][C:47]1[CH:48]=[N:49][C:50]2[C:55]([C:56]=1[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[Cl:63])=[CH:54][C:53]([CH3:64])=[CH:52][C:51]=2[CH3:65]>CN(C=O)C>[C:42]([C:39]1[CH:38]=[C:32]([CH:31]=[C:30]([C:26]([CH3:28])([CH3:27])[CH3:29])[C:40]=1[OH:41])[CH:33]=[CH:34][C:35]([NH:46][C:47]1[CH:48]=[N:49][C:50]2[C:55]([C:56]=1[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[Cl:63])=[CH:54][C:53]([CH3:64])=[CH:52][C:51]=2[CH3:65])=[O:36])([CH3:44])([CH3:45])[CH3:43]
Reactant: CC(C)(C)c1cc(C=CC(=O)O)cc(C(C)(C)C)c1O
Reactant: Cc1cc(C)c2ncc(N)c(-c3ccccc3Cl)c2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc(C)c2ncc(NC(=O)C=Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)c(-c3ccccc3Cl)c2c1
Temperature: 25 °C
Yield: 46.6 %

Procedure:
1-Hydroxybenzotriazole (154 mg) and dicyclohexylcarbodiimide (272 mg) were added to a solution of 3,5-di-tert-butyl-4-hydroxycinnamic acid (331 mg) in DMF (5 ml). The mixture was stirred at room temperature for minutes, and then, 3-amino-4-(2-chlorophenyl)-6,8-dimethylquinoline (288 mg) was added thereto. The resultant mixture was further stirred at room temperature for 24 hours. The insoluble materials were filtered off, while the filtrate was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4). The solvent was removed, and the residue was purified by a silica gel chromatography with benzene-acetone (9:1), then, crystallized from isopropyl ether to give 3-(3,5-di-tert-butyl-4-hydroxycinnamoylamino)-4-(2-chlorophenyl)-6,8-dimethylquinoline (257 mg, 47.5%) as colorless needles.
Reaction SMILES: [CH2:1]([CH:7]1[C:11](=[O:12])[CH2:10][CH2:9][CH:8]1[C:13]([OH:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:16]O.S(=O)(=O)(O)O>C(Cl)CCl>[CH2:1]([CH:7]1[C:11](=[O:12])[CH2:10][CH2:9][CH:8]1[C:13]([O:15][CH3:16])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CO
Reactant: CCCCCCC1C(=O)CCC1C(=O)O
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: CCCCCCC1C(=O)CCC1C(=O)OC

Procedure:
A solution of 17 g of 2-n-hexyl-3-oxo-cyclopentanecarboxylic acid, 10 ml of methanol and 1 g of concentrated sulphuric acid in 50 ml of ethylene chloride, is refluxed for 8 hours. The reaction mixture is then washed with water and sodium carbonate solution and dried over anhydrous sodium sulphate. The solvent is distilled off at a reduced pressure and the residue is distilled through a short Vigreux column. The product, methyl 2-n-hexyl-3-oxo-cyclopentanecarboxylate is collected at 85°C/0,06 mm, yield 17 g (93%), nD20 1.4562.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]([C:44](=[O:48])[NH:45][CH2:46][CH3:47])([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:7][O:8][C:9](=[O:37])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[C:21]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:19])=[C:13]([OH:36])[CH:12]=1)=[O:5])[CH3:2].C(N(CC)CC)C.Cl[C:57](Cl)([O:59]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)(Cl)Cl>[CH2:46]([NH:45][C:44]([C:6]([C:4](=[O:5])[NH:3][CH2:1][CH3:2])([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[CH2:7][O:8][C:9](=[O:37])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]2[N:17]([C:18]([C:20]3[C:21]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:33])[F:35])=[CH:28][CH:27]=4)=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:19])[C:57](=[O:59])[O:36][C:13]=2[CH:12]=1)=[O:48])[CH3:47]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCNC(=O)C(COC(=O)Cc1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c(O)c1)(C(=O)NCC)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCNC(=O)C(COC(=O)Cc1ccc2c(c1)oc(=O)n2C(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1)(C(=O)NCC)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 213.3 %

Procedure:
The {3-Hydroxy-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}acetic acid 2,2-bisethylcarbamoyl-2-phenylethyl ester (195 mg) obtained in Example 3-2was dissolved in chloroform (5 mL), and to this solution was added triethylamine (72 mg). The solution was cooled to 0° C. and triphosgene (35 mg) was added thereto. After stirring for one hour, the reaction solution was washed with water, dried over sodium sulfate and purified by column chromatography on silica gel with hexane:ethyl acetate=1:1 to give the title compound (173 mg) (see Table 59).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[C:32](=[O:36])[N:31]([CH:37]1[CH2:42][CH2:41][C:40](=[O:43])[NH:39][C:38]1=[O:44])[CH2:30]2.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[C:32](=[O:36])[N:31]([CH:37]1[CH2:42][CH2:41][C:40](=[O:43])[NH:39][C:38]1=[O:44])[CH2:30]2)=[O:7]
Reactant: Cc1ccc(C(=O)O)cc1Cl
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1Cl
Reaction time: 1 h
Yield: 65.7 %

Procedure:
A mixture of 3-chloro-4-methylbenzoic acid (0.17 g, 1.0 mmol) and CDI (0.17 g, 1.1 mmol) was stirred in DMF (20 mL) at 40° C. under N2 for 4 hours. 3-(5-(Aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (0.31 g, 1.0 mmol) was added and stirring continued for 1 h at this temperature. Water (40 mL) was added and the resulting precipitate was filtered, washed with 4% aqueous HCl (40 mL) and dried in vacuo providing 3-chloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-4-methyl-benzamide as a white solid (0.28 g, 65% yield); mp 229-231° C.; HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min. 240 nm, 40/60 CH3CN/0.1% H3PO4. 4.29 (97.85%); 1H NMR (DMSO-d6) δ 1.97-2.01 (m, 1H), 2.32-2.45 (m, 4H), 2.57-2.62 (m, 1H), 2.85-2.96 (m, 1H), 4.31 (d, 1H, J=17.4), 4.45 (d, 1H, J=17.4), 4.58 (d, 2H, J=6.0), 5.11 (dd, 1H, J=13.2, J=5.1), 7.47-7.49 (m, 2H), 7.54 (s, 1H), 7.70 (d, 1H, J=7.8), 7.79 (dd, 1H, J=7.8, J=1.5), 7.95 (d, 1H, J=1.5), 9.21 (t, 1H, J=5.7), 10.99 (s, 1H); 13C NMR (DMSO-d6) δ 19.5, 22.5, 31.2, 42.8, 47.1, 51.6, 122.1, 122.9, 126.0, 127.1, 127.5, 130.4, 131.2, 133.3, 133.6, 138.9, 142.4, 143.7, 164.8, 167.9, 171.0, 172.9; LCMS: MH=426, 428; Anal. Calcd for C22H20ClN3O4+0.36 CH2Cl2: C, 58.84; H, 4.58; N, 9.21. Found: C, 58.49; H, 4.45; N, 8.91.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:6]=[CH:5]2.[C:17](OC(=O)C)(=[O:19])[CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:17]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:6]=[CH:5]2)(=[O:19])[CH3:18]
Reactant: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)Oc1ccc2cc(C(C)C(=O)O)ccc2c1

Procedure:
A mixture of 2.2 g. of 6-hydroxy-2-naphthyl-α-methylacetic acid, 50 ml. of acetic anhydride, and 100 mg. of p-toluenesulfonic acid is stirred for four hours at 50° C. The mixture is evaporated, water is added, and the mixture is extracted with diethyl ether which is washed with water to neutrality, dried over sodium sulfate, and evaporated to yield 6-acetoxy-2-naphthyl-α-methylacetic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[F:18][C:19]([F:24])([F:23])[C:20](O)=[O:21].Cl>O1CCCC1.C(N(CC)CC)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:20](=[O:21])[C:19]([F:24])([F:23])[F:18])=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)CCc1cc(N)ccc1O
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCc1cc(NC(=O)C(F)(F)F)ccc1O
Reaction time: 2 h

Procedure:
t-Butyl 3-(1-hydroxy-4-aminobenzen-2-yl)propionate was disslolved in a mixture of tetrahydrofuran (100 ml) and triethylamine (7.1 ml). Anhydrous trifluoroacetic acid (6.0 ml) was added to the solution at 0° C. in an atmosphere of argon gas. The solution was stirred for 2 hr. at 0° C. The reaction solution was poured into a mixture of ice and 1N hydrochloric acid (100 ml). The reaction mixture was extracted with ethyl acetate (300 ml). The extract was washed with water, saturated aqueous solution of sodium bicarbonate, followed by brine, dried over anhydrous magnesium sulfate and evaporated. The residue was recrystallized from a mixture of ethyl acetate-n-hexane (1:5) to give the title compound having the following physical data.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=[O:10].Cl[C:23]1[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:26]=[CH:25][N:24]=1>>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]([N:2]1[CH2:3][CH:4]2[CH:5]([CH2:6][N:7]([C:23]3[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:8]2)[CH2:1]1)=[O:10]
Reactant: O=C(c1ccccc1-c1cccs1)N1CC2CNCC2C1
Reactant: FC(F)(F)c1cccnc1Cl
Product: O=C(c1ccccc1-c1cccs1)N1CC2CN(c3ncccc3C(F)(F)F)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 37 and 2-chloro-3-trifluoromethyl-pyridine. MS (ESI): mass calculated for C23H20F3N3OS, 443.49; m/z found 444.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.28 (dd, J=4.7, 1.4, 1H), 7.79 (dd, J=7.8, 1.8, 1H), 7.55-7.49 (m, 1H), 7.46-7.33 (m, 3H), 7.30-7.19 (m, 2H), 7.01 (br s, 1H), 6.71 (dd, J=7.7, 4.7, 1H), 3.98-2.54 (m, 10H).
Reaction SMILES: [N:1]1([C:7]2[C:16]3[O:15][C:14](=[O:17])[C:13]([NH:18]C(=O)C)=[CH:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl>>[NH2:18][C:13]1[C:14](=[O:17])[O:15][C:16]2[C:7]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[CH:8][CH:9]=[CH:10][C:11]=2[CH:12]=1
Reactant: CC(=O)Nc1cc2cccc(N3CCNCC3)c2oc1=O
Agent: Cl
Product: Nc1cc2cccc(N3CCNCC3)c2oc1=O

Procedure:
Step 5 was the hydrolysis of the amide function of N-(8-(1-piperazinyl)-2-oxo-2H-1-benzopyran-3-yl-)acetamide (5*) using hydrochloric acid. This resulted in the trihydrochloric acid salt of 3-amino-8-(1-piperazinyl)-2H-1-benzopyran-2-one (6*).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[C:15](=O)([O-])[O-].[K+].[K+].IC>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH3:15])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: [K+]
Solvent: CI
Product: COC(=O)c1ccc([N+](=O)[O-])cc1OC
Yield: 77.7 %

Procedure:
In a manner analogous to the preparation of N2,N4-bis[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine, 2-methoxy-4-nitrobenzoic acid (1 g, 5 mmol), potassium carbonate (1.4 g, 10 mmol) and iodomethane (0.47 mL, 7.5 mmol) gave methyl 2-methoxy-4-nitrobenzoate (820 mg, 77%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]3[O:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=4)=[CH:16][C:10]=3[C:9]2=[O:24])=[CH:4][C:3]=1[CH3:25].[N:26]([O-])=O.[Na+]>CC(O)=O.O>[Cl:23][C:19]1[CH:18]=[C:17]([C:15]2[O:14][C:11]3[CH:12]=[CH:13][N:8]([C:5]4[CH:4]=[C:3]5[C:2](=[CH:7][CH:6]=4)[NH:1][N:26]=[CH:25]5)[C:9](=[O:24])[C:10]=3[CH:16]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cc(-n2ccc3oc(-c4cccc(Cl)c4)cc3c2=O)ccc1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1c2cc(-c3cccc(Cl)c3)oc2ccn1-c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 39 %

Procedure:
A solution of 5-(4-amino-3-methylphenyl)-2-(3-chlorophenyl)furo[3,2-c]pyridine-4(5H)-one (1.02 g, 2.91 mmol) in AcOH (23 mL) was treated with a solution of NaNO2 (0.20 g, 2.9 mmol) in H2O (0.65 mL). After stirring at ambient temperature for 12 h, the reaction mixture was concentrated. The resulting solid was partitioned in CH2Cl2 and water. Any solids were removed by filtration. The filtrate was extracted with CH2Cl2 (4×30 mL). The organics were dried (Na2SO4), filtered, recombined with the removed solids and concentrated. Purification by flash chromatography (silica gel, CH2Cl2/MeOH, 100:0 to 90:10) gave the title compound (0.409 g, 40%) as a tan solid: 1H NMR (300 MHz, DMSO-d6) δ 13.29 (s, 1H), 8.17 (m, 1H), 7.96 (t, J=1.8 Hz, 1H), 7.87-7.83 (m, 2H), 7.73-7.71 (m, 2H), 7.65 (d, J=8.7 Hz, 1H), 7.52 (t, J=8.1 Hz, 1H), 7.46-7.43 (m, 1H), 7.38 (dd, J=9.0, 2.1 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH2:13]Cl)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[CH3:15][S-:16].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH2:13][S:16][CH3:15])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: C[S-]
Reactant: COC(=O)c1cc(CCl)ccc1OC
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(CSC)ccc1OC
Temperature: 75 °C
Reaction time: 5.5 h

Procedure:
Combine methyl 2-methoxy-5-chloromethylbenzoate (5 mmol) and dimethylformamide (10 mL). Cool in an ice bath and add sodium thiomethoxide (15 mmol). Heat to 75° C. After 5.5 hours, partition the reaction mixture between water and ethyl acetate. Extract the organic layer with water, dry over Na2SO4, filter, and concentrate in vacuo to give methyl 2-methoxy-5-(methylthiomethyl)benzoate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[CH:7]=1.[F:11][C:12]([F:24])([F:23])[O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:11][C:12]([F:23])([F:24])[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[N:9][N:10]=3)[CH:7]=2)=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Brc1ccc2nncn2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(-c2ccc3nncn3c2)cc1
Temperature: 150 °C
Yield: 43 %

Procedure:
In a 5 mL vial 6-bromo-[1,2,4]triazolo[4,3-a]pyridine (93 mg), 4-trifluoromethoxyphenylboronic acid (115 mg), and potassium carbonate (187 mg) were suspended in DMF (2 mL) that was previously degassed with nitrogen. Tetrakis(triphenylphosphine) palladium (20 mg) was added and the reaction mixture was heated in a microwave reactor at 150° C. for 30 min, filtered, and concentrated. The residue was subjected to gradient chromatography (MeOH/dichloromethane) to produce white powder, 56.4 mg (43% yield).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[N:13]=[C:14]([CH2:21][CH2:22][C:23]3([CH3:28])OCC[O:24]3)[N:15]([CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1.[OH-].[Na+].ClCCl>O>[NH2:2][C:3]1[C:12]2[N:13]=[C:14]([CH2:21][CH2:22][C:23](=[O:24])[CH3:28])[N:15]([CH2:16][C:17]([OH:19])([CH3:18])[CH3:20])[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1
Reactant: CC(C)(O)Cn1c(CCC2(C)OCCO2)nc2c(N)nc3ccccc3c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)CCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.3 %

Procedure:
Concentrated hydrochloric acid (0.20 mL, 2.4 mmol) was added to a stirred suspension of 1-{4-amino-2-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol (0.30 g, 0.81 mmol) in water (5 mL). A solution resulted and was stirred at room temperature for 3 hours. The solution was adjusted to pH 13 with 20% aqueous sodium hydroxide. A gummy solid formed. Dichloromethane was added, but the solid did not dissolved. The mixture was poured into a separatory funnel, then the contents of the funnel were filtered. The white solid isolated by filtration was washed with water and dried to yield 0.17 g of 4-[4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]butan-2-one as a white powder, mp 181-184° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:5]2=[N:6][CH:7]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.C([O-])([O-])=O.[Cs+].[Cs+]>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>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:8]2[C:5]3=[N:6][CH:7]=[C:2]([C:31]4[CH:30]=[CH:29][C:28]([N:25]5[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]5)=[CH:33][CH:32]=4)[CH:3]=[C:4]3[C:10]([CH3:11])=[N:9]2)=[CH:14][CH:15]=1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: COc1ccc(Cn2nc(C)c3cc(Br)cnc32)cc1
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: [Cs+]
Solvent: COCCOC
Product: COc1ccc(Cn2nc(C)c3cc(-c4ccc(N5CCN(C)CC5)cc4)cnc32)cc1
Temperature: 80 °C

Procedure:
The starting material 5-bromo-1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine (7) (145 mg, 0.44 mmol, 1 eq) and 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (159) (135 mg, 0.44 mmol, 1 eq) in DME (10 mL) was degassed and purged under argon atmosphere for 10 min. To this reaction mixture was charged Cs2CO3 (280 mg, 0.88 mmol, 2 eq) followed by addition of Pd(PPh3)4 (15 mg, 0.01 mmol), degassing and purging under argon for additional 10 min. The reaction mixture was heated at 80° C. for 12 h in a sealed tube. After completion of the reaction, the solvents were removed and reaction mixtures were extracted into EtOAc, dried over Na2SO4 and the solvents distilled off. The crude material was submitted for flash column purification using 5% MeOH/CHCl3 to obtain off-white solid compound 1-(4-methoxybenzyl)-3-methyl-5-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridine 160 in 65 mg quantity.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)#[N:15].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:13][CH:10]2[CH2:9][CH2:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)=[CH:18][CH:17]=1)#[N:15]
Reactant: NC1CCN(c2ccccc2)CC1
Reactant: N#Cc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1ccc(CNC2CCN(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Phenylpiperidin-4-ylamine (0.50 g, 2.84 mmol) (from Example 123) and 4-cyanobenzaldehyde (0.74 g, 5.64 mmol) were dissolved in anhydrous methanol (10 mL) and acetic acid (0.97 mL, 17 mmol) was added. The mixture was stirred for 2 hrs at room temperature, then cooled to 0° C. (ice-water) and sodium cyanoborohydride (0.267 g, 4.25 mmol) was added, then the reaction mixture was stirred at room temperature for 2 hrs. The solvent was evaporated under reduced pressure and the residue was partitioned between sat. NaHCO3(aq) (50 mL) and dichloromethane (25 mL), and the organic layer was extracted. The aqueous phase was extracted with dichloromethane (2×25 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with hexane—30% ethyl acetate to give the product as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].II.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1COCC1.[Zn]>[Cl:1][CH2:2][CH2:3][C:4]([OH:5])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: O=C(CCCl)c1ccccc1
Reactant: CCOC(=O)CBr
Agent: II
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)(CCCl)c1ccccc1
Yield: 52.8 %

Procedure:
To a stirred suspension of 3-chloro-1-phenylpropan-1-one (10 g, 0.059 mol) and active Zinc power (19 g, 0.295 mol) in THF (200 mL) was added iodine (9 g, 0.035 mol), then ethyl bromoacetate (20 g, 0.118 mol) was added dropwise at rt. The formed mixture was heated to reflux for 30 min. The reaction was quenched with water, and the mixture was filtered through a celite pad. The filtrate was extracted with EtOAc. The organic phase was dried over Na2SO4, and concentrated to give the crude product, which was purified by column chromatography to afford ethyl 5-chloro-3-hydroxy-3-phenylpentanoate (8.0 g, 53%). 1H NMR (CDCl3): δ=1.02 (t, 3H), 2.13-2.28 (m, 2H), 2.73 (d, 1H), 2.90 (d, 1H), 3.11 (1, 2H), 3.54 (m, 1H), 3.94 (q, 2H), 7.18 (m, 1H), 7.29 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6](C=C[CH:9]=[C:10]2[CH2:13][O:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.C[O:20]C1C=CC2OC=C(CON)C=2C=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:20][CH:9]=[C:10]([CH2:13][O:14][NH:15][C:16](=[O:18])[CH3:17])[C:11]=2[CH:12]=1
Reactant: COc1ccc2occ(CON)c2c1
Reactant: COc1ccc2cccc(CONC(C)=O)c2c1
Product: COc1ccc2occ(CONC(C)=O)c2c1

Procedure:
By carrying out the procedure in the same manner as for the synthesis of the compound of Example 1, but replacing O-[(7-methoxynaphth-1-yl)methyl]hydroxylamine with O-[(5-methoxybenzofuran-3-yl)methyl]hydroxylamine (preparation 9), the title compound is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:49])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH2:41][O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)[CH:36]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:49])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH2:41][O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)[CH:36]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(COC3CCCCO3)c2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(COC3CCCCO3)c2)c1

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J19) (311 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionic acid tert-butyl ester (Example K40) (412 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow solid (550 mg, 85%).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:23])[CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([CH2:18][CH2:19][CH2:20][OH:21])=[C:13]([CH3:22])[CH:12]=2)=[C:5]2[CH2:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH2:27][C:4]=12)[CH3:2].CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:23])[CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([CH2:18][CH2:19][CH2:20][O:21][S:40]([CH3:39])(=[O:42])=[O:41])=[C:13]([CH3:22])[CH:12]=2)=[C:5]2[CH2:24][CH2:25][C:26]([CH3:28])([CH3:29])[CH2:27][C:4]=12)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1sc(C(=O)CCc2cc(C)c(CCCO)c(C)c2)c2c1CC(C)(C)CC2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1sc(C(=O)CCc2cc(C)c(CCCOS(C)(=O)=O)c(C)c2)c2c1CC(C)(C)CC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 102.5 %

Procedure:
A solution of 1-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-[4-(3-hydroxy-propyl)-3,5-dimethyl-phenyl]-propan-1-one (135 mg, 0.328 mmol, Example 335) in DCM is treated with DIPEA (70 mg, 0.525 mmol) followed by methanesulfonylchloride (45 mg, 0.394 mmol). The mixture is stirred at rt for 1.5 h before it is diluted with DCM and washed with 0.5 M aq. citric acid solution followed by brine. The organic extract is dried over MgSO4, filtered and the solvent of the filtrate is evaporated to give methanesulfonic acid 3-{4-[3-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-oxo-propyl]-2,6-dimethyl-phenyl}-propyl ester (165 mg) as a yellow resin; LC-MS: tR=1.20 min, [M+1]+=491.36.