Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([NH:17][C:18]([N:20]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3[CH:27]=[C:28]([OH:31])[CH:29]=[CH:30][C:21]2=3)=[O:19])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1.[NH2:34][C:35]1[N:40]=[C:39](Cl)[CH:38]=[C:37]([Cl:42])[N:36]=1.[OH-].[Na+].CCOC(C)=O>CC(C)=O.O.CN1C(=O)N(C)CC1>[F:33][C:2]([F:32])([F:1])[C:3]1[CH:4]=[C:5]([NH:17][C:18]([N:20]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3[CH:27]=[C:28]([O:31][C:39]4[CH:38]=[C:37]([Cl:42])[N:36]=[C:35]([NH2:34])[N:40]=4)[CH:29]=[CH:30][C:21]2=3)=[O:19])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]1
Reactant: CN1CCN(Cc2ccc(NC(=O)N3CCCCc4cc(O)ccc43)cc2C(F)(F)F)CC1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CN1CCN(Cc2ccc(NC(=O)N3CCCCc4cc(Oc5cc(Cl)nc(N)n5)ccc43)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
A mixture of 300 mg (0.65 mMol) of 7-hydroxy-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid [3-trifluoromethyl-4-(4-methylpiperazin-1-ylmethyl)-phenyl]-amide (Step 12.2), 106 mg (0.65 mMol) 2-amino-4,6-dichloro-pyrimidine and 26 mg (0.65 mMol) NaOH in 2 ml acetone, 2 ml H2O and 1.2 ml DMEU is stirred at 60° C. for 12 h. Then the suspension is dissolved by addition of water and EtOAc, the aqueous phase separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Reversed phase MPLC (Gilson system) gives the title compound: MS: [M+1]+=590/592; HPLC: AtRet=12.7.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2[N:9]([CH2:13][C:14]3[N:19]=[CH:18][N:17]4[N:20]=[C:21]([OH:23])[N:22]=[C:16]4[C:15]=3[CH2:24][CH2:25][CH3:26])[CH:10]=[CH:11][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:34]([CH3:36])[CH3:35].O>CN(C=O)C>[F:1][C:2]1[C:3]([C:8]2[N:9]([CH2:13][C:14]3[N:19]=[CH:18][N:17]4[N:20]=[C:21]([O:23][CH:34]([CH3:36])[CH3:35])[N:22]=[C:16]4[C:15]=3[CH2:24][CH2:25][CH3:26])[CH:10]=[CH:11][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1c(Cn2ccnc2-c2ncccc2F)ncn2nc(O)nc12
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(Cn2ccnc2-c2ncccc2F)ncn2nc(OC(C)C)nc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To the solution of compound 177 in DMF (10 mL) is added anhydrous potassium carbonate (2 eq.) and 2-iodopropane (2 eq.). The resulting mixture is stirred at 60° C. overnight. On cooling the reaction mixture is poured into water (50 mL) and the mixture extracted with dichloromethane, dried over sodium sulfate. The organic solution is concentrated and purified with PTLC to give product 176 as sticky oil. LCMS (M+1) 396.3.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[S:25]([C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1)(=[O:28])(=[O:27])[NH2:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:32]4[CH:33]=[CH:34][C:29]([S:25](=[O:28])(=[O:27])[NH2:26])=[CH:30][CH:31]=4)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Reactant: O=C(NC1CC1)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Product: NS(=O)(=O)c1ccc(-c2cccc(-n3cc(C(=O)NC4CC4)c(=O)c4cccnc43)c2)cc1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A mixture of N-cyclopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide, boronate from Step 1 (1.2 eq), palladium acetate (0.1 eq), triphenylphosphine (0.35 eq) and 2M aqueous sodium carbonate (3.5 eq) in n-propanol (10 ml/mmol) was stirred at 85° C. for 1 hour. After cooling, the mixture was quenched with saturated aqueous ammonium chloride solution and partitioned between ethyl acetate and water, and the product from the organic phase was chromatographed on silica gel eluting with a 1:5:4 mixture of ethanol, ethyl acetate and methylene chloride to afford the N-Cyclopropyl-1-[3-(4-sulfamoylphenyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide compound as a solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].[CH:26]([NH2:29])([CH3:28])[CH3:27].O>C(O)C>[CH:26]([NH:29][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18])([CH3:28])[CH3:27]
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: CC(C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)Nc1ccc(-c2nc3ccccc3o2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 98.6 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (200 mg, 0.774 mmol) in ethanol (5 mL) was added potassium carbonate (214 mg, 1.55 mmol) and isopropylamine (137 mg, 2.32 mmol), and this was heated to reflux for 4 hours. After the reaction was complete, this was cooled to room temperature, water was added, and after the precipitated crystals were filtered and washed with water, they were dried to yield the title compound (227 mg, 99% yield).
Reaction SMILES: [C:1]([NH:5][C:6]([C@@H:8]1[CH2:12][S:11][CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:13]([O:20][C:21]([NH:23][C@@H:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@@H:25]1[O:27][CH2:26]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(C)C>[CH2:13]([O:20][C:21]([NH:23][C@@H:24]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C@H:25]([OH:27])[CH2:26][N:9]1[C@H:8]([C:6]([NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12][S:11][CH2:10]1)=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H]1CO1)OCc1ccccc1
Reactant: CC(C)(C)NC(=O)[C@@H]1CSCN1
Solvent: CC(C)O
Product: CC(C)(C)NC(=O)[C@@H]1CSCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 90 °C
Yield: 42.5 %

Procedure:
A solution of 3.2 g of N-tert.butyl-4(R)-thiazolidinecarboxamide and 5.0 g of 3(S)-(benzyloxyformamido)-1,2(S)-epoxy-4-phenylbutane in 130 ml of isopropanol was stirred under argon and heated at 90° C. under reflux for 3 days. The solution was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel using diethyl ethyl/n-hexane (2:1) for the elution. There were obtained 3.47 g of 3-[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-4(R)-thiazolidinecarboxamide. Recrystallization from ethyl acetate gave analytically pure material of melting point 62°-65° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@H:5]([OH:11])[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>>[CH3:1][NH:2][CH2:3][CH2:4][C@H:5]([O:11][C:20]1[C:21]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][CH:19]=1)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1
Reactant: CNCC[C@H](O)c1cccs1
Reactant: c1ccc2ccccc2c1
Product: CNCC[C@H](Oc1cccc2ccccc12)c1cccs1

Procedure:
contacting the (S)—N-methyl-3-hydroxy-3-(2-thienyl)-1-propanamine with an activated naphthalene in a reaction mixture under conditions sufficient to produce (3S)—N-methyl-3-naphthalen-1-yloxy-3-thiophen-2-yl-propan-1 amine (Duloxetine) having the structure of formula (VIII); and (d) recovering the (3S)—N-methyl-3-naphthalen-1-yloxy-3-thiophen-2-yl-propan-1-amine from the reaction mixture.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.ClCCCl.C(O)(=O)/C=C\C(O)=O.[NH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[N:32]=[CH:31]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(=O)(O)[O-].[Na+]>[C:37]([N:33]1[C:34]2[C:30](=[CH:29][C:28]([NH:27][CH:2]3[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]3)=[CH:36][CH:35]=2)[CH:31]=[N:32]1)(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)C(=O)n1ncc2cc(N)ccc21
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCCC(Nc2ccc3c(cnn3C(=O)C(C)(C)C)c2)C1
Temperature: 20 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
Into a 1 L 3-neck round bottom flask fitted with a nitrogen inlet and mechanical stirrer was added tert-butyl 3-oxopiperidine-1-carboxylate (14.2 g, 0.07 mol), 1,2-dichloroethane (300 mL), and 1-(5-amino-1H-indazol-1-yl)-2,2-dimethylpropan-1-one maleate salt (23.0 g, 0.07 mol). The vessel was purged with nitrogen and stirred at 20° C. for one hour. Sodium triacetoxyborohydride (19.0 g, 0.09 mol) was added, and the reaction was monitored by analytical TLC to completion. The reaction was diluted with 100 mL of saturated sodium bicarbonate. The organic phase was isolated, dried over MgSO4, filtered and evaporated to dryness to afford the title compound as a yellow solid (25.0 g, 91%).
Reaction SMILES: [CH3:1][N:2]1[C:17](=[O:18])[C:16]2[C:15]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:8][C:7]=3[C:6]3[NH:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:5]=3[C:4]=2[C:3]1=[O:26].[C:27]([NH2:31])(=[O:30])[CH:28]=[CH2:29].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:27]([CH2:28][CH2:29][N:19]1[C:6]2[C:7]3[NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:15]=3[C:16]3[C:17](=[O:18])[N:2]([CH3:1])[C:3](=[O:26])[C:4]=3[C:5]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)(=[O:30])[NH2:31]
Reactant: CN1C(=O)c2c(c3c4ccccc4[nH]c3c3[nH]c4ccccc4c23)C1=O
Reactant: C=CC(N)=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CN1C(=O)c2c(c3c4ccccc4n(CCC(N)=O)c3c3[nH]c4ccccc4c23)C1=O

Procedure:
500 mg (1.47 mmol) 6,7,12,13-tetrahydro-6-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole in 50 ml acetonitrile are stirred for 4 days at 20° C. with 1.05 g (14.8 mmol) acrylamide and 0.1 ml DBU. The suspension is evaporated, stirred with 30 ml dichloromethane/methanol (95:5 v/v) and the undissolved crystals are filtered off. 12-(2-carbamoylethyl)-6,7,12,13-tetrahydro-6-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo-[3,4-c]carbazole is obtained in the form of yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]1[C:16]([CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:15][CH:14]=[C:13]([C:24]3[C:25]([N:44]([CH3:49])[S:45]([CH3:48])(=[O:47])=[O:46])=[CH:26][C:27]4[O:31][C:30]([C:32]5[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=5)=[C:29]([C:39](=[O:42])[NH:40][CH3:41])[C:28]=4[CH:43]=3)[N:12]=1)[NH:6]2.O.[OH-].[Li+].CO.Cl>C1COCC1.CCOC(C)=O.O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]1[C:16]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:14]=[C:13]([C:24]3[C:25]([N:44]([CH3:49])[S:45]([CH3:48])(=[O:46])=[O:47])=[CH:26][C:27]4[O:31][C:30]([C:32]5[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=5)=[C:29]([C:39](=[O:42])[NH:40][CH3:41])[C:28]=4[CH:43]=3)[N:12]=1)[NH:6]2
Reactant: CCOC(=O)CCc1ccc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2N(C)S(C)(=O)=O)nc1-c1cc2c(F)cccc2[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(CCC(=O)O)c(-c4cc5c(F)cccc5[nH]4)n3)cc12

Procedure:
A mixture of ethyl 3-(2-(4-fluoro-1H-indol-2-yl)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)pyridin-3-yl)propanoate (91 mg, 0.133 mmol) and lithium hydroxide monohydrate (27.8 mg, 0.663 mmol) were suspended in THF (0.53 mL), MeOH (0.27 mL), and H2O (0.2 mL). The resultant mixture was stirred at ambient temperature overnight then cooled in an ice bath and acidified to pH 2 with 1 N HCl. The mixture was then diluted with EtOAc and H2O, separated into layers and the aqueous layer extracted with EtOAc (2×). The combined organic layers were washed with brine (4×) until last brine wash was pH 7 then were dried over MgSO4, filtered, and concentrated in vacuo. The resulting product was azeotroped from CH3CN (4×) and used as a tan solid without further purification. MS (M+H)+: 659.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.C(OC(N1CCC(=O)CC1)=O)(C)(C)C.C(N)C1C=CC=CC=1.[O-]S([O-])(=O)=O.[Mg+2].COC1C=CC(C=C[N+]([O-])=O)=CC=1>C1(C)C=CC=CC=1.O.[Sn](CCCC)(CCCC)(Cl)Cl>[CH2:25]([N:14]1[C:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]=2[C:16]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[CH:15]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1ccc(-c2cn(Cc3ccccc3)c3c2CN(C(=O)OC(C)(C)C)CC3)cc1
Agent: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: COc1ccc(C=C[N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: NCc1ccccc1
Product: COc1ccc(-c2cn(Cc3ccccc3)c3c2CNCC3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Benzyl-3-(4-methoxy-phenyl)-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester. To a solution of 0.50 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester and 260 μL of benzylamine in toluene (5 mL) was added 0.48 g of MgSO4 and 16.7 mg of Bu2SnCl2. After 1 h, 0.45 g of 1-methoxy-4-(2-nitro-vinyl)-benzene was added and the mixture was stirred for 16 h at RT. The mixture was then diluted with water (80 mL) and extracted with EtOAc (3×15 mL) and the combined organic layers were concentrated in vacuo. Chromatography on SiO2 (1 to 20% EtOAc/hexanes) afforded 0.38 g of the desired compound. MS (ESI): exact mass calculated for C26H30N2O3, 418.23; found, m/z 419.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH2:14][CH3:15].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[F:35][C:36]([F:46])([F:45])[C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Br)=[CH:39][CH:38]=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:41][C:40]2[CH:39]=[CH:38][C:37]([C:36]([F:35])([F:45])[F:46])=[CH:44][CH:43]=2)[C:6]=1[CH2:14][CH3:15]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCc1[nH]c2ncccc2c1CC(=O)OC
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(CC(=O)OC)c2cccnc2n1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To an ice-cooled stirring solution of (2-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (80 mg, 0.37 mmol) in DMF (1 ml) is added BEMP (171 μl, 0.59 mmol). The solution is stirred at room temperature for 40 minutes and then re-cooled. 4-(Trifluoromethyl)benzyl bromide ((91 μl, 0.59 mmol) is added and stirring continues while the reaction mixture gradually warmed up to room temperature overnight. The resulting mixture is poured into water (30 ml) and extracted with 1:1 EtOAc/ether. The organic layer is washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue is loaded on a pre-packed Isolute™ silica column and eluted with DCM to yield the titled compound as a pale yellow oil. (MH+ 377)
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[CH2:14][C:13]([C:16]([Cl:19])([Cl:18])[Cl:17])(O)[N:12]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(OC)C(C)C>[CH2:1]([O:8][CH2:9][C:10]1[CH:14]=[C:13]([C:16]([Cl:18])([Cl:19])[Cl:17])[N:12]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1(C(Cl)(Cl)Cl)CC(COCc2ccccc2)=NN1c1ncccc1Cl
Agent: COCC(C)C
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Clc1cccnc1-n1nc(COCc2ccccc2)cc1C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
4.35 g of 3-[(benzyloxy)methyl]-1-(3-chloropyridin-2-yl)-5-(trichloromethyl)-4,5-dihydro-1H-pyrazol-5-ol were dissolved in 30 ml of methyl isobutyl ether. Then 3 g of trifluoroacetic anhydride were added (exothermic reaction). The mixture was stirred at 25° C. for a further 2 h, in the course of which the precipitate was formed. The precipitate was filtered off and washed. The yield was 95%.
Reaction SMILES: [K].[SH:2][C:3]1[N:4]([CH3:13])[C:5](=[O:12])[C:6]2[CH:11]=[N:10][NH:9][C:7]=2[N:8]=1.[Cl:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1>CN(C=O)C.O>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25][S:2][C:3]3[N:4]([CH3:13])[C:5](=[O:12])[C:6]4[CH:11]=[N:10][NH:9][C:7]=4[N:8]=3)=[CH:23][CH:22]=2)=[O:20])=[CH:29][CH:30]=1
Reactant: Cn1c(S)nc2[nH]ncc2c1=O
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(SCc2ccc(C(=O)c3ccc(Cl)cc3)cc2)nc2[nH]ncc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a solution of 6-mercapto-5-methyl-1H-pyrazolo-[3,4-d]pyrimidin-4(5H)-one potassium (1.0 g) in DMF (10 ml) was added 4-(4-chlorobenzoyl)benzyl bromide (1.393 g) and the mixture was stirred at room temperature for 1 hour. This reaction mixture was poured in water and the resulting crystals were collected by filtration, rinsed with water and methanol, and recrystallized from methanol to provide the title compound as colorless solid (1.647 g). 1H-NMR (DMSO-d6) δ: 3.53(3H,s), 4.58(2H,s), 7.50(2H,t,J=8.6Hz),,7.65(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 7.74(2H,d,J=8.6Hz), 7.79(1H,s).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([CH:9]2[CH2:14][CH2:13][CH:12]([CH:15]3[CH2:20][CH2:19][C:18](=[O:21])[CH:17]=[CH:16]3)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)[CH3:2].[Cl-].[NH4+]>C1COCC1>[CH2:1]([C@H:3]1[CH2:4][CH2:5][C@H:6]([CH:9]2[CH2:14][CH2:13][CH:12]([CH:15]3[CH2:20][CH2:19][C:18]([CH2:2][CH2:1][CH2:3][CH2:4][CH3:5])([OH:21])[CH:17]=[CH:16]3)[CH2:11][CH2:10]2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CC[C@H]1CC[C@H](C2CCC(C3C=CC(=O)CC3)CC2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCC1(O)C=CC(C2CCC([C@H]3CC[C@H](CC)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, 4.0 g of 4-(4-(trans-4-ethylcyclohexyl)cyclohexyl)-2-cyclohexenone (r-7) was dissolved into 50 mL of THF, 16.8 mL of pentylmagnesium bromide THF solution (1 M/L) was added dropwise thereto at room temperature, and the resultant mixture was stirred at 50° C. for 30 minutes, and then stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added dropwise under ice-cooling, the resultant mixture was subjected to extraction with ethyl acetate, and then organic layers were combined, the resultant organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. A solvent was evaporated under reduced pressure, and the resultant residue was purified by fractionation on silica gel column chromatography (eluate:heptane:ethyl acetate=7:3 (in a volume ratio)), and thus 3.83 g of 4-(4-(trans-4-ethylcyclohexyl)cyclohexyl)-1-pentyl-2-cyclohexene-1-ol (compound (r-6)) was obtained.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2C=CC(O)=CC=2)(C)[CH3:9])=[CH:4][CH:3]=1.[OH-].[Na+].C1([OH:26])C=CC=CC=1>[Hg]>[C:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[OH:26])([CH3:11])=[CH2:9]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: Oc1ccccc1
Agent: [Hg]
Agent: [Na+]
Agent: [OH-]
Product: C=C(C)c1ccccc1O
Reaction time: 0.83 h

Procedure:
A distillation flask equipped with a Vigreux column was charged with 70.0 g. (0.31 mole) of bisphenol A [2,2-bis(p-hydroxyphenyl)propane] and 0.2 g. of sodium hydroxide. The bisphenol A was pyrolyzed under reduced pressure at a bath temperature of 200° C. to 270° C. Over a period of about 50 minutes and under 10 mm. of pressure (mercury) a distillate of 68.1 g. of a mixture of phenol and isopropenylphenol was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:20]=[N:21][C:22](Cl)=[CH:23][C:24]=2[C:25]2[CH:26]=[N:27][NH:28][CH:29]=2)=[CH:4][C:5]([F:17])=[C:6]([S:8]([NH:11][C:12]2[N:13]=[CH:14][S:15][CH:16]=2)(=[O:10])=[O:9])[CH:7]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[F:38].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.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>[Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:20]=[N:21][C:22]([C:35]3[CH:34]=[CH:33][C:32]([F:31])=[C:37]([F:38])[CH:36]=3)=[CH:23][C:24]=2[C:25]2[CH:29]=[N:28][NH:27][CH:26]=2)=[CH:4][C:5]([F:17])=[C:6]([S:8]([NH:11][C:12]2[N:13]=[CH:14][S:15][CH:16]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: O=S(=O)(Nc1cscn1)c1cc(Cl)c(Oc2cnc(Cl)cc2-c2cn[nH]c2)cc1F
Reactant: OB(O)c1ccc(F)c(F)c1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cscn1)c1cc(Cl)c(Oc2cnc(-c3ccc(F)c(F)c3)cc2-c2cn[nH]c2)cc1F
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
15.0 mg (0.03 mmol) of 5-chloro-4-((6-chloro-4-(1H-pyrazol-4-yl)pyridin-3-yl)oxy)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide was dissolved in 1.5 mL of 1,4-dioxane, and 7.1 mg (0.05 mmol) of (3,4-difluorophenyl)boronic acid was added thereto, and then 3.5 mg (10 mol %) of Pd(PPh3)4, 12.4 mg (0.09 mmol) of K2CO3, and 0.3 mL of H2O were added thereto. After reacting with microwave reactor at 150° C. for 30 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, dimethylchloride:methanol=20:1) to obtain 9.0 mg (31.9% yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[N:20](CC3C=CC=CC=3)[N:21]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=3)[CH:23]=2)[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(O)=O>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=3)[NH:21][N:20]=2)[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN(C)CCCOc2cc(-c3ccc(OC)c(OC)c3)nn2Cc2ccccc2)cc1OC
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: COc1ccc(CCN(C)CCCOc2cc(-c3ccc(OC)c(OC)c3)[nH]n2)cc1OC
Yield: 95.8 %

Procedure:
2 g of 3-{3-[N-(2-(3,4-Dimethoxyphenyl)-ethyl)-N-methylamino]-propyloxy}-5-(3,4-dimethoxyphenyl)-2-benzylpyrazole prepared according to Example 13 were dissolved in 10 ml of methanol and added to 2 g of palladium black under nitrogen. 5.5 ml of 98% strength formic acid were added to the solution, which was stirred under nitrogen. After the mixture had been stirred for 3 hours under nitrogen the catalyst was filtered out, and the filtrate was concentrated by evaporation. The oily residue was taken up in saturated sodium carbonate solution and extracted repeatedly with ethyl acetate. The combined organic phases were dried with sodium sulfate and concentrated by evaporation. 1.6 g of 3-{3-[N-(2-(3,4-Dimethoxyphenyl)-ethyl)-N-methylamino]-propyloxy}-5-(3,4-dimethoxyphenyl)-pyrazole were obtained as an oily base. This base was converted analogously to Example 1 E) into the hydrochloride having a melting point of 189° to 192° C.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:11]([N:14]1[CH2:16][CH2:15]1)(=[O:13])[CH3:12]>CO>[C:11]([NH:14][CH2:15][CH2:16][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)(=[O:13])[CH3:12]
Reactant: CC(=O)N1CC1
Reactant: c1ccc2c(c1)CCCN2
Solvent: CO
Product: CC(=O)NCCN1CCCc2ccccc21

Procedure:
13.3 g. (0.1 mol) 1,2,3,4-tetrahydroquinoline and 9.4 g. (0.11 mol) acetylaziridine were boiled overnight under reflux in 200 ml. anhydrous methanol. After evaporating in a rotary evaporator, the mixture obtained of unreacted starting material and reaction product (13 g.) was purified by column chromatography on silica gel (elution agent: chloroform/acetone=4/1 v/v; m.p. 102° C.