Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[S:14][C:13]3[CH:15]=[C:16]([O:19]C)[CH:17]=[CH:18][C:12]=3[C:11]=2[C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:25][CH:24]=2)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8]C.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[S:14][C:13]3[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:12]=3[C:11]=2[C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:25][CH:24]=2)=[O:22])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(OC)c(F)c3)sc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)c(F)c2)sc2cc(O)ccc12
Yield: 39.1 %

Procedure:
A solution of the product of Example 1 (0.65 g, 1.25 mmol), ethanethiol (0.46 mL, 6.32 mmol), and aluminum chloride (1.17 g, 8.78 mmol) in anhydrous CH2Cl2 (20 mL) was stirred for 3.5 h. The mixture was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicaronate and brine, dried (sodium sulfate), and concentrated. The residue was purified by chromatography (silica gel, 5-10% MeOH in CH2Cl2) and crystallized from MeOH/CH2Cl2 to give 240 mg (39%) of the title product as a yellow solid: 1H NMR (MeOD-d4) d 1.62 (m, 2H), 1.80 (m, 4H), 3.11 (m, 4H), 3.34 (t, J=6.0 Hz, 2H), 4.32 (t, J=6.0 Hz, 2H), 4.86 (br s, 2H), 6.75 t, J=8.6 Hz, 1H), 6.88 (dd, J=2.2 Hz, 8.8 Hz, 1H), 6.92 (d, J=8.8 Hz, 2H), 6.97-7.06 (m, 3H), 7.27 (d, J=2.2 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.73 (d, J=8.8 Hz, 2H); 13C NMR (DMSO-d6) d 21.8, 23.1, 53.0, 63.4, 107.1, 114.6, 115.4, 115.7, 116.0, 118.1, 123.4, 124.2, 125.0, 130.0, 130.4, 131.8, 131.9, 138.9, 139.3, 145.3, 145.5, 148.9, 152.1, 155.7, 162.0, 192.3; MS (FD) m/e 492 (MH+); Anal. calc'd. for C28H26FNO4S.0.75 H2O: C, 66.57; H, 5.65; N, 2.77. Found: C, 66.68; H, 5.78; N, 2.74.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH:8]=2)[CH2:3][CH2:2]1.C[O:23][C:24](=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Br)[CH:26]=1>>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[CH2:16][N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH:4]2[CH2:5][CH2:6][N:1]([CH2:31][C:27]3[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=3)[C:24]([OH:33])=[O:23])[CH2:2][CH2:3]2)=[CH:8]1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: c1csc(Cn2cc(C3CCNCC3)c3ccccc32)c1
Product: O=C(O)c1cccc(CN2CCC(c3cn(Cc4cccs4)c4ccccc34)CC2)c1
Yield: 176.2 %

Procedure:
This compound was prepared following the procedure described in example 13 (part D), starting with 4.35 mmol (15 mmol) of 3-piperidin-4-yl-1-thiophen-2-ylmethyl-1H-indole and 4.58 g (20 mmol) of 3-bromomethyl-benzoic acid methyl ester. After the standard work-up, 3.3 g of the corresponding acid was obtained. The crude mixture was purified by flash chromatography over silica gel affording 0.64 g (10% of yield) of the pure acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[C:8]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](O)=[O:11].[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[C:8]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:11]
Reactant: COc1c(C)c(Cc2cccc(C(=O)O)c2-c2cccnc2)c(OC)c(OC)c1OC
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1c(C)c(Cc2cccc(C(=O)N3CCCCC3)c2-c2cccnc2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.2 %

Procedure:
3-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-pyridyl)benzoic acid (21 mg, 0.0496 mmol) and piperidine (8.4 mg, 0.0988 mmol) were dissolved in methylene chloride (3 ml), then WSC-HCl (29 mg, 0.1512 mmol) was added thereto and the mixture was stirred at room temperature for 16 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=95:5) to give the title compound (11 mg, 0.0224 mmol, 45%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([CH:12]([F:14])[F:13])=[CH:10][C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[N:8][C:7]=12)#[CH:2].[OH:25][CH2:26][CH2:27][N:28]([CH2:38][CH2:39][OH:40])[S:29]([C:32]1[S:33][C:34](Br)=[CH:35][CH:36]=1)(=[O:31])=[O:30]>>[OH:25][CH2:26][CH2:27][N:28]([CH2:38][CH2:39][OH:40])[S:29]([C:32]1[S:33][C:34]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([CH:12]([F:14])[F:13])=[CH:10][C:9]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=4)=[N:8][C:7]=23)=[CH:35][CH:36]=1)(=[O:31])=[O:30]
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Reactant: O=S(=O)(c1ccc(Br)s1)N(CCO)CCO
Product: O=S(=O)(c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)s1)N(CCO)CCO

Procedure:
The title compound was prepared from 3-ethynyl-7-difluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.15) (169 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid bis-(2-hydroxy-ethyl)-amide (example B.53) (165 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (210 mg, 72%). MS (ISP) 587.1 [(M+H)+]; mp 174° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl.[NH2:23][OH:24]>CCO>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[N:23][OH:24])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC1CN(Cc2ccccc2)CCC1=NO

Procedure:
To a solution of 1-benzyl-3-methyl-piperidin-4-one (2.04 g, 10 mmol) in EtOH (20 mL), was added pyridine (20 mL, 0.25 mol) and hydroxylamine hydrochloride (0.70 g, 10 mmol). After being stirred at 90+ C. overnight, the resultant solution was concentrated in vacuo to give the crude product 1-benzyl-3-methyl-piperidin-4-one oxime. LC/MS m/z: 219 (M+H)+. This material was used without further purification.
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].Br[CH2:12][CH2:13][Cl:14]>>[Cl:14][CH2:13][CH2:12][C:3]([CH2:9][CH3:10])([CH2:1][CH3:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(CC)CC
Reactant: ClCCBr
Product: CCOC(=O)C(CC)(CC)CCCl

Procedure:
Using ethyl 2-ethylbutyrate and 1-bromo-2-chloroethane, the title compound was produced in the same manner as in Reference Example 6.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([I:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[I-].[K+].[OH-].[K+].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CS(C)=O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([I:15])=[CH:9][CH:10]=3)[C:5]([CH2:13][CH2:14][CH2:2][CH2:3][CH2:4][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8])([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)Cc1cc(I)ccc1-2
Reactant: CCCCCCCCCCBr
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(Br)ccc2-c2ccc(I)cc21
Reaction time: 24 h
Yield: 81 %

Procedure:
To a mechanically stirred mixture of 7-iodo-2-bromofluorene (from example 2; 41.34 g, 0.1114 mol), DMSO (100 mL), potassium iodide (1.7 g), and powdered potassium hydroxide (28 g) cooled in a cold water bath, 1-bromodecane (53 mL) was added dropwise, and the mixture was stirred for 24 hours. The oil that separated on dilution with water, was extracted with toluene. Toluene extract was washed with water, dried and concentrated. The residual oil was passed through a column of 300 g alumina. Elution with 900 mL hexanes gave the product as an oil, 65 g This was left in 200 mL of isopropanol, when the product solidified, 58.63 g (81% yield), m.p. 43-45° C. Mass Spec.: m/z 698 (M+ diiodo), 650,652 (M+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N+:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)([O-:7])=[O:6].[C:17]1([CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>C(=S)=S.O>[CH3:23][C:17]1[CH:22]=[CH:21][C:20]([C:12]([C:11]2[CH:15]=[CH:16][C:8]([N+:5]([O-:7])=[O:6])=[CH:9][CH:10]=2)=[O:13])=[CH:19][CH:18]=1
Reactant: Cc1ccccc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: O
Product: Cc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Aluminum chloride (9.3 g) was added in a single portion to a mixture of 4-nitrobenzoyl chloride (10 g) and toluene (6.3 mL) dissolved in carbon disulfide (35 mL). The mixture was warmed from room temperature to reflux and heated for 3 hours. Concentrated hydrochloric acid (19 mL) was slowly added, and the mixture stirred for an additional 30 minutes, poured into water, and extracted with dichloromethane (3×). The extract was washed with dilute ammonium hydroxide and water, dried (Na2SO4), and evaporated. Recrystallization from ethyl acetate gave 4-(4-methylbenzoyl)-nitrobenzene (10.6 g, 82%) as a pale yellow solid, m.p. 122.4-123.1° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:1][N:2]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[S:20]([CH3:19])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CNc1ccc(C(=O)OC)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(N(C)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 mg of methyl 4-(methylamino)benzoate was cooled to 0° C. in DCM with 270 μL of Pyridine before 260 μL Methanesulfonyl Chloride was added dropwise. Reaction was allowed to warm to room temperature and stir overnight. Solvent was concentrated and the crude material was dissolved in Ethyl Acetate and extracted with 0.1N NaOH solution twice. Crude material was dried over Magnesium Sulfate, filtered and concentrated to give methyl 4-(N-methylmethylsulfonamido)benzoate. 698 mg of methyl 4-(N-methylmethylsulfonamido)benzoate was hydrolyzed via Procedure M to give 4-(N-methylmethylsulfonamido)benzoic acid. 100 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(N-methylmethylsulfonamido)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield pure N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-methylmethylsulfonamido)benzamide. MS (Q1) 416.3 (M)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl.N1C=CC=CC=1>[CH3:14][S:15]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1)(=[O:17])=[O:16]
Reactant: COC(=O)CCc1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CCc1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 3-(4-aminophenyl)propanoate (250 mg, 1.39 mmol) was dissolved in DCM (2 ml) and pyridine (500 μl), then methanesulfonyl chloride was added (191 mg, 1.67 mmol), and the mixture was stirred at RT for 2 hours. The reaction was diluted with DCM, and the organic phase was washed with HCl 1N (2×) and brine, dried over Na2SO4 and evaporated under vacuum to give 250 mg of the desired product.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[C:10](Cl)(=[O:13])[CH2:11][CH3:12].Cl>ClCCl.N1C=CC=CC=1>[C:10]([O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])(=[O:13])[CH2:11][CH3:12]
Reactant: CCC(=O)Cl
Reactant: Oc1cccc(F)c1F
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)Oc1cccc(F)c1F
Reaction time: 2 h
Yield: 105.2 %

Procedure:
20 g (153.7 mmol) of 2,3-difluorophenol in 150 ml of dichloromethane and 17.5 ml of pyridine are admixed dropwise at 0° C. with 14 ml (161 mmol) of propionyl chloride. The mixture is stirred for two hours and 100 ml of 2 M hydrochloric acid are added. The mixture is extracted with dichloromethane and the extracts are washed with water. Drying over sodium sulphate and the removal of the solvent in vacuo give 30.1 g of 2,3-difluorophenyl propionate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:15]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH3:15])=[CH:6][CH:7]=1
Reactant: CI
Reactant: OCCCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCCc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
3-(4-Bromo-phenyl)-propan-1-ol (2.60 g, obtained in example 130, step 1) was dissolved in THF (35 mL). The mixture was cooled to 0° C. and sodium hydride (60% in mineral oil, 967 mg) was added in four portions to the cold mixture. Stirring was continued at 0° C. for 1 hour. Then, iodomethane (1.13 mL) was added dropwise over a period of 15 minutes to the reaction mixture. The mixture was warmed to room temperature over a period of 1 hour. The reaction mixture was poured into ice/water and was extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a light yellow liquid (2.61 g, 94%). MS (EI): 229.0 [M−].
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].[C:14](Cl)(=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1>>[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[C:9]=1[C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: CCCCc1cc2ccccc2o1
Product: CCCCc1oc2ccccc2c1C(=O)c1cccc(OC)c1

Procedure:
Acylation of 9.4 g. (0.054 mol.) of 2-n-butylbenzofuran with 9.9 g. (0.058 mol.) of m-anisoyl chloride according to the procedure described in Example 10 gave 2-n-butyl-3-(3'-methoxybenzoyl)benzofuran.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19]>ClCCl>[N+:18]([C:9]1[CH:10]=[C:11]([C:14]([F:15])([F:16])[F:17])[CH:12]=[CH:13][C:8]=1[CH2:7][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([O-:20])=[O:19]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1CCl
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1CN1CCCC1
Temperature: 20 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
0.35 cm3 (4.174 mmol) of pyrrolidine is added, at a temperature in the region of 20° C., under an argon atmosphere, to 0.5 g (2.087 mmol) of 1-chloromethyl-2-nitro-4-trifluoromethylbenzene in solution in 20 cm3 of dichloromethane. After stirring for 16 hours at a temperature in the region of 20° C., the reaction mixture is diluted with 250 cm3 of dichloromethane, washed with 3 times 200 cm3 of water, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (2.7 kPa), to give 458 mg of 1-(2-nitro-4-trifluoromethylbenzyl)pyrrolidine in the form of an oil;
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCBr
Reactant: CCOC(=O)c1ccc(O)cc1
Product: CCCCCCCOc1ccc(C(=O)O)cc1

Procedure:
Using ethyl p-hydroxybenzoate (33.3 g, 0.20 mol) and n-heptyl bromide (39.4 g, 0.22 mol), the reaction was carried out in the same manner as described in Example 21, (1), and then recrystallized from ethanol to give the title compound as a white microneedles; yield: 19.0 g (40.2%); mp 86.2°-90.3° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10](O)=[O:11])=[C:5]([CH3:16])[N:4]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH:25][C:26]([NH:28][S:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)(=[O:31])=[O:30])=[O:27])=[CH:19][CH:18]=2)[N:3]=1.C(=O)(O)[O-].[NH4+].[N:44]1C=CC=CC=1.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>CN(C)C=O>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([NH2:44])=[O:11])=[C:5]([CH3:16])[N:4]([C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][NH:25][C:26]([NH:28][S:29]([C:32]3[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=3)(=[O:31])=[O:30])=[O:27])=[CH:21][CH:22]=2)[N:3]=1
Reactant: c1ccncc1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3nc(C)c(-c4cccc(C(=O)O)c4)c3C)cc2)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3nc(C)c(-c4cccc(C(N)=O)c4)c3C)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 10 %

Procedure:
To a solution of 3-[3,5-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-pyrazol-4-yl]benzoic acid (step 6, 270 mg, 0.52 mmol) in N,N-dimethylformamide (1 mL) was added ammonium bicarbonate (45 mg, 0.57 mmol), pyridine (0.35 mL) and a solution of di-t-butyldicarbonate (120 mg, 0.57 mmol) in N,N-dimethylformamide (1 mL). The mixture was stirred at room temperature for 1 day. After dilution with water (10 mL), extraction with ethyl acetate (30 mL×3) was followed. The organic layer was dried (Na2SO4) and the solvent was removed under reduced pressure. The crude products was purified by TLC with dichloromethane/methanol (10:1) to afford 46 mg (10%) of the title compound as white solids: MS (ESI) m/z 532 [M+H]+, 530 [M−H]−.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[C:37]([F:39])[CH:38]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:35]3[CH:34]=[C:33]([F:32])[CH:38]=[C:37]([F:39])[CH:36]=3)[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cc(F)cc(F)c1)N1CCN(C2CCC2)CC1
Yield: 69 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 3,5-difluorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (69%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][CH:14]=1)=[O:11].Br[C:29]1[C:34]2[C:35]([NH2:38])=[N:36][NH:37][C:33]=2[CH:32]=[CH:31][N:30]=1>>[NH2:38][C:35]1[C:34]2[C:29](=[N:30][CH:31]=[CH:32][C:33]=2[C:16]2[CH:15]=[CH:14][C:13]([NH:12][C:10]([NH:9][C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[F:1])=[O:11])=[CH:18][CH:17]=2)[NH:37][N:36]=1
Reactant: Nc1n[nH]c2ccnc(Br)c12
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(-c3ccnc4[nH]nc(N)c34)cc2)c1

Procedure:
1-(2-Fluoro-5-methylphenyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]urea is coupled, by Suzuki reaction, with 4-bromo-1H-pyrazolo[4,3-c]pyrid-3-ylamine according to a protocol similar to that for the preparation of Example 3. A yellow powder of 1-[4-(3-amino-1H-pyrazolo[3,4-b]pyrid-4-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea is obtained, the characteristics of which are as follows:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12]3[N:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:15]=[C:16]([CH2:17][CH3:18])[C:11]=3[C:10](=[O:25])[CH:9]=2)=[CH:4][CH:3]=1.[CH:26]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:15]=[C:16]([CH2:17][CH3:18])[C:11]3=[C:10]([O:25][CH3:26])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCc1nn(-c2ccccc2)c2[nH]c(-c3ccc(Br)cc3)cc(=O)c12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CO
Solvent: C1CCOC1
Product: CCc1nn(-c2ccccc2)c2nc(-c3ccc(Br)cc3)cc(OC)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 6-(4-bromophenyl)-3-ethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4(7H)-one (200 mg, 0.51 mmol, 1.00 equiv) in tetrahydrofuran (2 mL), PPh3 (290 mg, 1.11 mmol, 2.17 equiv), methanol (18 mg, 0.56 mmol, 1.11 equiv). To the resulting mixture was then added DEAD (180 mg, 1.03 mmol, 2.03 equiv) dropwise with stirring at 0-5° C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of water (5 mL). The resulting solution was extracted with ethyl acetate (3×10 mL) and the organic layers combined. The resulting mixture was washed with water (1×10 mL). The resulting mixture was dried over anhydrous magnesium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (Petroleum Ether-1:100) to yield 6-(4-bromo-phenyl)-3-ethyl-4-methoxy-1-phenyl-1H-pyrazolo[3,4-b]pyridine as a white solid. MS (m/z): 409 [MH+].
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:25])=[C:4]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])[C:5](=[O:15])[O:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH3:37])=[O:35]>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([O:25][C:34]([O:36][CH3:37])=[O:35])=[C:4]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])[C:5](=[O:15])[O:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1
Reactant: COC(=O)Cl
Reactant: Cc1cc(C)c(-c2c(O)c(Cl)c(-c3ccc(Cl)cc3)oc2=O)c(C)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)Oc1c(Cl)c(-c2ccc(Cl)cc2)oc(=O)c1-c1c(C)cc(C)cc1C
Temperature: 20 °C
Reaction time: 20 h
Yield: 92.3 %

Procedure:
3.8 g (10 mmol) of 5-chloro-6-(4-chlorophenyl)-4-hydroxy-3-(2,4,6-trimethylphenyl)-2-pyrone (Example I-a-1) are initially charged in 25 ml of ethyl acetate. At 20° C., 1.0 g (10 mmol) of triethylamine are added and a solution of 0.95 g (10 mmol) of methyl chloroformate in 10 ml of ethyl acetate is added dropwise at 0° C. The mixture is subsequently stirred at 20° C. for 20 h. Precipitated triethylamine hydrochloride is filtered off with suction and washed with ethyl acetate. The combined mother liquors are washed twice with 50 ml of half-concentrated sodium chloride solution each time, dried over magnesium sulphate and concentrated under reduced pressure. 4.0 g (92.4% of theory) of crude 5-chloro-6-(4-chlorophenyl)-4-methoxycarbonyloxy-(2,4,6-trimethylphenyl)-2-pyrone are obtained. Recrystallization from 50 ml of cyclohexane affords 3.1 g (72% of theory) of pure product which melts at 136-138° C.