Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH2:7][CH2:6][C:5]2=[O:13].N1C=CN=C1.[CH:19]([Si:22](Cl)([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])([CH3:21])[CH3:20].O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][Si:22]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:19]([CH3:21])[CH3:20])[O:8][CH2:7][CH2:6][C:5]2=[O:13]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Cc1cc2c(cc1O)OCCC2=O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(cc1O[Si](C(C)C)(C(C)C)C(C)C)OCCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 6-methyl-7-hydroxychroman-4-one (the compound of Preparation 32, 1.50 g, 8.42 mmol), imidazole (1.15 g, 16.9 mmol), and triisopropylsilyl chloride (2.0 mL, 9.2 mmol) in dimethylformamide (30 mL) was stirred overnight at ambient temperature. The reaction was poured into water and extracted with ether (2×). The combined organic layer was washed with 1 N lithium chloride (2×), dried over magnesium sulfate, and concentrated to afford 3.01 g (100%) of 6-methyl-7-triisopropylsilyloxychroman-4-one as a dull yellow oil which had: NMR δ 7.64 (s, 1 H), 6.30 (s, 1 H), 4.45 (t, J=6.4 Hz, 2 H), 2.70 (t, J=6.4 Hz, 2 H), 2.14 (s, 3 H), 1.40-1.25 (m, 3 H), 1.09 (d, J=7.3 Hz, 18 H). The product also had a small silyl impurity and residual dimethylformamide present but was suitable for subsequent reaction.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:16]2[N:17]=[N:18][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[CH:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:15])[C:16]4[N:17]=[N:18][N:19]([CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[CH3:28])[CH:20]=4)=[CH:6][CH:7]=3)=[CH:39][CH:38]=2)[CH2:35][CH2:36]1)=[O:33])[CH3:30]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1ccccc1Cn1cc(C(O)c2c(C)noc2-c2ccc(Br)cc2)nn1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cn(Cc5ccccc5C)nn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(2-methyl-benzyl)-1H-[1,2,3]triazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH:13]=O)=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([O:19][C:20]1[C:21]([F:28])=[C:22]([NH2:27])[C:23]([F:26])=[CH:24][CH:25]=1)[CH3:18].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1>[CH:1]1([NH:6][C:7]2[C:12]([CH:13]=[N:27][C:22]3[C:23]([F:26])=[CH:24][CH:25]=[C:20]([O:19][CH2:17][CH3:18])[C:21]=3[F:28])=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSc1ncc(C=O)c(NC2CCCC2)n1
Reactant: CCOc1ccc(F)c(N)c1F
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: CCOc1ccc(F)c(N=Cc2cnc(SC)nc2NC2CCCC2)c1F
Reaction time: 48 h
Yield: 82 %

Procedure:
To a solution of the 8.22 g (34.7 mmol) of 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde in 170 mL of toluene was added 6.00 g 34.7 mmol, 1 equivalent) of 3-ethoxy-2,6-difluoro-phenylamine and 2.01 g (8.66 mmol, 0.25 equivalents) of camphorsulfonic acid. The reaction was warmed to reflux and the formed water was removed with the aid of a Dean-Stark trap. After reacting for 48 hours, the reaction was concentrated in vacuo. The residue was dissolved in dichloromethane and neutralized with a saturated aqueous solution of sodium bicarbonate. The resulting emulsion was filtered through fiberglass filter paper. The methylene chloride layer was isolated from the filtrate, then washed first with a saturated aqueous solution of sodium bicarbonate, followed by a saturated aqueous solution of sodium chloride. The methylene chloride layer was dried with magnesium sulfate and concentrated in vacuo. The residue was dissolved in dichloromethane, stirred with silica gel, and concentrated in vacuo. The residue was placed in the sample injection module of a Biotage FLASH 75 chromatographic apparatus. Chromatography of the crude material on a Biotage 500 g silica gel column with 4:1 hexane/ethyl acetate gave 11.1 g (82%) of the title compound as a solid: mp 136° C.–141° C. MS (APCI) (m+1)/z 393.2 Analysis calculated for C19H22F2N4SO: C, 58.15; H, 5.65; N, 14.28. Found: C, 58.22; H, 5.68; N, 14.26.
Reaction SMILES: Cl[CH2:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[I:11][C:12]1[CH:13]=[N:14][C:15](=[O:18])[NH:16][CH:17]=1.C(N(CC)CC)C>ClCCl>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:2][N:16]2[CH:17]=[C:12]([I:11])[CH:13]=[N:14][C:15]2=[O:18])=[CH:5][CH:6]=1
Reactant: ClCOc1ccc(Cl)cc1
Reactant: O=c1ncc(I)c[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1ncc(I)cn1COc1ccc(Cl)cc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 6, by adding a solution of 1-chloromethoxy-4-chlorobenzene (see Preparation 3) (10 mmol) in dichloromethane (10 ml) to a solution of 5-iodopyrimidin-2-one (10 mmol) and triethylamine (10 mmol) in dichloromethane (50 ml), and heating the resultant mixture under reflux for 3 h. The product, 2.05 g (56%), consisted of the N- and O-isomers in the ratio 4:1. The O-isomer was removed from the product by extraction with acetone and the remaining N-isomer was recrystallized from EtOAc; m.p. 216° C. (Found C36.64; H2.24 Calc. for C11H8ClIN2O2 : C36.44; H2.23) 1H NMR (DMSO-d6 /CDCl3); δ 5.85 (CH2), 6.9-7.5 (Ph), 8.68 and 8.82 (H-4 and H-6, respectively, J 3 Hz). IR (KBr) 1650 cm-1 (CO). MS (70 eV, m/z (% rel. int.)): 362 (37,M) 235 (100), 222 (6), 108 (22).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[C:16]1([CH2:22][CH2:23][CH2:24]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>C(O)C>[C:1]([NH:4][C:5]([CH2:24][CH2:23][CH2:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: BrCCCc1ccccc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(CCCc1ccccc1)(NC(C)=O)C(=O)OCC
Temperature: 50 °C

Procedure:
Sodium (0.23 g) was added to 15 ml of absolute ethanol and the mixture was stirred at room temperature for 30 minutes in a nitrogen flow to give a 10 mmol solution of sodium ethoxide in ethanol. To this solution, 1.98 g of diethyl 2-acetamidomalonate was added and the mixture was heated at 50° C. for 30 minutes in a stream of nitrogen. 3-Phenylpropyl bromide was added thereto at room temperature and the mixture was refluxed under heating for 24 hours. The mixture was neutralized with dilute hydrochloric acid and ethanol was distilled away. The resultant residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled away and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4-1:1) and recrystallized from diisopropyl ether-hexane to give 800 mg of diethyl 2-acetamido-2-(3-phenylpropyl)malonate as white crystals.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[NH:21][CH2:22][CH2:23][NH2:24]>>[F:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH:2]([OH:4])[CH2:3][NH:24][CH2:23][CH2:22][NH:21][C:15]2[C:16]([CH3:20])=[CH:17][CH:18]=[CH:19][C:14]=2[CH3:13])=[CH:7][CH:8]=1
Reactant: Cc1cccc(C)c1NCCN
Reactant: Fc1ccc(OCC2CO2)cc1
Product: Cc1cccc(C)c1NCCNCC(O)COc1ccc(F)cc1
Reaction time: 48 h

Procedure:
3.36 g. 4-Fluorophenyl glycidyl ether are left to stand for 2 days at ambient temperature with 6.6 g. N-(2,6-dimethylphenyl)-ethylenediamine. The reaction mixture is separated by chromatography on silica gel with the elution agent ethyl acetate-methanol-triethylamine (100:10:1 v/v/v) to give, after evaporation of the pure fractions, 5.0 g. of the desired product in the form of a viscous oil. After dissolving in diethyl ether and adding 2.5 g. benzoic acid, the corresponding benzoate precipitates out and is recrystallized from isopropyl alcohol. The desired product is obtained in a yield of 5.2 g. (57% of theory) in the form of colorless crystals; m.p. 105°-106° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34](O)=[O:35])[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:9][CH:8]=1.Cl.C[O:45][C:46](=[O:62])[C@@H:47]([NH2:61])[CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][N:58]=[CH:57][CH:56]=2)=[CH:51][CH:50]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34]([NH:61][C@@H:47]([CH2:48][C:49]5[CH:54]=[CH:53][C:52]([C:55]6[CH:56]=[CH:57][N:58]=[CH:59][CH:60]=6)=[CH:51][CH:50]=5)[C:46]([OH:62])=[O:45])=[O:35])[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:11][CH:12]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccncc2)cc1
Agent: Cl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccncc2)cc1)C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
The title compound (19 mg) was prepared from (3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (30 mg) and (S)-2-amino-3-(4-pyridin-4-yl-phenyl)-propionic acid methyl ester hydrochloride according to General Procedures L and B. LCMS (m/z): 829.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:3][N:2]([CH3:1])[CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: CN(C)CC1(c2cccc(O)c2)CCOCC1
Reactant: ClCCCN1CCCC1
Product: CN(C)CC1(c2cccc(OCCCN3CCCC3)c2)CCOCC1

Procedure:
Alkylation of 3-[4-(dimethylamino)methyltetrahydro-2H-pyran-4-yl]phenol (0.1 g, 0.425 mmol) with 1-(3-chloropropyl)pyrrolidine (0.125 g, 0.85 mmol) according to general procedure B gave the desired compound after purification by flash chromatography (0.030 g, 20%). 1H NMR (400 MHz, CDCl3) δ7.27-7.18 (m, 1H), 6.92-6.84 (m, 2H), 6.75 (dd, 1H), 4.05 (t, 2H), 3.8-3.7 (m, 2H), 3.55 (t, 2H), 2.65 (t, 2H), 2.6-2.5 (m, 4H), 2.4 (s, 2H), 2.15-1.85 (m, 6H), 2.0 (s, 6H), 1.85-1.75 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(-c3ccccc3)c2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc2[nH]nc(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.9 %

Procedure:
A suspension of 5-nitro-3-phenyl-1H-indazole (0.239 g, 1.0 mmol) and palladium (10 wt % on activated carbon, 30 mg) in ethyl acetate (10 mL) was stirred under hydrogen at ambient temperature for 18 hours. It was filtered with celite and washed with ethyl acetate. The filtrate was concentrated and the residue was then purified by chromatography (SiO2, 30–50% ethyl acetate/hexane) to provide the title compound (0.184 g, 88% yield): mp 104° C.; 1H NMR (CDCl3) δ 10.40 (br s, 1H), 7.94 (d, 2H), 7.51 (m, 2H), 7.20–7.42 (m, 3H), 6.90 (m, 1H), 3.6 (br, 2H); EI-MS (m/z) 209 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)[CH2:14][S:15][CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[O:10])=[C:4]([C:28](=[O:43])[NH:29][C:30]2[CH:34]=[CH:33][N:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([CH3:42])[CH:36]=3)[N:31]=2)[CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)[CH2:14][S:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:10])=[C:4]([C:28](=[O:43])[NH:29][C:30]2[CH:34]=[CH:33][N:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([CH3:42])[CH:36]=3)[N:31]=2)[CH:3]=1
Reactant: Cc1ccc(-n2ccc(NC(=O)c3cc(Cl)ccc3NC(=O)c3cccc(CSCCC(=O)OC(C)(C)C)c3)n2)cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-n2ccc(NC(=O)c3cc(Cl)ccc3NC(=O)c3cccc(CSCCC(=O)O)c3)n2)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.9 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-(4-chloro-2-(1-(3,4-dimethylphenyl)-1H-pyrazol-3-ylcarbamoyl)phenylcarbamoyl)benzylthio)propanoate (150 mg, 0.24 mmol, 1.00 equiv) in dichloromethane (4 mL), and 2,2,2-trifluoroacetic acid (2 mL). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 36.3 mg (27%) of a white solid. 1H-NMR (300 MHz, DMSO, ppm): δ 11.82(s, 1H), 11.48(s, 1H), 8.52(d, J=8.70 Hz, 1H), 8.41(s, 1H), 8.11(s, 1H), 7.92(s, 1H), 7.79(m, 1H), 7.67(m, 1H), 7.57(m, 4H), 7.26(m, 1H), 6.92(d, J=1.8 Hz, 1H), 3.86(s, 2H), 2.60(m, 2H), 2.29(m, 6H). MS (ES, m/z): 563 [M+H]+.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:18]=[CH:17][C:16]([C:19]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=2)=[CH:20][C:21](O)=[O:22])=[CH:15][CH:14]=1.C(=O)=O.[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>O1CCCC1>[C:13]1([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:14]=[CH:15][C:16]([C:19]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=2)=[CH:20][C:21]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[O:22])=[CH:17][CH:18]=1
Reactant: COc1ccc(C(=CC(=O)O)c2ccc(-c3ccccc3)cc2)cc1OC
Reactant: C1COCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: C1CCOC1
Product: COc1ccc(C(=CC(=O)N2CCOCC2)c2ccc(-c3ccccc3)cc2)cc1OC
Reaction time: 1 h
Yield: 55.3 %

Procedure:
4.7 g of carbonyldiimidazole were added in portions to a solution of 9.4 g of 3-(biphenyl-4-yl)-3-(3,4-dimethoxyphenyl)acrylic acid in 50 ml of anhydrous tetrahydrofuran. After the evolution of CO2 had subsided, 2.5 g of morpholine were added, and the mixture was boiled for 1 hour. After evaporation, the residue was taken up in toluene/water, and the aqueous phase was discarded. The organic phase was washed once more with water, then dried and evaporated. The crude title compound was isolated with a yield of 10.5 g. The crude product was purified on silica gel with toluene/ acetone (9:1). 6.2 g of the title compound were obtained in the form of a yellow resin, Rf: 0.56 ]l (silica gel, toluene/ acetone 7:3).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([CH3:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH3:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2C)cn1
Reactant: C1CCNC1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCCC5)c34)cc2C)cn1
Yield: 47 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 15) and pyrrolidine to give the title compound in 47% yield; NMR Spectrum: 1.67 (br s, 4H), 2.19 (s, 3H), 2.44 (s, 3H), 2.56 (br s, 4H), 2.89 (t, 2H), 4.44 (t, 2H), 6.95 (d, 1H), 7.18-7.25 (m, 2H), 7.60-7.64 (m, 2H), 8.16 (s, 1H), 8.31 (s, 1H); Mass Spectrum: 446 (MH+).
Reaction SMILES: [CH:1]1[C:11]2[C:6](=[CH:7][C:8]([OH:24])=[C:9]([O:12][C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[CH:10]=2)[O:5][C:3](=[O:4])[CH:2]=1.O.[CH2:26](I)[CH3:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:26]([O:24][C:8]1[C:9]([OH:12])=[CH:10][C:11]2[CH:1]=[CH:2][C:3](=[O:4])[O:5][C:6]=2[CH:7]=1)[CH3:27]
Reactant: CCI
Reactant: O=c1ccc2cc(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(O)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc2oc(=O)ccc2cc1O
Reaction time: 5 h

Procedure:
110 g (300 mmol) esculine×1.5 H2O, 70 g (450 mmol) ethyl iodide and 82.8 g (600 mmol) of potassium carbonate are agitated in 400 ml DMF for 30 h at 85° C. This was followed by filtration, reduction of the filtrate to approximately 250 ml, the addition of approximately 200 ml ethanol and crystallization at 0° C. The crystals were boiled in 800 ml of 2N sulfuric acid for 5 h under reflux. The product was vacuum filtered, washed with water and recrystallized from water and ethanol: yield 43.2 g (70%), fusion point 145° to 146° C.
Reaction SMILES: BrB(Br)Br.[F:5][C:6]1[CH:7]=[C:8]([CH2:15][C:16]([OH:18])=[O:17])[CH:9]=[C:10]([F:14])[C:11]=1[O:12]C.[CH3:19]O>ClCCl>[F:5][C:6]1[CH:7]=[C:8]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:9]=[C:10]([F:14])[C:11]=1[OH:12]
Reactant: CO
Reactant: COc1c(F)cc(CC(=O)O)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)Cc1cc(F)c(O)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
Tribromoborane (2.357 mL, 24.93 mmol) was added dropwise to 2-(3,5-difluoro-4-methoxyphenyl)acetic acid (0.84 g, 4.16 mmol) in dichloromethane (5 mL) at ambient temperature under nitrogen. The resulting solution was stirred at ambient temperature for 16 hours. Methanol (8.41 mL, 207.76 mmol) was added dropwise (—care reaction is vigorous and exothermic—mixture maintained a reflux during the addition) and the mixture was stirred for a further 20 minutes. The reaction mixture was evaporated to dryness and redissolved in DCM (50 mL), and washed sequentially with saturated NaHCO3 (50 mL) and water (50 mL). The organic layer was dried by passing through a phase seperating cartridge and evaporated to afford desired product methyl 2-(3,5-difluoro-4-hydroxyphenyl)acetate (0.660 g, 79%).
Reaction SMILES: C1(C)C=CC(S(CC[O:12][C:13](=[O:49])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([S:21]([N:24]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[N:26]=[C:25]3[S:33]([CH2:35][C:36]3[C:41]([CH3:42])=[C:40]([O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48])[CH:39]=[CH:38][N:37]=3)=[O:34])(=[O:23])=[O:22])[CH:15]=2)(=O)=O)=CC=1.C([O-])(O)=O.[Na+:55]>CC#N.O>[Na+:55].[CH3:48][O:47][CH2:46][CH2:45][CH2:44][O:43][C:40]1[CH:39]=[CH:38][N:37]=[C:36]([CH2:35][S:33]([C:25]2[N:24]([S:21]([C:16]3[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=3[CH3:20])[C:13]([O-:49])=[O:12])(=[O:23])=[O:22])[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=2)=[O:34])[C:41]=1[CH3:42]
Reactant: COCCCOc1ccnc(CS(=O)c2nc3ccccc3n2S(=O)(=O)c2cc(C(=O)OCCS(=O)(=O)c3ccc(C)cc3)ccc2C)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3n2S(=O)(=O)c2cc(C(=O)[O-])ccc2C)c1C
Temperature: 65 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To the solution of 3-{2-[4-(3-methoxy-propoxy)-3-methyl-pyridin-2-yl-methanesulfinyl]-benzimidazole-1-sulfonyl}-4-methylbenzoic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 53, 1.5 g, 1.97 mmol) in 15 mL of CH3CN was added a solution of NaHCO3 (200 mg, 2.36 mmol, 1.2 eq) in 7 mL of H2O at room temperature, and then the mixture was heated to 65° C. for 2 h. Thereafter most of the CH3CN was removed, the mixture was extracted with EtOAc, and the aqueous layer was lyophilized overnight. The solid was dissolved in CH2Cl2, and then the mixture was filtered to remove insoluble solids. The filtrate was concentrated to near dryness. The residual oil was dissolved in about 2 mL of CH2Cl2 and EtOAc-hexane (7:1) was added to precipitate a white solid. The precipitate was collected by filtration, washed with EtOAc-hexane (7:1), and dried under vacuum to give 950 mg (80%) of 3-{2-[4-(3-methoxy-propoxy)-3-methyl-pyridin-2-yl-methanesulfinyl]-benzimidazole-1-sulfonyl}-4-methylbenzoic acid sodium salt (Compound 28) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH2:18][OH:19])=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24](=[O:41])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1)[CH3:22]>>[CH2:21]([O:23][C:24](=[O:41])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH2:18][OH:19])=[CH:4][CH:3]=1)[CH3:22]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCCO
Reactant: CCOC(=O)Cc1ccccc1B1OC(C)(C)C(C)(C)O1
Product: CCOC(=O)Cc1ccccc1-c1ccc(-c2onc(C)c2NC(C)CCCO)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 4-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamino]-pentan-1-ol and [2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Cl:34][CH2:35][C:36](Cl)=[O:37]>C(Cl)Cl>[Cl:34][CH2:35][C:36]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:24])[C:10]2[CH:11]=[C:12]([C:20]([F:21])([F:22])[F:23])[CH:13]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:15]=2)[CH2:3][CH2:2]1)=[O:37]
Reactant: O=C(Cl)CCl
Reactant: O=C(NCC1CCNCC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCC1CCN(C(=O)CCl)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 8 h
Yield: 82 %

Procedure:
A solution of N-(piperidin-4-ylmethyl)-3,5-bis(trifluoromethyl)benzamide (2.0 g, 5.66 mmol) and DIPEA (1.2 mL) in CH2Cl2 (10 mL) was added 2-chloroacetyl chloride (0.64, 5.66 mmol) dropwise, the mixture was stirred overnight. The mixture was washed with water, dried with Na2SO4, filtered, and the solvent was removed in vacuo. The residue was purified by automated flash chromatography to yield the product (2.0 g, 82%).
Reaction SMILES: [SH:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:10](=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:21])[CH:8]=2)[N:3]=1.Cl.Cl[CH2:24][C:25]1[C:30]([CH3:31])=[C:29]([O:32][CH3:33])[CH:28]=[CH:27][N:26]=1>>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][N:26]=[C:25]([CH2:24][S:1][C:2]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:10](=[O:20])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:21])[CH:8]=3)[N:3]=2)[C:30]=1[CH3:31]
Reactant: COc1ccnc(CCl)c1C
Reactant: COc1ccc(-n2c(S)nc3ccc(C)cc3c2=O)cc1
Agent: Cl
Product: COc1ccc(-n2c(SCc3nccc(OC)c3C)nc3ccc(C)cc3c2=O)cc1
Yield: 51.6 %

Procedure:
The title compound was prepared in a yield of 51.6%, using 2-mercapto-3-(4-methoxyphenyl)-6-methyl-4(3H)-quinazolinone in place of 2-mercapto-6-methyl-3-phenyl-4(3H)-quinazolinone and 2-chloromethyl-4-methoxy-3-methylpyridine hydrochloride in place of 2-chloromethylpyridine hydrochloride.