Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[N:4]=1.[Cl:10][C:11]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>>[Cl:10][C:11]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:12]=1[C:13]([O:9][C:5]1[N:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=1)=[O:14]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Oc1cccc(O)n1
Agent: Cl
Product: O=C(Oc1cccc(O)n1)c1ccc(Cl)cc1Cl
Yield: 77.7 %

Procedure:
The general procedure of Example 81 was followed using 3.00 g of 2,6-dihydroxypyridine hydrogen-chloride and 4.26 g of 2,4-dichlorobenzoyl chloride, thereby producing 4.49 g of the title compound in a yield of 78%.
Reaction SMILES: [C:1]1([C:7]#[C:8]/[CH:9]=[CH:10]/[CH2:11]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CS([Cl:24])(=O)=O>ClCCl>[Cl:24][CH2:11]/[CH:10]=[CH:9]/[C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: OC/C=C/C#Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: ClC/C=C/C#Cc1ccccc1
Reaction time: 8 h
Yield: 82.2 %

Procedure:
To a mixture of (E)-5-phenyl-pent-2-en-4-yn-1-ol (Method 1b) (4.9 g, 31.0 mmol) and triethylamine (3.8 g, 38.0 mmol) in dry dichloromethane (200 mL) was added methanesulfonyl chloride (3.8 g, 33 mmol) dropwise. Stirring was continued at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue washed with heptane/dichloromethane (×2) to give 4.5 g (82%) crude (E)-(5-chloro-pent-3-en-1-ynyl)-benzene.
Reaction SMILES: [Na].[CH3:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].Cl[C:14]1[N:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CCO>[Cl:23][C:21]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[C:14]([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)=[O:4])[N:22]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [Na]
Solvent: CCO
Product: COc1ccc(C(=O)Cc2nc(Cl)ccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.9 %

Procedure:
Elemental sodium (173 mg, 7.5 mmol) was added to 40 mL of absolute EtOH stirring under nitrogen. After all of the sodium reacted, 4-methoxyacetophenone (1.44 g, 7.5 mmol) was added, and the reaction stirred an additional 15 minutes . 2,6-Dichloronicotinic acid (1 g, 5.2 mmol) and copper acetate (80 mg, 0.65 mmol) was added and the reaction was stirred at reflux for 16 hours. The reaction was cooled to room temperature and quenched with 1 mL concentrated acetic acid. The mixture was concentrated to a solid, and redissolved in EtOAc. A small portion of fine inorganic precipitate was filtered off. The organic layer was extracted with 3×100 mL 1N NaOH. This was acidified with 1 N HCl to a pH of ˜4. A precipitate formed and was collected by vacuum filtration, yielding 6-chloro-2-[2-(4-methoxyphenyl)-2-oxo-ethyl]-nicotinic acid (1 g, 63%) as a tan solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[CH:4]([CH2:5][CH2:6][C:7]3[C:8]4[C@:16]([CH3:24])([CH2:17][CH2:18][C:19]=32)[C@@H:11]([C@H:12]([CH3:15])[CH:13]=O)[CH2:10][CH:9]=4)[C:3]1([CH3:26])[CH3:25].[C:27]1([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:27]1([N:33]2[CH2:38][CH2:37][N:36]([CH2:15][C@H:12]([C@@H:11]3[C@:16]4([CH3:24])[C:8]([C:7]5[CH2:6][CH2:5][C@@H:4]6[C@:20]([C:19]=5[CH2:18][CH2:17]4)([CH3:23])[CH2:21][CH2:22][C@H:2]([OH:1])[C:3]6([CH3:26])[CH3:25])=[CH:9][CH2:10]3)[CH3:13])[CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C[C@H](C=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)C1CC3
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: C[C@H](CN1CCN(c2ccccc2)CC1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
(20S)-3β-hydroxy-4,4,20-trimethyl-pregna-8,14-dien-21-al was treated with N-phenyl-piperazine and sodium tris(acetoxy)borohydride as described in Example 1h). (20S)-20-[(4-phenylpiperazin-1-yl)methyl]-4,4-dimethyl-5α-pregna-8,14-dien-3β-ol was isolated as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][NH2:16])=[CH:9][CH:8]=1)[CH3:2].C(N(CC)CC)C.[C:28](Cl)(=[O:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][NH:16][C:28](=[O:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCCCCCC(=O)Cl
Reactant: CCOC(=O)C(Cc1ccc(OCCN)cc1)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCC(=O)NCCOc1ccc(CC(OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound obtained in Step c (55 mg) was dissolved in methylene chloride (2 ml), added with triethylamine (56 μl and added with n-heptanoyl chloride (39 μl, produced by Tokyo Kasei Kogyo). The reaction mixture was stirred at room temperature for 30 minutes, diluted with methylene chloride, washed with saturated aqueous sodium hydrogencarbonate, dried over magnesium sulfate and concentrated. The resulting residue was applied on a silica gel column and eluted with hexane/ethyl acetate (3:2) to obtain the title compound (47.3 mg).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:40]([O:42][CH3:43])=[O:41]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH3:43])=[O:41])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OC)cc1)n2C)c1ccccn1
Yield: 48 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and methyl chloroformate. Yield: 48% of theory, C29H31N7O5 (557.6) Rf value: 0.62 (silica gel; dichloromethane/methanol=9:1) ##EQU72##
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.[F:13][C:14]([F:28])([F:27])[C:15]1[CH:16]=[C:17]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([N:24]2[CH2:23][CH2:22][N:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:27])([F:28])[F:13])[CH:16]=3)[CH2:26][CH2:25]2)=[O:12])[CH:3]=[CH:2]1
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Solvent: CN(C)C=O
Product: O=C(c1cccc2cc[nH]c12)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 75 %

Procedure:
To a cooled solution of indole 7-carboxylic acid (3.22 g; 0.02 moles) in 30ml dimethylformamide was added N,N'-carbonyldiimidazole (3.24 g; 0.02 moles). After 45 minutes, a solution of 4-(3-(trifluoromethyl)phenyl)piperazine (5.76 g; 0.025 moles) in 10 ml DMFwas added. This was stirred for 18 hours at ambient temperature. The solvent was then concentrated off and the resulting oil was partitioned between ethyl acetate and water. The aqueous was extracted twice with ethyl acetate and the organics were washed with water and dried (saturatedNaCl, MgSO4). The desired amine was purified via flash chromatography (10% ethyl acetate/dichloromethane), to give 5.6 g (77%) of a solid, m.p. 147°-151° C. The solid was recrystallized from methanol to give 3.14 g (43%) of 1-(1H-indol-7-ylcarbonyl)-4-[3(trifuoromethyl)phenyl]piperazine, m.p. 149°-151° C.
Reaction SMILES: [O:1]=[C:2]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:17][CH2:18][CH2:19][C:20]1[C:25](O)=[C:24]([C:27]([CH3:29])=[O:28])[CH:23]=[CH:22][C:21]=1[OH:30].N1CCCC1>C1(C)C=CC=CC=1>[O:28]=[C:27]1[C:24]2[CH:23]=[CH:22][C:21]([OH:30])=[C:20]([CH2:19][CH2:18][CH3:17])[C:25]=2[O:1][C:2]([CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:29]1
Reactant: CCOC(=O)CCC(=O)CCC(=O)OCC
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CCCc1c(O)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Reaction time: 4 h

Procedure:
A stirred solution of 12.3 g (53.5 mmol) of diethyl 4-oxopimelate, 10.4 g (53.5 mmol) of 2,4-dihydroxy-3-propylacetophenone, and 3.8 g (55 mmol) of pyrrolidine in 62 ml of toluene was refluxed under a water separator. After 4 hours, the mixture was allowed to cool. The solvent was removed under reduced pressure and the resultant oil was chromatographed on silica gel using ethyl acetate-hexane as eluent. The titled diester (4.98 g) was found to be homogeneous by thin-layer chromatography (20% by volume ethyl acetate/hexane on silica gel plates) and was used in subsequent reactions without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[O:20][C:19]([CH:21]=O)=[CH:18][CH:17]=3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[CH3:35][S:36]([CH2:39][CH2:40][NH2:41])(=[O:38])=[O:37]>O>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]4[O:20][C:19]([CH2:21][NH:41][CH2:40][CH2:39][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:18][CH:17]=4)[CH:14]=3)[N:9]=[CH:8][N:7]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1
Reactant: CS(=O)(=O)CCN
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(F)c4)c3c2)o1
Solvent: O
Product: CS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(F)c4)c3c2)o1

Procedure:
Prepared according to Procedure D from 5-(4-{3-fluoro-4-(3-fluorobenzyloxy)anilino}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). 1H NMR 400 MHz (DMSO-d6) 9.61 (bs, 2H); 9.28 (bs, 1H); 8.80 (s, 1H); 8.34 (d, 1H); 7.87 (m, 2H); 7.59 (d, 1H); 7.44 (m, 1H); 7.2-7.36 (m, 4H); 7.18 (m, 1H); 6.83 (s, 1H); 5.25 (s, 2H); 4.42 (s, 2H); 3.60 (m, 2H); 3.45 (m, 2H), obscured by water peak); 3.16 (s, 3H); MS m/z 565 (M+1).
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.ClC(OC)=O.[NH3:27].[OH-].[Na+]>C(N(CC)CC)C.O1CCCC1>[NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH2:27])=[O:19])=[CH:20][CH:21]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: O=C(O)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Reactant: N
Agent: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzoic acid (1.05 g) and dry tetrahydrofuran (30 ml) was stirred at ambient temperature whilst triethylamine (1.1 ml) was added. The mixture was stirred at ambient temperature for 0.5 h then cooled to 3° C. and methyl chloroformate (1.2 ml) was added dropwise over 5 to 10 minutes at 3-9° C. The mixture was stirred for 1 hour at 3-9° C. and then added to concentrated aqueous ammonia solution (70 ml, SG 0.880) with rapid stirring. The mixture was stirred for 2 hours at 5° C. and allowed to warm up to ambient temperature. The mixture was concentrated under reduced pressure and then treated with 1M sodium hydroxide solution (200 ml). The mixture was stirred for 0.5 hour and then filtered. The solid obtained was stirred with 2M sodium hydroxide solution (50 ml) for 6 hours and then allowed to stand at ambient temperature for 18 hours. The mixture was filtered to give a solid which was washed with water and dried. This solid was purified by flash column chromatography on silica using dichloromethane/industrial methylated spirit/triethylamine (25:2.5:1.5) as the mobile phase. The appropriate fractions were combined and concentrated to give a residue which was washed with water and dried under vacuum at 40° C. to give 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide, m.p. 290-293° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[S:10](=[O:13])([OH:12])[O-:11].[Na+:14]>C(O)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[S:10]([O-:13])(=[O:12])=[O:11].[Na+:14]
Reactant: O=S([O-])O
Reactant: c1ccc2[nH]ccc2c1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)([O-])c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.4 %

Procedure:
A solution of 5 g indole in 10 mL ethanol was added to a solution of 8.8 g sodium bisulfite in 30 mL water. The mixture was stirred at room temperature for 12 hrs. The solid precipitate was filtered, washed with ether, and dried to yield sodium indole-2-sulfonate (7.8 g, 91%) as a white solid. The product was used in the next step without further purification. MP>320° C.; IR (KBr, cm−1) 3470, 3250, 1650, 1600, 1490, 1460, 1210, 1170, 1040, 760, 750.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([CH:15]=O)[CH2:14][CH2:13][C:8]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[CH3:17][C:18]([S:21]([NH2:23])=[O:22])([CH3:20])[CH3:19].O>O1CCCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH:1]1([CH2:4][C:5]2([CH:15]=[N:23][S:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH2:6][CH2:7][C:8]3([O:9][CH2:10][CH2:11][O:12]3)[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: O=CC1(CC2CC2)CCC2(CC1)OCCO2
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=CC1(CC2CC2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The crude aldehyde was dissolved in tetrahydrofuran (40 mL) and 2-methyl-2-propanesulfinamide (1.81 g, 14.9 mmol, 1.1 eq.) and titanium(IV) ethoxide (4.27 mL, 20.3 mmol, 1.5 eq.) were added. The resulting mixture was stirred for 5 h under reflux and 16 h at room temperature, before being treated with water (10 mL) and filtered through celite. The filter cake was washed with ethyl acetate, the aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulphate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 0%→100% ethyl acetate in heptane) to yield 1.90 g of the title compound (19). Rt=1.58 min (Method B). Detected mass: 328.3 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][C:22](=[O:35])[CH2:23][CH2:24][CH2:25][CH2:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:4][C:3]=1[NH:21][C:22](=[O:35])[CH2:23][CH2:24][CH2:25][CH2:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)c(NC(=O)CCCCC(=O)c3ccccc3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCCCC(=O)c1ccccc1)Nc1cc(C2CCNCC2)ccc1F
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
Into a solution of tert-butyl 4-{4-fluoro-3-[(6-oxo-6-phenylhexanoyl)amino]phenyl}-1-piperidine carboxylate (49.0 mg, 0.101 mmol) in CH2Cl2 (3.0 mL) was added trifluoroacetic acid (114 mg, 1.01 mmol) at room temperature. The reaction mixture was stirred for 30 min and concentrated in vacuo. The residue was dissolved in CHCl3/i-PrOH (3:1, 10 mL) and was basified to pH 11 with 5% KOH solution. The organic layer was separated and the aqueous layer was extracted with CHCl3/i-PrOH (3:1, 3×10 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford N-[2-fluoro-5-(4-piperidinyl)phenyl]-6-oxo-6-phenylhexanamide (35.5 mg, 86.0%). HCl salt: 1H NMR (400 MHz, CDCl3) δ 8.14-8.01 (br, 1H), 8.01-7.89 (m, 2H), 7.65-7.52 (m, 1H), 7.52-7.43 (m, 2H), 7.43-7.26 (br, 1H), 7.13-7.00 (m, 1H), 7.00-6.88 (br, 1H), 3.68-3.43 (m, 2H), 3.19-2.92 (br, 4H), 2.89-2.67 (m, 1H), 2.61-2.36 (br, 2H), 2.26-2.06 (m, 2H), 2.06-1.93 (m, 2H), 1.93-1.71 (br, 4H); ESMS m/e: 383.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:32])=O)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[C:33]([O:36]C(=O)C)(=[O:35])[CH3:34]>>[C:33]([O:36][CH2:32][S:30][C:27]1[CH:28]=[CH:29][C:24]([C:9]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=2)=[CH:25][CH:26]=1)(=[O:35])[CH3:34]
Reactant: CS(=O)c1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCSc1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Reaction time: 5 h

Procedure:
To a solution of 5-(4-chloro-phenyl)-6-(4-methanesulfinyl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (1.20 g, 2.60 mmol) in dry acetic anhydride (12 mL) sodium acetate (0.800 g, 9.76 mmol) is added and the resulting mixture is heated to reflux. After 5 h, the reaction mixture is concentrated. The crude product is purified by column chromatography (silica gel, 60-120 mesh) to afford (4-(5-(4-chlorophenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenylthio)methyl acetate.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=2/[CH:26]=[CH:27]\[CH3:28])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[C:35](O)=[C:34]([F:37])[C:33]([F:38])=[C:32]([F:39])[C:31]=1[F:40].C1(N=C=NC2CCCCC2)CCCCC1.O>C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([O:23][C:35]3[C:34]([F:37])=[C:33]([F:38])[C:32]([F:39])=[C:31]([F:40])[C:30]=3[F:29])=[O:22])=[CH:19][C:18]=2/[CH:26]=[CH:27]\[CH3:28])[CH2:15][CH2:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C/C=C\c1cc(C(=O)O)ccc1N1CCN(CCOCc2ccccc2)CC1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: CCOC(C)=O
Product: C/C=C\c1cc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1N1CCN(CCOCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 88.4 %

Procedure:
(Z)-4-{4-[2-(benzyloxy)ethyl]piperazin-1-yl}-3-(prop-1-en-1-yl)benzoic acid (13 mg, 0.0331 mmol) was dissolved in ethyl acetate (3.3 mL). At room temperature, pentafluorophenol (7.3 mg, 0.0397 mmol) and N,N′-dicyclohexylcarbodiimide (8.2 mg, 0.0397 mmol) were added sequentially, and the mixture was stirred at room temperature for 14 hours. The reaction solution was added water, extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone). The title compound (16 mg (yield 86%)) was obtained as a pale yellow crystal.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=[CH:10][CH:9]=1.[N:27]1([S:32](Cl)(=[O:34])=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28]1>>[N:27]1([S:32]([N:21]2[CH2:20][CH2:19][C:16]3([C:15](=[O:24])[N:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][C:6]([F:5])([F:25])[F:26])=[CH:9][CH:10]=4)[CH2:18][CH2:17]3)[CH2:23][CH2:22]2)(=[O:34])=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: O=S(=O)(Cl)N1CCCC1
Solvent: CC(=O)O
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)N1CCCC1)CC2

Procedure:
The title compound was prepared in analogy to example 180 step D from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and pyrrolidine-1-sulfonyl chloride. Off-white solid. MS (ESI): 448.2 (MH+).
Reaction SMILES: [CH2:1]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:24]=[N:25][C:26]([N:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[CH:27][CH:28]=4)[CH:21]=3)[N:16]([S:35]([C:38]3[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:15]=2)[CH:11]=[N:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:45][C@H:46]1[CH2:48][O:47]1.CCN(C(C)C)C(C)C>C(O)C>[CH2:1]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH2:34][CH2:33][N:32]([CH2:45][C@@H:46]([OH:47])[CH3:48])[CH2:31][CH2:30]5)=[N:25][CH:24]=4)[CH:21]=3)[N:16]([S:35]([C:38]3[CH:39]=[CH:40][C:41]([CH3:42])=[CH:43][CH:44]=3)(=[O:36])=[O:37])[CH:15]=2)[CH:11]=[N:10]1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Reactant: C[C@H]1CO1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1
Yield: 86.3 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-phenethyl-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (product of step 2 of example 140) (85 mg, 0.14 mmol) was alkylated using (S)-2-methyloxirane (10 mg, 0.169 mmol), DIPEA (22 mg, 0.169 mmol) and ethanol (3 mL) to get 80 mg (86%) of the titled compound. MS: m/z=662.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])[CH:5]=[N:6][C:7]=1Cl.[CH3:14][C@@H:15]1[CH2:20][NH:19][CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])[CH:5]=[N:6][C:7]=1[N:19]1[CH2:18][CH2:17][NH:16][C@H:15]([CH3:14])[CH2:20]1
Reactant: CC(=O)NCc1cnc(Cl)c(Cl)c1
Reactant: C[C@@H]1CNCCN1
Product: CC(=O)NCc1cnc(N2CCN[C@H](C)C2)c(Cl)c1

Procedure:
A mixture of N-(5,6-dichloro-pyridin-3-ylmethyl)-acetamide from step (d) above (250 mg, 1.14 mmol) and (R)-(−)-2-methyl-piperazine (126 mg, 1.26 mmol, Aldrich) reacted under the conditions of Example 3a to give the title compound. MS (ESI, pos. ion) m/z: 283 (M+1).
Reaction SMILES: [CH2:1]([CH:4]([CH2:8][CH2:9][CH3:10])[C:5]([OH:7])=[O:6])[CH2:2][CH3:3].[CH2:11](O)[CH2:12][CH2:13][OH:14]>CS(O)(=O)=O.C1(C)C=CC=CC=1>[CH2:1]([CH:4]([CH2:8][CH2:9][CH3:10])[C:5]([O:7][CH2:11][CH2:12][CH2:13][OH:14])=[O:6])[CH2:2][CH3:3]
Reactant: CCCC(CCC)C(=O)O
Reactant: OCCCO
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CCCC(CCC)C(=O)OCCCO
Yield: 86.6 %

Procedure:
2-propylpentanoic acid (10.0 g, 69.3 mmol) was mixed with propane-1-3-diol (42.1 g, 555.0 mmol) and methyl-sulfonic acid (5 drops) in toluene (200 ml) and the mixture was heated under reflux using a Dean Stark trap for 12 h. After that, toluene was removed under reduced pressure and the crude mixture was dissolved in dichloromethane (200 ml) and extracted with water (pH 5, 3×200 ml). The combined organic layers were dried over sodium sulfate and the volatiles were removed under reduced pressure giving a clear oil (14.0 g, 60.0 mmol, 99%).