Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:32])=[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1)[C:10]([O:17][CH:18]([F:20])[F:19])=[N:11]2.CO.[OH-].[Li+].O>C(O)(=O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:33])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([O:17][CH:18]([F:20])[F:19])[C:9]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=1)=[C:8]2[CH3:32]
Reactant: COC(=O)COc1ccc(Cl)c2nc(OC(F)F)c(Cc3ccc(S(C)(=O)=O)cc3)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1c(Cc2ccc(S(C)(=O)=O)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)O)c12
Yield: 95.5 %

Procedure:
A solution of [8-chloro-2-difluoromethoxy-3-(4-methanesulfonylbenzyl)-4-methylquinolin-5-yloxy]acetic acid methyl ester (0.14 g), methanol (5.0 mL), saturated aqueous lithium hydroxide solution (0.5 mL) and water (0.4 mL) was stirred at room temperature for 35 minutes. The pH of the solution was adjusted to 5 by the addition of glacial acetic acid and the methanol removed under reduced pressure. The resulting precipitate was collected by filtration, washed with water and dried to afford title compound as a white solid 0.13 g.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[N:19]1([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH:28]=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[CH:2]1[N:1]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:26]=2)[C:5](=[O:7])[CH2:4][CH2:3]1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(N2CCCCC2)c1
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1cccc(N2CCCCC2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with commercially available 3-(piperidin-1-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.57 min.; [M+H]+: 394.99 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](F)(F)F.[Al+3].[Cl-:13].[Cl-:14].[Cl-].[C:16]1([CH3:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:22][C:16]1[CH:21]=[CH:20][C:19]([C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])([Cl:14])[Cl:13])=[CH:18][CH:17]=1
Reactant: FC(F)(F)c1ccccc1Cl
Reactant: [Cl-]
Reactant: Cc1ccccc1
Agent: [Al+3]
Product: Cc1ccc(C(Cl)(Cl)c2ccccc2Cl)cc1

Procedure:
From 2-chlorobenzotrifluoride (180 mg, 1 mmol), AlCl3 (400 mg, 3 mmol) and toluene (92 mg, 1 mmol), light yellow oil (345 mg, 120% crude).
Reaction SMILES: C(O[C:6](=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[C:14]([CH3:22])([CH3:21])[C:13]2=[O:23])[CH2:9]1)(C)(C)C.ClC1[N:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH2:32]([C:29]1[CH:28]=[N:27][C:6]([NH:7][C@H:8]2[CH2:9][C@H:10]([N:12]3[C:16]4=[N:17][CH:18]=[CH:19][CH:20]=[C:15]4[C:14]([CH3:21])([CH3:22])[C:13]3=[O:23])[CH2:11]2)=[N:31][CH:30]=1)[CH3:33]
Reactant: CCc1cnc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](N2C(=O)C(C)(C)c3cccnc32)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCc1cnc(N[C@H]2C[C@H](N3C(=O)C(C)(C)c4cccnc43)C2)nc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
1-(Trans-3-aminocyclobutyl)-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one hydrochloride (intermediate 26, 100 mg, 0.329 mmol), 2-chloro-5-ethylpyrimidine (0.047 mL, 0.329 mmol), and potassium carbonate (0.079 mL, 1.315 mmol) were mixed in DMSO (0.7 mL) in a microwave vial. The reaction mixture was stirred at 80° C. for 16 hours. The temperature was increased to 100° C. and the reaction stirred for another 9 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated. The resulting crude product was purified via silica gel flash column chromatography eluting with 0 to 100% ethyl acetate in hexanes to yield 1-(trans-3-((5-ethylpyrimidin-2-yl)amino)cyclobutyl)-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one as an off-white solid. M+1: 338.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (t, J=7.63 Hz, 3 H) 1.31 (s, 6 H) 2.26-2.37 (m, 2 H) 2.43 (q, J=7.63 Hz, 2 H) 3.15-3.26 (m, 2 H) 4.47-4.62 (m, 1 H) 5.16 (quin, J=8.20 Hz, 1 H) 7.07 (dd, J=7.24, 5.28 Hz, 1 H) 7.48 (d, J=6.46 Hz, 1 H) 7.75 (dd, J=7.24, 1.76 Hz, 1 H) 8.21 (dd, J=5.28, 1.56 Hz, 2 H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[F:21][C:22]1[CH:31]=[CH:30][C:25]([CH:26]=[CH:27][CH2:28]Br)=[CH:24][CH:23]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:16][CH2:17][N:18]([CH2:28]/[CH:27]=[CH:26]/[C:25]4[CH:30]=[CH:31][C:22]([F:21])=[CH:23][CH:24]=4)[CH2:19][CH2:20]3)=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(Cc2ccc(N3CCNCC3)cc2)cc1
Reactant: Fc1ccc(C=CCBr)cc1
Product: Fc1ccc(/C=C/CN2CCN(c3ccc(Cc4ccc(F)cc4)cc3)CC2)cc1

Procedure:
The same procedure was followed as in Example 11 using the compound (10) synthesized in Example 3 and 4-fluorocinnamyl bromide to produce the above.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[C:19]([C:21]#[C:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[S:14][C:13]([CH3:15])=[N:12][C:11]=2[CH:16]=1)=[O:5].[Se](=O)=[O:28]>O1CCOCC1>[S:14]1[C:10]2[CH:9]=[CH:8][C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:17]=[CH:18][C:19]([C:21]#[C:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[CH:20][C:2]=3[CH3:1])=[CH:16][C:11]=2[N:12]=[CH:13]1.[OH:28][CH2:15][C:13]1[S:14][C:10]2[CH:9]=[CH:8][C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:17]=[CH:18][C:19]([C:21]#[C:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:20][C:2]=3[CH3:1])=[CH:16][C:11]=2[N:12]=1
Reactant: Cc1nc2cc(NC(=O)c3ccc(C#CC(C)(C)C)cc3C)ccc2s1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: Cc1cc(C#CC(C)(C)C)ccc1C(=O)Nc1ccc2sc(CO)nc2c1
Product: Cc1cc(C#CC(C)(C)C)ccc1C(=O)Nc1ccc2scnc2c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 2-methyl-N-(2-methylbenzo[d]thiazol-5-yl)-4-(3,3-dimethylbut-1-ynyl)benzamide (50 mg, 0.14 mmol), selenium dioxide (46 mg, 0.41 mmol), and 1,4-dioxane (10 mL) was stirred under an atmosphere of nitrogen at 80° C. overnight. After cooling, the mixture was filtered through Celite® and the filtrate was treated with aq. NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), and concentrated under vacuum. The residue was dissolved in THF-H2O (2:1) (10 mL) and NaBH4 (50 mg) was added slowly. The mixture was stirred at rt for 2 h and then acidified with 1N HCl. After treated with aq. NaHCO3, the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated under vacuum. The residue was purified by preparative thin-layer chromatography to give N-(benzo[d]thiazol-5-yl)-2-methyl-4-(3,3-dimethylbut-1-ynyl)benzamide (compound 198-11 mg) as a light yellow solid and N-(2-(hydroxymethyl)benzo[d]thiazol-5-yl)-2-methyl-4-(3,3-dimethylbut-1-ynyl)benzamide (compound 197-27 mg) as a light yellow solid.
Reaction SMILES: [CH:1]1[C:17]2[CH2:16][C@H:15]3[N:18]([CH2:20][CH2:21][C@@:7]45[C@H:14]3[CH:13]=[CH:12][C@H:10]([OH:11])[C@@H:8]4[O:9][C:5]([C:6]=25)=[C:3]([OH:4])[CH:2]=1)[CH3:19].[OH-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO.O>[CH2:24]([C:3]1([OH:4])[C:5]2[O:9][C@@H:8]3[C@@:7]45[CH2:21][CH2:20][N:18]([CH3:19])[C@@H:15]([C@@H:14]4[CH:13]=[CH:12][C@@H:10]3[OH:11])[CH2:16][C:17]([C:6]5=2)=[CH:1][CH2:2]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1CC[C@]23C4=C5O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1CC4=CCC5(O)Cc1ccccc1
Reaction time: 3.5 h
Yield: 70.1 %

Procedure:
A solution of morphine (14.27 g, 50.0 mmol), NaOH (2.04 g, 51.0 mmol), and benzylbromide (8.47 g, 49.5 mmol) in MeOH (150 ml) and water (50 ml) was stirred at rt. for 3.5 hr., evaporated in vacuo to remove MeOH. The residue was extracted with CH2Cl2 (120 ml). The extract was dried over anhydrous Na2SO4 and evaporated in vacuo to dryness to give a crude residue, which was chromatographed on silica gel (column: d=6.5 cm, I=10.5 cm; eluting solvent: 15% MeOH in CH2Cl2) to obtain 3-benzylmorphine (13.1 g, 70% yield). The Rf value in TLC and the IR spectrum of the product were comparable to those obtained from an authentic sample.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5]([N:11]=1)=[N:6][CH:7]=[CH:8][C:9]=2[CH3:10].ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[NH:3][C:4]2[C:5]([N:11]=1)=[N+:6]([O-:20])[CH:7]=[CH:8][C:9]=2[CH3:10]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nc2nccc(C)c2[nH]1
Solvent: ClC(Cl)Cl
Product: Cc1nc2c([nH]1)c(C)cc[n+]2[O-]
Temperature: 25 °C
Yield: 96.9 %

Procedure:
To a solution of 2,7-dimethyl-1H-imidazo[4,5-b]pyridine (4.29 g) in chloroform (43 ml) was added m-chloroperbenzoic acid (80%, 7.55 g) at room temperature, and the mixture was refluxed under heating for 1 hr. After cooling to room temperature, the reaction mixture was directly purified by silica gel column chromatography (chloroform/methanol=9/1) and pulverized in ethyl acetate to give the objective compound (4.61 g) as a brown powder.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]3[CH:20]=[C:21]([S:23](=[O:37])(=[O:36])[NH:24][C:25]4[CH:30]=[C:29]([O:31][CH3:32])[C:28]([Cl:33])=[CH:27][C:26]=4[O:34][CH3:35])[S:22][C:18]=3[CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.S1C2C=CC=NC=2C=C1>C(#N)C>[ClH:33].[Cl:33][C:28]1[C:29]([O:31][CH3:32])=[CH:30][C:25]([NH:24][S:23]([C:21]2[S:22][C:18]3[CH:17]=[CH:16][N:15]=[C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[C:19]=3[CH:20]=2)(=[O:37])=[O:36])=[C:26]([O:34][CH3:35])[CH:27]=1
Reactant: COc1cc(NS(=O)(=O)c2cc3c(N4CCN(C(=O)OC(C)(C)C)CC4)nccc3s2)c(OC)cc1Cl
Agent: c1cnc2ccsc2c1
Solvent: CC#N
Product: COc1cc(NS(=O)(=O)c2cc3c(N4CCNCC4)nccc3s2)c(OC)cc1Cl
Product: Cl

Procedure:
The synthesis was preformed essentially as described in Method H-L from 4-[2-(4-chloro-2,5-dimethoxy-phenylsulfamoyl)-thieno[3,2-c]pyridin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.112 mmol, 1 equiv.) was used as the thienopyridine in Method C. Yield: 14.7 mg. LC/MS: tR=0.610 (System: 30% to 60% ACN in 1.5 min, YMC), Purity: 92%. MS: 469 (M+1) 1H NMR (270 MHz, DMSO-d6) δ ppm 3.17 (s, 1H) 3.27 (s, 4H) 3.38 (s, 3H) 3.58 (d, J=4.22 Hz, 4H) 3.77 (s, 3H) 7.08 (s, 1H) 7.69 (d, J=5.81 Hz, 1H) 7.81 (s, 1H) 8.16 (d, J=5.81 Hz, 1H) 9.07 (s, 1H) 10.17 (s, 1H).
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[S:39](Cl)(=[O:41])=[O:40]>N.CO>[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[S:39]([N:11]1[C:12]2[C:8](=[C:7]3[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]3=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)(=[O:40])=[O:41]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc2ccccc2c1)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 27.5 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. Naphthalene-2-sulfonyl chloride (23 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (5.2 mg). MS m/z 379 [M+H]+.
Reaction SMILES: [CH2:1]([N:13]1[N:17]=[N:16][C:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].ClC(Cl)(O[C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[F:37][C:38]1[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:39]=1[NH2:40]>>[F:37][C:38]1[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:39]=1[NH:40][C:29](=[O:35])[N:18]([C:15]1[N:16]=[N:17][N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(F)cc1F
Reactant: CCCCCCCCCCCCn1nnc(Nc2ccccc2)n1
Product: CCCCCCCCCCCCn1nnc(N(C(=O)Nc2ccc(F)cc2F)c2ccccc2)n1

Procedure:
In a manner similar to Example 1, 2-dodecyl-N-phenyl-2H-tetrazol-5-amine was reacted with triphosgene and 2,4-difluoroaniline to give the title compound, mp=55°-57° C.
Reaction SMILES: C(O)(=O)[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)C(O)=[O:5].[CH:13]([OH:16])([CH3:15])[CH3:14].[CH:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:2]1([OH:16])[CH:3]=[CH:7][CH:8]=[CH:9][CH:10]=1.[CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:5])([CH3:15])[CH3:14]
Reactant: CC(C)O
Reactant: O=C(O)c1ccccc1C(=O)O
Reactant: c1ccccc1
Product: CC(C)c1ccccc1O
Product: Oc1ccccc1

Procedure:
Besides the phthalic acid (with quantitative reclamation) it was also possible to isolate considerable amounts of isopropanol, benzene, phenol, isopropylphenol, and cresols from the reaction mixture—by distillation and extraction.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.Cl[C:19]([O:21][CH3:22])=[O:20].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:19](=[O:20])[O:21][CH3:22])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: COC(=O)Cl
Reactant: Cc1nnc2ccc(-c3cccc(N)c3)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 3 h

Procedure:
To a solution of 1.0 g of 3-methyl-6-[3-(amino)phenyl]-1,2,4-triazolo[4,3-b]pyridazine in 200 ml of dichloromethane was added 0.36 ml of methyl chloroformate and 0.81 ml of diisopropylethylamine. The mixture was stirred for 3 hours and the solid collected, giving 0.9 g of [3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]carbamic acid, methyl ester. A 0.8 g portion of this compound was suspended in 100 ml of dimethylformamide together with 0.15 g of hexane washed sodium hydride (50% in oil). After 30 minutes, 0.22 ml of ethyl iodide was added. This mixture was stirred 2 hours, then poured into saturated aqueous sodium bicarbonate and extracted with dichloromethane. The extracts were combined, dried and evaporated in vacuo. The residue in dichloromethane:methanol (95:5) was filtered through a short pad of silica gel and the filtration was concentrated. The resulting solid was recrystallized from dichloromethane-hexane, giving 0.32 g of the desired product as off-white crystals, mp 176°-178° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[O:11]1[CH:15]=[CH:14][C:13]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([NH2:25])[CH:23]=3)[NH:18][CH:17]=2)=[CH:12]1.CCN(CC)CC>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:25][C:22]2[CH:23]=[C:24]3[C:16]([C:13]4[CH:14]=[CH:15][O:11][CH:12]=4)=[CH:17][NH:18][C:19]3=[N:20][CH:21]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1cnc2[nH]cc(-c3ccoc3)c2c1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cnc2[nH]cc(-c3ccoc3)c2c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.3 %

Procedure:
4-Fluorobenzoyl chloride (29.7 mg, 0.19 mmol) was added to a solution of amine 48 (25 mg, 0.125 mmol), DMAP (1.53 mg, 12.5 μmol) and Et3N (12.6 mg, 0.125 mmol) in DMF (0.6 mL). The mixture was stirred at r.t. overnight, concentrated and separated by means of LCMS (column LUNA 10 μ C18(2) 00G-4253-V0 250×50 mm) using water—MeCN (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to afford 49 (2.13 mg, 5%). 1H NMR (400 MHz; CDCl3+3 drops of CD3OD) δ 6.45 (dd, J=1.9, 0.9 Hz, 1H), 6.91 (t, J=1.8 Hz, 2H), 7.22 (s, 1H), 7.23 (t, J=1.7 Hz, 1H), 7.56 (m, 1H), 7.73-7.76 (m, 2H), 8.15 (d, J=2.1 Hz, 1H), 8.25 (d, J=2.3 Hz, 1H); MS (ES) m/z 363 (MH++MeCN).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])(C)C.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][CH2:30]Br)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].BrC[C:34]1[CH:43]=[C:42]2C(C(Cl)=NC=N2)=[CH:36][CH:35]=1>>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:30][CH2:29][CH2:28][CH:25]2[CH2:26][CH2:27][N:22]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH2:23][CH2:24]2)[C:10](=[O:14])[CH2:9]1)=[O:7])[C:4]1[CH:42]=[CH:43][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCBr)CC1
Reactant: Clc1ncnc2cc(CBr)ccc12
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Product: CC(C)(C)OC(=O)N1CCC(CCCN2CCN(C(=O)OCc3ccccc3)CC2=O)CC1

Procedure:
The title compound is prepared as described in EXAMPLE 72, Part A, substituting 3-oxopiperazine-1-carboxylic acid benzyl ester for 3-oxopiperazine-1-carboxylic acid tert-butyl ester and 4-(3-bromopropyl)-piperidine-1-carboxylic acid tert-butyl ester for 7-bromomethyl-4-chloroquinazoline. The title compound is obtained as a white foam. 1H NMR (CDCl3, 300 MHz) δ7.38 (m, 5H), 5.12 (s, 2H), 4.18 (m, 4H), 3.73 (m, 2H), 3.33 (m, 4H), 2.66 (m, 2H), 1.58 (m, 6H), 1.42 (s, 9H), 1.38 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4]N1CC(C)(C)N(CC2C=C(C3C=CC(O)=CC=3F)N=C3NN=C(C)C=23)CC1(C)C.[CH3:35][O:36][CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[N:50]=[C:49]3[N:51]([CH:55]4[CH2:60][CH2:59][CH2:58][CH2:57][O:56]4)[N:52]=[C:53]([CH3:54])[C:48]3=[C:47]([CH2:61][N:62]3[CH2:67][C:66]([CH3:69])([CH3:68])[NH:65][CH2:64][C:63]3([CH3:71])[CH3:70])[CH:46]=2)=[CH:41][CH:40]=1.BrCC(OC)=O>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][N:65]1[CH2:64][C:63]([CH3:71])([CH3:70])[N:62]([CH2:61][C:47]2[CH:46]=[C:45]([C:42]3[CH:41]=[CH:40][C:39]([O:38][CH2:37][O:36][CH3:35])=[CH:44][CH:43]=3)[N:50]=[C:49]3[N:51]([CH:55]4[CH2:60][CH2:59][CH2:58][CH2:57][O:56]4)[N:52]=[C:53]([CH3:54])[C:48]=23)[CH2:67][C:66]1([CH3:69])[CH3:68]
Reactant: COCOc1ccc(-c2cc(CN3CC(C)(C)NCC3(C)C)c3c(C)nn(C4CCCCO4)c3n2)cc1
Reactant: COC(=O)CN1CC(C)(C)N(Cc2cc(-c3ccc(O)cc3F)nc3[nH]nc(C)c23)CC1(C)C
Agent: COC(=O)CBr
Product: COCOc1ccc(-c2cc(CN3CC(C)(C)N(CC(=O)OC)CC3(C)C)c3c(C)nn(C4CCCCO4)c3n2)cc1

Procedure:
The title compound was prepared in analogy to Example 74 ({4-[6-(2-Fluoro-4-hydroxy-phenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ylmethyl]-2,2,5,5-tetramethyl-piperazin-1-yl}-acetic acid methyl ester employing 6-(4-Methoxymethoxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-4-(2,2,5,5-tetramethyl-piperazin-1-ylmethyl)-1H-pyrazolo[3,4-b]pyridine and methyl bromoacetate and was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][N:10]([C:19](=[S:30])[NH:20][S:21]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)(=[O:23])=[O:22])[N:9]=2)=[CH:4][CH:3]=1.[CH2:31](N(CC)CC)C.CI>CC(C)=O>[CH3:31][S:30][C:19]([N:10]1[CH2:11][CH:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:9]1)=[N:20][S:21]([N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)(=[O:22])=[O:23]
Reactant: CCN(CC)CC
Reactant: O=S(=O)(NC(=S)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1)N1CCCCC1
Solvent: CI
Solvent: CC(C)=O
Product: CSC(=NS(=O)(=O)N1CCCCC1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.1 %

Procedure:
Part B: To a stirred solution of 3-(4-chlorophenyl)-4-phenyl-N-((piperidin-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-thiocarboxamide (30 gram, 64.9 mmol) in acetone (1 L) is added triethylamine (18.0 mL, 130 mmol). To the resulting yellow solution is added methyl iodide (9.12 g, 64 mmol) and the resulting solution is stirred for 16 hours at room temperature. The formed precipitate is removed by filtration. The filtrate is washed with water, concentrated in vacuo to give a yellow solid. Recrystallisation from MTBE gives 3-(4-chlorophenyl)-N-((piperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidothioic acid methyl ester (27.9 gram, 90% yield). MP: 192-194° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:9][CH2:8][C:6]=2[N:7]=1.O.C(O)(=O)C>CC(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][NH:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1ncc2c(n1)CCN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Solvent: CC(=O)O
Solvent: CC(C)=O
Solvent: O
Product: Nc1ncc2c(n1)CCNC2
Yield: 80 %

Procedure:
2-Amino-5,6,7,8-tetrahydro-6-triphenylmethylpyrido-[4,3-d]pyrimidine (80 mg, 0.20 mmol) was mixed with water (0.5 ml) and acetic acid (0.5 ml) and heated on a steam bath for 5 minutes. Addition of acetone provided a homogeneous mixture. Removal of solvents gave an oil, which was purified by flash column chromatography (eluant: 89:10:1 chloroform:methanol:concentrated ammonium hydroxide) to provide the title product (24.3 mg, 0.16 mmol, 80% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[OH:18][CH2:19][CH2:20][N:21]([CH2:32][CH2:33]O)[S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23].Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:33][CH2:32][N:21]([CH2:20][CH2:19][OH:18])[S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])=[O:15])[CH:7]=[CH:6]2
Reactant: Cc1ccc(S(=O)(=O)N(CCO)CCO)cc1
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2cc([C@H](C)C(=O)OCCN(CCO)S(=O)(=O)c3ccc(C)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid(naproxen, 5.0 g, 21.7 mmol), N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide (16.89 g, 65.1 mmol) and N,N-dimethylaminopyridine (DMAP, 0.530 g, 4.34 mmol) in CH2Cl2 (250 mL) and DMF (3 mL) at room temperature was added 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDAC, 4.99 g, 26.05 mmol). The reaction mixture was stirred overnight at room temperature, and then partitioned between CH2Cl2 and HCl (1N). The aqueous layer was washed with CH2Cl2 and the combined organic extracts were washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with EtOAC/hexane (1:1) to give the title compound as a thick oil (7.15 g, 15.16 mmol, 70% yield): 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J=8.6 Hz, 2H), 7.66 (m, 1H), 7.67 (d, J=8.6 Hz, 2H), 7.40 (dd, J=1.7, 8.5 Hz, 1H), 7.29 (d, J=8.1 Hz, 2H), 7.18 (dd, J=2.5, 8.8 Hz, 1H), 7.14 (d, J=2.4 Hz, 1H), 4.28 (m, 2H), 3.95 (s, 3H), 3.88 (q, J=7.2 Hz, 1H), 3.38 (m, 2H), 3.09 (t, J=5.1 Hz, 2H), 2.44 (s, 3H), 2.18 (t, J=6.0 Hz, 1H), 1.61 (d, J=7.2 Hz, 3H). Mass spectrum (API-TIS) m/z 472 (MH+), 489 (M+18+).