Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:15])=[C:4]([CH:12]=[CH:13][CH:14]=1)[NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8].[CH2:16]([Li])[CH2:17][CH2:18]C.ICCC>C1COCC1.CCCCCC.O>[CH2:15]([C:3]1[C:2]([Cl:1])=[CH:14][CH:13]=[CH:12][C:4]=1[NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:16][CH2:17][CH3:18]
Reactant: Cc1c(Cl)cccc1NC(=O)C(C)(C)C
Reactant: [Li]CCCC
Solvent: CCCI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCc1c(Cl)cccc1NC(=O)C(C)(C)C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
A solution of 3-chloro-N-(2,2-dimethylpropionyl)-2-methylaniline (9.79 g) in dry THF (150 ml) was stirred under nitrogen at 0° while a solution of n-butyllithium in hexane was added in a dropwise fashion until a slight orange color was noted. The volume of n-butyllithium solution which had been added was noted, and an equal volume of this n-butyllithium solution was then added in order to complete formation of the dianion of the starting material. The final deep orange solution was then stirred at 0° for 15 min before adding iodopropane (7.92 g). After 15 min, the reaction mixture was cautiously diluted with water (250 ml) and was extracted with ethyl ether (300 ml). The organic layer was washed with brine, dried (MgSO4), and evaporated to afford the title compound as a white solid, 11.38 g (97% yield). Recrystallization from hexane provided an analytical sample, m.p. 88°-89°.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH2:11][CH2:10][CH2:9][C:8]=1[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[B:27](OC(C)C)([O:32]C(C)C)[O:28]C(C)C.Cl>O1CCCC1.CCOCC>[CH2:20]([O:19][C:13]1[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=1[C:8]1[CH2:9][CH2:10][CH2:11][C:7]=1[B:27]([OH:32])[OH:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Clc1ccc(OCc2ccccc2)c(C2=C(Br)CCC2)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: OB(O)C1=C(c2cc(Cl)ccc2OCc2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.7 %

Procedure:
A solution of n-butyllithium (0.73 ml, 1.6M in hexanes, 1.17 mmol) was added to a solution of 1-bromo-2-(2-benzyloxy-5-chlorophenyl)cyclopentene (424 mg, 1.17 mmol) in anhydrous tetrahydrofuran (12 ml) at −78° C. under nitrogen. The resulting solution was stirred for 15 minutes and triisopropyl borate (440 mg, 2.34 mmol) was added. The mixture was allowed to warm to room temperature, 1M hydrochloric acid (20 ml) was added and stirred vigorously for 15 minutes. After diluting with ether the organic phase was dried (magnesium sulphate), evaporated and purified by chromatography on silica (1:4 ethyl acetate/iso-hexane) to give the title compound as a white solid (214 mg, 58%). LC/MS: Rt 3.4, [2 MH−] 637.3.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[N+:14]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19])([O-:16])=[O:15].Cl.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N+:14]([O-:16])=[O:15])=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1cc2ncnc(Nc3ccccc3[N+](=O)[O-])c2cn1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 33.3 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (220 mg, 1.15 mmole) and 2-nitroaniline (2.00 g, 14.5 mmole) is heated to 100° C., then excess dry HCl gas is added to the hot stirred solution, and the mixture stirred at 160° C. for 20 min. The resulting product is neutralized with excess NaHCO3, dissolved in MeOH/CHCl3, dried onto silica gel and chromatographed over silica gel (2-4% MeOH/CH2Cl2) to give 7-amino-4-(2-nitroanilino)pyrido[4,3-d]pyrimidine (108 mg, 33%) as a yellow brown solid. 1H NMR (DMSO) δ 10.40 (1H, brs), 9.24 (1H, brs), 8.20 (1H, brs), 8.12 (1H, brs), 8.01 (2H, brs), 7.75 (1H, brs), 6.70 (2H, brs), 6.43 (1H, brs).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[C:7](=[N:10][OH:11])[C:8]#[N:9].[CH3:12][N:13]=[C:14]=[O:15]>C(OCC)(=O)C.C(N(CC)CC)C>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[C:7](=[N:10][O:11][C:14]([NH:13][CH3:12])=[O:15])[C:8]#[N:9]
Reactant: CN=C=O
Reactant: CN1CCN=C1C(C#N)=NO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CNC(=O)ON=C(C#N)C1=NCCN1C

Procedure:
15.2 g (0.1 mol) of α-[1-methyl-imidazolin-2-yl]-α-oximino-acetonitrile and 6.4 g (0.11 mol) of methyl isocyanate are stirred in 200 ml of ethyl acetate with a few drops of triethylamine for 16 hours. 16 g (76.5% of theory) of end product are filtered off and this is washed with a little ethyl acetate; melting point 186°-190° C. (decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH:12]1([N:18]=[C:19]=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([NH:18][C:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[CH:5]3)=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Nc1ccc2ncccc2c1
Reactant: O=C=NC1CCCCC1
Product: O=C(Nc1ccc2ncccc2c1)NC1CCCCC1

Procedure:
Prepared from 6-aminoquinoline and cyclohexyl isocyanate. m/z (ES+) 270 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[OH:25].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[O:25][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Reactant: Cc1cccc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc(C)c1OCc1ccc(-c2cc(C(N)=O)on2)cc1
Temperature: 90 °C
Yield: 81.2 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 2,6-dimethylphenol (22 mg, 0.18 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 90° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(2,6-dimethyl-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (28 mg, 81%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.39 (br. s., 1H), 8.01 (br. s., 1H), 7.94 (d, J=8.4 Hz, 2H), 7.55-7.69 (m, 3H), 7.00-7.09 (m, 2H), 6.88-6.98 (m, 1H), 4.86 (s, 2H), 2.25 (s, 6H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([N:7]2[C:11]3=[C:12]4[CH:18]=[CH:17][NH:16][C:13]4=[N:14][CH:15]=[C:10]3[NH:9][C:8]2=[O:19])[CH2:2]1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C([O-])([O-])=O.[K+].[K+].[I-].[K+]>O.C(Cl)(Cl)Cl>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([N:7]2[C:11]3=[C:12]4[CH:18]=[CH:17][NH:16][C:13]4=[N:14][CH:15]=[C:10]3[NH:9][C:8]2=[O:19])[CH2:2]1)[CH3:26]
Reactant: CCOC(=O)CBr
Reactant: O=c1[nH]c2cnc3[nH]ccc3c2n1C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)CN1CCCC(n2c(=O)[nH]c3cnc4[nH]ccc4c32)C1
Temperature: 90 °C

Procedure:
A mixture of 1-piperidin-3-yl-3,6-dihydroimidazo[4,5-d]-pyrrolo[2,3-b]pyridin-2(1H)-one (0.030M solution in NMP, 1.00 mL), ethyl bromoacetate (6.7 mg), K2CO3(8.3 mg), potassium iodide (0.3 mg) was heated at 90° C. for 16 hours. Chloroform (4 mL) and water (2 mL) was added and was mixed with Bortex Mixer. The organic phase was separated with 1PS Filter Tube (from Whatman) and evaporated. Purification by preparative high performance liquid chromatography gave ethyl[3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)piperidin-1-yl]acetate (2.8 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:39][O:40][CH2:41][CH2:42][NH:43][CH2:44][CH2:45][O:46][CH3:47]>>[CH3:39][O:40][CH2:41][CH2:42][N:43]([CH2:44][CH2:45][O:46][CH3:47])[C:32]([N:12]1[C:13]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)([CH3:24])[C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)([CH3:16])[N:15]=[C:11]1[C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:6][C:7]=1[O:35][CH:36]([CH3:37])[CH3:38])=[O:33]
Reactant: COCCNCCOC
Reactant: CC(C)Oc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: COCCN(CCOC)C(=O)N1C(c2ccc(C(C)(C)C)cc2OC(C)C)=NC(C)(c2ccc(Cl)cc2)C1(C)c1ccc(Cl)cc1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with bis-(2-methoxyethyl)-amine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C37H49N4O5SCl2 [(M+H)+] 668.3017, observed 668.3010.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH:16]1([N:19]2[CH:24]=[CH:23][C:22](O)=[CH:21][C:20]2=[O:26])[CH2:18][CH2:17]1.CCN(CC)CC>ClCCl>[CH:16]1([N:19]2[CH:24]=[CH:23][C:22]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:21][C:20]2=[O:26])[CH2:18][CH2:17]1
Reactant: O=c1cc(O)ccn1C1CC1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1cc(OS(=O)(=O)C(F)(F)F)ccn1C1CC1
Temperature: 25 °C

Procedure:
Trifluoromethanesulfonic anhydride (0.12 mL) was added to a flask charged with a stir bar, 1-cyclopropyl-4-hydroxy-1H-pyridin-2-one (0.10 g), NEt3 (0.24 mL), and dichloromethane (8 mL) and chilled in an ice/EtOH bath. The resulting mixture was stirred with cooling for 2 h and at ambient temperature for another 2 h. Then, the solution was diluted with dichloro-methane and washed in succession with water, aqueous NaHCO3 solution, and water. The organic solution was dried (MgSO4), the solvent was removed, and the residue was purified by chromatography on silica gel (dichloromethane/methanol 99:1→90:10) to afford the title compound as a resin-like solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([Br:12])=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:13]([N:16]=[C:17]=[O:18])[CH2:14][CH3:15]>C(Cl)(Cl)Cl>[Br:12][C:9]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]([NH:1][C:17]([NH:16][CH2:13][CH2:14][CH3:15])=[O:18])=[N:11][CH:10]=1
Reactant: CCCN=C=O
Reactant: COC(=O)c1cc(N)ncc1Br
Solvent: ClC(Cl)Cl
Product: CCCNC(=O)Nc1cc(C(=O)OC)c(Br)cn1
Temperature: 55 °C
Yield: 94.2 %

Procedure:
Methyl 2-amino-5-bromoisonicotinate (100 g, 433 mmol) was dissolved in chloroform (600 mL) and placed into a 1 L sealed tube. Propyl isocyanate (122.5 mL, 1.29 mol) was then added. The reactor was heated at 55° C. for 72 h at which time the reaction was determined to be complete. The mixture was then cooled to room temperature, concentrated under reduced pressure, and the solid was dissolved in 2:1 ethyl acetate: tetrahydrofuran (3 L). This solution was washed with water (2×200 mL), and the water was back extracted with ethyl acetate (300 mL). The organic layers were then dried with sodium sulfate, filtered, and concentrated yielding 129 g (95%) of methyl 5-bromo-2-(3-propylureido)isonicotinate as a dark yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].CN(C=[O:38])C>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:38])[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(-c2nnc3n2CCCC3c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1cc(-c2nnc3n2CCCC3(O)c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Reaction time: 0.5 h

Procedure:
To a mixture of 8-(3,4-dichlorophenyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine (100 mg) in DMF (2 mL) was added sodium hydride (60%, 9.4 mg) at room temperature, and the mixture was stirred for 30 min in the air. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (40.3 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]([N:8]2[C:12](I)=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:20]([Cu])#[N:21]>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]([N:8]2[C:12]([C:20]#[N:21])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#C[Cu]
Reactant: COc1c(Cl)cccc1-n1nc(C(F)(F)F)cc1I
Solvent: CN1CCCC1=O
Product: COc1c(Cl)cccc1-n1nc(C(F)(F)F)cc1C#N
Temperature: 200 °C
Yield: 33.8 %

Procedure:
To a stirred solution of 1-(3-chloro-2-methoxyphenyl)-5-iodo-3-(trifluoromethyl)-1H-pyrazole (0.2 g, 0.49 mmol, 1.0 eq) in NMP (5 mL) was added CuCN (0.044 g, 0.49 mmol, 1.0 eq) and heated to 200° C. for 2 h. The reaction mixture was passed through celite pad and washed with excess of ethyl acetate. The filtrate was washed with water and ethyl acetate layer was separated, dried (Na2SO4), and the solvent evaporated. The resulting residue was purified by CC using ethyl acetate/PE (1:19) to get 1-(3-chloro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carbonitrile (0.05 g, crude, yellow solid; TLC system: EtOAc/PE (1:9) Rf: 0.5).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.Cl[CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCCN1CCCCC1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(CCN3CCCCC3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 86.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.77 g) and 1-(2-chloroethyl)piperidine hydrochloride (0.55 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-piperidinoethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.76 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, 5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-piperidinoethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide dihydrochloride (0.54 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[C:16]([CH3:18])[CH:15]=[N:14]2)[N:3]=1.SC[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([N:13]2[CH:17]=[C:16]([CH3:18])[CH:15]=[N:14]2)[C:5]([C:11]#[N:12])=[C:6]([S:8][CH2:10][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:7]=1
Reactant: Cc1cnn(-c2nc(N)nc(S(C)=O)c2C#N)c1
Reactant: SCCc1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1cnn(-c2nc(N)nc(SCCc3ccccn3)c2C#N)c1

Procedure:
From 2-amino-4-methanesulfinyl-6-(4-methyl-pyrazol-1-yl)-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 338 (M+H+, 100).
Reaction SMILES: [F:1][C:2]([F:17])([S:13]([OH:16])(=[O:15])=[O:14])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].[OH-].[CH3:19][N+:20]([CH3:23])([CH3:22])[CH3:21]>>[CH3:19][N+:20]([CH3:23])([CH3:22])[CH3:21].[F:17][C:2]([F:1])([S:13]([O-:16])(=[O:15])=[O:14])[C:3]([F:11])([F:12])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6]
Reactant: O=S(=O)(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: C[N+](C)(C)C
Agent: [OH-]
Product: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
Perfluorobutanesulfonic acid tetramethylammonium salt is prepared by neutralising perfluorobutanesulfonic acid and tetramethylammonium hydroxide in aqueous solution. Tetramethylammonium hydroxide is obtainable from Aldrich.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:12])[CH:3]=1.[CH2:13](O)[CH3:14].O.C(=O)(O)[O-]>Cl>[NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([O:8][CH2:13][CH3:14])=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: Nc1cc(F)c(C(=O)O)cc1F
Reactant: CCO
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Product: CCOC(=O)c1cc(F)c(N)cc1F
Yield: 92 %

Procedure:
A solution of 4-amino-2,5-difluorobenzoic acid (intermediate 137; 2.7 g; 0.015 mol) in hydrogen chloride 1.25 mL in ethanol (91 mL, 0.113 mol) was stirred for 24 hours at 60° C. The solvent was removed under reduced pressure and the crude obtained was treated with water and solid bicarbonate to obtain a basic pH, after few minutes stirring an extraction with ethyl acetate was done. The organic layer was washed with brine, dried and the solvent was removed under reduced pressure to give the title compound as a white solid (92%), which was used in the next step without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:33]([C:29]4[CH:30]=[CH:31][CH:32]=[C:27]([CH3:26])[CH:28]=4)(=[O:35])=[O:34])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cccc(C)c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 3-methylbenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:19])[N:9]=[C:10]([C:11]3[O:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=3)[C:3]=12.[CH3:20][NH:21][CH3:22]>C(OCC)(=O)C>[CH3:20][N:21]([CH3:22])[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:19])[N:9]=[C:10]([C:11]3[O:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=3)[C:3]=12
Reactant: CNC
Reactant: Cn1nc(-c2ccc([N+](=O)[O-])o2)c2c(Cl)ncnc21
Solvent: CCOC(C)=O
Product: CN(C)c1ncnc2c1c(-c1ccc([N+](=O)[O-])o1)nn2C

Procedure:
A mixture of 10.0 grams of 4-chloro-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine, 6.0 grams of dimethylamine and 600 milliliters of ethyl acetate was heated at reflux for 30 minutes, cooled and filtered. The filtrate was extracted with three 100 milliliters portions of water. The organic layer was dried over anhydrous magnesium sulphate and evaporated down to dryness. The crystalline product was collected, washed with ethanol and dried. Recrystallisation from ethyl acetate gave 4-dimethylamino-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine having melting point 161°C.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([O:9]CC)=[O:8].[OH-].[Na+].C(O)(=O)C.[Br:18][CH:19]([CH:22]=O)[CH:20]=O>C(O)C>[Br:18][C:19]1[CH:20]=[N:1][C:2]2[N:6]([N:5]=[CH:4][C:3]=2[C:7]([OH:9])=[O:8])[CH:22]=1
Reactant: CCOC(=O)c1cn[nH]c1N
Reactant: O=CC(Br)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)c1cnn2cc(Br)cnc12
Temperature: 70 °C
Yield: 50.9 %

Procedure:
A solution of ethyl 5-amino-1H-pyrazole-4-carboxylate (2 g, 12.89 mmol) and sodium hydroxide (19.34 mL, 38.7 mmol) (aqueous, 2M) in ethanol (30 mL) was heated at 80° C. overnight. The reaction mixture was concentrated in vacuo to give a crude mixture of carboxylate and sodium hydroxide. The crude mixture was dissolved in ethanol (4 mL) and acetic acid (14 mL, 245 mmol). Whilst stirring the mixture, bromomalonaldehyde (1.947 g, 12.90 mmol) was added and then the mixture heated to 70° C. for 1 h. The reaction mixture was allowed to cool and the precipitate was filtered and washed with ethanol. The solid product was dried in a vacuum oven to give the title compound (1.589 g).
Reaction SMILES: [C:1]1(Br)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Mg].[Mg].BrC1C2C(=CC=CC=2)C=CC=1.[CH2:25]([N:27]([CH2:41][CH3:42])[CH2:28][CH2:29][N:30]1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40])[CH3:26]>O1CCCC1>[CH2:41]([N:27]([CH2:25][CH3:26])[CH2:28][CH2:29][N:30]1[C:34]([OH:35])([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:33]2[C:32](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:31]1=[O:40])[CH3:42]
Reactant: Brc1cccc2ccccc12
Reactant: CCN(CC)CCN1C(=O)c2ccccc2C1=O
Agent: [Mg]
Solvent: C1CCOC1
Product: CCN(CC)CCN1C(=O)c2ccccc2C1(O)c1cccc2ccccc12
Reaction time: 2 h

Procedure:
To a tetrahydrofuran solution of magnesium 1-naphthylbromide prepared from 1.22 g of metallic magnesium and 10.35 g of α-bromonaphthalene in 50 ml of tetrahydrofuran was added a solution of 6.16 g of N-(2-diethylaminoethyl)-phthalimide in 10 ml of tetrahydrofuran under ice cooling. After stirring for 2 hours under ice cooling, the mixture was concentrated under reduced pressure. To the residue were added 6.61 g of ammonium sulfate, 100 ml of ethyl ether and 100 ml of water. After shaking, the aqueous layer was discarded and 100 ml of water was added to the organic layer. The pH was adjusted to 1.5 with 4N-hydrochloric acid. After shaking, the organic layer was discarded and 100 ml of ethyl ether was added to the aqueous layer. The pH was adjusted to 11.5 with 10N-sodium hydroxide solution. After shaking, the aqueous layer was discarded. After the organic layer was washed with saturated aqueous sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The crude crystals obtained were recrystallized from diisopropyl ether to give 2.85 g of 2-(2-diethylaminoethyl)-3-hydroxy-3-(1-naphthyl)isoindolin-1-one (Compound 20).