Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:13]=[C:12]([O:14][CH:15]([F:17])[F:16])[N:11]([CH3:18])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O-])(=O)C.[Na+].[Cl:24]Cl>C(O)(=O)C>[F:1][C:2]1[C:3]([C:9]2[C:13]([Cl:24])=[C:12]([O:14][CH:15]([F:16])[F:17])[N:11]([CH3:18])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cn1nc(-c2ncc(Cl)cc2F)cc1OC(F)F
Reactant: ClCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cn1nc(-c2ncc(Cl)cc2F)c(Cl)c1OC(F)F
Temperature: 60 °C

Procedure:
17.92 g of 3-(3-fluoro-5-chloro-2-pyridyl)-5-difluoromethoxy-1-methyl-[1H]-pyrazole (Example H15) are initially introduced into 60 ml of glacial acetic acid together with 10.6 g of sodium acetate. The mixture is heated up to 60° C., while stirring, and a saturated solution of chlorine in glacial acetic acid is added until TLC analysis of a worked-up sample shows a complete conversion (silica gel 60 F254; eluting agent: n-hexane/ethyl acetate 2/1; UV; Rf value of the starting material 0.34; Rf value of the product 0.48). The mixture is then concentrated to dryness in vacuo and the resulting residue is partitioned between sodium bicarbonate solution and ethyl acetate. The organic phase is washed with brine, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. 19.8 g of the desired target compound (pure according to TLC) are obtained. Melting point 95-96° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[C:5]([CH3:9])([CH3:8])[CH2:6][OH:7])[CH3:2].[CH3:11]I>CC#N>[CH2:1]([O:3][C:4](=[O:10])[C:5]([CH3:9])([CH3:8])[CH2:6][O:7][CH3:11])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)C(C)(C)CO
Solvent: CC#N
Product: CCOC(=O)C(C)(C)COC
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.6 %

Procedure:
To a solution of 2,2-dimethyl-3-hydroxypropionic acid ethyl ester (1.3 g, 10.0 mmol) in CH3CN (30 mL) was added Ag2O (11.5 g, 50.0 mmol) and methyl iodide (0.56 mL, 11 mmol). The reaction mixture was stirred at rt for 12 h and quenched with a saturated aqueous NH4Cl. The mixture was filtered though Celite, the filtrate concentrated in vacuo, and the residue was purified by column chromatography (EtOAc/Hex=1/10) to give the title compound (1.34 g, 91.2%).
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26].[S:29]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30]1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][N:8]1[C:9](=[O:11])[C:10]2[C:2]([C:31]3[CH:32]=[CH:33][S:29][CH:30]=3)=[C:3]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[S:4][C:5]=2[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7]1=[O:13]
Reactant: OB(O)c1ccsc1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Br)c(Cc3ccccc3C(F)(F)F)sc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3ccsc3)c(Cc3ccccc3C(F)(F)F)sc21
Temperature: 80 °C

Procedure:
5-Bromo-3-methyl-1-(2-methylpropyl)-6-[[2-(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione, (0.35 g, Example 1c)), thiophene-3-boronic acid (0.053 g), barium hydroxide octahydrate (0.15 g) and tetrakis(triphenylphosphine)palladium (0) (0.0097 g) in ethylene glycol dimethyl ether (6 ml) and water (1 ml) were combined in a sealed vial and stirred with heating at 80° C. for 18 hours. After cooling, the reaction mixture was absorbed onto silica and purified by flash silica chromatography eluting with 25% ethyl acetate in isohexane to give an oil. The oil was triturated with isohexane, filtered and dried under vacuum to give the title compound as a beige solid (0.020 g).
Reaction SMILES: [CH:1]12[O:7][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2]2.[N-:8]=[N+:9]=[N-:10].[Na+]>CC(C)=O.O>[N:8]([CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][CH:1]1[OH:7])=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=[N-]
Reactant: C1CCC2OC2C1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NC1CCCCC1O
Yield: 10.6 %

Procedure:
To a solution of 7-oxa-bicyclo[4.1.0]heptane (0.300 g, 3.06 mmol) in acetone (3 mL) was added sodium azide (0.504 g, 7.75 mmol) in water (3 mL). The reaction mixture was refluxed for 12 h. The acetone was removed in vacuo and the product was extracted with ethyl acetate (5 mL). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to provide the title compound (46 mg).
Reaction SMILES: C([N:5]1[C:9](C)=[C:8]([C:11]2[CH:16]=[CH:15]C=CC=2)C=N1)CC#C.[CH2:17]([N:21]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([CH3:32])=[N:22]1)[CH2:18][C:19]#[CH:20].CC1N(CCC#CC2C=CC=CN=2)N=CC=1C1C=CC=CC=1>>[CH3:32][C:23]1[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:25][N:21]([CH2:17][CH2:18][C:19]#[C:20][C:9]2[CH:8]=[CH:11][CH:16]=[CH:15][N:5]=2)[N:22]=1
Reactant: C#CCCn1ncc(-c2ccccc2)c1C
Reactant: C#CCCn1cc(-c2ccccc2)c(C)n1
Agent: Cc1c(-c2ccccc2)cnn1CCC#Cc1ccccn1
Product: Cc1nn(CCC#Cc2ccccn2)cc1-c1ccccc1
Yield: 10 %

Procedure:
The title compounds were prepared in accordance with the general method of Example 1, from 255 mg (1.21 mmol) of 1-but-3-ynyl-5-methyl-4-phenyl-1H-pyrazole and 1-but-3-ynyl-3-methyl-4-phenyl-1H-pyrazole. The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 33 mg (0.11 mol, 10%) of 2-(4-(3-methyl-4-phenyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine and 2-(4-(5-methyl-4-phenyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine as a orange oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)[C:12]([F:23])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH2:29]([O:28][C:26]([CH:25]=[N:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:17]=3)[C:12]([F:23])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1)=[O:27])[CH3:30]
Reactant: CCOC(=O)CBr
Reactant: Nc1cccc(Nc2ncc(F)c(Nc3cccc(N)c3)n2)c1
Product: CCOC(=O)C=Nc1cccc(Nc2nc(N(CC(=O)OCC)c3cccc(N=CC(=O)OCC)c3)ncc2F)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine, N2,N4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and ethyl bromoacetate were reacted together to give N2,N4-bis(3-ethoxycarbonylmethyleneaminophenyl)-N2-(ethoxycarbonylmethyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 25.65 min.; purity: 92.5%; MS (m/e): 569.08 (MH+).
Reaction SMILES: Cl.[N:2]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.Cl.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:40]=[CH:41][CH:42]=1)[CH2:24][N:25]1[C:29]2=[N:30][CH:31]=[N:32][C:33]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[C:28]2[CH:27]=[N:26]1)[CH3:19].ON1C2C=CC=CC=2N=N1.N=C=N.C(=O)([O-])[O-]>CN(C)C=O.C(N(CC)CC)C.C(Cl)Cl>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:40]=[CH:41][CH:42]=1)[CH2:24][N:25]1[C:29]2=[N:30][CH:31]=[N:32][C:33]([N:34]3[CH2:35][CH2:36][N:37]([C:13]([C@H:10]4[CH2:9][CH2:8][C@H:7]([N:2]5[CH2:3][CH2:4][CH2:5][CH2:6]5)[CH2:12][CH2:11]4)=[O:15])[CH2:38][CH2:39]3)=[C:28]2[CH:27]=[N:26]1)[CH3:19]
Reactant: CCOc1cccc(Cn2ncc3c(N4CCNCC4)ncnc32)c1
Reactant: O=C(O)[C@H]1CC[C@H](N2CCCC2)CC1
Agent: Cl
Agent: N=C=N
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1cccc(Cn2ncc3c(N4CCN(C(=O)[C@H]5CC[C@H](N6CCCC6)CC5)CC4)ncnc32)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To trans-4-(1-pyrrolidinyl)cyclohexanecarboxylate hydrochloride (26 mg; compound obtained in Reference example 87(2)) is added successively methylene chloride (3.5 mL), 1-(3-ethoxybenzyl)-4-piperazin-1-yl-1H-pyrazolo[3,4-d]pyrimidine dihydrochloride (30 mg), 0.5M 1-hydroxybenzotriazole in N,N-dimethylformamide (219 μL), triethylamine (35.6 μL) and N-cyclohexylcarbodiimide-N′-propyloxymethylpolystylene (310.4 mg, PS-Carbodiimide, 0.94 mmol/g, Argonaut Technology) and the mixture is stirred at room temperature for 24 hours by using a parallel synthesizer (Quest 210; Argonaut Technology). To the reaction mixture is added macroporous triethylammoniummethylpolystylene carbonate (120 mg, MP-Carbonate 3.04 mmol/g; Argonaut Technology) and the mixture is stirred at room temperature for 3 hours. The liquid layer is separated from the reaction mixture and the residual resin is washed successively with chloroform and methanol. The liquid layer and the washings are combined and concentrated by centrifugal concentrator. The resultant crude product is purified by HPLC (XTerra PerpMS C18 column; Waters Inc., Solvent; 10 mM ammonium carbonate:methanol=1:1→5:95) to give 1-(3-ethoxybenzyl)-4-[4-[[trans-4-(1-pyrrolidinyl)cyclohexyl]carbonyl]piperazin-1-yl]-1H-pyrazolo[3,4-d]-pyrimidine (27 mg, yield; 71%) as an amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:15])=[C:4]([C:11](F)(F)[F:12])[C:5]([F:10])=[C:6]([Cl:9])[C:7]=1[F:8].ClS(O)(=O)=[O:18]>>[Cl:1][C:2]1[C:3]([F:15])=[C:4]([C:5]([F:10])=[C:6]([Cl:9])[C:7]=1[F:8])[C:11]([F:12])=[O:18]
Reactant: O=S(=O)(O)Cl
Reactant: Fc1c(Cl)c(F)c(C(F)(F)F)c(F)c1Cl
Product: O=C(F)c1c(F)c(Cl)c(F)c(Cl)c1F
Yield: 82.1 %

Procedure:
A mixture of 520 g of 3,5-dichloro-2,4,6-trifluorobenzotrifluoride and 400 g of chlorosulphonic acid is heated for 4 hours, whilst stirring, as described in Example 1. 392 g of 3,5-dichloro-2,4,6-trifluorobenzoyl fluoride (82% of the theoretical yield) of boiling point 90° to 95° C./15 mbars and nD20 :1.5007 are obtained by distillation.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].Cl[C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:18])[C:8]=1[NH:19][C:20](=[O:22])[CH3:21].O>C1C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:18])[C:8]=1[NH:19][C:20](=[O:22])[CH3:21]
Reactant: CC(=O)NC1=C(Cl)C(=O)c2ccccc2C1=O
Reactant: COCCN
Solvent: O
Solvent: c1ccccc1
Product: COCCNC1=C(NC(C)=O)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Methoxyethylamine (0.8 ml) was added to a solution of N-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphthalenyl)acetamide (1.0 g) in benzene (20 ml) and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution and the mixture was extracted with chloroform. The organic layer was washed with water and brine and then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was recrystallized from ethyl acetate to give N-[3-(2-methoxyethyl)amino-1,4-dihydro-1,4-dioxo-2-naphthalenyl]acetamide (0.87 g) as a red powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[N:4][N:5]([CH2:8][C:9]([OH:11])=O)[C:6]=1[CH3:7].[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:31]3[CH2:30][CH2:29][CH2:28][NH:27][C:26]=3[CH:25]=[N:24]2)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[N:4][N:5]([CH2:8][C:9]([N:27]2[CH2:28][CH2:29][CH2:30][C:31]3[N:23]([C:20]4[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=4)[N:24]=[CH:25][C:26]2=3)=[O:11])[C:6]=1[CH3:7]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCCc2c1cnn2-c1ccc(F)cc1

Procedure:
The compound was prepared from 2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method B. The product mixture was washed with 2×1 M NaHSO4 and 2×1.5 M KOH and the organics were eluted through a silica plug. The resulting slurry was concentrated to a white solid that was triturated with 1:1 hexanes:EtOAc to give the title compound as a crystalline white solid (75.9 mg). 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 8.34 (s, 0.7H), 7.57 (s, 0.3H), 7.44 (m, 2H), 7.15 (m, 2H), 5.24 (s, 0.4H), 5.13 (s, 1.6H), 3.92 (m, 0.5H), 3.84 (m, 1.5H), 2.87 (m, 2H), 2.33 (s, 2.3H), 2.32 (s, 0.7H), 2.12 (m, 1.5H), 2.05 (m, 0.5H); MS: (ES) m/z calculated for C19H17ClF4N5O [M+H]+ 442.1, found 442.0.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.[C:27](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH3:27])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Yield: 84 %

Procedure:
A suspension of 6.90 g of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 4, 10.4 g of potassium carbonate, and 2.3 mL of methyl iodide in 40 mL of DMF is stirred at 90° C. for 4 hours, then cooled and diluted with 350 mL of water. The resulting solid is filtered, washed well with water, and dried under vacuum. Flash chromatography of the solid on silica using 3-5% methanol in dichloromethane provides 6.02 g of the title compound as a solid.
Reaction SMILES: [C@@H:1]1([NH:10][C:11]2[N:16]=[CH:15][N:14]=[C:13]([NH:17][C@@H:18]3[CH2:22][C@H:21]([CH2:23][O:24][S:25]([NH:28]C(=O)OC(C)(C)C)(=[O:27])=[O:26])[C@@H:20]([OH:36])[CH2:19]3)[CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[S:25](=[O:27])(=[O:26])([O:24][CH2:23][C@H:21]1[CH2:22][C@@H:18]([NH:17][C:13]2[CH:12]=[C:11]([NH:10][C@@H:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]3)[N:16]=[CH:15][N:14]=2)[CH2:19][C@@H:20]1[OH:36])[NH2:28]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)OC[C@H]1C[C@@H](Nc2cc(N[C@H]3CCc4ccccc43)ncn2)C[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)OC[C@H]1C[C@@H](Nc2cc(N[C@H]3CCc4ccccc43)ncn2)C[C@@H]1O
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
To a solution of tert-butyl ({[(1R,2S,4R)-4-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}amino)-2-hydroxycyclopentyl]methoxy}sulfonyl)carbamate (50.0 mg, 0.0962 mmol) in DCM (2.00 mL) was added trifluoroacetic acid (0.500 mL, 6.49 mmol), and the mixture was stirred for 30 min. The mixture was concentrated in vacuo and the residue was purified via silica gel chromatography eluting with 10% MeOH in DCM, and the product was dissolved in MeOH and treated with solid NaHCO3. The suspension was filtered and the filtrate was purified via silica gel chromatography eluting with 10% MeOH/DCM to afford the title compound as an amorphous solid (12.0 mg, 30%). 1H NMR (CD3OD, 400 MHz) δ: 7.94 (s, 1H), 7.29-7.12 (m, 4H), 5.53 (s, 1H), 5.32 (bs, 1H), 4.23-4.08 (m, 4H), 3.06-2.96 (m, 1H), 2.93-2.82 (m, 1H), 2.61-2.50 (m, 1H), 2.45-2.34 (m, 1H), 2.26-2.15 (m, 1H), 2.08-1.98 (m, 1H), 1.95-1.78 (m, 2H), 1.37-1.25 (m, 2H) ppm. LC/MS: Rt=1.29 min, ES+ 420. (AA standard).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[CH:9][C:8]=2[CH:12]=1)N.[CH2:13]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)[CH2:14][CH3:15]>>[CH2:13]([N:16]1[CH2:21][CH2:20][C:19]2[NH:2][C:4]3[C:12]([C:18]=2[CH2:17]1)=[C:8]1[CH:9]=[CH:10][S:11][C:7]1=[CH:6][CH:5]=3)[CH2:14][CH3:15]
Reactant: NNc1ccc2sccc2c1
Reactant: CCCN1CCC(=O)CC1
Agent: Cl
Product: CCCN1CCc2[nH]c3ccc4sccc4c3c2C1

Procedure:
This compound is formed analogously to that described in Example 15, from 2 g of 5-hydrazinobenzothiophene hydrochloride and 1.7 g of 1-propyl-4-piperidone. Melting point: 143°-144° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:14](=O)[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[CH2:19][CH2:18]1.B.[Na].Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1.C(O)C>[ClH:29].[CH3:2][C:3]1[N:7]([C:8]2[N:9]=[CH:10][CH:11]=[CH:12][N:13]=2)[N:6]=[CH:5][C:4]=1/[CH:14]=[CH:15]/[CH2:16][N:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[CH2:21][CH2:22]1
Reactant: Cc1c(C(=O)CCN2CCN(c3cccc(Cl)c3)CC2)cnn1-c1ncccn1
Agent: B
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(/C=C/CN2CCN(c3cccc(Cl)c3)CC2)cnn1-c1ncccn1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 83 %

Procedure:
10 g of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-[4-(3-chlorophenyl)-1-piperazinyl]-1-propanone hydrochloride was dissolved in a solvent mixture comprising 600 ml of tetrahydrofuran and 600 ml of ethanol. After cooling to 0° C., 2.5 g of sodium boron hydride was added thereto and the resulting mixture was stirred at the same temperature for 45 minutes. To the reaction mixture was further added 500 mg of sodium boron hydride followed by stirring for 1 hour. After adding 30 ml of 4N hydrochloric acid to the reaction mixture, the solvent was distilled off. To the residue thus obtained were added 1,200 ml of tetrahydrofuran and 5.9 g of p-toluenesulfonic acid monohydrate. Then the mixture was heated under reflux for 2 hours. After evaporating the solvent, it was neutralized with an aqueous solution of sodium hydroxide and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was dissolved in ethyl acetate. Then 22 ml of a 1N hydrochloric acid/ethanol solution was added thereto. The insoluble matters were collected by filtration and recrystallized from ethanol. Thus 4.0 g of the title compound was obtained.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[CH:4][N:3]=1.[CH3:19][NH:20][CH3:21]>>[CH3:19][N:20]([C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[CH:4][N:3]=1)[CH3:21]
Reactant: Fc1ccccc1Cn1cnc2cnc(Cl)nc21
Reactant: CNC
Product: CN(C)c1ncc2ncn(Cc3ccccc3F)c2n1

Procedure:
In a manner analogous to that described in Example 2 it is also possible, by reacting 2-chloro-9-(2-fluorobenzyl)-9H-purine (Example 7) with N,N-dimethylamine, to obtain the 2-(N,N-dimethylamino)-9-(2-fluorobenzyl)-9H-purine, which has a melting range of from 112° to 113° (methanol/diethyl ether), the reaction mixture being heated for 24 hours at from 80° to 85°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:13]=3[NH:14][N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[BH4-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]3[CH:22]([OH:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:13]=3[NH:14][N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2n[nH]c3c2C(=O)c2ccccc2-3)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2n[nH]c3c2C(O)c2ccccc2-3)cc1OC

Procedure:
A mixture of 3-(3,4-dimethoxyphenyl)indeno[1,2-c]pyrazol-4(1H)-one (0.6 g) and sodium borohydride (0.16 g) in absolute ethanol (100 ml) was boiled under reflux for 5 hours. The reaction mixture was cooled and the ethanol removed under reduced pressure. Water (20 ml) was added and the mixture was extracted with ethyl acetate (3×50 ml). The combined ethyl acetate extracts were washed with water, dried, filtered and evaporated to give a solid which was purified by preparative high performance liquid chromatography on a Dynamax C18 reverse phase (41.4×250 mm) column using acetonitrile/triethylammonium formate buffer as eluant to give 3-(3,4-dimethoxyphenyl)-1,4-dihydroindeno[1,2-c]pyrazol-4-ol, m.p. 197-199° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[N:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][CH:6]=1)#[N:2].[C:13](OC)(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[SH:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:21]=[C:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[S:16][C:11]([C:9]2[N:10]=[C:5]([CH2:4][CH2:3][C:1]#[N:2])[CH:6]=[CH:7][CH:8]=2)=[N:12]1
Reactant: COC(=O)c1ccccc1S
Reactant: N#CCCc1cccc(C#N)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: N#CCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 53 %

Procedure:
6-(2-Cyanoethyl)-2-pyridinecarbonitrile (0.28 g, 1.8 mmol) and methyl thiosalicylate (0.36 g, 2.1 mmol) were dissolved in toluene (2 ml), and triethylamine (0.37 ml, 2.7 mmol) was added thereto. The reaction mixture was refluxed for 6 hrs and kept at room temperature. The precipitated crystals were collected, washed with toluene and recrystallized from ethanol to give the titled compound (0.28 g, 54%) as white crystals.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:14][O:15][C:16]1[C:29]2[C:28](=[O:30])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[O:31][CH3:32])[C:21](=[O:33])[C:20]=2[CH:19]=[C:18]([CH:34]=[N:35]O)[CH:17]=1.FC(F)(F)C(O)=O>N1C=CC=CC=1.O1CCOCC1>[CH3:14][O:15][C:16]1[C:29]2[C:28](=[O:30])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[O:31][CH3:32])[C:21](=[O:33])[C:20]=2[CH:19]=[C:18]([C:34]#[N:35])[CH:17]=1
Reactant: COc1cccc2c1C(=O)c1c(OC)cc(C=NO)cc1C2=O
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Product: COc1cccc2c1C(=O)c1c(OC)cc(C#N)cc1C2=O
Temperature: 65 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic anhydride (4.62 ml, 6.87 g), was added dropwise with magnetic stirring to a suspension of 9,10-dihydro-4,5-dimethoxy-9,10-dioxoanthracene-2-aldoxime (10.74 ml, 9.24 g) in pyridine (10.5 ml, 10.336 g) and dioxan (100 ml) at room temperature under nitrogen. The temperature rose from 23° C. to 31° C. The mixture was then heated at 65° C. for 2 hours. More trifluoroacetic anhydride (4.62 ml, 6.87 g) was added at 65° C. and the mixture was stirred for a further 1 hour at 65° C. More trifluoroacetic acid (1 ml, 1.487 g) was added and the mixture stirred for 16 hours at 65° C., cooled, filtered, washed with water (200 ml) and dried in vacuo at 70° C. to give the nitrile, m.p. 266°-268° C.
Reaction SMILES: C(O[Si:4]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])C.[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15]>>[CH2:14]([N:16]([Si:4]([O:5][CH2:6][CH3:7])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])[CH2:17][CH3:18])[CH3:15]
Reactant: CCNCC
Reactant: CCO[Si](OCC)(OCC)OCC
Product: CCO[Si](OCC)(OCC)N(CC)CC
Reaction time: 8 h

Procedure:
Comparative experiment 6 to The reacted product 13 was performed by direct amino group substitution of tetraethoxy silane not via Grignard reagent. Namely, a 200 mL-volume flask, equipped with an agitating blade and a soxhlet extractor loaded with a monocular shive 4A-stuffed cylindrical paper filter, was employed, of which inside was substituted for nitrogen using a vacuum pump. Then, 83.3 g (0.40 mol) of tetraethoxysilane and 73.1 g (1.0 mol) of diethylamine were fed into the flask, and heated and revolved for 8 hours. Analysis of the resultant reacted solution by gas chromatography confirmed no target amino-substituted product but tetraethoxysilane of the starting substance only.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[Cl:7][C:8]1[CH:16]=[C:15]([Cl:17])[C:14]([S:18](Cl)(=[O:20])=[O:19])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[OH-].[Na+].Cl>O>[Cl:17][C:15]1[CH:16]=[C:8]([Cl:7])[C:9]([C:10]([OH:12])=[O:11])=[CH:13][C:14]=1[S:18]([OH:20])=[O:19]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)c(Cl)cc1Cl
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(S(=O)O)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A three liter flask equipped with a mechanical stirrer, thermometer and dropping funnel is charged with sodium sulfite (378 g,; 3.0 moles) and water (1 liter). The solution is cooled in an ice bath and treated with 2,4-dichloro-5-chlorosulfonylbenzoic acid (290 g.; 1.0 mole) and 10N sodium hydroxide (290 ml.) simultaneously in small portions over a period of 1.5 hours keeping the temperature below 20° C. and the pH of the reaction at 9. When the addition of the reagents is complete, the reaction is stirred for 3 hours at 25° C. then cooled to 10° C. and acidified with concentrated hydrochloric acid (440 ml.). The 2,4-dichloro-5-carboxybenzenesulfinic acid which precipitates is filtered, washed with ice water, then used in the next step without further purification.