Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([NH:11][CH:12]([C:14](Cl)=[O:15])[CH3:13])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:17]([NH2:19])[CH3:18]>ClCCl>[CH2:17]([NH:19][C:14](=[O:15])[CH:12]([CH3:13])[NH:11][S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2])[CH3:18]
Reactant: Cc1ccc(S(=O)(=O)NC(C)C(=O)Cl)cc1
Reactant: CCN
Solvent: ClCCl
Product: CCNC(=O)C(C)NS(=O)(=O)c1ccc(C)cc1

Procedure:
A solution of 125 grams of tosyl-DL-alanyl chloride (A. F. Beecham, J. Am. Chem. Soc., 79, 325-7) in 800 ml. of dichloromethane was added with stirring to 73 grams of anhydrous ethylamine and 400 ml. of dichloromethane in a reaction flask equipped with a dry ice condenser. The mixture was refluxed 4 hours after addition was completed. The reaction mixture was extracted with water then dried over magnesium sulfate. The solvent was removed in vacuo. The residue was slurried with diethyl ether and filtered to obtain tosyl-DL-alanine ethylamide, m.p. 106°-107°C.
Reaction SMILES: C([Sn]([C:14]1[N:15]([CH3:19])[CH:16]=[CH:17][CH:18]=1)(CCCC)CCCC)CCC.C(C1(C)C(O)=C(C(C)(C)C)C=CC1)(C)(C)C.Cl[C:37]1[O:38][C:39]2[C:40](=[C:42]([C:54]#[N:55])[C:43]([CH3:53])=[C:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:45]=2[F:46])[N:41]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[F:46][C:45]1[C:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[C:43]([CH3:53])[C:42]([C:54]#[N:55])=[C:40]2[C:39]=1[O:38][C:37]([C:14]1[N:15]([CH3:19])[CH:16]=[CH:17][CH:18]=1)=[N:41]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)C1=C(O)C(C)(C(C)(C)C)CC=C1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2)c(F)c2oc(-c3cccn3C)nc2c1C#N

Procedure:
Tributylstannyl-1-methylpyrrole (389 mg, 1.05 mmol), bis(triphenylphosphine)palladium(II) dichloride (49 mg, 0.07 mmol), and a catalytic amount of 2,6-di-tert-butylcresol (2 mg) were added to a toluene (20 ml) solution of 2-chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (200 mg, 0.70 mol), followed by stirring under heat under nitrogen atmosphere for 3 hours. After cooling, the reaction liquid was filtered, and the solvent of the filtrate was evaporate away under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of n-hexane/ethyl acetate (9:1, v/v→5:1, v/v) to obtain a main product. After washing with isopropyl ether, the entitled compound (50 mg, 22%) was collected by filtration as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@H:5]([CH2:7][CH2:8][OH:9])[CH2:4][O:3]1.O[N:12]1C(=O)C2C(=CC=CC=2)C1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.O.NN>C(Cl)Cl>[CH3:1][C:2]1([CH3:10])[O:6][C@H:5]([CH2:7][CH2:8][O:9][NH2:12])[CH2:4][O:3]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC1(C)OC[C@@H](CCO)O1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: NN
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC1(C)OC[C@@H](CCON)O1
Yield: 43.4 %

Procedure:
The title compound was prepared using the procedure described for Example 2K by using (R)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol (4.28 mL, 30 mmol), CH2Cl2 (100 mL), 2-hydroxyisoindoline-1,3-dione (4.9 g, 30 mmol), triphenylphosphine (11.8 g, 45 mmol), diisopropylazodicarboxylate (8.8 ml, 45 mmol) and hydrazine hydrate (6.0 mL, 60 mmol) to afford 2.1 g (43%, over two steps) of (R)—O-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)hydroxylamine (2X) as a pale yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.13 (s, 3H), 1.18 (s, 3H), 1.53-1.71 (m, 2H), 3.53 (m, 2H), 3.79-3.89 (m, 1H), 3.89-4.01 (m, 1H), 4.63-4.81 (m, 1H). MS (ES) [M+H] calculated for C2H16NO3, 162.11; found 162.0.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH:5]([CH:8]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH:9]1[CH3:20])([CH3:7])[CH3:6].[C:21](Cl)(=[O:23])[CH3:22]>[N+](C)([O-])=O>[C:21]([C:14]1[CH:15]=[C:16]2[C:11]([C:10]([CH3:19])([CH3:18])[CH:9]([CH3:20])[CH:8]2[CH:5]([CH3:7])[CH3:6])=[CH:12][C:13]=1[CH3:17])(=[O:23])[CH3:22]
Reactant: Cc1ccc2c(c1)C(C)(C)C(C)C2C(C)C
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CC(=O)c1cc2c(cc1C)C(C)(C)C(C)C2C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
At 0°-5° C. a solution of 4 g AlCl3 in 50 ml nitromethane is added to a mixture of 6 g 1-isopropyl-2,3,3,5-tetramethyl indan (obtained according to example I or II) and 25 g acetyl chloride. Then the reaction mixture is stirred at room temperature during 30 min. and poured out into ice and extracted three times with ether. The solution in ether is washed neutral, dried and evaporated. The residue is distilled under diminished pressure to obtain 6-acetyl-1-isopropyl-2,3,3,5-tetramethyl indan in a yield of 95%. B.p. 144°-146° C./1 mm Hg; n20D =1,5301.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([C:16]([O:18]CC)=O)[C:11](OCC)=[O:12].C(N(CC)CC)C.[NH2:28][C:29]1[N:33]=[CH:32][NH:31][N:30]=1.[OH-].[Na+]>O>[OH:18][C:16]1[C:10]([C:3]2[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=2[F:9])=[C:11]([OH:12])[N:30]2[N:31]=[CH:32][N:33]=[C:29]2[N:28]=1
Reactant: Nc1nc[nH]n1
Reactant: CCOC(=O)C(C(=O)OCC)c1c(F)cc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Product: Oc1nc2ncnn2c(O)c1-c1c(F)cc(F)cc1F
Temperature: 180 °C
Reaction time: 6 h

Procedure:
A mixture of 22 mmol of diethyl 2-(2,4,6-trifluorophenyl)malonate, 24 mmol of triethylamine and 22 mmol of 3-amino-1,2,4-triazole was heated with stirring at 180° C. for 6 hours. The reaction mixture was then cooled to 50° C., admixed with a solution of 2.2 g of sodium hydroxide in 25 ml of water and stirred for 30 minutes. The aqueous phase was washed with ether and then acidified with conc. hydrochloric acid. The precipitated colorless solid was filtered off, washed with water and diisopropyl ether and dried. The yield of the title compound was 85% (m.p.: 200-201° C.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10]([N:40]1[CH2:41][CH2:42][CH:37]([CH3:36])[CH2:38][CH2:39]1)=[O:12])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1CCNCC1
Reactant: CC(C)(C)OC(=O)NC(CCc1ccccc1Cl)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC1CCN(C(=O)C(CCc2ccccc2Cl)NC(=O)OC(C)(C)C)CC1
Reaction time: 0.17 h
Yield: 84.4 %

Procedure:
A mixture of 1.7 g (5.4 mmol) of 2-[(tert-butoxycarbonyl)amino]-4-(2-chlorophenyl)butanoic acid, 2.1 g (11 mmol) of EDC, 1.5 g (11 mmol) HOBt, and 1.9 mL (11 mmol) of iPrNEt in 25 mL of CH2Cl2 is stirred for 10 min, and 0.77 mL (6.5 mmol) of 4-methylpiperidine is added. After stirring overnight, the mixture is washed twice with 10% citric acid, and once each with water, saturated NaHCO3, water, and brine. The extract is concentrated to provide 1.8 g (85%) of tert-butyl{3-(2-chlorophenyl)-1-[(4-methylpiperidin-1-yl)carbonyl]propyl}carbamate.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[C:3](=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[O:2]1.[OH-:12].[K+]>CCO.O.[N+]([O-])([O-])=O.[Ag+]>[CH2:1]1[O:11][C:10]2[C:3](=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]([OH:12])=[O:6])[O:2]1
Reactant: [OH-]
Reactant: O=Cc1cccc2c1OCO2
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cccc2c1OCO2
Reaction time: 2 h

Procedure:
To a solution of 0.85 g (5.66 mmol) of 2,3-methylenedioxybenzaldehyde (Aldrich) in EtOH at 0° C. was added a solution of 2.12 g (12.45 mmol) of AgNO3 in 7.5 mL of H2O. To this was then added a solution of 1.74 g (31.4 mmol) of KOH in 12 mL of H2O. After 2 h, the reaction mixture was filtered and the filter was washed with EtOH. The filtrate was concentrated and the pH was adjusted to pH=2 to 3 with 6N HCl. The title compound precipitated out and was isolated by filtration to give the title compound. 1H NMR (CDCl3) δ6.16 (s, 2H), 6.92 (t, 1H, J=8 Hz), 7.04 (d, 1H, J=8 Hz), 7.48 (d, 1H, J=8 Hz);
Reaction SMILES: [C@H:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl[C:16]1[N:17]=[N:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][CH:21]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:22]1([C:19]2[N:18]=[N:17][C:16]([N:5]3[CH2:6][CH:1]4[CH2:7][C@H:4]3[CH2:3][N:2]4[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:21][CH:20]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CC2C[C@H]1CN2
Reactant: Clc1ccc(-c2ccccc2)nn1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CC1CN2c1ccc(-c2ccccc2)nn1

Procedure:
1.0 g (5.0 mmol) of 1,1-dimethylethyl (1S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, 1.14 g (6.0 mmol) of 3-chloro-6-phenylpyridazine and 0.84 ml (6.0 mmol) of triethylamine in 45 ml of toluene are introduced into a 100 ml three-necked round-bottomed flask and the mixture is refluxed for 72 h.
Reaction SMILES: [Mg].[CH2:2](Br)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].CN([CH:24]=[O:25])C>CCOCC>[CH:24](=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CN(C)C=O
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCBr
Agent: [Mg]
Solvent: CCOCC
Product: CCCCC/C=C\C/C=C\CCCCCCCCC=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 218.2 %

Procedure:
A 100 mL round bottom flask charged with magnesium turnings (462 mg, 19.0 mmol) and a stir bar was dried with a high temperature heat gun for 5 minutes. The flask was cooled to room temperature under nitrogen then charged with THF (25 mL). Linoleyl bromide (1.9 g, 5.76 mmol) was added drop wise and the solution was heated to 45° C. for 3 hours under nitrogen. Upon completion, DMF (1.3 mL, 16.7 mmol) was added slowly and the solution was stirred for 1 hour at room temperature. The solution was diluted with ether (75 mL) and washed with 5% HCl (3×50 mL). The ether solution was dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography (column: 2″×10″; eluted with 2% ether/hexanes) to afford the title compound as a colorless oil (3.5 g, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[I-].[NH2:23][N+:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]3[N:23]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: N[n+]1ccccc1
Reactant: CCOC(=O)/C=C/c1ccc(-c2ccccn2)c(OC)c1
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccc(-c3ccccn3)c(OC)c2)nn2ccccc12

Procedure:
A solution of ethyl(2E)-3-(3-methoxy-4-pyridin-2-ylphenyl)prop-2-enoate (55 mg, 0.2 mmol) and 1-aminopyridinium iodide (86 mg, 0.4 mmol) in DMF (1 mL) was stirred at rt for 2 days open to the atmosphere. The deep purple reaction mixture was diluted with CH2Cl2 (25 mL) and washed with a saturated solution of sodium thiosulfate (25 mL) and brine (25 mL), then dried (MgSO4) and concentrated. The residue was purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (1:9 to 3:2) to afford the desired ethyl 2-(3-methoxy-4-pyridin-2-ylphenyl)pyrazolo[1,5-a]pyridin-3-carboxylate as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][CH:4]=1)=O.[F:13][C:14]([F:31])([F:30])[CH2:15]P(=O)(C1C=CC=CC=1)C1C=CC=CC=1>>[F:13][C:14]([F:31])([F:30])[CH:15]=[CH:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1
Reactant: O=P(CC(F)(F)F)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Product: O=C(O)c1ccc(C=CC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
4 Å molecular sieves (7 g; activated powder) were suspended in 8.8 ml of 1.0 m tbaf in thf and stirred overnight at room temperature under nitrogen. To the solution was added methyl 4-formylbenzoate (160 mg; 0.97 mmol) and 2,2,2-trifluoroethyldiphenylphosphine oxide (415 mg; 1.46 mmol) in 10 ml of anhydrous thf. After stirring overnight, the solvents were evaporated to dryness. The residue was dissolved in EtOAc and washed with water and brine. The organic was dried over Na2SO4, filtered and evaporated. The residue was dissolved in 10 ml of thf and 10 ml of 1N NaOH and refluxed for 30 minutes. The mixture was acidified with concentrated HCl and extracted three times with EtOAc. The organic layers were washed with brine and dried over Na2SO4, filtered and evaporated to give the desired product as a brown powder (125 mg; 60%). M/z=217 (m+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7]Br.[CH3:13][O-:14].[Na+]>CO>[N+:10]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH2:7][O:14][CH3:13])([O-:12])=[O:11]
Reactant: C[O-]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CBr
Agent: [Na+]
Solvent: CO
Product: COCc1cc(Cl)ccc1[N+](=O)[O-]
Yield: 92.5 %

Procedure:
2.15 g of 5-chloro-2-nitrobenzylbromide is dissolved in approximately 25 ml methanol at room temperature. 1.86 g of 25% sodium methoxide in methanol is added and stirring continued for 0° C. 1 hour after which 10 wt % additional sodium methoxide is added to complete the conversion. The solvent is evaporated and the residue is dissolved in 100 ml dichloromethane and washed with 25 ml water (2X). Evaporation provided 1.6 g of 4-nitro-3-methoxymethylchlorobenzene. 1H-NMR (500 MHz, CDC13) δ (ppm) 3.527 (s, 3H), 4.838 (s, 2H), 7.399-7.416 (dd, 1H), 7.824-7.826 (d, 1H), 8.066-8.084 (d, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[N:9]=[CH:10][C:11]([C:26]2[CH:36]=[CH:35][C:29]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])=[CH:28][CH:27]=2)=[N:12][C:13]=1[C:14]1[O:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[OH:25])=[N:17][N:18]=1.Br[CH2:38][CH3:39].O>CN(C=O)C>[NH2:7][C:8]1[N:9]=[CH:10][C:11]([C:26]2[CH:36]=[CH:35][C:29]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])=[CH:28][CH:27]=2)=[N:12][C:13]=1[C:14]1[O:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH2:38][CH3:39])=[N:17][N:18]=1
Reactant: CCBr
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccccc4O)o3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccccc1-c1nnc(-c2nc(-c3ccc(C(=O)N(C)C)cc3)cnc2N)o1
Temperature: 62.5 °C
Reaction time: 0.33 h
Yield: 72.5 %

Procedure:
Potassium carbonate (25.46 mg, 0.1842 mmol) was added to a mixture of 4-[5-amino-6-[5-(2-hydroxyphenyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-N,N-dimethyl-benzamide (50 mg, 0.1228 mmol) in DMF (1 mL) at room temperature. Colour change observed from yellow to orange. The resulting suspension was heated at 60-65° C. and bromoethane (14.72 mg, 10.01 μL, 0.1351 mmol) was added slowly. After the addition is complete the reaction heated at 60-65° C. for 30 min. The reaction mixture was cooled to room temperature. Water (2 mL) was added slowly at and the mixture stirred at room temperature for 20 min. A precipitate formed and was filtered and washed with water. The solid was re-dissolved in DCM and dried over MgSO4, filtered and evaporated to dryness. The solid was triturated with acetonitrile to give the product as a yellow solid (38.3 mg, 73% yield); 1H NMR (400.0 MHz, DMSO) d 1.49 (t, 3H), 2.97-3.02 (m, 6H), 4.24-4.29 (m, 2H), 7.17-7.18 (m, 1H), 7.20 (d, 1H), 7.32-7.35 (m, 2H), 7.53 (d, 1H), 7.65 (br s, 2H), 8.05 (d, 1H), 8.17 (d, 2H) and 8.99 (s, 1H) ppm; MS (ES+) 431.24
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:18][CH2:17][NH:16][CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:26](Cl)=[O:27])[CH2:22][CH2:21]1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:18][CH2:17][N:16]([C:26]([N:23]4[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]4)=[O:27])[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(C#CC2=NOC3(CCNC3)C2)c1
Reactant: CN1CCN(C(=O)Cl)CC1
Solvent: ClCCl
Product: CN1CCN(C(=O)N2CCC3(CC(C#Cc4cccc(Cl)c4)=NO3)C2)CC1
Reaction time: 20 h
Yield: 40.6 %

Procedure:
To a solution of Compound 27d (150 mg, 0.58 mmol) in dichloromethane (10 mL) was added TEA (0.248 mL, 1.73 mmol) followed by 4-methyl-1-piperazinecarbonyl chloride (122 mg, 0.748 mmol). The reaction mixture was kept under stirring for 20 h. After evaporation the residue was purified by means of automated isocratic RP chromatography (SP01®TM-Biotage; NH4HCO3/AcCN 55:45) affording 91 mg of the title compound as a gummy oil. Yield: 49%.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([I:14])=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][CH2:18][C:17]3([O:23][CH2:22][CH2:21][O:20]3)[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:24]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[CH2:1]([C:8]1[C:13]([I:14])=[CH:12][C:11]([Cl:24])=[C:10]([N:15]2[CH2:19][CH2:18][C:17]3([O:20][CH2:21][CH2:22][O:23]3)[CH2:16]2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Ic1ccc(N2CCC3(C2)OCCO3)nc1Cc1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cc(I)c(Cc2ccccc2)nc1N1CCC2(C1)OCCO2
Yield: 59.2 %

Procedure:
A mixture of 500 mg of 2-benzyl-3-iodo-6-(3,3-ethylenedioxypyrrolidine-1-yl)pyridine obtained in Example 118c, 174 mg of N-chlorosuccinimide and 5 ml of N,N-dimethylformamide was stirred under heating for 5 hours in an oil bath kept at 60° C. 1 ml of aqueous solution containing 1 mol of sodium thiosulfate was added to the reaction solution, the mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography using 5-10% ethyl acetate/hexane, to give 320 mg of 2-benzyl-3-iodo-5-chloro-6-(3,3-ethylenedioxypyrrolidine-1-yl)pyridine, and then the title compound was obtained in the same procedures as in Example 118d.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[N:6]([CH3:14])[C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[CH:9][N:8]=2.O[C:16]1[CH:48]=[CH:47][C:19]([CH2:20][CH:21]2[S:25][C:24](=[O:26])[N:23]([C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]2=[O:46])=[CH:18][CH:17]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:14][N:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[N:13]=[C:5]1[CH2:4][CH2:3][CH2:2][O:1][C:16]1[CH:48]=[CH:47][C:19]([CH2:20][CH:21]2[S:25][C:24](=[O:26])[N:23]([C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]2=[O:46])=[CH:18][CH:17]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1c(CCCO)nc2cccnc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cn1c(CCCOc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cccnc21

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 750 mg of 2-(3-hydroxypropyl)-3-methylimidazo[5,4-b]pyridine (prepared as described in Preparation 34), 1.83 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.98 ml of tributylphosphine, 990 mg of 1,1'-(azodicarbonyl)dipiperidine and 20 ml of toluene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 1:1 to 0:1 by volume as the eluent, to give 550 mg of the title compound, melting at 76°-81° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:30][C:31]([O:33]C)=O)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=4[Cl:28])(=[O:20])=[O:19])=[C:13]([F:29])[CH:12]=3)[C:3]=12.[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][CH2:39][NH2:40]>>[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][CH2:39][NH:40][C:31](=[O:33])[CH2:30][N:8]1[C:4]2=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]2[C:10]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=3[Cl:28])(=[O:20])=[O:19])=[C:13]([F:29])[CH:12]=2)=[N:9]1
Reactant: CN(C)CCCN
Reactant: COC(=O)Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)c2c(N)ncnc21
Product: CN(C)CCCNC(=O)Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)c2c(N)ncnc21

Procedure:
The representative procedure for amide formation was used in the reaction of methyl 2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetate (0.025 g, 0.048 mmol) with 3-(dimethylamino)propylamine (1 mL). Purification by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 6.7-7.3 min) afforded N1-[3-(dimethylamino)propyl]-2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetamide as an off-white powder (0.015 g, 0.025 mmol): 1H NMR (DMSO-d6, 400 MHz) δ 8.20 (m, 1H), 7.96 (m, 1H), 7.76 (m, 1H), 7.43 (t, 1H), 7.30 (m, 2H), 4.93 (s, 2H), 3.12 (m, 2H), 2.82 (m, 2H), 2.50 (s, 6H), 1.73 (m, 2H); MS (M−H)− 593.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23]2[N:27]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:26]3[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=3[N:24]=2)[CH2:18][CH2:17]1)=S.[S]>[Hg]=O.O1CCCC1>[F:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][N:27]2[C:26]3[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=3[N:24]=[C:23]2[NH:22][CH:19]2[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]3[NH:1][C:2]4[CH:7]=[CH:6][N:5]=[CH:4][C:3]=4[N:8]=3)[CH2:17][CH2:18]2)=[CH:30][CH:31]=1
Reactant: Nc1ccncc1NC(=S)NCCCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: O=[Hg]
Agent: [S]
Solvent: C1CCOC1
Product: Fc1ccc(Cn2c(NC3CCN(CCCCNc4nc5cnccc5[nH]4)CC3)nc3ccccc32)cc1
Yield: 29 %

Procedure:
A mixture of 18 parts of N-(4-amino-3-pyridinyl)-N'-[4-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]butyl]thiourea, 7 parts of mercury(II)oxide, 1 part of sulfur and 180 parts of tetrahydrofuran was stirred and refluxed for 5 hours. The reaction mixture was filtered hot over Hyflo and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol saturated with ammonia, (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of tetrahydrofuran and trichloromethane, yielding 5 parts (29%) of N-[4-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]butyl]-1H-imidazo[4,5-c]pyridin-2-amine; mp. 228.2° C. (compound 121).