Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.[Br:17][C:18]1[S:19][CH:20]=[C:21]([CH2:23]Cl)[N:22]=1>>[Br:17][C:18]1[S:19][CH:20]=[C:21]([CH2:23][N:3]2[C:4]3[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])[N:22]=1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: ClCc1csc(Br)n1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1csc(Br)n1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 2-bromo-4-(chloromethyl)-1,3-thiazole (Example 311A): MS (ES) m/z 400 (M+1) and 402 (M+1, isotope).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4]Br.C(=O)([O-])[O-].[K+].[K+].[Br:12][C:13]1[C:14]([F:23])=[C:15]([OH:22])[C:16]([OH:21])=[C:17]([O:19][CH3:20])[CH:18]=1.Cl>CN(C=O)C>[Br:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]2[O:21][CH2:2][CH2:3][CH2:4][O:22][C:15]=2[C:14]=1[F:23]
Reactant: BrCCCBr
Reactant: COc1cc(Br)c(F)c(O)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Br)c(F)c2c1OCCCO2
Temperature: 80 °C
Reaction time: 6 h
Yield: 53.3 %

Procedure:
After adding 830 mg of 1,3-dibromopropane and 1.4 g of potassium carbonate to a solution of 880 mg of 4-bromo-3-fluoro-6-methoxybenzene-1,2-diol (Example (41a)) in 10 ml of DMF, the mixture was stirred at 80° C. for 6 hours. After adding 1N hydrochloric acid to the reaction mixture, the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate-heptane) to give the title compound (548 mg) as a solid.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7](C(OC(C)(C)C)=O)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[CH2:16]Br)=[O:5].[CH3:25][NH:26][CH3:27]>C1COCC1>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[CH2:16][N:26]([CH3:27])[CH3:25])=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(Cl)cc(CBr)c2n1C(=O)OC(C)(C)C
Reactant: CNC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(Cl)cc(CN(C)C)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 0.200 g (0.48 mmol) of 7-bromomethyl-5-chloro-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (previously described) in THF (3 ml) at RT, 0.17 ml of dimethyl amine (5.6 M in EtOH) was added. The reaction mixture was stirred at RT for one hour and concentrated under vacuo. The crude was dissolved in CH2Cl2 (1 m) and at RT 0.2 ml of TFA was added and stirring was continued over night. Preparative HPLC (30% CH3CN/H2O) afforded 67 mg (50%) of 5-chloro-7-dimethylaminomethyl-1H-indole-2-carboxylic acid ethyl ester as colorless oil. ES-MS m/e (%): 281.3 (M+H+).
Reaction SMILES: C[Al](C)C.[C:5]1([SH:11])[CH:10]=[CH:9][CH:8]=CC=1.[OH:12][CH:13]([CH2:18][CH3:19])[CH2:14][C:15]([O-:17])=[O:16].Cl>ClCCl>[S:11]1[CH:8]=[CH:9][CH:10]=[C:5]1[O:17][C:15](=[O:16])[CH2:14][CH:13]([OH:12])[CH2:18][CH3:19]
Reactant: CCC(O)CC(=O)[O-]
Reactant: Sc1ccccc1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CCC(O)CC(=O)Oc1cccs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a dry flask on ice, 3 ml of dehydrated dichloromethane was stirred and 1 ml of 2M trimethyl aluminum was slowly added thereto under a nitrogen stream. After that, 1 mmol of thiophenol was slowly added thereto. The mixture was stirred at room temperature for 30 minutes and then 3-hydroxyvalerate dissolved in 3 ml of dehydrated dichloromethane was added thereto. The reaction was monitored by a TLC. To this mixed solution was added 10 ml of dichloromethane and, until generation of bubbles stopped, 10 ml of 3% hydrochloric acid solution was added. The mixed solution was transferred to a separating funnel, washed with 3% hydrochloric acid solution for two times and with saturated saline for two times, dried over magnesium sulfate and evaporated in vacuo to give 258 mg of crude oily 3-hydroxyvalerate thiophenyl ester in dark yellow color. This was purified by a column chromatography (20 cm×1 cm diameter; eluent was hexane:ethyl acetate=2:1) using silica gel 60 to give 44 mg of pure 3-hydroxyvalerate thiophenyl ester as a transparent oil. The yield to the unpurified substance was 17%. Result of NMR analysis of this compound is as follows.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.S(Cl)(Cl)=O.[CH3:26]O>>[CH3:26][O:10][C:9](=[O:11])[CH2:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][CH:13]=2)=[CH:5][CH:6]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CC(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: -10 °C
Reaction time: 2 h

Procedure:
A solution of 2.55 g (8.63 mmol) of the above prepared [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid in 25 ml of methanol was cooled to −10° C.; 1.88 ml (25.9 mmol) of thionyl chloride was added. The reaction mixture was then stirred at ambient temperature for 2 hours. Subsequently, the solution was stirred with ice water, then extracted with three portions of 50 ml of tert.-butyl methyl ether. The combined organic layers were washed with water, aqueous sodium hydrogen carbonate and brine, and dried over anhydrous sodium sulfate. After evaporation of the solvent, 2.6 g of the title compound was obtained as light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][NH2:24]>>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][NH:24][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13]
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Reactant: COc1ccccc1CCN
Product: COc1ccccc1CCNC(=O)c1cc2cc(Cl)ncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 2-(2-methoxyphenyl)ethylamine. The product was purified by chromatography on silica gel eluting with methanol/dichloromethane (3:97) to give the title compound as a yellow solid. δH (CD3OD): 2.94 (2H, t), 3.59 (2H, t), 3.78 (3H, s), 6.84 (1H, t), 6.89 (1H, d), 6.97 (1H, s), 7.12–7.18 (2H, m), 7.60 (1H, s), 8.55 (1H, s); m/z (ES+)=330 [M+H]+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.[O:27]1C[CH:28]1[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:40]=[C:39]([C:41]3[O:45][N:44]=[C:43]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:42]=3[C:52]([F:55])([F:54])[F:53])[O:38][N:37]=2)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[OH:27][CH:28]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:40]=[C:39]([C:41]3[O:45][N:44]=[C:43]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:42]=3[C:52]([F:55])([F:54])[F:53])[O:38][N:37]=2)=[CH:32][CH:31]=1)[CH2:6][N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1
Reactant: FC(F)(F)c1c(-c2ccccc2)noc1-c1nc(-c2ccc(C3CO3)cc2)no1
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CN(CC(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)CCO1
Temperature: 80 °C

Procedure:
4-(tert-Butoxycarbonyl)morpholine-2-carboxylic acid (69.5 mg, 0.301 mmol) was treated with TFA/DCM for 1 hour. Solvents were removed in vacuo and the resulting material was dried. The solids were dissolved in 2-propanol (2 mL) and DMSO (1 mL). 3-(4-(oxiran-2-yl)phenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole (30 mg, 0.075 mmol) and cesium carbonate (98 mg, 0.301 mmol) were added. The reaction mixture was heated at 80° C. overnight. LCMS indicated almost complete conversion to desired product and no starting material. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 21 mg of 4-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)morpholine-2-carboxylic acid as a TFA salt. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.23 (2H, d, J=7.91 Hz), 7.69 (4H, dd, J=12.08, 7.69 Hz), 7.54-7.65 (3H, m), 5.29 (1H, td, J=6.81, 4.39 Hz), 4.41-4.65 (1H, m), 4.08-4.37 (1H, m), 3.92-4.05 (2H, m), 3.56-3.91 (1H, m), 3.44 (3H, t, J=6.81 Hz), 3.12-3.38 (1H, m). MS (m+1)=531. HPLC Peak RT=3.24 minutes (Analytical Method A). Purity=85%.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][O:15][C:16]1[CH:31]=[CH:30][C:19]([C:20]([NH:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][C:28]=2[NH2:29])=[O:21])=[CH:18][CH:17]=1>>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:29][C:28]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[NH:22][C:20](=[O:21])[C:19]2[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:31][CH:30]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(C(=O)Nc2cnccc2N)cc1
Product: COc1ccc(C(=O)Nc2cnccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 49 %

Procedure:
Using 4-tert-butylbenzoyl chloride and a similar procedure to that described for Example 2, Part C, N3-(4-methoxybenzoyl)-3,4-pyridinediamine (300 mg, 1.23 mmol) yielded 243 mg (49%) of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:36]=[CH:35][C:7]2[N:8]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:22]([NH:24][S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])=[O:23])=[CH:15][CH:14]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[CH3:37][Mg]I.O>O1CCCC1>[CH2:11]([C:9]1[N:8]([C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH:21][C:22]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:26])=[O:27])=[O:23])=[CH:17][CH:18]=2)[C:7]2[CH:35]=[CH:36][C:4]([C:1]([OH:3])([CH3:37])[CH3:2])=[CH:5][C:6]=2[N:10]=1)[CH3:12]
Reactant: C[Mg]I
Reactant: CCc1nc2cc(C(C)=O)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2cc(C(C)(C)O)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
A solution of N-[({2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide (Example 78, 100 mg, 0.19 mmol) in tetrahydrofurane (15 ml) was added MeMgI (1.2 ml, 0.99 mmol) dropwise under nitrogen at 0° C. The mixture was stirred at 0° C. for 1 h and then was stirred at rt for 30 min. The mixture was added water (10 ml) and extracted with CH2Cl2(50 ml). The organic layer was washed with brine (10 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with CH2Cl2:methanol (30:1/20:1/10:1) to afford 100 mg (97%) of the title compound as white solids.
Reaction SMILES: C([O:5][C:6](=[O:46])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:29])[NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24](Cl)=[CH:23][C:22]=3[CH3:28])=[CH:17][CH:16]=2)=[CH:9][C:8]=1[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH2:43][CH2:42][C:41]([CH3:45])([CH3:44])[CH2:40][CH:39]=2)[CH:33]=1)(C)(C)C.FC(F)(F)C(O)=O.[ClH:54]>C(Cl)Cl>[Cl:54][C:22]1([CH3:28])[CH2:23][CH:24]=[CH:25][CH:26]=[C:21]1[C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:13]([C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:46])=[O:5])=[C:8]([CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]4[CH2:43][CH2:42][C:41]([CH3:45])([CH3:44])[CH2:40][CH:39]=4)[CH:33]=3)[CH:9]=2)=[O:29])=[CH:20][CH:19]=1
Reactant: Cl
Reactant: Cc1cc(Cl)ccc1-c1ccc(NC(=O)c2ccc(C(=O)OC(C)(C)C)c(CCc3cccc(C4=CCC(C)(C)CC4)c3)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CC=C(c2cccc(CCc3cc(C(=O)Nc4ccc(C5=CC=CCC5(C)Cl)cc4)ccc3C(=O)O)c2)CC1
Reaction time: 8 h

Procedure:
To a stirred solution of 4-{4′-chloro-2′-methyl-biphenyl-4-ylcarbamoyl)-2-[(3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-ethyl}-benzoic acid tert-butyl ester (0.82 g, 1.29 mmol) in CH2Cl2 (30 mL) at room temperature, added trifluoroacetic acid (2.5 ml), and conc HCl (1.0 mL) The reaction mixture was stirred overnight. The organic solvents were removed under reduced pressure. The residue was extracted with ethyl acetate (2×100 mL), dried over MgSO4 and concentrated o afford 4-{2′-chloro-2′-methyl-biphenyl-4-ylcarbamoyl)-2-[(3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-ethyl}-benzoic acid as a solid. 1H NMR (500 MHz, DMSO-d6): 10.05 (s, 1 H), 7.73 (d, J=8.0 Hz, 2 H), 7.48 (d, J=8.5 Hz, 2 H), 7.40 (s, 1 H), 7.29-7.05 (m, 10 H), 5.99 (s, 1 H), 3.96 (t, J=10.5 Hz. 1 H), 2.95 (dd, J=5.0, 14.0 Hz, 1 H), 2.20-2.18 (m, 1 H), 2.14 (t, J=7.5 Hz, 1 H), 2.09 (s, 3 H), 1.89 (bs, 2 H), 1.49 (t, J=7.5 Hz, 1 H), 1.39 (t, J=6.0 Hz, 2 H), 0.84 (s, 6 H). Chiral HPLC conditions: Chiralcel OD-H T=23° C.; mobile phase=10-30% hexane/IPA; flow rate=1.0 mL/min; detection=254, 280, 220 nm retention time in min: 19.81 min (enantiomeric excess: 70.8%)
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][C:5]1=O)[CH:2]=[CH2:3].C1(P(=[CH:40][C:41]([O:43][CH3:44])=[O:42])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.ClCCl>[CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][C:5]1=[CH:40][C:41]([O:43][CH3:44])=[O:42])[CH:2]=[CH2:3]
Reactant: C=CCC1CCN(C(=O)OCc2ccccc2)CC1=O
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=CCC1CCN(C(=O)OCc2ccccc2)CC1=CC(=O)OC
Temperature: 20 °C

Procedure:
A solution containing 16.3 g of (4RS)-4-allyl-1-benzyloxycarbonylpiperidin-3-one in 200 cm3 of toluene was stirred under reflux with methyl (triphenylphosphoranylidene)acetate, under an inert atmosphere, for 16 hours. After cooling to about 20° C., the reaction mixture was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C., the residue obtained, solubilized in 50 cm3 of dichloromethane in the hot state, was purified by chromatography, under a nitrogen pressure of 50 kPa, on a column of silica gel (particle size 20-45μ; diameter 10 cm; height 45 cm), eluting with a cyclohexane-ethyl acetate (80/20 by volume) mixture. 250-cm3 fractions were collected. Fractions 13 to 15 were combined and then concentrated as above. 5.8 g of methyl (4RS)-4-allyl-1-benzyloxycarbonylpiperidin-3-ylidenacetate (Z isomer) were obtained in the form of a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:8]([C:11]1[CH:29]=[CH:28][C:14]2[O:15][CH2:16][C:17](=[O:27])[N:18](CCCC(OCC)=O)[C:13]=2[CH:12]=1)(=[O:10])[CH3:9]>>[C:8]([C:11]1[CH:29]=[CH:28][C:14]2[O:15][CH2:16][C:17](=[O:27])[N:18]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:13]=2[CH:12]=1)(=[O:10])[CH3:9]
Reactant: CCOC(=O)CCCN1C(=O)COc2ccc(C(C)=O)cc21
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CN1C(=O)COc2ccc(C(C)=O)cc21

Procedure:
The compound 23b was synthesized by reacting 22 and 6d following the same protocol described for the synthesis of compound 23a. White solid (0.47 g, 32%). 1H NMR (400 MHz, CDCl3): δ 1.30 (t, J=7.2 Hz, 3H); 2.55 (s, 3H); 4.25 (q, J=7.2 Hz, 2H); 4.70 (s, 2H); 4.74 (s, 2H); 7.05 (dd, J=1.6, 8.4 Hz, 1H); 7.41-7.42 (m, 1H); 7.60-7.63 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([S:8][CH3:9])=[CH:6][CH:7]=1.[O:10]1[CH2:14][CH2:13][N:12]=[C:11]1[C:15]1[CH:30]=[CH:29][C:18]([O:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[O:10]1[CH2:14][CH2:13][N:12]=[C:11]1[C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][N:26]([C:2]3[N:3]=[N:4][C:5]([S:8][CH3:9])=[CH:6][CH:7]=3)[CH2:27][CH2:28]2)=[CH:29][CH:30]=1
Reactant: CSc1ccc(Cl)nn1
Reactant: c1cc(C2=NCCO2)ccc1OCCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CSc1ccc(N2CCN(CCCOc3ccc(C4=NCCO4)cc3)CC2)nn1
Reaction time: 120 h
Yield: 11.2 %

Procedure:
A mixture of 2.4 parts of 3-chloro-6-(methylthio)pyridazine, 4.5 parts of 1-[3-[4-(4,5-dihydro-2-oxazolyl)phenoxy]propyl]piperazine, 1.6 parts of sodium carbonate and 80 parts of 1-butanol was stirred for 5 days at reflux temperature. The reaction mixture was evaporated and the residue was dissolved in trichloromethane. The organic phase was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 0.7 parts (11.2%) of 3-[4-[3-[4-(4,5-dihydro-2-oxazolyl)phenoxy]-propyl]-1-piperazinyl]-6-(methylthio)pyridazine; mp. 163.1° C. (comp. 83).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:28])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21]O)=[N:19][N:18]=[C:17]1[CH2:23][CH2:24][N:25]([CH3:27])[CH3:26].[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>COCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:28])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][N:33]2[C:29](=[O:39])[C:30]3=[CH:38][CH:37]=[CH:36][CH:35]=[C:31]3[C:32]2=[O:34])=[N:19][N:18]=[C:17]1[CH2:23][CH2:24][N:25]([CH3:26])[CH3:27]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CN(C)CCc1nnc(CO)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CN(C)CCc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 1B, 2',5-dichloro-2-[3-[2-(dimethylamino)ethyl]-5-(hydroxymethyl)-4H-1,2,4-triazol-4-yl]benzophenone in 1,2-dimethoxyethane is treated with phthalimide, triphenylphosphine and diethyl azodicarboxylate to give 2',5-dichloro-2-[3-[2-(dimethylamino)ethyl]-5-(phthalimidomethyl)-4H-1,2,4,-triazol-4-yl]benzophenone.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Br[CH2:23][CH:24]1[CH2:26][CH2:25]1>>[CH:24]1([CH2:23][N:8]2[C:9]([C:10](=[O:19])[C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]2=[O:20])[CH2:26][CH2:25]1
Reactant: BrCC1CC1
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2CC2CC2)c1
Yield: 46.4 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and bromomethyl cyclopropane were reacted by the same way with the example 1 to obtain the titled compound (158 mg, yield: 46.4%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[S:21]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NNC(=O)c1cccc(I)c1
Solvent: Cc1ccccc1
Product: NNC(=S)c1cccc(I)c1
Yield: 73.6 %

Procedure:
3-Iodobenzohydrazide (500 mg, 1.91 mmol) obtained in Step 1 of Example 52 was suspended in toluene (10 mL), and the mixture was refluxed for 1 hour after adding Lawesson's reagent (772 mg, 1.91 mmol). The mixture was then purified by silica gel column chromatography to give 3-iodothiobenzohydrazide (391 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N+:15]([O-])=O.Cl>[Fe].CO>[NH2:15][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:2]=1[Cl:1])[CH2:6][NH:7][C:8]([CH:10]1[CH2:12][CH2:11]1)=[O:9]
Reactant: O=C(NCc1ccc(Cl)c([N+](=O)[O-])c1)C1CC1
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: Nc1cc(CNC(=O)C2CC2)ccc1Cl
Yield: 56.7 %

Procedure:
The title compound was prepared by following the procedure as described in step-2 of Intermediate-28 by using N-(4-chloro-3-nitrobenzyl)cyclopropanecarboxamide (0.400 g), methanol (10 mL), iron powder (catalytic) and conc. HCl (5 mL). The reaction mass was refluxed for 2 h. The reaction mass was quenched in water and basified with NaHCO3 and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 0.200 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.65 (d, J=8.4 Hz, 4H), 1.57 (m, 1H), 4.11 (d, J=5.4 Hz, 2H), 5.34 (s, 2H), 6.41 (d, J=7.2 Hz, 1H), 7.10 (d, J=7.8 Hz, 1H), 8.50 (br s, 1H); MS (m/z): 225.07 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH3:13]>CO>[NH2:13][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: N
Reactant: O=[N+]([O-])c1cc(CO)ccc1Cl
Solvent: CO
Product: Nc1ccc(CO)cc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 6 h
Yield: 52 %

Procedure:
Fifty grams (0.27 mole) of 4-chloro-3-nitrobenzyl alcohol, 250 ml. of methanol and 200 ml. of liquid ammonia were loaded into a cold autoclave. The autoclave was sealed and heated to a temperature of 150° C. The reaction was continued for 6 hours. After cooling the autoclave was vented and the reaction mixture was evaporated in vacuo. The residue was taken up in ether and the ether solution was filtered to separate the ammonium chloride. The ether filtrate was evaporated in vacuo to yield a solid product. The product was recrystallized from 2-B ethanol/ethyl acetate to give 23.6 g. (52 percent yield) of 4-amino-3-nitrobenzyl alcohol, mp. 100°-101° C.
Reaction SMILES: C(O[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([C:20]3[N:25]=[C:24]4[N:26]([CH:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[N:27]=[C:28]([CH2:29][CH3:30])[C:23]4=[CH:22][CH:21]=3)=[CH:18][CH:17]=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([OH:39])C>[Pd]>[CH2:29]([C:28]1[C:23]2[C:24](=[N:25][C:20]([C:19]3[N:15]([C:12]4[CH:13]=[C:14]([OH:39])[CH:9]=[CH:10][CH:11]=4)[N:16]=[CH:17][CH:18]=3)=[CH:21][CH:22]=2)[N:26]([CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:27]=1)[CH3:30]
Reactant: CCO
Reactant: CCc1nn(C2CCOCC2)c2nc(-c3ccnn3-c3ccc(OCc4ccccc4)cc3)ccc12
Agent: [Pd]
Product: CCc1nn(C2CCOCC2)c2nc(-c3ccnn3-c3cccc(O)c3)ccc12
Reaction time: 4 h

Procedure:
6-{1-[4-(benzyloxy)phenyl]-1H-pyrazol-5-yl}-3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine (290 mg, 0.60 mmol) and ethanol (30 mL) were added to a Parr bottle. 10% Pd/C (150 mg, 0.14 mmol) was added, and the mixture was shaken under an atmosphere of hydrogen (45 psi) for 4 hours. The reaction was degassed under reduced pressure, flushed with argon for 5 minutes, filtered through Celite and concentrated to yield 0.23 g 3-{5-[3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-1H-pyrazol-1-yl}phenol as an oil. LC/MS (EI) tR 2.87 (Method E), m/z 390.2 (M++1). 1H NMR (CDCl3) δ 1.4 (t, 3H); 1.7 (m, 2H); 2.2 (m, 2H); 3.0 (q, 2H); 3.5 (t, 2H); 4.0 (m, 2H); 4.5 (m, 1H); 6.7-6.9 (m, 3H); 7.0 (s, 1H); 7.2 (m, 1H); 7.3 (d, 2H); 7.7 (s, 1H); 8.0 (m, 1H).