Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][CH:34]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[CH2:31][CH2:30][CH2:29][CH2:28][C:12]=2[C:13]=1[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:19][CH:18]=1)=[O:15])=[O:7].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>CN(C=O)C>[ClH:1].[ClH:1].[CH2:24]([N:23]([CH2:26][CH3:27])[C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:14]([C:13]2[C:12]3[CH2:28][CH2:29][CH2:30][CH2:31][C:11]=3[S:10][C:9]=2[NH:8][C:6](=[O:7])[C:5]2[CH:32]=[CH:33][CH:34]=[C:3]([CH2:2][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:4]=2)=[O:15])=[CH:22][CH:21]=1)[CH3:25]
Reactant: CCN(CC)c1ccc(NC(=O)c2c(NC(=O)c3cccc(CCl)c3)sc3c2CCCC3)cc1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(NC(=O)c2c(NC(=O)c3cccc(CN4CCOCC4)c3)sc3c2CCCC3)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 200 mg of 2-{[3-(chloromethyl)benzoyl]amino}-N-[4-(diethylamino)phenyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide and 8 mL of DMF was added 1.0 mL of morpholine, followed by stirring for 3 days at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol:aqueous ammonia solution=50:1:0.1). The obtained residue was dissolved in a mixed solution of ethyl acetate and ethanol (4:1), and 1.0 mL of 4.0 M hydrogen chloride/ethyl acetate solution was further added thereto. The precipitated solid was collected by filtration, thereby obtaining 183 mg of N-[4-(diethylamino)phenyl]-2-{[3-(morpholin-4-ylmethyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide dihydrochloride.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]Cl)=[C:12]2[C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.[K].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][N:35]1[C:31](=[O:41])[C:32]3[C:33](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:34]1=[O:36])=[C:12]2[C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Cn1c(CCl)c(-c2cccs2)c2cc(OCc3ccccc3)ccc2c1=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(CN2C(=O)c3ccccc3C2=O)c(-c2cccs2)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 86.3 %

Procedure:
A solution of 6-(benzyloxy)-3-(chloromethyl)-2-isobutyl-4-(2-thienyl)-1(2H)-isoquinolinone (1.31 g, 3 mmol) and potassium phthalimide (0.83 g, 4.5 mmol) in N,N-dimethylformamide (20 ml) was stirred at room temperature for 3 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-{[6-(benzyloxy)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methyl}-1H-isoindole-1,3(2H)-dione (1.42 g, 86.6%) as an amorphous solid.
Reaction SMILES: Cl.BrC1SC2=NC(N)=CN2C=1.C(OC(N[C@H](C1C=CC=CC=1)C(N1CCC[C@H]1C(O)=O)=O)=O)(C)(C)C.[C:37]([O:41][C:42](=[O:70])[NH:43][C@@H:44]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[C:45]([N:47]1[CH2:51][CH2:50][CH2:49][C@H:48]1[C:52](=[O:63])[NH:53][C:54]1[N:55]=[C:56]2[N:60]([CH:61]=1)[CH:59]=[C:58]([Br:62])[S:57]2)=[O:46])(C)(C)C>>[CH3:37][O:41][C:42](=[O:70])[NH:43][C@@H:44]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[C:45]([N:47]1[CH2:51][CH2:50][CH2:49][C@@H:48]1[C:52](=[O:63])[NH:53][C:54]1[N:55]=[C:56]2[N:60]([CH:61]=1)[CH:59]=[C:58]([Br:62])[S:57]2)=[O:46]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1cn2cc(Br)sc2n1)c1ccccc1
Agent: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Agent: Cl
Agent: Nc1cn2cc(Br)sc2n1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@@H]1C(=O)Nc1cn2cc(Br)sc2n1)c1ccccc1
Yield: 44 %

Procedure:
Compound 34 was synthesized from compound 11 (0.471 mmol) and compound 33 (0.707 mmol), following the procedure as described for compound 23, as a yellow solid in 44% yield. MS (ESI, EI+) m/z=505.93-507.95 (MH+).
Reaction SMILES: [N:1]1([C:8]([NH:10][C@H:11]([C:16]([OH:18])=O)[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][C@@H:20]([C:31]([OH:33])=[O:32])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1.[CH:34]1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[CH3:34][O:32][C:31](=[O:33])[C@@H:20]([CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)[NH:19][C:16](=[O:18])[C@H:11]([CH2:12][CH:13]([CH3:14])[CH3:15])[NH:10][C:8]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9]
Reactant: On1nnc2ccccc21
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)N1CCCCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The compound obtained in (2) (1.08 g) and DTrp-Ome.Hcl (1.02 g) were dissolved in DMF (10 ml), and TEA (0.57 ml), HOBT.H2O (613 mg) and EDCI.HCl (805 mg) were added at 0°~5° C. The reaction mixture was stirred at 0°~5° C. for 1.5 h and at room temperature for 4 h. Water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with 1N HCl and sat. NaHCO3, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by MPLC (Merck, LiChroprep Si 60) with dichloromethane/methanol=30/1 for elution to give the product (1.55 g) as a colorless powder.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([CH2:9][CH3:10])[CH3:8].Cl[CH2:20][C:21]1[O:25][N:24]=[C:23]([CH3:26])[CH:22]=1>CN(C)C=O>[CH:7]([O:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:20][C:21]2[O:25][N:24]=[C:23]([CH3:26])[CH:22]=2)=[CH:16][CH:17]=1)([CH2:9][CH3:10])[CH3:8]
Reactant: Cc1cc(CCl)on1
Reactant: CCC(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C)Oc1ccc(OCc2cc(C)no2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
4.6 g of anhydrous potassium carbonate is added to 5.0 g of 4-sec-butyloxyphenol in 80 ml of absolute dimethylformamide, and the mixture is stirred for one hour at 80° C. At this temperature, 3.9 g of 5-chloromethyl-3-methylisoxazole is dripped in and the mixture is stirred for a further seven hours at 90° C. The batch is then stirred into 300 ml of ice water, extracted three times, each time with 100 ml of methyl tert-butyl ether and the organic phase is washed twice with 2N sodium hydroxide solution (50 ml in each instance) and then three times with water (50 ml in each instance). Drying over sodium sulfate and removal of the solvent under reduced pressure give 6.6 g of 5-[4(sec-butyloxy)-phenoxymethyl]-3-methylisoxazole, which is obtained, after chromatography over silica gel using toluene/ethyl acetate(1:1) as eluant, as a viscous oil. According to 1H-NMR spectroscopy, the oil is pure.
Reaction SMILES: [N+:1]([C:4]1[C:8]([C:9]#[N:10])=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H][H].[O:13]=O.[OH-].[Na+:16]>CO>[Na+:16].[N+:1]([C:4]1[C:8]([C:9]([NH-:10])=[O:13])=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2]
Reactant: O=O
Reactant: N#Cc1c[nH]nc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: [NH-]C(=O)c1c[nH]nc1[N+](=O)[O-]
Temperature: 45 °C
Reaction time: 4 h

Procedure:
A solution was made of 8 gm. of 1-sodium salt of 3-nitro-4-pyrazolecarbonitrile in methanol, and 75 ml. of 15% H2 O2 was added, followed by 5 ml. of 6N NaOH. The reaction mixture was heated to 45° C., at which point external cooling was needed to maintain the mixture at 45°-50° C. After the exothermic reaction has subsided, the mixture was held at 45°-50° C. and stirred for 4 hours. Then the mixture was cooled and the methanol was evaporated under vacuum. The liquid remaining was cooled in an ice bath and the product was separated by filtration and dried under vacuum. The dry product was determined to be 8 gm. of 3-nitro-4-pyrazolecarboxamide sodium salt, m.p. >300° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[N:10][C:11]([NH2:12])=[C:6]2[C:5](I)=[N:4]1)[CH3:2].[CH3:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22]([N:24]2[C:32]3[C:27](=[CH:28][C:29](B4OC(C)(C)C(C)(C)O4)=[CH:30][CH:31]=3)[CH2:26][CH2:25]2)=[O:23])[CH:18]=[CH:19][CH:20]=1.C(=O)(O)[O-].[Na+].O1CCOCC1>O>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[N:10][C:11]([NH2:12])=[C:6]2[C:5]([C:29]2[CH:28]=[C:27]3[C:32](=[CH:31][CH:30]=2)[N:24]([C:22](=[O:23])[CH2:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([CH3:14])[CH:16]=2)[CH2:25][CH2:26]3)=[N:4]1)[CH3:2]
Reactant: CCn1nc(I)c2c(N)ncnc21
Reactant: Cc1cccc(CC(=O)N2CCc3cc(B4OC(C)(C)C(C)(C)O4)ccc32)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCn1nc(-c2ccc3c(c2)CCN3C(=O)Cc2cccc(C)c2)c2c(N)ncnc21
Temperature: 120 °C

Procedure:
A 25 mL microwave pressure tube was charged 1-ethyl-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (105 mg, 0.363 mmol), 1-[(3-methylphenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (137 mg, 0.363 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (14.83 mg, 0.018 mmol), and sodium bicarbonate (61.0 mg, 0.726 mmol) followed by dioxane (4 mL), and water (1 mL). The reaction was sealed and heated at 120° C. for 40 minutes in a microwave reactor. The reaction was cooled to room temperature, the mixture was transferred into a 100 mL flask, rinsed by EtOAc, with the water layer and black greasy solid stayed in tube (total 50 mL of EtOAc was added to the mixture). The EtOAc solution was evaporated to dryness, and re-dissolved with CH2Cl2/MeOH (4 mL/1 mL). It was purified by flash column 25-100% EtOAc/hexane, then 0-10% MeOH/EtOAc (Analogix Si SF15-24g cartridge), to afford a brown solid. The brown solid was further purified by recrystallization from CH3CN to give the title compound as a brown solid. LC/MS (ES) m/z=413.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) ppm 1.41 (t, J=7.20 Hz, 3H), 2.31 (s, 3H), 3.21-3.29 (m, 2H), 3.85 (s, 2H), 4.23 (t, J=8.46 Hz, 2H), 4.32-4.40 (m, 2H), 7.07-7.14 (m, 3H), 7.21-7.28 (m, 1H), 7.44-7.46 (m, 1H), 7.51 (s, 1H), 8.21 (d, J=8.34 Hz, 1H), 8.24 (s, 1H).
Reaction SMILES: [F:1][C:2]1([F:41])[CH2:5][CH:4]([NH:6][C:7]([NH:9][C@:10]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([CH:39]=O)[CH:33]=2)([C:18]2[CH:23]=[C:22]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[CH:21]=[C:20]([F:31])[CH:19]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])[CH2:3]1.[NH:42]([CH3:44])[CH3:43].C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[F:1][C:2]1([F:41])[CH2:5][CH:4]([NH:6][C:7]([NH:9][C@:10]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([CH2:39][N:42]([CH3:44])[CH3:43])[CH:33]=2)([C:18]2[CH:23]=[C:22]([O:24][C:25]([F:30])([F:29])[CH:26]([F:27])[F:28])[CH:21]=[C:20]([F:31])[CH:19]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])[CH2:3]1
Reactant: O=Cc1cc([C@@](Cc2ccccc2)(NC(=O)NC2CC(F)(F)C2)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(C)Cc1cc([C@@](Cc2ccccc2)(NC(=O)NC2CC(F)(F)C2)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a solution of (R)-1-(3,3-difluorocyclobutyl)-3-(1-(4-fluoro-3-formylphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)urea (20 mg, 0.03 mmol) in MeOH (2 mL) was added NHMe2 (0.009 mL) and a drop of acetic acid. The reaction mixture was stirred at rt for 30 min, followed by addition of NaCNBH3 (2 mg, 0.03 mmol). The reaction mixture was stirred at rt for 1 h. The solvent was removed under reduced pressure and the residue was partitioned between sat. NaHCO3 and EtOAc. The organic phase was concentrated and purified by prep HPLC (Phemomenex Luna 5u C18 Axia column, 21×100 mm, 10%-90% H2O/ACN with 0.1% TFA/, monitoring at 220 nm) to yield (R)-1-(3,3-difluorocyclobutyl)-3-(1-(3-((dimethylamino)methyl)-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)urea (Example 328, 8 mg, 44% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.28 (d, J=2.27 Hz, 1H), 7.09 (m, 7H), 6.88 (d, J=8.84 Hz, 1H), 6.63 (d, J=7.07 Hz, 2H), 6.51 (br. s., 1H), 5.88 (m, 1H), 4.34 (d, J=12.63 Hz, 1H), 4.10 (m, 2H), 3.87 (m, 1H), 3.31 (d, J=12.63 Hz, 2H), 2.92 (m, 3 H), 2.74 (d, J=2.78 Hz, 3H), 2.70 (d, J=3.28 Hz, 3H), 2.46 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[C:9]2([CH3:10])[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4](=[O:11])[CH:3]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH3:30]>>[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]([CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]1[C:4](=[O:11])[N:5]3[C:9]([CH3:10])([CH2:8][CH2:7][CH2:6]3)[C:2]=1[OH:1])=[C:24]2[CH3:30]
Reactant: CC12CCCN1C(=O)C=C2O
Reactant: O=Cc1ccccc1
Reactant: Cc1c[nH]c2ccc(F)cc12
Product: Cc1c(C(C2=C(O)C3(C)CCCN3C2=O)c2ccccc2)[nH]c2ccc(F)cc12

Procedure:
Using general procedure D, rac-1-hydroxy-7a-methyl-5,6,7,7a-tetrahydro-pyrrolizin-3-one (Example C) was reacted with benzaldehyde and 5-fluoro-3-methyl-1H-indole to give the title compound as a red solid. MS: 391.1 ([M+H]+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1.C(N(CC)CC)C.[NH:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>S(Cl)(Cl)=O.ClCCl>[Cl:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:20]2[CH2:24][CH2:23][CH2:22][C@H:21]2[CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:10])=[CH:11][CH:12]=1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: O=C(O)c1ccc(CCCl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(c1ccc(CCCl)cc1)N1CCC[C@H]1CN1CCCC1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
4-(2-Chloroethyl)benzoic acid (1.00 g, 5.4 mmol) is dissolved in thionyl chloride (6.0 mL) and stirred at 50° C. for 30 min. The excess thionyl chloride is removed in vacuo and the residue is dissolved in dichloromethane (2 mL) to make a solution of the acid chloride. Triethylamine (656 mg, 6.5 mmol) and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (1.00 g, 6.5 mmol) are dissolved in dichloromethane (30 mL) and cooled to 0° C. The acid chloride solution is added to this mixture at 0° C. and stirred at room temperature for 2 h. The reaction mixture is diluted with CH2Cl2, washed with brine, dried over Na2SO4, and evaporated. The crude product is purified by silica-gel column chromatography (CH2Cl2:2M NH3 in MeOH=40:1) to give 1.35 g (80%) of the title compound. MS (APCI+) 321 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][CH2:10][C@@H:9]([NH:13][C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:20]=[C:19]4[C:44]3[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=3)=[O:15])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>CS(C)=O>[C:1]1([N:7]2[CH2:12][CH2:11][CH2:10][C@@H:9]([NH:13][C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][N:20]=[C:19]4[C:44]3[CH:45]=[CH:46][N:47]=[CH:48][CH:49]=3)=[O:15])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(N[C@@H]1CCCN(c2ccccc2)C1)c1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1CCCN(c2ccccc2)C1)c1ccc2[nH]nc(-c3ccncc3)c2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Crude N-[(3R)-1-phenylpiperidin-3-yl]-3-(pyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide (129 mg, 0.202 mmol) was stirred with TFA (0.5 ml) at room temperature for 45 minutes. Addition TFA (1 ml) was added and the reaction mixture was stirred at room temperature for 1.5 hours. Triethylsilane (100 μl, 0.626 mmol) was added and then the reaction mixture diluted with DMSO purified by mass-triggered reverse-phase HPLC to provide N-[(3R)-1-phenylpiperidin-3-yl]-3-(pyridin-4-yl)-1H-indazole-5-carboxamide.
Reaction SMILES: [C:1]1([C:7](=[C:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][CH2:17][N:18](CC)CC.ClCC#N>C1COCC1>[C:17]([CH2:16][N:13]1[CH2:14][CH2:15][C:10](=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]#[N:9])[CH2:11][CH2:12]1)#[N:18]
Reactant: CCN(CC)CC
Reactant: N#CC(=C1CCNCC1)c1ccccc1
Agent: N#CCCl
Solvent: C1CCOC1
Product: N#CCN1CCC(=C(C#N)c2ccccc2)CC1
Reaction time: 16 h
Yield: 21.2 %

Procedure:
To a solution of 2-phenyl-2-(piperidin-4-ylidene)acetonitrile (6.8 g, 34 mmol) in THF (150 mL) was added NEt3 (40 mL, 300 mmol) and chloroacetonitrile (20 mL, 315 mmol) and the reaction was stirred 16 h. The precipitates was filtered away and the filtrate concentrated to dryness. The residues was purified by silica gel chromatography (Biotage 40-short, 20% EtOAc/Hex to 50% EtOAc/Hex) to yield 42 (1.7 g, 7.2 mmol, 21%) as a yellow waxy solid. 1H NMR: (500 MHz, CDCl3) δ 7.44-7.34 (m, 3H), 7.30-7.27 (m, 2H), 3.65 (s, 2H), 2.96 (t, J=5.3 Hz, 2H), 2.90 (t, J=5.3 Hz, 2H), 2.70 (t, J=5.6 Hz, 2H), 2.62 (t, J=5.6 Hz, 2H); LC/MS: (ES+) m/z (M+H)+=238; HPLC Rt=1.33 min., column 0, conditions B.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-])=O)[C:5]([O:7][CH3:8])=[O:6].C(Cl)Cl.O>C(O)(=O)C.[Fe]>[NH2:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Agent: [Fe]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(N)c(F)c1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 96.9 %

Procedure:
A mixture of methyl 3-fluoro-4-nitrobenzoate(2.14 g, 10.8 mmol) and iron powder(2.63 g) in acetic acid(22 ml) was stirred at 50° C. for 2.5 h. After cooling down to room temperature, CH2Cl2(100 ml) and water(300 ml) was added to the mixture and filtered to remove iron powder. The organic layer was separated and the aqueous layer was extracted with CH2Cl2(70 mlx2). The CH2Cl2 solution was combined, washed with water, brine, dried(Na2SO4), and concentrated to give 1.77 g(97%) of pale brown solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Product: Cc1c(C(=O)Cl)cccc1[N+](=O)[O-]
Yield: 95 %

Procedure:
A mixture of 2-methyl-3-nitrobenzoic acid (9.2 grams; 0.05 mole) and 15 mls. of thionyl chloride was heated at reflux for 6 hours. The excess thionyl chloride was removed by distillation to obtain 2-methyl-3-nitrobenzoyl chloride (9.5 grams; 95% yield; m.p. 68-70° C.).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:25]3[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH:26]=3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]>CCOC(C)=O.[Pd].[O-2].[O-2].[Mn+4]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C@H:25]3[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27][CH2:26]3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(Oc2nccnc2C2=CCC(O)CC2)cc1)c1nc2ccccc2[nH]1
Agent: [Mn+4]
Agent: [Pd]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Oc2nccnc2[C@H]2CC[C@@H](O)CC2)cc1)c1nc2ccccc2[nH]1
Reaction time: 2 h

Procedure:
1H-benzimidazol-2-yl(4-((3-(4-hydroxy-1-cyclohexen-1-yl)-2-pyrazinyl)oxy)-phenyl)methanone (0.27 g, 0.66 mmol) was suspended in 20 mL of EtOAc in a pressure tube. Palladium on carbon, 10% (0.20 g) was added. The mixture was hydrogenated at 50 psi. After 60 hours the mixture was filtered through a plug of celite and eluted with 50 mL of 9:1 chloroform:isopropanol. The solvent was removed under reduced pressure. The residue was taken up in 50 mL of dichloromethane. The mixture was sonicated for 5 minutes to dissolve the starting material. Manganese dioxide (0.84 g, 9.7 mmol) was added. After 2 hours, the mixture was filtered through celite, eluted with 50 mL of 9:1 chloroform/isopropanol, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0 to 2.5% MeOH/dichloromethane). Two products of identical mass that co-eluted were isolated. The mixture was further purified by preparatory HPLC (Phenomenex Gemini column [C18, 10 micro, 150×30 mm] 15% to 100% MeCN/water over 20 min at 35 mL/min) affording 1H-benzimidazol-2-yl(4-((3-(cis-4-hydroxycyclohexyl)-2-pyrazinyl)oxy)phenyl)methanone (MS m/z: 401(M+1) and 1H-benzimidazol-2-yl(4-((3-(trans-4-hydroxycyclohexyl)-2-pyrazinyl)oxy)-phenyl)methanone. MS (ESI, pos. ion) m/z: 401 (M+1). IC50 (uM) +++++.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][N:11]1[C:15](=[O:16])[CH2:14][C:13]([C:17]([F:20])([F:19])[F:18])=[N:12]1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([O:16][C:15]2[N:11]([CH3:10])[N:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: CN1N=C(C(F)(F)F)CC1=O
Reactant: Cc1cc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(Oc2cc(C(F)(F)F)nn2C)nc(Cl)n1
Yield: 68 %

Procedure:
5 g 2,4-Dichloro-6-methylpyrimidine, 5.3 g 1-methyl-3-trifluoromethyl-2-pyrazolin-5-one, and 6.2 g potassium carbonate in 100 mL dry acetonitrile are refluxed for 2 hours. The mixture is poured into water, extracted with ethyl acetate and chromatographed to give 6.1 g of the title compound (m.p. 65° C.)
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].[CH2:6]([O:10][C:11]1[N:12]=[N:13][C:14](Cl)=[CH:15][CH:16]=1)[CH2:7][CH2:8][CH3:9]>CO>[CH2:6]([O:10][C:11]1[N:12]=[N:13][C:14]([S:5][CH2:2][CH:3]=[CH2:4])=[CH:15][CH:16]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOc1ccc(Cl)nn1
Reactant: C=CCS
Agent: [Na]
Solvent: CO
Product: C=CCSc1ccc(OCCCC)nn1

Procedure:
1.15 g(0.05 mol) of metallic sodium was dissolved in 75 ml of absolute methanol and then mixed with 4.98 ml(0.05 mol) of allylmercaptan. To this mixture was added 9.33 g(0.05 mol) of 3-(n-butoxy)-6-chloropyridazine. The reaction solution was refluxed for 24 hours and then treated according to the same manner as Example 1 to obtain the title compound as a pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([C:15]([OH:17])=O)=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1)#[N:2].[NH2:18][C@H:19]([CH3:36])[C@:20]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[F:35])([OH:27])[CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][C:11]([C:15]([NH:18][C@H:19]([CH3:36])[C@:20]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[F:35])([OH:27])[CH2:21][N:22]3[CH:26]=[CH:25][N:24]=[CH:23]3)=[O:17])=[C:12]([CH3:14])[N:13]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1nc(-c2ccc(C#N)cc2)sc1C(=O)O
Reactant: C[C@@H](N)[C@](O)(Cn1ccnc1)c1ccc(F)cc1F
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(C#N)cc2)sc1C(=O)N[C@H](C)[C@](O)(Cn1ccnc1)c1ccc(F)cc1F

Procedure:
Following a similar procedure to that described in example 1 but using 2-(4-cyanophenyl)-4-methylthiazole-5-carboxylic acid (reference example 24) and (2R,3R)-3-amino-2-(2,4-difluorophenyl)-1-(1H-imidazol-1 -yl)-2-butanol (75 mg, 0.28 mmol, obtained following the general procedure described in J. Org. Chem., 1995, 60, 3000-3012) in DMF (5 mL) the title compound was obtained as a white solid: mp 126°-128° C.; 1H NMR (300 MHz, CDCl3) δ (TMS) 8.05 (dt, Jt =2, Jd =8.4, 2H, arom), 7.50 (dt, Jt =2, Jd =8.4, 2H, arom), 7.47 (dt, Jd =6.5, Jt =8.8, 1H, arom), 7.24 (s, 1H, imidazole), 6.84.6 (m, 2H, arom), 6.52 (br d, J=9.5, 1H, NH, 6.51 (s, 1H, imidazole), 6.32 (s, 1H, imidazole), 4.85 (br quint, J=7, 1H, CHMe), 4.68 (d, J=14.5, 1H, ImCH(H)), 4.29 (d, J=14.5, 1H, ImCH(H)), 2.80 (s, 3H, Me-thiazole), 1.06 (d, J=6.8, 3H, MeCH); MS 227 (acyl group, C12H7N2OS), 223 (Im--CH2COHAr, C11H9F2N2O); [α]D =-20.4° (c 1, CHCl3). Analysis calculated for C25H21F2N5O2S: C 60.84; H 4.29; N 14.19; S 6.50 Found: C 60.85; H 4.31; N 13.75; S 6.18.