Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:45]([CH3:46])=[CH:44][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[C:32](=[CH:33][CH:34]=4)[N:31]=[C:30]([NH:35]C(C4CCCCC4)=O)[CH:29]=[CH:28]5)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:47]1[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[NH2:35][C:30]1[CH:29]=[CH:28][C:27]2[C:32](=[CH:33][CH:34]=[C:25]([C:21]3[CH:20]=[C:19]([C:17]4[S:18][C:14]5[C:13]([C:47]6[CH:48]=[CH:49][C:50]([Cl:53])=[CH:51][CH:52]=6)=[C:12]([C@H:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[C:7]([OH:9])=[O:8])[C:45]([CH3:46])=[CH:44][C:15]=5[N:16]=4)[CH:24]=[CH:23][N:22]=3)[CH:26]=2)[N:31]=1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5nc(NC(=O)C6CCCCC6)ccc5c4)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2nc(-c3ccnc(-c4ccc5nc(N)ccc5c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(2-(cyclohexanecarboxamido)quinolin-6-yl)pyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (12.0 mg, 0.016 mmol) in THF (0.4 mL) and methanol (0.4 mL) was added 1N NaOH solution (0.4 mL, excess). The reaction mixture was stirred at 50° C. for 2 h and then purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C34H30ClN4O3S: 609.2; found: 609.2. 1H NMR (400 MHz, CDCl3) δ 8.90 (d, J=5.6 Hz, 1H), 8.51 (s, 1H), 8.45 (s, 1H), 8.29 (d, J=8.4 Hz, 1H), 8.16 (d, J=9.2 Hz, 1H), 8.06 (d, J=0.8 Hz, 1H), 8.00 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.59-7.45 (m, 3H), 6.94 (d, J=8.8 Hz, 1H), 5.36 (s, 1H), 2.62 (s, 3H), 1.03 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][C:6]1[NH:7][CH:8]=[N:9][C:10]=1[Cl:11].C(N(CC)C(C)C)(C)C.ClCCl.[CH3:25][Si:26]([CH3:33])([CH3:32])[CH2:27][CH2:28][O:29][CH2:30]Cl>C(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][C:6]1[N:7]([CH2:30][O:29][CH2:28][CH2:27][Si:26]([CH3:33])([CH3:32])[CH3:25])[CH:8]=[N:9][C:10]=1[Cl:11]
Reactant: COC(=O)CCc1[nH]cnc1Cl
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COC(=O)CCc1c(Cl)ncn1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 0.40 g of 3-(5-chloro-3H-imidazol-4-yl)-propionic acid methyl ester, 0.5 mL of N,N-diisopropylethylamine, 15 mL of dichloromethane and 0.4 mL of 2-(trimethylsilyl)ethoxymethyl chloride was stirred at room temperature for 24 h. The reaction mixture was diluted with 50 mL chloroform and 10 mL saturated aqueous Na2CO3 and the layers separated. The aqueous layer was extracted with 2×25 mL of chloroform and the combined organic layers dried over magnesium sulfate and concentrated under reduced pressure. Purification by chromatography eluting with ethyl acetate gave 0.8 g of 3-[5-chloro-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-propionic acid methyl ester as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C@H:7]([NH:18][S@:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])[CH2:8][C:9]2[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=2[F:17])[CH2:3][CH2:2]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH:48]1([S:54][CH2:55][C:56](O)=[O:57])[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1.CN(C=O)C>ClCCl>[CH:48]1([S:54][CH2:55][C:56]([N:1]2[CH2:6][CH2:5][CH:4]([C@H:7]([NH:18][S@:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])[CH2:8][C:9]3[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=3[F:17])[CH2:3][CH2:2]2)=[O:57])[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1
Reactant: CC(C)(C)[S@](=O)N[C@H](Cc1cc(F)c(F)cc1F)C1CCNCC1
Reactant: O=C(O)CSC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[S@](=O)N[C@H](Cc1cc(F)c(F)cc1F)C1CCN(C(=O)CSC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To (S)-2-Methyl-propane-2-sulfinic acid [(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide (200 mg, 0.552 mmol) in dichloromethane (1 mL) are added EDC (127 mg, 0.662 mmol), HOBt (97 mg, 0.718 mmol), DIPEA (283 uL, 1.656 mmol) and cyclohexylsulfanyl-acetic acid in DMF (2 mL, 1.2 mmol). After stirring at rt during 3 days, the mixture is washed with an aqueous 1N HCl solution, the organic phase is dried and evaporated to give the title compound.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[CH2:26]([O:28][C:29]1[CH:30]=[C:31](/[CH:43]=[C:44](\[CH3:50])/[C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:32]=[CH:33][C:34]=1OS(C(F)(F)F)(=O)=O)[CH3:27].[CH3:51][NH:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55](B2OC(C)(C)C(C)(C)O2)[CH:54]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:26]([O:28][C:29]1[CH:30]=[C:31](/[CH:43]=[C:44](\[CH3:50])/[C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:32]=[CH:33][C:34]=1[C:55]1[CH:56]=[CH:57][CH:58]=[C:53]([NH:52][CH3:51])[CH:54]=1)[CH3:27]
Reactant: CCOC(=O)/C(C)=C/c1ccc(OS(=O)(=O)C(F)(F)F)c(OCC)c1
Reactant: CNc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(C)=C/c1ccc(-c2cccc(NC)c2)c(OCC)c1
Temperature: 92.5 °C
Yield: 25.5 %

Procedure:
45 mg (0.2 mmol) of palladium acetate and then 140 mg (0.4 mmol) of 2-(dicyclohexylphosphino)biphenyl are added to a mixture of 1.65 g (4 mmol) of ethyl (E)-3-(3-ethoxy-4-trifluoromethanesulfonyloxyphenyl)-2-methylacrylate, 1.1 g (4.8 mmol) of methyl[3-(4,4,5,5-tetramethyl[1.3.2]dioxaborolan-2-yl)phenyl]amine (prepared as described in Example 28a) and 2 mL of aqueous 2 M potassium phosphate solution in 8 mL of dimethylformamide. The reaction mixture is heated at 90-95° C. for 4 hours. The medium is hydrolyzed with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent is evaporated off and the brown oil obtained (2.7 g) is purified by chromatography on a column of silica eluted with a 90/10 heptane/ethyl acetate mixture. 346 mg (17%) of ethyl (E)-3-(2-ethoxy-3′ methylaminobiphenyl-4-yl)-2-methylacrylate are obtained in the form of a yellow oil.
Reaction SMILES: [C:1]1([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[CH2:11][C:10]([CH2:15][O:16][C:17]2[C:18]([F:27])=[C:19]([C:23]([F:26])=[CH:24][CH:25]=2)[C:20]([NH2:22])=[O:21])=[CH:9]3)[CH2:5][CH2:4][CH2:3][CH:2]=1>CO.[Pd]>[CH:1]1([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[CH2:11][C:10]([CH2:15][O:16][C:17]2[C:18]([F:27])=[C:19]([C:23]([F:26])=[CH:24][CH:25]=2)[C:20]([NH2:22])=[O:21])=[CH:9]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)c1c(F)ccc(OCC2=Cc3cc(C4=CCCC4)ccc3C2)c1F
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1c(F)ccc(OCC2=Cc3cc(C4CCCC4)ccc3C2)c1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 13.5 %

Procedure:
To a solution of 3-(5-Cyclopent-1-enyl-1H-inden-2-ylmethoxy)-2,6-difluoro-benzamide (0.05 g, 0.10 mmol) in 5 ml of anhydrous methanol was added Pd—C (10%, 100 mg). The reaction mixture was stirred at 25° C. for 48 h under hydrogen atmosphere. The reaction mixture was filtered over the bed of celite and evaporated to dryness under reduced pressure to give the title compound as white solid (0.005 g, 10%). 1H NMR (DMSO-d6, 400 MHz); δ 1.22 (m, 2H), 1.67 (m, 4H), 1.80 (m, 2H), 2.07 (m, 2H), 3.20 (m, 1H), 5.67 (s, 2H), 7.09 (m, 1H), 7.37 (m, 2H), 7.87 (m, 2H), 8.0 (m, 1H) and 8.18 (br s, 1H). MS ES+ (389.12), HPLC (method II) Rt=18.19 min.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17].CCOC(C)=O>C1COCC1>[F:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:16](=[O:17])[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)nc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)nc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.4 %

Procedure:
6-Fluoropyridin-3-amine (224 mg, 2.00 mmol) was dissolved in THF (4 mL). Pyridine (202 μL, 2.50 mmol) was added, followed by phenyl chloroformate (258 μL, 2.06 mmol). The reaction was stirred at rt for 2 h, then EtOAc (20 mL) was added. The reaction was washed with 1 M HCl (10 mL), water (10 mL), saturated aqueous NaHCO3 (10 mL), and brine (10 mL), then dried (MgSO4), filtered, and concentrated in vacuo to give slightly impure 16A (471 mg, >100%). 16A had an analytical HPLC retention time=2.437 min (Phenomenex Luna 3.0×50 mm, 10-90% aqueous MeOH over 5 min containing 0.1% TFA) and a LC/MS M++1=233.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[Br:21][CH2:22][CH:23]=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[CH:23][CH2:22][Br:21])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: O=CCBr
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCC(NN=CCBr)=N2

Procedure:
In the manner given in Example 1, 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine can be reacted with α-bromoacetaldehyde to give 7-chloro-2-[(2-bromoethylidene)hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]1[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([F:14])[CH:13]=1.[CH3:16][O:17][C:18](=[O:27])/[CH:19]=[C:20](\[NH:22][C:23](=[O:26])[CH2:24]Br)/[CH3:21]>CC(C)=O>[CH3:16][O:17][C:18](=[O:27])/[CH:19]=[C:20](\[NH:22][C:23](=[O:26])[CH2:24][O:15][C:10]1[CH:9]=[C:8]([F:7])[CH:13]=[C:12]([F:14])[CH:11]=1)/[CH3:21]
Reactant: Oc1cc(F)cc(F)c1
Reactant: COC(=O)/C=C(/C)NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)/C=C(/C)NC(=O)COc1cc(F)cc(F)c1
Temperature: 25 °C
Yield: 82.7 %

Procedure:
To a suspension of K2CO3 (1.38 g, 10.0 mmol) in acetone (50 mL) were added 3,5-difluorophenol (0.78 g, 6.00 mmol) and (Z)-methyl-3-(2-bromoacetamido)but-2-enoate (1.18 g, 5.00 mmol) and the mixture was refluxed for 5 h. The mixture was cooled to rt and filtered and the filtrate was concentrated in vacuo. To the residue was added DCM (100 mL) and the mixture was washed with water (100 mL×2) and brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=5:1) to give the title compound as a white solid (1.18 g, 83%).
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[CH3:10][O:11][C:12]([C:14]1[C:19]([F:20])=[CH:18][C:17](Br)=[C:16]([NH2:22])[N:15]=1)=[O:13].CCOC(C)=O>CN(C=O)C>[CH3:10][O:11][C:12]([C:14]1[C:19]([F:20])=[CH:18][C:17]([S:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:16]([NH2:22])[N:15]=1)=[O:13]
Reactant: CCOC(=O)CS
Reactant: COC(=O)c1nc(N)c(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CSc1cc(F)c(C(=O)OC)nc1N

Procedure:
A solution of ethyl mercaptoacetate (1.15 ml) in DMF (40 ml) was ice-cooled under argon, treated with sodium hydride (420 mg of a 60% dispersion in oil) and stirred until all was in solution (about 1 hour). The ester (a) (2.48 g) was added, the mixture allowed to warm to room temp. and stirred overnight. EtOAc (150 ml) was added, the solution washed with water (3×150 ml), dried and evaporated. Chromatography of the residue (40% EtOAc in hexane) gave an oil (1.7 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]([NH2:14])=[O:13])([O-:3])=[O:2].CS(C)=O.C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl.CO.CC(O)=O>[C:26]([NH:14][C:12](=[O:13])[CH2:11][NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NC(=O)CNc1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Solvent: CO
Product: O=C(CNc1ccccc1[N+](=O)[O-])NC(=O)c1ccccc1

Procedure:
2-Nitrophenylglycine amide, 1 DMSO (500 mg, 1.83 mmol) was suspended in chloroform (20 ml) and triethylamine (390 μl, 2.80 mmol) was added. Subsequently benzoyl chloride (330 μl, 2.8 mmol) was added with stirring. The reaction was followed by TLC using as eluent: CH2Cl2 /MeOH/AcOH (85:10:5) and after 1 h at 20° C. the reaction mixture was treated with a saturated solution of NaHCO3, dried over anhydrous MgSO4 and evaporated to dryness. The product was recrystallized from absolute ethanol. Yield: 600 mg (77%); mp 178°-180° C., identified by 1H NMR spectroscopy. ##STR13##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:24])=[C:6]([C:8]([NH:17][S@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])([CH:14]([F:16])[F:15])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:7]=1>C(O)C.CCCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:24])=[C:6]([C@:8]([NH:17][S@:18]([C:20]([CH3:22])([CH3:21])[CH3:23])=[O:19])([CH:14]([F:16])[F:15])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:7]=1
Reactant: COC(=O)CC(N[S@@](=O)C(C)(C)C)(c1cc(Br)ccc1F)C(F)F
Solvent: CCCCCCC
Solvent: CCO
Product: COC(=O)C[C@](N[S@@](=O)C(C)(C)C)(c1cc(Br)ccc1F)C(F)F
Yield: 40.8 %

Procedure:
Chiral separation of methyl 3-(5-bromo-2-fluorophenyl)-3-((S)-1,1-dimethylethylsulfinamido)-4,4-difluorobutanoate (3.8 g, 8.83 mmol) (intermediate A3.14) by preparative chiral HPLC on Reprosil Chiral NR column with a mixture of 5% ethanol/n-heptane as the eluent yielded the (S)-methyl 3-(5-bromo-2-fluorophenyl)-3-((S)-1,1-dimethylethylsulfinamido)-4,4-difluorobutanoate (1.55 g, 40.8% yield) (intermediate A3.15) as a colorless oil and the (R)-methyl 3-(5-bromo-2-fluorophenyl)-3-((S)-1,1-dimethylethylsulfinamido)-4,4-difluorobutanoate (1.65 g, 43.4% yield)) (intermediate A3.15) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[CH3:17])[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:18]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[Br:18][CH2:17][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:9]=[CH:10]2
Reactant: Cc1cccc2ccn(C(=O)OC(C)(C)C)c12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1ccc2cccc(CBr)c21

Procedure:
200 mg (865 μmol) of the compound from Example 5A were introduced into 10 ml of tetrachloromethane, 169 mg (951 μmol) of N-bromosuccinimide were added, and the mixture was heated under reflux while irradiating with a sun lamp for 4 h. The residue after concentration was purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate gradient) to result in 168 mg (63% of theory) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][S:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:7]=1)[CH3:2].[C:29](Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:17][C:16]=2[CH2:22][S:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:7]=1)[CH3:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CSC(C)(C)C)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)C(C)(C)C)cc2CSC(C)(C)C)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 6, using the following starting materials: [3-(4-amino-2-tert-butylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and pivaloyl chloride.
Reaction SMILES: C([O:4][CH:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([O:18]C(=O)C)=[CH:12][CH:13]=3)[C:8]([CH3:23])([CH3:22])[C:7]=2[C:6]1=[O:24])(=O)C.O.[OH-].[Li+].Cl>C(O)CO>[OH:4][CH:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([OH:18])=[CH:12][CH:13]=3)[C:8]([CH3:22])([CH3:23])[C:7]=2[C:6]1=[O:24]
Reactant: CC(=O)Oc1ccc2c(c1)C(C)(C)C1=C2C=CC(OC(C)=O)C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CC1(C)C2=C(C=CC(O)C2=O)c2ccc(O)cc21
Yield: 74.6 %

Procedure:
Under a nitrogen atmosphere, 2,7-diacetoxy-9,9,-dimethylfluorenone (5.00 g) and lithium hydroxide monohydrate (2.00 g) were dissolved in ethylene glycol (50 mL), and the solution was refluxed under heating for 2 hours. The reaction solution was poured into hydrochloric acid, and after extracting with ethyl acetate, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was recrystallized from a chloroform/ethyl acetate mixed solvent to obtain 2,7-dihydroxy-9,9,-dimethylfluorenone (2.77 g). (Melting point: 177 to 180° C.)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[N:15]1[CH2:20][C@@H:19]([CH3:21])[C@@H:18](CS([O-])(=O)=O)[C@@H:17]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:42]=[N+:43]=[N-:44].[Na+]>CN(C=O)C>[N:42]([C@H:18]1[C@@H:19]([CH3:21])[CH2:20][N:15]([C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:8]([C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH2:16][C@H:17]1[NH:27][C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])=[N+:43]=[N-:44]
Reactant: C[C@@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)[C@@H]1CS(=O)(=O)[O-]
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
To a solution of (3R,4R,5S)-1-(3-(bis(tert-butoxycarbonyl)amino)pyridin-4-yl)-3-((tert-butoxycarbonyl)amino)-5-methylpiperidin-4-ylmethanesulfonate (1.0 equiv.) in DMF (0.13 M) was added NaN3 (5.0 equiv.). The solution was submerged in an 80° C. oil bath and left stirring under Ar for 24 hrs. The solution was cooled to rt and left stirring under Ar overnight. The solution was partitioned between EtOAc and H2O. The organic layer was washed with Na2CO3(sat.), NaCl(sat.), dried over MgSO4, filtered, concentrated to yield tert-butyl (4-((3R,4S,5S)-4-azido-3-((tert-butoxycarbonyl)amino)-5-methylpiperidin-1-yl)pyridin-3-yl)(tert-butoxycarbonyl)carbamate in 60% yield. LC/MS (m/z)=548.4 (MH+), Rt=0.94 min. 1H NMR (400 MHz, <cdcl3>) δ ppm 0.97-1.13 (m, 3H), 1.33-1.52 (m, 30H), 2.03-2.19 (m, 1H), 2.66-2.87 (m, 2H), 3.16 (dd, J=12.72, 2.15 Hz, 1H), 3.22-3.32 (m, 1H), 3.81-4.01 (m, 2H), 4.78 (d, J=9.00 Hz, 1H), 6.76-6.88 (m, 1H), 8.05-8.18 (m, 1H), 8.26-8.37 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=1.C(O)C(N)(CO)CO.[C:32]1([N:38]=[C:39]=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([NH:19][C:39]([NH:38][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:40])[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1cccc(OCc2nccn2Cc2cc(Cl)cc(Cl)c2)c1
Reactant: O=C=Nc1ccccc1
Agent: NC(CO)(CO)CO
Solvent: ClCCl
Product: O=C(Nc1ccccc1)Nc1cccc(OCc2nccn2Cc2cc(Cl)cc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 52 %

Procedure:
A solution of 3-[1-(3,5-Dichloro-benzyl)-1H-imidazol-2-ylmethoxy]-phenylamine (see Example 21) in CH2Cl2 and phenyl isocyanate in CH2Cl2 (0.4 mL) were combined and the reaction was shaken at room temperature. After 72 h, LC/MS showed the reaction had progressed to completion. Trisamine resin was added and the reaction was shaken at room temperature. After 4 h, the reaction was filtered and the resin was washed with CH2Cl2 (2 mL). The filtrates were combined and concentrated in vacuo. Preparatory TLC (silica, 20:1 CH2Cl2:MeOH; Rf=0.5) yielded 1-{3-[1-(3,5-dichloro-benzyl)-1H-imidazol-2-ylmethoxy]-phenyl}-3-phenyl-urea (25a) as a white solid (22 mg, 52%); MS m/z 467 [C24H20Cl2N4O2+H]+.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][N:16]([C:17]4[N:22]=[C:21]([N:23]5[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)[CH:20]=[CH:19][CH:18]=4)[C:10]=3[CH:9]=2)[CH:5]=[N:4]1)[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][N:16]([C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([N:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]5)[N:22]=4)[C:10]=3[CH:9]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CCNCC3)n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
A mixture of tert-butyl 4-(6-(6-(1-ethyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperazine-1-carboxylate (0.2486 mmol; 118 mg) in DCM (5 mL) and TFA (5 mL) was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 6-(1-ethyl-1H-pyrazol-4-yl)-1-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine 101 (47.5 mg, 50%). 1H NMR (400 MHz, DMSO) δ 9.15-9.11 (s, 1H), 8.67-8.65 (s, 1H), 8.54-8.51 (s, 1H), 8.27-8.24 (s, 1H), 7.91-7.88 (s, 1H), 7.78-7.72 (t, J=8.1 Hz, 1H), 7.24-7.18 (d, J=7.7 Hz, 1H), 6.80-6.74 (d, J=8.4 Hz, 1H), 4.26-4.17 (q, J=7.3 Hz, 2H), 3.65-3.56 (m, 4H), 2.96-2.86 (m, 4H), 1.46-1.41 (t, J=7.3 Hz, 3H); MS (ESI) m/z: 375.1 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C:7]([CH3:31])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][NH:17][C:18]([C:20]2[CH:21]=[N:22][N:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:24]=2)=O)[N:14]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].CO>O1CCCC1>[C:1]([O:5][C:6](=[O:32])[C:7]([CH3:8])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][NH:17][CH2:18][C:20]2[CH:21]=[N:22][N:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:24]=2)[N:14]=1)[CH3:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNC(=O)c2cnn(-c3ccccc3)c2)cs1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNCc2cnn(-c3ccccc3)c2)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.4 %

Procedure:
2-Methyl-2-{[4-(2-{[(1-phenyl-1H-pyrazol-4-yl)carbonyl]amino}ethyl)-1,3-thiazol-2-yl]thio}propionic acid tert-butyl ester (16.2 g) obtained in Example 451-1 was dissolved in tetrahydrofuran (20 mL), 1 mol/L-borane/tetrahydrofuran complex (160 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was ice-cooled, and methanol (200 mL) was added dropwise. After warming to room temperature, the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, piperidine (60 mL) was added, and the mixture was stirred at 60° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; dichloromethane:methanol=20:1 to 10:1) to give the title compound (9.5 g) as a slightly yellow oil.