Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([S:22]([CH3:25])(=[O:24])=[O:23])[C:19]([F:26])=[CH:18][C:3]=1[O:4][C@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:6]1=[O:17].F[C:28]1[C:33]([F:34])=[CH:32][C:31]([C:35]([F:38])([F:37])[F:36])=[CH:30][N:29]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:21]=[C:20]([S:22]([CH3:25])(=[O:24])=[O:23])[C:19]([F:26])=[CH:18][C:3]=1[O:4][C@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([CH:11]2[CH2:16][CH2:15][N:14]([C:28]3[C:33]([F:34])=[CH:32][C:31]([C:35]([F:38])([F:36])[F:37])=[CH:30][N:29]=3)[CH2:13][CH2:12]2)[C:6]1=[O:17]
Reactant: CS(=O)(=O)c1cc(F)c(O[C@H]2CCCN(C3CCNCC3)C2=O)cc1F
Reactant: Fc1cc(C(F)(F)F)cnc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cc(F)c(O[C@H]2CCCN(C3CCN(c4ncc(C(F)(F)F)cc4F)CC3)C2=O)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.5 %

Procedure:
To a solution of (S)-3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-[1,4′-bipiperidin]-2-one (Preparation G; 30 mg, 0.077 mmol) in DMF was added 2,3-difluoro-5-(trifluoromethyl)pyridine (42 mg, 0.23 mmol) and DIEA (30 μL, 0.23 mmol) and the reaction was stirred at ambient temperature for 18 hours. The reaction was diluted with EtOAc and washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC (EtOAc/DCM 4:1) to give (S)-3-(2,5-difluoro-4-(methyl-sulfonyl)phenoxy)-1′-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-[1,4′-bipiperidin]-2-one as a white solid (20 mg, 0.035 mmol, 46% yield). Mass spectrum (apci) m/z=552.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/C=C/C=O)=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][CH:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[C:21]#N)=[CH:15][CH:14]=1.[OH-].[K+].[CH2:35](O)[CH3:36]>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:36]=[CH:35][C:21]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)=[C:20]2[C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=2)=[CH:15][CH:14]=1
Reactant: CCO
Reactant: CC(C)(C)c1ccc(C(C#N)Nc2ccc(Br)cc2)cc1
Reactant: O=C/C=C/c1ccc(Br)cc1
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C)c1ccc(-c2c(-c3ccc(Br)cc3)ccn2-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 10 %

Procedure:
To the product of Example 7.1C (0.676 g, 3.2 mmol) and the product from Example 7.1A (1.0 g, 2.91 mmol) was added ethanol (30 mL) followed by potassium hydroxide (0.163 g, 2.91 mmol), and the mixture was stirred at room temperature for 16 hours. Afterwards the mixture was concentrated. The residue was partitioned between water and ethyl acetate. The organic layers were combined, dried and then concentrated. The residue was purified by chromatography (silica gel, hexanes in ethyl acetate) which afforded 150 mg, (10%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.37 (m, 3H), 7.32 (d, J=8.5, 2H), 7.21 (d, J=8.4 Hz, 2H), 7.06 (d, J=8.3 Hz, 2H), 6.93 (m, 4H), 6.51 (dd, J=2.9 Hz, 1H), 1.29 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[I:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:3][CH:4]=1
Reactant: C1CCNCC1
Reactant: Clc1ccc(I)cn1
Product: Ic1ccc(N2CCCCC2)nc1

Procedure:
Prepared from 2-chloro-5-iodopyridine and piperidine by the method of Example 9 (d).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:3].Cl.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([CH2:28][NH:29][CH3:30])[CH2:24][CH2:23]1.Cl>O.O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>[F:12][C:11]([F:14])([F:13])[C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2](=[O:3])[N:29]([CH2:28][C@H:25]2[CH2:26][CH2:27][C@H:22]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][Br:16])[CH2:23][CH2:24]2)[CH3:30])=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccc(C(F)(F)F)cc1
Reactant: CNC[C@H]1CC[C@H](CCCCCBr)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C[C@H]1CC[C@H](CCCCCBr)CC1)C(=O)Oc1ccc(C(F)(F)F)cc1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
0.515 ml Diisopropyl-aethylamine, 0.674 g (3.00 mmol) 4-trifluoromethylphenyl chloroformate [Org. Lett. (2000), 2(8), 1049-1051] and 0.828 mg potassium carbonate (dissolved in the minimal amount of water) were added to a suspension of 0.625 g (2.00 mmol) trans-[4-(5-bromo-pentyl)-cyclohexylmethyl]-methyl-amine hydrochloride in 20.0 ml of tetrahydrofuran kept at −10° C. The reaction mixture was then intensively stirred for 1 hour at −10° C. and for 3 hour at room temperature. 0.200 g 4-trifluoromethylphenyl chloroformate were added and stirring at room temperature continued for additional 2 hours. The reaction mixture was subsequently acidified with dilute hydrogen chloride solution. It was then evaporated, poured into 50 ml of an ice/water mixture and extracted 3 times with 50 ml of dichloromethane. The combined dichloromethane phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 1:1 v/v mixture of hexane and dichloromethane as the eluent giving 0.90 g (96.9%) trans-[4-(5-bromo-pentyl)-cyclohexylmethyl]-methyl-carbamic acid 4-trifluoromethyl-phenyl ester as colorless viscous oil, MS: 464 (MH+, 1Br).
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH2:8][C@H:7]([N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCCCC>[CH:1]([C@@H:4]1[CH2:9][CH2:8][C@H:7]([N:10]2[CH2:15][CH2:14][C:13](=[N:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: Nc1ccccc1
Reactant: CC(C)[C@H]1CC[C@@H](N2CCC(=O)CC2)CC1
Solvent: CCCCC
Product: CC(C)[C@H]1CC[C@@H](N2CCC(=Nc3ccccc3)CC2)CC1

Procedure:
cis-1-(4-Isopropyl-cyclohexyl)-piperidine-4-on (5.0 g, 23.4 mmol), aniline (3.3 g, 35.3 mmol) and molecular sieves (20 g, 4A) were stirred in 100 ml pentane at room temperature for 6 days. The molecular sieves was filtered off and the solvent was evaporated. The crude product was used without any further purification for the following step.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:18]C)=[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=1.B(Br)(Br)[Br:21]>ClCCl>[BrH:21].[NH:3]1[CH2:4][CH2:5][N:1]=[C:2]1[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:18])=[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=1
Reactant: BrB(Br)Br
Reactant: COc1ccc(CC2=NCCN2)cc1NS(C)(=O)=O
Solvent: ClCCl
Product: Br
Product: CS(=O)(=O)Nc1cc(CC2=NCCN2)ccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 420 mg of N-[5-(4,5-dihydro-1H-imidazol-2-ylmethyl)-2-methoxy-phenyl]-methanesulfonamide (free base) in 24 ml of dichloromethane was cooled in an ice bath and treated with 10.3 ml of 1M boron tribromide in dichloromethane. Removed the ice bath, stirred at room temperature for 3 hr, added methanol, and evaporated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane/methanol/concentrated ammonium hydroxide (85:5:3) and crystallized from ethanol/ether to afford 58 mg of N-[5-(4,5-dihydro-1H-imidazol-2-ylmethyl)-2-hydroxy-phenyl]-methanesulfonamide hydrobromide, mp 209-209.5° C.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[S:14][C:13]2[CH2:12][CH2:11][CH2:10][O:9][C:8]=2[CH:7]=1.CC1C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[S:14]1[C:13]2[CH2:12][CH2:11][CH2:10][O:9][C:8]=2[CH:7]=[C:6]1[CH:2]=[O:1]
Reactant: c1c(C2OCCO2)sc2c1OCCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: O=Cc1cc2c(s1)CCCO2

Procedure:
2-(1,3-Dioxolan-2-yl)-6,7-dihydro-5H-thieno[3,2-b]pyran (0.48 g, 2.24 mmol) was dissolved in acetone (25 ml) and water (25 drops) and stirred with polystyrene-sulfonic acid resin (MP-TsOH, Argonaut Technologies inc, 1.35 mmol/g, 200 mg, 0.27 mmol) overnight. The reaction mixture was filtered, the filtrate evaporated and azeotroped with toluene. The title compound was obtained as a pale orange oil (0.44 g).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]#[N:12].F[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=1[N+:24]([O-:26])=[O:25].[OH-].[Li+].O>CS(C)=O.ClCCl>[N+:24]([C:15]1[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:14]=1[NH:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]#[N:12])([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: N#Cc1c(N)sc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1c(Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])sc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
Combine 2-amino-benzo[b]thiophene-3-carbonitrile (3.48 g, 20.0 mmol), 1-Fluoro-2-nitro-4-trifluoromethyl-benzene (4.31 g, 20.0 mmol), and lithium hydroxide (0.958 g, 40.0 mmol) in anhydrous dimethylsulfoxide (50 mL), and heat at 55° C. for 2 hours. Cool to ambient temperature, pour into a beaker filled with ice/deionized water (50 mL), and stir for 30 minutes. Add deionized water and dichloromethane and then separate the organic layer. Extract the aqueous layer with dichloromethane many times. Then wash the organics with deionized water (3×). Combine the washes and back extract them with dichloromethane. Wash the organics with a saturated solution of sodium chloride, and back extract the combined washes with dichloromethane. Dry (sodium sulfate), filter, and concentrate the organics under reduced pressure to a residue. After triturating the residue with methanol, isolate the resulting solid by suction filtration, wash with methanol, and dry at ambient temperature under reduced pressure to give the title compound (4.61 g). Concentrate the filtrate under reduced pressure and purify by flash chromatography, eluting with a gradient of ethyl acetate: dichloromethane: hexane (0.25:5:5, 0-100% in hexane) to give the title compound (0.53 g). Total solid: 5.14 g (70.8%). NMR (1H, 300 MHz, CDCl3), δ (ppm): 10.26 (s, 1H), 8.63-8.56 (m, 1H), 7.93-7.85 (m, 1H), 7.84-7.75 (m, 2H), 7.64-7.45 (m, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.S(Cl)(Cl)=O.CN(C)C=O.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH2:31]>N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:31][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=4)=[O:15])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Nc1ccccn1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccccn1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.5 %

Procedure:
1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (41 mg, 0.20 mmol) was placed in an oven-dried flask under nitrogen. Thionyl chloride (0.3 mL) and N,N-dimethylformamide (0.03 mL) were added and the solution was allowed to stir for 10 minutes at room temperature. The excess thionyl chloride was removed under vacuum and the resulting solid was suspended in anhydrous pyridine (1 mL). This solution was then slowly added to a solution of pyridin-2-amine (19 mg, 0.20 mmol) in anhydrous pyridine (1 mL). The resulting mixture was allowed to stir for 15 hours at 110° C. The crude product was then filtered, evaporated to dryness, dissolved in N,N-dimethylformamide (1 mL) and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield the pure product (5.9 mg, 0.021 mmol, 10%). ESI-MS m/z calc. 282.1. found 283.1 (M+1)+. Retention time 2.13 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH:14]=[CH2:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO.CCCCCC>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH:14]=[CH2:15])[C:10]([O:12][CH3:16])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C=CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CO
Product: C=CC[C@@H](NC(=O)OC(C)(C)C)C(=O)OC
Reaction time: 0.25 h

Procedure:
To a stirred solution of (2R)-2-[(tert-butoxycarbonyl)amino]pent-4-enoic acid (2.15 g, 10.0 mmol) in CH2Cl2 (20 mL) and MeOH (1.5 mL) was added a 2.0 M solution of trimethylsilyldiazomethane in hexane (10 mL) dropwise. After the yellow color persisted and gas evolution ceased, the solution was stirred for 15 min, and then quenched with two drops of HOAc. The reaction mixture was washed with sat. NaHCO3, the aqueous layer extracted with CH2Cl2, the combined organic layers dried over Na2SO4, treated with activated carbon and concentrated at reduced pressure to give 2.2 g of methyl (2R)-2-[(tert-butoxycarbonyl)amino]pent-4-enoate as a yellow oil. This material was dissolved in 20 mL ether, and treated with a solution of diazomethane (prepared by the portionwise treatment of a stirred mixture of 35 mL ether and 10 mL 25% KOH at 0° C. with 3.32 g (22.5 mmol) 1-methyl-3-nitro-1-nitrosoguanidine). The resulting cold (0° C.) stirred solution was treated with a very small portion of Pd(OAc)2 which caused vigorous gas evolution. The cold bath was removed, and stirring continued for 1 h. The reaction mixture was filtered through a 1 cm pad of SiO2 and eluted with ether. The filtrate was concentrated to give a yellow oil that was chromatographed on a 110 g Redi-Sep column using a 0–40% EtOAc-hexane gradient over 40 min, 40 mL/min. The pure fractions were combined and concentrated at reduced pressure to give 1.0 g of the title compound as a colorless oil: 1H NMR (300 MHz, CDCl3): δ 5.10–5.20 (br d, J=6.1 Hz, 1H), 4.34–4.43 (m, 1H), 3.74 (s, 3H), 1.66 (t, J=6.5 Hz, 2H), 1.45 (s, 9H), 0.65–0.75 (m, 1H), 0.4–0.55 (m, 2H), 0.01–0.14 (m, 2H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]#[CH:21])[CH:15]=[CH:14][C:13]=2[NH:22][CH2:23][C:24]2[C:25]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[N:26][CH:27]=[CH:28][CH:29]=2)=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[O-:35][C:36]#[N:37].[Na+]>C(O)(=O)C>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:12]3[C:13](=[CH:14][CH:15]=[C:16]([O:18][CH2:19][C:20]#[CH:21])[CH:17]=3)[N:22]([CH2:23][C:24]3[C:25]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[N:26][CH:27]=[CH:28][CH:29]=3)[C:36](=[O:35])[N:37]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: C#CCOc1ccc(NCc2cccnc2OCCOC)c(C(=O)c2ccc(C(C)C)cc2)c1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccnc1OCCOC
Reaction time: 2 h

Procedure:
To a solution of 200 mg (0.436 mmol) (4-Isopropyl-phenyl)-(2-{[2-(2-methoxy-ethoxy)-pyridin-3-ylmethyl]-amino}-5-prop-2-ynyloxy-phenyl)-methanone in 1.5 ml acetic acid is added 28 mg (0.436 mmol) sodium cyanate. After stirring for 2 h the solvent is removed in vacuo and the residue is partitioned between CH2Cl2 and water. The organic layer is dried and evaporated. Purification of the crude product by flash-chromatography (CH2Cl2/ether 3:7) affords a yellow oil.
Reaction SMILES: [CH3:1][C:2](=[CH2:5])[CH2:3][NH2:4].C(N(CC)C(C)C)(C)C.Cl[CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:5][C:2](=[CH2:1])[CH2:3][NH:4][S:18]([CH:17]=[CH2:16])(=[O:20])=[O:19]
Reactant: C=C(C)CN
Reactant: O=S(=O)(Cl)CCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CS(=O)(=O)NCC(=C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.3 %

Procedure:
To a stirred solution of 2-methylprop-2-en-1-amine (0.500 g, 7.0 mmol), N,N-diisopropylethylamine (3.486 mL, 21.1 mmol) and N,N-4-dimethylaminopyridine (0.043 g, 0.4 mmol) in methylene chloride (20 mL) at 0° C. was slowly added 2-chloroethanesulfonyl chloride (0.734 mL, 7.0 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 16 hrs. The mixture was concentrated and the residue purified by silica gel chromatography (0-80% ethyl acetate/hexanes) to afford the product as a colorless oil (0.59 g, 52%). 1H NMR (300 MHz, CDCl3) δ 6.54 (dd, 1H, J=16.5, 9.6 Hz), 6.27 (d, 1H, J=16.5 Hz), 5.96 (d, 1H, J=9.6 Hz), 4.97 (s, 1H), 4.93 (s, 1H), 4.37 (br s, 1H), 3.60 (d, 2H, J=6.3 Hz), 1.79 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:5]=[CH:4][C:3]=1[NH:16][C:17]1[O:18][CH2:19][C:20](=[O:25])[C:21]=1[C:22]([O-:24])=[O:23].[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][N:33]=2)[C:28]([CH:35]=O)=[CH:27]1.N1CCC[CH2:39][CH2:38]1>C(O)C>[C:22]([OH:24])(=[O:23])[CH3:21].[NH:26]1[C:34]2=[N:33][CH:32]=[CH:31][CH:30]=[C:29]2[C:28]([CH:35]=[C:19]2[O:18][C:17]([NH:16][C:3]3[CH:4]=[CH:5][C:6]([NH:8][CH2:9][CH2:10][N:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)=[CH:7][C:2]=3[CH3:1])=[C:21]([C:22]([O:24][CH2:38][CH3:39])=[O:23])[C:20]2=[O:25])=[CH:27]1
Reactant: C1CCNCC1
Reactant: Cc1cc(NCCN2CCCC2)ccc1NC1=C(C(=O)[O-])C(=O)CO1
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: CCO
Product: CC(=O)O
Product: CCOC(=O)C1=C(Nc2ccc(NCCN3CCCC3)cc2C)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 4.2 %

Procedure:
To a solution of 2-[(2-methyl-4-{[2-(pyrrolidino)ethyl]amino}phenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.32 g, 0.85 mmol) which similarly prepared according to the procedure described in the Example 125, First step to Third step and 7-azaindole-3-carboxaldehyde (0.13 g, 0.85 mmol) in ethanol (5.0 mL), piperidine (0.10 mL, 1.0 mmol) was added at ambient temperature. The mixture was refluxed for 24 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC (aqueous ammonium acetate/acetonitrile) to afford the titled compound as solid (0.010 g, y. 3%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:13]([C:14](=[O:16])[NH2:15])=[CH:12][N:11]([C:17]3([CH2:30][C:31]#[N:32])[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[N:10]=2)=[CH:4][CH:3]=1.[CH3:33][C:34]1[C:38](B2OC(C)(C)C(C)(C)O2)=[C:37]([CH3:48])[O:36][N:35]=1.C(=O)([O-])[O-].[K+].[K+].C1COCC1>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:14]([C:13]1[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([C:38]3[C:34]([CH3:33])=[N:35][O:36][C:37]=3[CH3:48])=[CH:3][CH:4]=2)=[N:10][N:11]([C:17]2([CH2:30][C:31]#[N:32])[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:12]=1)(=[O:16])[NH2:15]
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(C(N)=O)c(Nc3ccc(Br)cc3)n2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1ccc(Nc2nn(C3(CC#N)CCN(C(=O)OC(C)(C)C)CC3)cc2C(N)=O)cc1
Temperature: 25 °C

Procedure:
tert-Butyl 4-{3-[(4-bromophenyl)amino]-4-carbamoyl-1H pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate (Example #2-2) (50 mg, 0.10 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (22 mg, 0.10 mmol), potassium carbonate (55 mg, 0.40 mmol), and tetrakis(triphenylphosphine)palladium (0) (6 mg, 0.005 mmol) was suspended in 2:1 THF:water (1.2 mL) and heated to 100° C. for 16 hours. The mixture was then cooled to ambient temperature, diluted with MeOH, and filtered through a 0.45 micron nylon syringe filter. The filtrate was concentrated in vacuo and the residue was purified by reverse-phase preparative HPLC (using a gradient elution of 35-70% MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were identified, combined, and lyophilized to afford the title compound, Example #14.
Reaction SMILES: [CH:1]1[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+]([O-])(O)=[O:16]>C(O)(=O)C.O>[CH:11]1[C:12]2[S:13][C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[S:6](=[O:16])[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: c1ccc2c(c1)Sc1ccccc1S2
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: O=S1c2ccccc2Sc2ccccc21
Reaction time: 5 h

Procedure:
Thianthrene (20 g) was refluxed in 300 ml of acetic acid, and 36 ml of dilute nitric acid was gradually added dropwise thereto. After allowing the reaction to proceed for 5 hours, the reaction solution obtained was poured in 1.2 liter of water to precipitate a crystal. The crystal was collected by filtration and then recrystallized from acetonitrile to obtain 12 g of thianthrene-S-oxide. 1H-NMR (400 MHz, CDCl3): δ 7.42 (t, 2H), 7.56 (t, 2H), 7.63 (d, 2H), 7.93 (d, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6](O)[CH:5]=[CH:4][N:3]=1.[F:9][C:10]([F:20])([F:19])[C:11]1[CH:12]=[C:13]([NH:17]N)[CH:14]=[CH:15][CH:16]=1.C1(C)C=CC=CC=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[F:9][C:10]([F:19])([F:20])[C:11]1[CH:16]=[CH:15][C:14]2[C:7]3[C:2]([OH:1])=[N:3][CH:4]=[CH:5][C:6]=3[NH:17][C:13]=2[CH:12]=1
Reactant: Oc1ccnc(O)c1
Reactant: NNc1cccc(C(F)(F)F)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Oc1nccc2[nH]c3cc(C(F)(F)F)ccc3c12
Temperature: 25 °C

Procedure:
A mixture 2,4-dihydroxypyridine and 3-trifluoromethylphenylhydrazine (2.6 equiv) in diphenyl ether was heated at reflux with a Dean Stark apparatus for 2 h as described by C. H. Nguyen in Tetrahedron 1987, 43, 527. The reaction was cooled to room temperature followed by the addition of toluene. The solid was collected and washed with toluene. The solid was then dissolved in EtOAc and purified by flash chromatography (EtOAc to 5% MeOH in EtOAc) to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][N:33]([C:36]4[C:41]([Cl:42])=[CH:40][CH:39]=[CH:38][C:37]=4[NH2:43])[CH2:32][CH2:31]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:44][S:45](Cl)(=[O:47])=[O:46].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][N:33]([C:36]4[C:37]([NH:43][S:45]([CH3:44])(=[O:47])=[O:46])=[CH:38][CH:39]=[CH:40][C:41]=4[Cl:42])[CH2:32][CH2:31]3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCN(c3c(N)cccc3Cl)CC2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCN(c3c(Cl)cccc3NS(C)(=O)=O)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-{3-[4-(2-amino-6-chloro-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (257 mg, 0.42 mmol) in 4 mL of CH2Cl2 was treated with 32 □L (0.42 mmol, 1.0 eq) of methanesulfonyl chloride and 116 □L (0.83 mmol, 2 eq) of triethylamine and the reaction mixture stirred at 25° C. for 1 h. EtOAc (40 mL) and sat. NaHCO3 (20 mL) were added. The organic layer was separated and washed with H2O (20 mL), brine (20 mL), dried over Na2SO4, and concentrated to afford the crude 1-{3-[4-(2-chloro-6-methanesulfonylamino-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester. TLC (silica, 10% MeOH/CH2Cl2): Rf=0.3. MS (electrospray): exact mass calculated for C32H40ClF3N6O4S, 696.25; m/z found, 697.2 [M+H]+.