Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([NH2:10])=[O:9])[C:6]([OH:12])=[CH:5][CH:4]=1.[Na].Br[CH2:15][CH2:16][CH3:17]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:12][CH2:15][CH2:16][CH3:17])=[C:7]([CH:11]=1)[C:8]([NH2:10])=[O:9]
Reactant: COc1ccc(O)c(C(N)=O)c1
Reactant: CCCBr
Agent: [Na]
Solvent: CCO
Product: CCCOc1ccc(OC)cc1C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
5-Methoxysalicylamide (56.0 g., 0.335 mole) was added to a cooled, stirred solution of sodium (8.55 g., 0.372 g-atom) in ethanol (335 ml.). To the resulting suspension was added 1-bromopropane (41.3 g., 0.335 mole) dropwise over 20 minutes. The mixture was stirred at room temperature for one hour, then was heated under reflux for 19 hours. The solvent was removed under reduced pressure. The residue was treated with cold water (500 ml.). The solid was collected by filtration and recrystallized from acetonitrile to give 5-methoxy-2-n-propoxybenzamide (29.0 g., 41.4%), m.p. 83°-87°.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][CH:16]([NH:19][CH3:20])[CH2:15][CH2:14]1.C([O-])(=O)C.[Na+].C(O)C>O>[CH3:12][N:13]1[CH2:18][CH2:17][CH:16]([NH:19][CH2:20][C:2]2[CH:3]=[C:4]([F:11])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=2)[CH2:15][CH2:14]1
Reactant: CNC1CCN(C)CC1
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN1CCC(NCc2cc(F)cc([N+](=O)[O-])c2)CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 1.4 %

Procedure:
Combine 1,3-difluoro-5-nitro-benzene (1.78 mL, 15.7 mmol), 1-methyl-4-(methylamino)piperidine (2.74 mL, 18.85 mmol), sodium acetate (2.45 g, 29.8 mmol) and absolute ethanol (10 mL) in a sealed tube. Heat and stir at 100° C. for 16 hr. Cool the reaction mixture to ambient temperature and pour into water (100 mL). Extract with ethyl acetate (2×100 mL). Wash combined organic layers with saturated aqueous NaCl solution (100 mL), dry over sodium sulfate, filter, and concentrate. Purify residue by silica gel flash chromatography eluting with 10% (2M NH3 in methanol) in CH2Cl2 to obtain 0.06 g (1.4%) of the title intermediate: 1H NMR (CDCl3): 7.3 (m, 1H), 7.2 (m, 1H), 6.7 (m, 1H), 3.6 (m, 1H), 3.0 (m, 2H), 2.8 (s, 3H), 2.3 (s, 3H), 2.2 (m, 2H), 1.9 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C@H:16]([CH3:17])[CH2:15][N:14]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:19])[C@@H:13]([CH3:28])[CH2:12]2)=[CH:7][C:6]=1[C:29]([F:32])([F:31])[F:30])#[N:4].[CH3:33]I.O>CN(C=O)C>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C@H:16]([CH3:17])[CH2:15][N:14]([C:18]([N:20]([CH3:33])[C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:19])[C@@H:13]([CH3:28])[CH2:12]2)=[CH:7][C:6]=1[C:29]([F:31])([F:32])[F:30])#[N:4]
Reactant: C[C@@H]1CN(C(=O)Nc2ccc(F)cc2)[C@@H](C)CN1c1ccc(C#N)c(C(F)(F)F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CN(C(=O)N(C)c2ccc(F)cc2)[C@@H](C)CN1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
A 69 mg portion of 60% sodium hydride was suspended in 6 ml of DMF, 660 mg of trans-4-(4-cyano-3-trifluoromethylphenyl)-4′-fluoro-2,5-dimethylpiperazine-1-carboxanilide synthesized in Example 1-1 was added to the suspension under ice-cooling, and then the mixture was stirred at 50° C. for 10 minutes. The reaction solution was ice-cooled, 0.11 ml of methyl iodide was added dropwise thereto, and then the mixture was stirred at room temperature for 2 hours. The reaction mixture was mixed with water, extracted with ethyl acetate, washed with saturated brine and then dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by a silica gel column chromatography to obtain 620 mg of the title compound from ethyl acetate-hexane eluate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH3:31])[C:15]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[N:25]=3)=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=3)[C:10]=2[C:9]1=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:33]([C:36]1[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=1)=[C:34]=[O:35]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH3:31])[C:15]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[N:25]=3)=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:34]([NH:33][C:36]4[CH:37]=[CH:38][C:39]([C:42]([F:43])([F:44])[F:45])=[CH:40][CH:41]=4)=[O:35])[CH:18]=3)[C:10]=2[C:9]1=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c2c(c(-c3cccc(N)c3)c1-c1ccnc(N)n1)C(=O)N(C(=O)OC(C)(C)C)CC2
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Product: Cn1c2c(c(-c3cccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)c3)c1-c1ccnc(N)n1)C(=O)N(C(=O)OC(C)(C)C)CC2
Yield: 61.2 %

Procedure:
To a solution of 3-(3-amino-phenyl)-2-(2-amino-pyrimidin-4-yl)-1-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (40 mg, 0.092 mmol) (prepared as described in Example 1) in dichloromethane (1 mL), 1-isocyanato-4-trifluoromethyl-benzene (0.014 mL, 0.101 mmol) was added. The mixture was stirred until disappearance of the starting material. The solvent was evaporated and the resided was suspended in diethylether and filtered to give 35 mg of 2-(2-Amino-pyrimidin-4-yl)-1-methyl-4-oxo-3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester. (y: 61%)
Reaction SMILES: [CH3:1][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[C:14]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[NH:25]1[C:33]2[CH2:32][CH2:31][CH2:30][C:29](=[O:34])[C:28]=2[CH:27]=[CH:26]1.[O-]CC.[Na+]>C(O)C.C(OCC)(=O)C>[OH:5][C:4]([C:7]([F:9])([F:8])[F:10])([CH2:3][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[C:14]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:13]=1)([CH3:11])[CH3:1])[CH2:6][N:25]1[C:33]2[CH2:32][CH2:31][CH2:30][C:29](=[O:34])[C:28]=2[CH:27]=[CH:26]1
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cc(S(C)(=O)=O)cc2c1OCC2
Reactant: O=C1CCCc2[nH]ccc21
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(CC(O)(Cn1ccc2c1CCCC2=O)C(F)(F)F)c1cc(S(C)(=O)=O)cc2c1OCC2
Temperature: 85 °C
Yield: 48.5 %

Procedure:
To a suspension of 7-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]-5-methanesulfonyl-2,3-dihydrobenzofuran (101 mg, 0.33 mmol) and 1,5,6,7-tetrahydroindol-4-one (74.9 mg, 0.56 mmol) in 0.75 mL of anhydrous ethanol was added sodium ethoxide (21 wt. % solution in ethanol, 103 μL). After heating at 85° C. for 16 hours, the reaction mixture was diluted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 50% to 60% ethyl acetate-hexanes) to give 80.0 mg (58% yield) of the title compound as a white solid, m.p. 207° C.-208° C.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[CH2:6]1)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1>[CH3:22][O:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=1[CH2:12][N:7]1[C:8](=[O:11])[CH2:9][CH2:10][CH:5]([C:3]([OH:4])=[O:2])[CH2:6]1
Reactant: COC(=O)C1CCC(=O)N(Cc2ccc(OC)cc2OC)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CN2CC(C(=O)O)CCC2=O)c(OC)c1
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of the crude product of 1-(2,4-dimethoxybenzyl)-6-oxopiperidine-3-carboxylic acid methyl ester (26.8 g) in methanol/tetrahydrofuran (1/1, 174 ml) was added a 1M aqueous solution of sodium hydroxide (174 ml) at room temperature, and the mixture was stirred overnight. To this reaction solution was added a 1M aqueous solution of hydrochloric acid (174 ml), the mixture was stirred. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the titled compound (15.1 g).
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:5][C@@:4]1([CH2:12][N:13]([CH3:23])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[CH2:24]([C:31]1[N:35]=[C:34]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[O:33][N:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([C:31]1[N:35]=[C:34]([CH:36]2[CH2:41][CH2:40][N:39]([CH2:1][C@@H:3]3[CH2:5][C@@:4]3([CH2:12][N:13]([CH3:23])[S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:38][CH2:37]2)[O:33][N:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CN(C[C@@]1(c2ccccc2)C[C@H]1C=O)S(=O)(=O)c1ccccc1
Reactant: c1ccc(Cc2noc(C3CCNCC3)n2)cc1
Product: CN(C[C@@]1(c2ccccc2)C[C@H]1CN1CCC(c2nc(Cc3ccccc3)no2)CC1)S(=O)(=O)c1ccccc1

Procedure:
N-{[(1S,2R)-2-formyl-1-phenylcyclopropyl]methyl}-N-methylbenzenesulfonamide and 4-(3-benzyl-1,2,4-oxadiazol-5-yl)piperidine (incorporating by reference as needed WO 00/39125) were reacted as per Preparation 10 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 7.69-7.55 (m, 5H), 7.36-7.18 (m, 10H), 4.08 (s, 2H), 3.91 (d, J=13.2 Hz, 1H), 3.08-2.98 (m, 2H), 2.81 (d, J=13.2 Hz, 1H), 2.84-2.78 (m, 1H), 2.59-2.43 (m, 2H), 2.52 (s, 3H), 2.27-1.97 (m, 4H), 1.80-1.66 (m, 2H), 1.45-1.39 (m, 1H), 1.09-0.99 (m, 1H), 0.80 (m, 1H). ES-LCMS m/z 557.2 (M+H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[C:13]([CH2:15]O)[CH:12]=[CH:11][N:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:39]>C1COCC1>[Br:39][CH2:15][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:18])([F:17])[F:1])[CH:14]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccnc(-c2ccccc2C(F)(F)F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)(F)c1ccccc1-c1cc(CBr)ccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
495 mg (1.96 mmol) of the compound from Example 61A and 615 mg (2.35 mmol) of triphenylphosphine were dissolved in 15 ml of THF, and 778 mg (2.35 mmol) of carbon tetrabromide were added at RT. After the addition had ended, the mixture was stirred ar RT for 16 h. For work-up, the mixture was filtered through 20 g of kieselguhr and the filtrate was concentrated under reduced pressure. The residue was purified chromatographically on silica gel (mobile phase: first cyclohexane/ethyl acetate 70:30, then ethyl acetate). This gave, in a purity of 90%, 149 mg (22% of theory) of the target compound, which were immediately reacted further.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2].[CH2:10]=[O:11]>>[CH2:1]([C:3]([CH2:10][OH:11])([CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2]
Reactant: C=O
Reactant: CCCCC(C=O)CC
Product: CCCCC(C=O)(CC)CO

Procedure:
The same also applies to U.S. Pat. No. 5,235,118, which relates to the reaction of 2-ethylhexanal with formaldehyde to give 2-ethyl-2-(hydroxymethyl)hexanal. Here too, formaldehyde is used in substoichiometric amounts relative to the 2-ethylhexanal, and only a small residue of formaldehyde is present in the product solution. The addition of water with subsequent distillation serves for effective removal of unreacted 2-ethylhexanal.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:17]([CH3:19])[CH3:18])[CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:16])=[CH:5][CH:4]=1.O.[CH2:21]([Mg]Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[ClH:2].[CH2:21]([C:11]1([OH:16])[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]1[CH:9]([C:6]1[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=1)[N:17]([CH3:19])[CH3:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CN(C)C(c1ccc(Cl)cc1)C1CCCCC1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(c1ccc(Cl)cc1)C1CCCCC1(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 46.7 %

Procedure:
The base was freed from 2.5 g (8.27 mmole) of the hydrochloride of 2-[(4-chlorophenyl)dimethylaminomethyl]cyclohexanone obtained according to stage 1 with 30 ml of water and 5 ml of amnonia solution (25 vol. %), was extracted three times with 30 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator without heating (500 to 10 mbar). 1.80 g (6.75 mmole) of this base were dissolved in 10 ml of tetrahydrofuran, added dropwise while cooling in an ice bath to 4.05 ml (8.13 mmole) of benzylmagnesium chloride (2 M solution in tetrahydro-furan), and stirred for 15 hours at RT. 2.30 g of crude base (94.9% of theory) were obtained, from which 1.24 g of 1-benzyl-2-[(4-chlorophenyl)dimethylaminomethyl]cyclohexanol, hydrochloride (46.7% of theory) were obtained according to the procedure described in Example 1 (3rd Stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 130° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[CH:9]=[CH:10][C:11]([O:17]C(=O)C)=[CH:12][C:13]=32)[CH2:6]1)=[O:4].C([O-])(O)=O.[Na+]>CO>[F:22][C:2]([F:1])([F:21])[C:3]([N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[CH:9]=[CH:10][C:11]([OH:17])=[CH:12][C:13]=32)[CH2:6]1)=[O:4]
Reactant: CC(=O)Oc1ccc2c(c1)C1CC2CN(C(=O)C(F)(F)F)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C(N1CC2CC(C1)c1cc(O)ccc12)C(F)(F)F

Procedure:
Acetic acid 10-trifluoroacetyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-4-yl ester (900 mg, 2.87 mmol) was stirred in MeOH (20 mL) and saturated aqueous NaHCO3 solution (15 mL) for 48 hours. The mixture was concentrated, diluted with H2O and extracted with CH2Cl2 (3×20 mL) then dried through a cotton plug. Chromatography on Silica gel provided pure product (420 mg, 54%). (TLC 5% MeOH/CH2Cl2 Rf 0.44). 1H NMR (400 MHz, CDCl3) δ 7.05 (m, 1H), 6.70 (m, 1H), 6.62 (m, 1H), 4.32 (m, 1H), 3.84 (m, 1H), 3.48 (m, 1H), 3.21 (br s, 1H), 3.16 (br s, 1H), 3.09 (m, 1H), 2.38 (m, 1H), 1.97 (d, J=11.0 Hz, 1H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:12]([NH2:14])[CH3:13])[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]([CH3:18])=O>ClCCCl>[CH:16]([NH:14][CH:12]([C:9]1[NH:10][CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)[CH3:13])([CH3:18])[CH3:15]
Reactant: CC(C)=O
Reactant: CC(N)c1nc(-c2ccccc2)c[nH]1
Solvent: ClCCCl
Product: CC(C)NC(C)c1nc(-c2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(4-Phenyl-1H-imidazol-2-yl)-ethylamine (0.20 g, 1.07 mmol) and acetone (0.062 g, 1.07 mmol) were mixed in 1,2-dichloroethane (4 mL), followed by the addition of NaBH(OAC)3 (0.34 g, 1.61 mmol). The resulting mixture was stirred at rt for 3 h. The reaction was quenched with saturated NaHCO3 solution. The mixture was extracted with EtOAc and the combined extracts were dried over Na2SO4. Filtration followed by evaporation to dryness under reduced pressure yielded crude isopropyl-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amine, which was used for the next reaction without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:11]1[CH:12]=[C:13]([C:31]([OH:40])([C:36]([F:39])([F:38])[F:37])[C:32]([F:35])([F:34])[F:33])[CH:14]=[CH:15][C:16]=1[N:17]1[CH2:22][CH2:21][N:20]([S:23]([C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)(=[O:25])=[O:24])[CH2:19][CH2:18]1>>[F:39][C:36]([F:37])([F:38])[C:31]([C:13]1[CH:12]=[CH:11][C:16]([N:17]2[CH2:22][CH2:21][N:20]([S:23]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)(=[O:24])=[O:25])[CH2:19][CH2:18]2)=[C:15]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:14]=1)([OH:40])[C:32]([F:35])([F:34])[F:33]
Reactant: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2Br)CC1
Reactant: OB(O)c1cccnc1
Product: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2-c2cccnc2)CC1

Procedure:
Following the procedure outlined for Example 69, 3-pyridineboronic acid (21.33 mg, 0.173 mmol) was coupled to 2-(3-bromo-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol to afford 1,1,1,3,3,3-hexafluoro-2-(3-(3-pyridinyl)-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1H NMR (400 MHz, CD3OD) δ 8.67 (d, J=1.6 Hz, 1H), 8.47 (dd, J=4.9, 1.6 Hz, 1H), 8.02-7.94 (m, 1H), 7.89 (dd, J=5.1, 1.2 Hz, 1H), 7.71 (d, J=9.2 Hz, 1H), 7.60-7.53 (m, 2H), 7.43 (dd, J=7.8, 4.9 Hz, 1H), 7.31-7.22 (m, 2H), 2.97 (s, 8H). m/z (ESI, +ve ion) 551.6 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=0.775 μM; GK-GKRP EC50 (LC MS/MS)=0.783 μM.
Reaction SMILES: C([O:9][C:10]1[C:11]([CH3:17])=[N:12][N:13]([CH3:16])[C:14]=1[CH3:15])(=O)C1C=CC=CC=1.[OH-].[Na+]>C(O)C>[CH3:16][N:13]1[C:14]([CH3:15])=[C:10]([OH:9])[C:11]([CH3:17])=[N:12]1
Reactant: Cc1nn(C)c(C)c1OC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(C)c(C)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
A flask was charged with 1,3,5-trimethyl-1H-pyrazol-4-yl benzoate (80 g, 347 mmol), and 500 mL ethanol was added. 3M NaOH (174 ml, 521 mmol) was added and the reaction was stirred at ambient temperature for 2 hours. The ethanol was removed in vacuo and the aqueous layer was extracted with dichloromethane, ethyl acetate and dichloromethane:isopropyl alcohol (4:1). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford 1,3,5-trimethyl-1H-pyrazol-4-ol (34 g, 78% yield) as white solid.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[C:24]([N:26]([CH3:28])[CH3:27])[CH:23]=[C:22](Cl)[N:21]=2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][C:37]=1[Cl:38])[NH2:34].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:21]=[C:22]([NH:34][C:33]3[CH:35]=[CH:36][C:37]([Cl:38])=[C:31]([Cl:30])[CH:32]=3)[CH:23]=[C:24]([N:26]([CH3:28])[CH3:27])[N:25]=2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CN(C)c1cc(Cl)nc(N2CCN(Cc3ccccc3)CC2)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Product: CN(C)c1cc(Nc2ccc(Cl)c(Cl)c2)nc(N2CCN(Cc3ccccc3)CC2)n1
Temperature: 110 °C
Reaction time: 7 h
Yield: 65.8 %

Procedure:
Potassium tert-butoxide (1.6 mmol, 1 M in 2-methyl 2-propanol) was added to a solution of N-[2-(4-benzyl-1-piperazinyl)-6-chloro-4-pyrimidinyl]-N,N-dimethylamine (0.331 g, 0.997 mmol) and 3,4 dichloroaniline (0.178 g, 1.10 mmol) in dioxane (2 mL). Subsequently, tris(dibenzylidineacetone)dipalladium (40 mg, 0.04 mmol) and 2,2′-Bis(diphenylphosphino)-1,1′binapthyl (44 mg, 0.070 mmol) were added and the mixture was stirred for 7 h at 110° C. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with saturated NaHCO3 (50 mL) and extracted with CH2Cl2 (3×50 mL). The organic layer was washed with brine (2×100 mL), dried over Na2SO4, concentrated in vacuo, and purified by preparative TLC using hexane/EtOAc to give the desired product (300 mg, 65%).
Reaction SMILES: CO[C:3]1[C:8]([C:9]([C:11](=[C:17](SC)SC)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10])=[CH:7][N:6]=[C:5]([S:22][CH3:23])[N:4]=1.[NH2:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([NH2:29])=[O:28].[H-].[Na+]>C(Cl)Cl.O>[CH2:15]([O:14][C:12]([C:11]1[C:9](=[O:10])[C:8]2[CH:7]=[N:6][C:5]([S:22][CH3:23])=[N:4][C:3]=2[N:24]2[C:17]=1[NH:29][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[CH:33][C:25]2=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)C(C(=O)c1cnc(SC)nc1OC)=C(SC)SC
Reactant: NC(=O)c1ccccc1N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1c(=O)c2cnc(SC)nc2n2c1[nH]c(=O)c1ccccc12
Temperature: 140 °C
Reaction time: 1 h
Yield: 19.6 %

Procedure:
A solution of ethyl 2-(4-methoxy-2-(methylthio)pyrimidine-5-carbonyl)-3,3-bis(methylthio)acrylate (250 mg, 0.668 mmol) and 2-aminobenzamide (118 mg, 0.867 mmol) in DCM (5 mL) was heated over stream of nitrogen allowing DCM to evaporate and continued heating as neat at 140° C. for over night. The residue was dissolved in DMF (7 mL) after cooling to rt and treated with NaH (60 mg, 1.500 mmol). The reaction was stirred at rt for 1 h and diluted with DCM (20 mL) and H2O (20 mL). The layers were separated and DCM was removed under reduced pressure. Trituration of the crude in Et2O (10 mL) afforded the desired product as a yellow solid (50 mg, 20%). MS (m/z): 383 (MH+). 1H NMR (CDCl3) δ: 13.58 (br s, 1H), 9.43 (s, 1H), 8.60 (d, 1H), 8.33 (dd, 1H), 7.79 (m, 1H), 7.59 (m, 1H), 4.48 (q, 2H), 2.62 (s, 3H), 1.46 (t, 3H).
Reaction SMILES: CO[C:3](=[O:20])[C@@H:4]([NH2:19])[CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[NH3:21]>CO>[CH2:12]([O:11][C:9](=[O:10])[NH:8][CH2:7][CH2:6][CH2:5][C@H:4]([NH2:19])[C:3](=[O:20])[NH2:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N
Reactant: COC(=O)[C@@H](N)CCCNC(=O)OCc1ccccc1
Solvent: CO
Product: NC(=O)[C@@H](N)CCCNC(=O)OCc1ccccc1

Procedure:
(S)-2-Amino-5-benzyloxycarbonylamino-pentanoic acid methyl ester (2.80 g, 9.99 mmol) and 7M NH3 in MeOH (20 ml) is stirred at room temperature for 72 hours. The reaction mixture is evaporated to dryness in vacuo to yield a white solid. The white solid is suspended in diethyl ether before filtration and drying to yield ((S)-4-Amino-4-carbamoyl-butyl)-carbamic acid benzyl ester.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([S:23](OC1C(F)=C(F)C(F)=C(F)C=1F)(=[O:25])=[O:24])=[CH:18]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:38]1[CH:42]=[CH:41][N:40]=[C:39]1[NH2:43].C1COCC1.CC([O-])(C)C.[Li+]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([S:23]([NH:43][C:39]1[S:38][CH:42]=[CH:41][N:40]=1)(=[O:25])=[O:24])=[CH:18]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nccs1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(C3CCCN3Cc3ccccc3)cccc2c1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=S(=O)(Nc1nccs1)c1ccc2c(C3CCCN3Cc3ccccc3)cccc2c1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 87.5 %

Procedure:
A flask was charged with perfluorophenyl 5-(1-benzylpyrrolidin-2-yl)naphthalene-2-sulfonate (Intermediate LL, 21.5 mg, 0.040 mmol), thiazol-2-amine (4.84 mg, 0.048 mmol), and THF (403 μl) to give a clear, colorless solution. The flask was cooled in an dry ice-acetone bath for 5 min, then lithium 2-methylpropan-2-olate (1M in hexane) (89 μl, 0.089 mmol) was added dropwise. The resulting mixture was stirred for 1 min, then the flask was lowered into an ice-bath. After 1 h, the mixture was warmed to room temperature then was loaded directly onto a 5-g silica gel loading column with the aid of DCM. The column was dried under vacuum, then eluted onto a prequilibrated 12-g column with 0 to 10% MeOH/DCM to give 5-(1-benzylpyrrolidin-2-yl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide (15.85 mg, 0.035 mmol, 87% yield) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=12.97-12.23 (m, 1H), 8.51 (d, J=9.1 Hz, 1H), 8.46 (d, J=1.9 Hz, 1H), 8.09-7.96 (m, 2H), 7.83 (dd, J=2.1, 9.0 Hz, 1H), 7.69-7.61 (m, 1H), 7.29 (d, J=4.4 Hz, 4H), 7.27-7.24 (m, 1H), 7.24-7.20 (m, 1H), 6.83 (d, J=4.6 Hz, 1H), 4.16 (t, J=8.2 Hz, 1H), 3.78 (d, J=13.2 Hz, 1H), 3.15 (d, J=13.2 Hz, 1H), 3.07 (td, J=4.6, 9.1 Hz, 1H), 2.47-2.38 (m, 1H), 2.30 (q, J=8.6 Hz, 1H), 1.89-1.79 (m, 2H), 1.68-1.57 (m, 1H); m/z (ESI) 450.4 (M+H)+.