Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[CH:4]([C:11](Cl)=[O:12])[C:3]2=O.C(N(CC)CC)C.C(O[C:27]([N:29](C)[NH:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl>[CH3:27][N:29]1[C:3]2[C@:2]3([CH3:1])[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]3)[C:4]=2[C:11](=[O:12])[N:30]1[C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1
Reactant: CN(Nc1ccc2ccccc2c1)C(=O)OC(C)(C)C
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: C1COCCO1
Product: Cn1c2c(c(=O)n1-c1ccc3ccccc3c1)[C@@H]1CC[C@@]2(C)C1(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 31 %

Procedure:
A solution of (1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 25; 530 mg, 2.47 mmol) in 1,2-dichloroethane (12 mL) was added to a cooled (0° C.) solution of triethylamine (470 μL, 3.37 mmol) and N-methyl-N′-naphthalen-2-yl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 36; 450 mg, 1.65 mmol) in 1,2-dichloroethane (6 mL) over 1 min. The reaction mixture was stirred at room temperature for 90 min. A solution of HCl in dioxane (4 M; 10 mL, 40 mmol) was added and the reaction mixture was heated at reflux for 90 min, and allowed to cool. The solvent was evaporated. The residue was purified twice using ISCO 40 g columns. The first column was eluted with 50-100% ethyl acetate and then with 10% methanol/ethyl acetate. The second column was eluted with 60-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated and the residue was co-evaporated with methanol and then with diethyl ether, and dried under high vacuum at room temperature to give (4R,7S)-1,7,8,8-tetramethyl-2-naphthalen-2-yl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (170 mg, 31%) as an off-white foam. ES(+)-MS (M+H) 333.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]([N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[O:14])[C:9]=2[C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH2:14].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[C:9]=2[C:28]2[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2n[nH]c(-c3ccc(F)cc3)c2-c2ccncc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O
Product: O=C(c1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1)N1CCNCC1
Yield: 96.4 %

Procedure:
A solution of 1,1-dimethylethyl 4-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]carbonyl]-1-piperazinecarboxylate (0.6349 g; 1.4077 mmol; prepared as set forth in step 2 of Example A-313) in methylene chloride (3.5 mL) and TFA (1.1 mL, 14.077 mmol) was stirred at room temperature under N2 for 2 hours. The solvents were removed under reduced pressure, and TFA was chased by methylene chloride and methanol. The resulting colorless oily residue was triturated with methanol. The resulting solid was collected by filtration and dried in a vacuum oven overnight to give the desired product 1-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]carbonyl]piperazine, monohydrate (0.7860 g, 96.4%). Anal. Calc'd for C19H18N5F.2TFA.H2O: C, 46.24; H, 3.71; N, 11.72; Found: C, 45.87; H, 3.43; N, 11.45. MS (MH+): 352 (base peak).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:3]=1[CH:4]=[CH:5][C:6](O)=[O:7].CCN=C=NCCC[N:22]([CH3:24])C.Cl.C(N(CC)CC)C.N[O:34][CH3:35].Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([N:22]([O:34][CH3:35])[CH3:24])=[O:7]
Reactant: CCN=C=NCCCN(C)C
Reactant: CON
Reactant: O=C(O)C=Cc1cc(F)ccc1F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C=Cc1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.3 %

Procedure:
A mixture of 2,5-difluorocinnamic acid (18.4 g), EDAC.HCl (23 g), DMAP (12.2 g), triethylamine (28 mL), and NH2OMe.HCl (12 g) in CH2Cl2 (300 mL) was stirred at room temperature for 16 h. The reaction was quenched with water, and the organic layer was washed with brine, dried over MgSO4 and filtered. The filtrated was evaporated in vacuo, and the crude product was purified by silica gel flash chromatography eluting with 33% hexanes in ethyl acetate gave the title compound (22.1 g) as a solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C:3]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:2]1.[Cl:16][CH2:17][CH2:18][O:19][CH3:20].[I-].[K+]>>[ClH:16].[CH3:20][O:19][CH2:18][CH2:17][N:1]1[CH2:6][CH2:5][CH2:4][C:3]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:2]1
Reactant: COCCCl
Reactant: O=C1Nc2ccccc2C12CCCNC2
Agent: [I-]
Agent: [K+]
Product: COCCN1CCCC2(C1)C(=O)Nc1ccccc12
Product: Cl
Yield: 74 %

Procedure:
The compound was prepared according to PROCEDURE 1, Method B by reaction with spiro[indoline-3,3′-piperidin]-2-one and 2-chloroethyl methylether (1.2 equivalents) and potassium iodide (catalytic amount). EtOAc was used for extraction. Yield: 74% 13C NMR (CDCl3): δ 21.8, 31.8, 48.8, 54.2, 58.0, 58.8, 59.2, 70.8, 109.8, 122.0, 126.4, 127.6, 134.8, 140.2, 182.0. The HCl salt was prepared. MS (TSP): m/z (rel. int.) 262/261 (M+, 16/100).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][S:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:20](Cl)(=[O:22])[CH3:21].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][S:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([NH:17][C:20](=[O:22])[CH3:21])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc2oc(SCc3ccc(Cl)cc3)nc2c1
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2oc(SCc3ccc(Cl)cc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.1 %

Procedure:
To a solution of 2-(4-chlorobenzylthio)benzo[d]oxazol-5-amine (87 mg, 0.30 mmol) in dry pyridine (3 mL) at room temperature was added acetyl chloride (21 μL, 0.30 mmol). The resulting solution was stirred at room temperature for 16 h. Water was then added, the precipitate was collected by filtration, washed with diluted aqueous hydrochloric acid and then with water. Trituration with diethyl ether afforded 40 mg (40%) of the title compound (LCMS RT=6.40 min, MH+ 333.1)
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]([NH2:38])[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C:32]([CH3:35])([CH3:34])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.CN1CCOCC1.[CH2:46]([O:48][C:49]([NH:51][C@H:52]([C:56](O)=[O:57])[CH:53]([CH3:55])[CH3:54])=[O:50])[CH3:47].[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C>CN(C=O)C>[S:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH2:12][N:13]([NH:38][C:56](=[O:57])[C@H:52]([CH:53]([CH3:55])[CH3:54])[NH:51][C:49]([O:48][CH2:46][CH3:47])=[O:50])[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C:32]([CH3:34])([CH3:35])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:10][CH:11]=2)=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cncs2)cc1)C(C)(C)C
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2cncs2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, 344 mg of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl-2-azahexane (Example 2d) and 191 μl (1.74 mmol) of NMM in 5.6 ml of DMF are added to 132 mg (0.7 mmol) of N-ethoxycarbonyl-(L)-valine (EP 0 604 368, Example 9a) and 173 mg (0.58 mmol) of TPTU in 2.9 ml of DMF, and the mixture is stirred at room temperature overnight and worked up analogously to Example 3, yielding the title compound: TLC: Rf =0.45 (methylene chloride/THF 4:1); HPLC20-100 : tRet =14.7; FAB MS (M+H)+ =711.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:44]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[CH2:47][NH:46][CH2:45]2.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:44]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[CH2:47][N:46]([C:20]([C:17]1[CH:16]=[CH:15][C:14]([O:13][CH:10]3[CH2:11][CH2:12][NH:8][CH2:9]3)=[CH:19][CH:18]=1)=[O:22])[CH2:45]2
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)O)cc2)C1
Reactant: C1CC2CCC1CNC2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(OC2CCNC2)cc1)N1CC2CCC(CC2)C1
Reaction time: 0.17 h
Yield: 53.6 %

Procedure:
To a solution of 3-(4-carboxy-phenoxy)-pyrrolidine-1-carboxylic acid t-butyl ester (2.0 g, 6.53 mmol) in DMF (75 mL) was added HOBt (1.1 g, 7.83 mmol) and EDAC (1.5 g, 7.83 mmol) and the resulting mixture was stirred for 10 min. 3-Aza-bicyclo-[3.2.2]nonane (1 g, 7.83 mmol) and DIPEA (1.4 mL) were added and stirring was continued for 16 hrs at ambient temperature. The volatiles were evaporated in vacuo and to the residue was added water (50 mL) and diethyl ether (25 mL). A precipitate was forme, filtered off and redissolved in DCM (25 mL) followed by addition of TFA (10 mL). The mixture was stirred at room temperature for 16 hrs and the volatiles evaporated in vacuo. The residue was dissolved in water (50 mL) and washed with diethyl ether (2×10 mL). The pH of the aqueous phase was adjusted to ˜11 by addition of 32% NaOH followed by extraction with diethyl ether (2×50 mL). The combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo. The crude residue was stirred with EtOAc (20 mL) and the precipitate formed was filtered off. The filtrate was evaporated to dryness affording crude 1.1 g (55%) of (3-aza-bicyclo[3.2.2]non-3-yl)-[4-(pyrrolidin-3-yloxy)-phenyl]-methanone which was used without further purification.
Reaction SMILES: [CH2:1]([P:3]([O-:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2].[CH:10](=[O:13])[CH:11]=[CH2:12]>C1(C)C=CC=CC=1>[CH2:1]([P:3]([CH2:12][CH2:11][CH:10]=[O:13])(=[O:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCCCOP([O-])CC
Reactant: C=CC=O
Solvent: Cc1ccccc1
Product: CCCCOP(=O)(CC)CCC=O
Yield: 82.9 %

Procedure:
149 g (1 mol) of butyl ethyiphosphonite (produced as in Example 2) and 67 g (1.2 mol) of 2-propenal in 217 g of toluene are heated to about 100° C. While stirring, 124 g of a 10% strength solution of WakoV65 in toluene are added by metered addition. The solvent is distilled off in vacuo to leave 171 g (78% of theory) of butyl ethyl(2-formylethyl)phosphinate.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([OH:18])=[C:10]([C:19](OCC)=[O:20])[C:9]1=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C[O-].[Na+].[NH2:28][OH:29]>CO>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([OH:18])=[C:10]([C:19]([NH:28][OH:29])=[O:20])[C:9]1=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: NO
Reactant: CCCCCCCn1c(=O)c(C(=O)OCC)c(O)c2ccccc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCn1c(=O)c(C(=O)NO)c(O)c2ccccc21
Reaction time: 24 h
Yield: 40 %

Procedure:
A round-bottomed flask was charged with the product from step (1) (493 mg, 1.49 mmole), sodium methoxide (208 mg, 3.85 mmole), hydroxylamine (278 mg, 4.0 mmole) and methanol (10 mL). The reaction was stirred for 24 hrs and the precipitated product was collected by filtration, washed with water and dried in vacuo to give the title compound (40% yield). That the expected product was obtained was confirmed by the spectral data: M.S. (FAB): m/e 319 (M·+ +H); NMR (DMSO-d6): δ8.25 (1 H, d), 7.85 (1H, dd), 7.7 (1H, d), 7.45 (dd), 4.4 (2H, m, CH2N), 2.95 (br s, exchangeable protons), 1.8 (2H, m), 1.55 (8H, m), 0.95 (3H, t, CH3).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[F:16].FC(F)(F)C(O[Si](C)(C)C)=O.[CH:28](OCC)(OCC)OCC.[N:38]([Si](C)(C)C)=[N+:39]=[N-:40]>CCOC(C)=O>[F:16][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH:6]=[N:7][C:2]=1[N:1]1[CH:28]=[N:38][N:39]=[N:40]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)Cc1cnc(N)c(F)c1
Reactant: CCOC(OCC)OCC
Agent: C[Si](C)(C)OC(=O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cc1cnc(-n2cnnn2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl 2-(6-amino-5-fluoropyridin-3-yl)acetate (120 mg, 0.53 mmol) in EtOAc (2.6 mL) was added trimethylsilyl trifluoroacetate (156 μL, 0.90 mmol), triethyl orthoformate (156 μl, 0.94 mmol), and azidotrimethylsilane (112 μL, 0.85 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was concentrated to give the crude product, which was purified by column chromatography to give title compound: LC/MS: [(M+1-56-28)]+=196.4;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([CH2:27][CH3:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:17]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:12]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:13]2[CH:26]=[C:25]([CH2:27][CH3:28])[S:24][C:14]=2[N:15]=1
Reactant: CCc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: CCc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-2-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-dichlorobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=O)[CH2:5][C:6]([O:8][CH3:9])=[O:7].[CH3:11]OC(OC)N(C)C.Cl.[C:20]1([NH:26][NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:1][O:2][CH2:3][C:4]1[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:11][N:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:27]=1
Reactant: NNc1ccccc1
Reactant: COCC(=O)CC(=O)OC
Reactant: COC(OC)N(C)C
Agent: Cl
Product: COCc1nn(-c2ccccc2)cc1C(=O)OC
Yield: 55 %

Procedure:
Using methyl 4-methoxyacetoacetate (7.9 g), dimethylformamide dimethylacetal (7.2 mL) and phenylhydrazine hydrochloride (5.8 g) and in the same manner as in Example 15(1), the title object compound (7.3 g, 55%) was obtained as a pale-yellow solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[C:11](OCC)(=[O:13])C.C(O)(=O)[CH2:18][C:19]([CH2:24]C(O)=O)([C:21](O)=O)[OH:20]>[OH-].[Na+].O1CCOCC1.C(#N)C>[C:19]([O:20][C:11]([NH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1)=[O:13])([CH3:18])([CH3:21])[CH3:24]
Reactant: NC1CCC(C(=O)O)CC1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CCOC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCC(C(=O)O)CC1
Reaction time: 20 h
Yield: 125 %

Procedure:
To a solution of 2.86 g (20 mmol) of 4-aminocyclohexane carboxylic acid in 40 mL of 0.5M aqueous NaOH solution, 20 mL of dioxane and 4 mL of acetonitrile was added a total of 6.5 g (30 mmol) of tBoc anhydride at room temperature. After 20 h, 100 mL of ethyl acetate and 100 mL of 10% aqueous citric acid solution were introduced. The aqueous layer which formed was separated and extracted with three-50 mL portions of ethyl acetate. The organic phases were combined, dried (sodium sulfate) and concentrated in vacuo to give 6.0 g (125%) of crude 4-(t-butoxycarbonylamino)cyclohexane carboxylic acid as a colorless oil which solidified upon standing.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:24]=[CH:23][C:12]([CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=[O:21])[CH2:16][CH2:15]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[F:25][C:26]([F:38])([F:37])[O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[F:25][C:26]([F:37])([F:38])[O:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:3]=[N:4][C:5]([NH:8][C:9]3[CH:24]=[CH:23][C:12]([CH2:13][N:14]4[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=[O:21])[CH2:16][CH2:15]4)=[CH:11][CH:10]=3)=[N:6][CH:7]=2)=[CH:30][CH:29]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)C1CCN(Cc2ccc(Nc3ncc(Br)cn3)cc2)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: [Na+]
Solvent: C1COCCO1
Product: O=C(O)C1CCN(Cc2ccc(Nc3ncc(-c4ccc(OC(F)(F)F)cc4)cn3)cc2)CC1
Temperature: 150 °C

Procedure:
To a solution of 1-(4-(5-bromopyrimidin-2-ylamino)benzyl)piperidine-4-carboxylic acid 17 (0.05 mmol) in 1,4-dioxane (1.0 mL) is added 4-(trifluoromethoxy)phenylboronic acid (0.05 mmol), 3M Na2CO3 (0.15 mmol) and Pd(PPh3)4 (0.0025 mmol). The reaction is evacuated and backfilled with nitrogen twice then heated at 150° C. for 10 min. Purification by preparative HPLC (ACN gradient 10-70%) affords 1-(4-(5-(4-(trifluoromethoxy)phenyl)pyrimidin-2-ylamino)benzyl)piperidine-4-carboxylic acid A5. 1H NMR (400 MHz, d6-DMSO) δ 10.06 (s, 1H), 8.89 (s, 2H), 7.88 (M, 4H), 7.48 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 4.23 (s, 2H), 2.95 (m, 1H), 2.51 (m, 4H), 2.09 (m, 2H), 1.71 (m, 2H). MS (m/z) (M+1)+: 473.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:22][CH2:23]CC(OC)=O)[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[ClH:35].[Cl:36]C[CH2:38][N:39]1[CH:43]=[CH:42][N:41]=[CH:40]1.Cl>>[ClH:36].[ClH:35].[N:39]1([CH2:38][CH2:23][S:22][C:11]2[CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:14]([NH:15][C:16]3[S:17][CH:18]=[C:19]([CH3:21])[N:20]=3)=[N:13][CH:12]=2)[CH:43]=[CH:42][N:41]=[CH:40]1
Reactant: ClCCn1ccnc1
Reactant: COC(=O)CCSc1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: Cc1csc(Nc2ncc(SCCn3ccnc3)cc2OCc2ccccc2)n1
Yield: 33.3 %

Procedure:
Methyl 3-(5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)propanoate (prepared according to Example 42; 70 mg, 0.17 mmol), KOtBu (0.59 mL, 0.59 mmol) and 1-(2-chloroethyl)-1H-imidazole hydrochloride (28.1 mg, 0.17 mmol) were reacted according to the method of Example 43 to afford 5-(2-(1H-imidazol-1-yl)ethylthio)-3-(benzyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine dihydrochloride (28.1 mg, 33.6% yield) as a tan solid after HCl salt formation. 1H NMR (d6-DMSO) δ 9.16 (t, 1H), 7.96 (d, 1H), 7.75 (t, 1H), 7.66 (t, 1H), 7.64-7.59 (m, 3H), 7.45-7.33 (m, 3H), 6.77 (s, 1H), 5.34 (s, 2H), 4.35 (t, 2H), 3.47 (t, 2H), 2.29 (d, 3H); Mass spectrum (apci) m/z=424.0 (100) 328.0 (75) 238.0 (35).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([CH2:13][N:14]([CH3:16])[CH3:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1.[I:18][CH3:19]>C(O)(C)C>[I-:18].[Br:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[CH2:5][CH:4]([C:3]([O:2][CH3:1])=[O:17])[CH2:13][N+:14]([CH3:19])([CH3:16])[CH3:15]
Reactant: COC(=O)C(Cc1cccc(Br)c1)CN(C)C
Reactant: CI
Solvent: CC(C)O
Product: COC(=O)C(Cc1cccc(Br)c1)C[N+](C)(C)C
Product: [I-]
Reaction time: 8 h
Yield: 85 %

Procedure:
To a 10 ml pear-shaped flask containing 3-(3-bromophenyl)-2-dimethylaminomethylpropionic acid methyl ester (0.762 g, 2.54 mmol) were added isopropanol (5 ml) and iodomethane (480 μl, 1.09 g, 7.68 mmol). The mixture was stirred overnight, and the resultant white suspension was filtered and the solid was washed with isopropanol and air-dried to give 2-(3-bromobenzyl)-3-methoxy-N,N,N-trimethyl-3-oxo-1-propanaminium iodide, 0.95 g, 85% yield. 2-(4-Bromobenzyl)-3-methoxy-N,N,N-trimethyl-3-oxo-1-propanaminium iodide was prepared similarly from 3-(4-bromophenyl)-2-dimethylaminomethylpropionic acid methyl ester in 82% yield. MS (ES+) [M−I−]: 314, 316. HPLC purity: 95%.
Reaction SMILES: C[O-].[Na+].C(O)(=O)C.[CH:8]([NH2:10])=[NH:9].[CH3:11][CH:12]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:13]([C:18](OC)=[O:19])[C:14](OC)=[O:15]>CO.C1(C)C=CC=CC=1>[OH:19][C:18]1[C:13]([CH:12]([CH3:11])[CH2:22][C:23]([O:25][CH3:26])=[O:24])=[C:14]([OH:15])[N:10]=[CH:8][N:9]=1
Reactant: N=CN
Reactant: COC(=O)CC(C)C(C(=O)OC)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)CC(C)c1c(O)ncnc1O
Temperature: 3.0999999046325684 °C
Reaction time: 1.5 h
Yield: 86.9 %

Procedure:
A 12-L, 4-necked reactor, equipped with a mechanical stirrer, was charged with 2.80 L of methanol and sparged with nitrogen. The solvent was treated with NaOMe (1969 mL, 8612 mmol) and transfer washed with 250 mL of methanol. The mixture was left to stir for 1.5 hours before the solution was treated with formamidine acetate (246.6 g, 2368 mmol) in one sum (granular-homogenized). The mixture was allowed to stir for 20 minutes (the solids dissolved within about 10 minutes post addition) to afford a homogeneous solution. Trimethyl 2-methylpropane-1,1,3-tricarboxylate (500 g, 2153 mmol) was added via dropping funnel as a solution in 500 mL of methanol over a five minute period, followed by 200 mL more of methanol to complete transfer. The reaction (clear, bright yellow) was allowed to stir at ambient temperature overnight to completion as measured by NMR analysis (alliquot of 250 uL was removed via pipet and treated with five drops of aq. 3N HCl, reduced under vacuum to dryness, dissolved in d6-DMSO and then filtered) after 16 hours. The reaction was placed in an ice-bath and cooled to about 3.1° C. over a one hour period. A three-pound bottle of HCl (g) was used to quench the reaction (bubbling gas into solution via teflon tubing) over a one hour ten minute period reaching an endpoint of about pH=2.5 (via paper). The temperature was maintained below about 9.6° C. throughout the addition, and the yellow solution changed to an off-white suspension. The suspension was concentrated using vacuum distillation (35-37° C. @ 200 Torr) of the methanol (removed 3.34 L) in vacuo to afford a white/tan paste. The mixture was suspended in 3.75 L of toluene (7.5× volume) and stirred for 30 minutes. The suspension was filtered off (table top filter/polypropylene cloth, pad washed with 2×500 mL portions of toluene). The pad of product was allowed to air-dry under suction overnight on the filter then broken up with a spatula to give 396.8 grams, 86.9% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([NH:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:35]=[CH:34][C:26]([C:27]([O:29]C(C)(C)C)=[O:28])=[CH:25][N:24]=4)[CH2:19][CH2:18]3)=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([NH:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:35]=[CH:34][C:26]([C:27]([OH:29])=[O:28])=[CH:25][N:24]=4)[CH2:19][CH2:18]3)=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CCC(NC(=O)c3ccc(-c4cccc(F)c4)nc3)CC2)nc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(N2CCC(NC(=O)c3ccc(-c4cccc(F)c4)nc3)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round-bottom flask containing tert-butyl 6-[4-({[6-(3-fluorophenyl)pyridin-3-yl]carbonyl}amino)piperidin-1-yl]nicotinate was added DCM (50 mL) and TFA (18 mL). After stirring at rt overnight the reaction was diluted with toluene (10 mL) and the solvent removed to give 6-[4-({[6-(3-fluorophenyl)pyridin-3-yl]carbonyl}amino)piperidin-1-yl]nicotinic acid, as a white solid (30 mg, 78%). 1H NMR (400 MHz, DMSO-d6) □ ppm 9.06 (1H, s), 8.62 (1H, s), 8.47 (1H, d, J=7.9 Hz), 8.22-8.32 (1H, m), 8.10 (1H, d, J=8.1 Hz), 7.85-8.01 (3H, m), 7.47-7.60 (1H, m), 7.29 (1H, t, J=7.8 Hz), 6.89 (1H, d, J=9.3 Hz), 4.42 (2H, d, J=13.2 Hz), 3.10 (2H, t, J=12.7 Hz), 2.33-2.54 (2H, m), 1.91 (2 h, d, J=13.2 Hz), 1.41-1.63 (2H, m). HRMS (TOF, ES+) calculated: 421.1676; observed 421.1722.