Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:35]=[CH:36][CH:37]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:20]=[CH:21][C:22]3[N:23]([CH:25]=[C:26]([NH:28]C(=O)C(F)(F)F)[N:27]=3)[CH:24]=2)[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].[OH-].[Na+].O>C(O)C>[NH2:28][C:26]1[N:27]=[C:22]2[CH:21]=[CH:20][C:19]([O:18][C:14]3[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]4[CH:35]=[CH:36][CH:37]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=4)[CH:17]=[CH:16][CH:15]=3)=[CH:24][N:23]2[CH:25]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C(F)(F)F)cn4c3)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)cn4c3)c2)c1
Temperature: 45 °C
Reaction time: 12 h
Yield: 107.9 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)-N-[3-({2-[(trifluoroacetyl)amino]imidazo[1,2-a]pyridin-6-yl}oxy)phenyl]benzamide (400 mg, 0.788 mmol) in ethanol (4.0 mL) was added 1N aqueous sodium hydroxide solution (8.0 mL), and the mixture was stirred at 45° C. for 12 hr. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/methanol=100/0→80/20), and fractions containing the desired product were concentrated under reduced pressure to give the title compound (0.35 g, quantitative) as a colorless solid.
Reaction SMILES: C([NH:4][C:5]1(C(OCC)=O)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:15])(=O)C>Cl>[NH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:15]
Reactant: CCOC(=O)C1(NC(C)=O)Cc2ccccc2NC1=O
Agent: Cl
Product: NC1Cc2ccccc2NC1=O
Temperature: 100 °C
Yield: 72 %

Procedure:
3-(N-Acetylamino)-3-carboethoxy-1,2,3,4-tetrahydroquinolin-2-one (0.75 g, 100M %) was suspended in 6N HCl (25 mL) and the mixture was heated to 100° C. for 3 hours. The reaction was cooled, rotoevaporated to a residue and then partitioned between water and ethyl acetate. The water was extracted with ethyl acetate (3×) and the combined ethyl acetate extracts were then washed with water (3×) and then brine (1×). Treatment with MgSO4 followed by rotoevaporation yielded 3-(R,S)-amino-1,2,3,4-tetrahydroquinolin-2-one (72% yield).
Reaction SMILES: Cl[C:2]1[C:3](=[O:27])[O:4][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([Cl:26])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:6][C:7]=1[OH:8].ClC1C(=O)OC(CCC2CCCCC=2)(C2CCCC2)CC=1O.[Cl:50][C:51]1[CH:60]=[CH:59][C:54]2[N:55]=[C:56]([SH:58])[NH:57][C:53]=2[CH:52]=1.N1C=CC(C2NC(S)=NN=2)=CC=1>>[Cl:50][C:51]1[CH:60]=[CH:59][C:54]2[NH:55][C:56]([S:58][C:2]3[C:3](=[O:27])[O:4][C:5]([CH2:14][CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[C:18]([Cl:26])[CH:17]=4)([CH:9]4[CH2:10][CH2:11][CH2:12][CH2:13]4)[CH2:6][C:7]=3[OH:8])=[N:57][C:53]=2[CH:52]=1
Reactant: Sc1nc2ccc(Cl)cc2[nH]1
Reactant: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(O)=C(Cl)C(=O)O2)cc1Cl
Agent: O=C1OC(CCC2=CCCCC2)(C2CCCC2)CC(O)=C1Cl
Agent: Sc1nnc(-c2ccncc2)[nH]1
Product: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nc4cc(Cl)ccc4[nH]3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared analogously to Example C(4), where 3-Chloro-6-[2-(3-chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one was substituted in place of 3-Chloro-6-(2-cyclohex-1-enyl-ethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one and 5-Chloro-benzimidazole-2-thiol was substituted in place of 5-Pyridin-4-yl-4H-[1,2,4]triazole-3-thiol of that example.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][N:7]([C:9]([C@H:11]2[C@H:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=3[F:23])[C@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[C@H:13]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[NH:12]2)=[O:10])[CH2:6]1)=[O:4].[Li+].[OH-]>C1COCC1.CO>[Cl:22][C:18]1[C:17]([F:23])=[C:16]([C@@H:15]2[C@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[C@H:13]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[NH:12][C@H:11]2[C:9]([N:7]2[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:8]2)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)C1CN(C(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)N2CC(C(=O)O)C2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.43 mmol), azetidine-3-carboxylate methyl ester hydrochloride (200 mg, 1.32 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 243.3 mg, 0.64 mmol) and iPr2NEt (0.22 mL, 1.2 mmol) in CH2Cl2 (10 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to yield 1-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-azetidine-3-carboxylic acid methyl ester (26 mg, 10.7%). The ester was taken directly to the hydrolysis step by dissolved in THF (0.6 mL) and methanol (0.2 mL), then 2N LiOH (0.2 mL) was added and stirred at room temperature for 3 hours. The mixture was concentrated and diluted with water and ethyl acetate. The organic phase was separated then concentrated to rac-1-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-azetidine-3-carboxylic acid (11.8 mg, 46.6%) as an off-white powder. HRMS (ES+) m/z Calcd for C27H27Cl2F2N3O3+H [(M+H)+]: 550.1471. found: 550.1471.
Reaction SMILES: [C:1]1([CH:7]2[C:14]3([CH2:18][CH2:17][C:16](=[S:19])[NH:15]3)[CH:11]3[CH2:12][CH2:13][CH:8]2[CH2:9][CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][I:21]>CC(C)=O>[IH:21].[CH3:20][S:19][C:16]1[CH2:17][CH2:18][C:14]2([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]3[CH2:13][CH2:12][CH:11]2[CH2:10][CH2:9]3)[N:15]=1
Reactant: CI
Reactant: S=C1CCC2(N1)C1CCC(CC1)C2c1ccccc1
Solvent: CC(C)=O
Product: CSC1=NC2(CC1)C1CCC(CC1)C2c1ccccc1
Product: I

Procedure:
24 mmoles of 3-phenyl-spiro[bicyclo[2.2.2]-octane-2,2'-pyrrolidine]-5'-thione and 3 ml of methyl iodide are heated in 50 ml of acetone for 10 minutes. After cooling, the mixture is filtered. Crystals of melting point 192°-193° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([OH:14])=O)[CH:3]=1.Cl.[NH2:16][C@H:17]1[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]1[OH:23].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:16][C@H:17]2[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]2[OH:23])=[O:14])[CH:3]=1
Reactant: N[C@H]1CCOC[C@@H]1O
Reactant: O=C(O)c1cc(Br)c2ccccc2n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCOC[C@@H]1O)c1cc(Br)c2ccccc2n1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 4-bromoquinoline-2-carboxylic acid (A3) (0.5 g, 2.0 mmol) in 10 mL CH2Cl2 was added (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol hydrogen chloride (0.37 g, 2.4 mmol), BOP reagent (1.1 g, 2.6 mmol), and triethylamine (0.83 mL, 6.0 mmol). The reaction was stirred at room temperature for 4.5 h, diluted with CH2Cl2, washed twice with water, dried over sodium sulfate, filtered, and concentrated. The resultant residue was subjected to silica gel chromatography eluting with 30-100% ethyl acetate in hexanes to afford 4-bromo-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide (O1) that gave a mass ion (ES+) of 353.2 (81Br) for M+H+.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][C:23]#[N:24])[C:15]=2[C:14]2[C:9]1=[C:10]([F:25])[CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.CSC>C1COCC1>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23][NH2:24])[C:15]=2[C:14]2[C:9]1=[C:10]([F:25])[CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCOc1cccc2c1c1cccc(F)c1n2Cc1ccccc1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: NCCOc1cccc2c1c1cccc(F)c1n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 43.3 %

Procedure:
A mixture of 2-[(9-benzyl-8-fluoro-9H-carbazol-4-yl)oxy]acetonitrile (0.7685 g, 0.0023 mol), dry THF (20 mL) and borane-methyl sulfide (0.71 mL, 0.0075 mol) is stirred at room temperature for 3.5 h. Additional borane-methyl sulfide (0.20 mL, 0.0021 mol) is added and the mixture is stirred overnight. The excess borane is cautiously quenched with methanol and the mixture is concentrated under reduced pressure. Methanol and dichloromethane are added to the residue and the solution is again concentrated under reduced pressure (repeated twice). The solids are then dissolved in methanol/dichloromethane and conc. HCl (3 mL) is added. After the mixture stirred for 50 min, the solvent is removed under reduced pressure and the residue is partitioned between dichloromethane and aq. sodium bicarbonate. The combined organic layers are dried over sodium sulfate and concentrated to dryness. The residue is chromatographed on silica gel (100 mL) using methanol/dichloromethane (2/98 and 4/96) and recrystallized from ethyl acetate/dichloromethane/heptane to give 0.333 g (43%) of the title compound; mp 122.25-123° C.; MS (ESI+) for C21H19FN2O m/z 335.2 (M+H)+; IR (drift) 1602, 1577, 1498, 1456, 1443, 1352, 1337, 1325, 1269, 1254, 1242, 1228, 1141, 792, 736 cm−1; 1H NMR (CDCl3) δ3.30, 4.28, 5.30, 6.70, 7.01, 7.11, 7.22, 7.36, 8.10, NH2 not seen. Anal. Calcd for C21H19FN2O: C, 75.43; H, 5.73; N, 8.38. Found: C, 75.25; H, 5.79; N, 8.28.
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[F:16][C:17]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=1[NH:27][C:28]1[C:29]2[O:36][CH:35]=[C:34]([CH:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)[C:30]=2[N:31]=[CH:32][N:33]=1.O>C(#N)C>[CH:1]1([S:4]([N:40]2[CH2:39][CH2:38][CH:37]([C:34]3[C:30]4[N:31]=[CH:32][N:33]=[C:28]([NH:27][C:18]5[CH:19]=[CH:20][C:21]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:22][C:17]=5[F:16])[C:29]=4[O:36][CH:35]=3)[CH2:42][CH2:41]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc3c(C4CCNCC4)coc23)c(F)c1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(Nc2ncnc3c(C4CCN(S(=O)(=O)C5CC5)CC4)coc23)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
A solution of cyclopropanesulfonyl chloride (4 mg, 0.028 mmol) in anhydrous acetonitrile (0.2 mL), and triethylamine (10 μL, 0.069 mmol) were added to N-[2-fluoro-4-(methylsulfonyl)phenyl]-7-(piperidin-4-yl)furo[3,2-d]pyrimidine-4-amine hydrochloride (10 mg, 0.023 mmol) under ice-cooling, followed by stirring at room temperature for 2 hours. Water was added to the reaction liquid, followed by extraction with chloroform, and the organic layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure, and the obtained residue was purified by silica gel preparative thin layer chromatography (chloroform:methanol=50:1) to give the titled compound (8.5 mg, 75%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[CH:16](I)([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O.C(OCC)C>[Cl:1][C:2]1[N:6]([CH:16]([CH3:18])[CH3:17])[C:5]([CH3:7])=[N:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: CC(C)I
Reactant: COc1ccc(-c2nc(C)[nH]c2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: O
Product: COc1ccc(-c2nc(C)n(C(C)C)c2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 8.9 grams (0.04 mole) of 5-chloro-4-(4-methoxyphenyl)-2-methyl-imidazole, 34.0 grams (0.20 mole) of isopropyl iodide, and 27.8 grams (0.02 mole) of potassium carbonate in 200 mL of acetone is stirred at ambient temperature for about 18 hours. After this time the reaction mixture is shaken with 100 mL of water and 100 mL of diethyl ether. The organic layer is separated, washed with water, and dried with magnesium sulfate. The mixture is filtered and the filtrate is concentrated under reduced pressure to a residue. The residue is purified with column chromatography, yielding 5-chloro-1-(1-methylethyl)-4-(4-methoxyphenyl)-2-methylimidazole.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=2)[N:5]=[CH:4][CH:3]=1.CN([C:18]([O:22][N:23]1N=NC2C=CC=N[C:24]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl.O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([N:23]([O:22][CH3:18])[CH3:24])=[O:14])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc2nccc(Br)c2c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc2nccc(Br)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-bromoquinoline-6-carboxylic acid (5 g), CH3ONH(CH3) hydrochloride salt (1.8 eq. 3.5 g), and HATU (1.15 eq. 8.67 g) in CH2Cl2 (100 mL) was slowly added triethylamine (4 eq. 11 mL) at 0° C. and the resulting reaction mixture was stirred at room temperature overnight. The reaction was diluted with CH2Cl2 and water. The combined organics were washed with water several times, concentrated and then purified by chromatography (60-70% EtOAc/hexanes) to yield 4-bromo-N-methoxy-N-methylquinoline-6-carboxamide as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.C[N:9](C)CC=C.[S:14]([C:18]1[CH:19]=[C:20]([N:32]=[C:33]=[S:34])[C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([S:28]([OH:31])(=[O:30])=[O:29])=[CH:23][CH:22]=2)([OH:17])(=[O:16])=[O:15].[Na:35]>ClCCl.O>[S:14]([C:18]1[CH:19]=[C:20]([NH:32][C:33]([NH2:9])=[S:34])[C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([S:28]([OH:31])(=[O:29])=[O:30])=[CH:23][CH:22]=2)([OH:17])(=[O:16])=[O:15].[Na:35]
Reactant: C=CCN(C)C
Reactant: O=S(=O)(O)c1ccc2c(N=C=S)cc(S(=O)(=O)O)cc2c1
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: NC(=S)Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (2 ml) was added to a suspension of BHAlyslys2lys4lys8DBL16 (73 mg; 0.01 mmol) in dry dichloromethane (2 ml) under nitrogen A vigorous evolution of gas was observed for a short time and the resulting solution was stirred at room temperature for two hours and then concentrated. The residual syrup was dissolved in water (5 ml), the solution passed through a column of Amberlite IRA-401 (OH) and the filtrate concentrated to give BHAlyslys2lys4lys8lys16 as a viscous oil. The oil was redissolved in water (5 ml) and N,N-dimethyl-N-allylamine buffer (pH 9.5; 3 ml) added. Solid sodium 3,6-disulfonapthylisothiocyanate (234 mg; 0.60 mmol) was then added and the resulting solution heated under nitrogen at 53° for two hours and then cooled. The solution was concentrated and the brownish solid residue purified by gel filtration (Sephadex LH20; water). The pure fractions were combined, passed through a column of Amberlite IR 120(Na) and freeze dried to give BHAlyslys2lys4lys8lys16 terminated with 32 sodium 3,6-disulfonapthylthiourea groups as a fluffy off-white solid (119 mg). 1H nmr (D2O): δ 1.0-2.0; 3.18; 3.43; 4.31; 7.22; 7.80; 7.89; 8.25. 13C nmr (D2O): δ 27.2; 32.4; 35.3; 43.7; 49.0; 58.5; 63.6; 128.4; 129.1; 131.4; 136.1; 136.6; 138.6; 139.0; 145.1; 145.6; 178.4; 184.8; 186.7.
Reaction SMILES: [CH:1]1([N:7]([C@H:21]2[CH2:26][CH2:25][C@H:24](COC)[CH2:23][CH2:22]2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16]C(O)=O)=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N[C@H]2CC[C@H]([CH2:43][O:44][CH3:45])CC2)CCCCC1.C([O:48][C:49](=[O:59])[CH:50](SC1SC(N)=NC=1)C)C>>[CH:1]1([N:7]([C@H:21]2[CH2:22][CH2:23][C@H:24]([CH2:45][O:44][CH3:43])[CH2:25][CH2:26]2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][CH2:50][C:49]([OH:59])=[O:48])=[CH:13][N:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCCC2)CC1
Reactant: COC[C@H]1CC[C@H](NC2CCCCC2)CC1
Reactant: CCOC(=O)C(C)Sc1cnc(N)s1
Product: COC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCCC(=O)O)s2)C2CCCCC2)CC1

Procedure:
Prepared in a similar manner to {2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via cyclohexyl-(trans-4-methoxymethyl-cyclohexyl)-amine and (2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:23]2[CH:27]=[N:26][N:25]=[N:24]2)=[C:6]([CH:22]=1)[CH2:7][NH:8][C:9]([C@@H:11]([NH:14]C(=O)OC(C)(C)C)[CH2:12][CH3:13])=[O:10].Cl.CO.Cl.O1CCOCC1>CCOC(C)=O.O1CCOCC1>[NH2:14][C@@H:11]([CH2:12][CH3:13])[C:9]([NH:8][CH2:7][C:6]1[CH:22]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N:23]1[CH:27]=[N:26][N:25]=[N:24]1)=[O:10]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1cc(Cl)ccc1-n1cnnn1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC[C@H](N)C(=O)NCc1cc(Cl)ccc1-n1cnnn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of tert-butyl (1S)-1-({[5-chloro-2-(1H-tetraazol-1-yl)benzyl]amino}carbonyl)propylcarbamate (237 mg, 0.60 mmol) in EtOAc (3.5 mL) at rt was added 4 M HCl in dioxane (0.6 mL, excess). After 30 min, a small amount of MeOH was added to keep product in solution. After 3 h, another 0.6 mL of 4 M HCl/dioxane was added and continued to stir overnight at rt. Solvent was removed in vacuo to give the title compound as a foamy yellow solid. LCMS (M+H): 295.0. 1H NMR (400 MHz, CD3OD): δ 9.58 (s, 1 H), 8.79 (m, 1 H), 7.68 (d, J=2.4 Hz, 1 H), 7.58 (dd, J=2.0 Hz, 8.4 Hz, 1 H), 7.52 (d, J=8.4 Hz, 1 H), 4.30–4.29 (m, 2 H), 3.79 (app t, J=6.2 Hz, 1 H), 1.87–1.80 (m, 2 H), 0.97 (t, J=7.6 Hz, 3 H).
Reaction SMILES: [O:1]([C:8]1[C:9]([NH:24][C:25]2[S:26][CH:27]=[C:28]([CH:30]3[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]3)[N:29]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[CH:21]=[CH:22][S:23][C:16]=23)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.Cl>C(Cl)Cl.O1CCOCC1>[O:1]([C:8]1[C:9]([NH:24][C:25]2[S:26][CH:27]=[C:28]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[N:29]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[CH:21]=[CH:22][S:23][C:16]=23)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2csc(Nc3ncc(Sc4ccnc5ccsc45)cc3Oc3ccccc3)n2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: c1ccc(Oc2cc(Sc3ccnc4ccsc34)cnc2Nc2nc(C3CCNCC3)cs2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
tert-Butyl 4-(2-(3-phenoxy-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate was dissolved in 1:1 CH2Cl2:methanol and 4N HCl in dioxane added and stirred for 1 hour at room temperature. The reaction was concentrated and the residue was partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated to afford 3-phenoxy-N-(4-(piperidin-4-yl)thiazol-2-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-amine (238 mg, 52.5% yield over 2 steps) as a white solid
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[CH3:11][C:12]([CH3:17])([CH3:16])[CH2:13][CH:14]=O.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[CH:9][C:5](/[C:6](=[CH:14]/[CH2:13][C:12]([CH3:17])([CH3:16])[CH3:11])/[C:7]#[N:8])=[CH:4][CH:3]=1
Reactant: CC(C)(C)CC=O
Reactant: N#CCc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)C/C=C(\C#N)c1ccc(Cl)cc1
Yield: 71.3 %

Procedure:
In a manner similar to the method described in Example 1b, 4-chlorobenzyl cyanide (4.5 g, 30 mmol) was reacted with 3,3-dimethyl-butyraldehyde (Aldrich) (3 g, 30 mmol), methanolic solution (25 wt %) of sodium methoxide (7 mL, 30 mmol) in methanol (130 mL) at room temperature for 3 h to give (Z)-2-(4-chloro-phenyl)-5,5-dimethyl-hex-2-enenitrile as a colorless oil (5 g, 71%).
Reaction SMILES: F[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][N:15]=[C:14]([S:18][CH3:19])[N:13]=1)=O.[NH2:20][OH:21].C1CCN2C(=NCCC2)CC1>C(O)C.CCOC(C)=O>[CH3:9][O:8][C:7]1[C:2]2[O:21][N:20]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([S:18][CH3:19])[N:13]=3)[C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: NO
Reactant: COc1cccc(C(=O)c2ccnc(SC)n2)c1F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cccc2c(-c3ccnc(SC)n3)noc12
Temperature: 25 °C

Procedure:
A mixture of (2-fluoro-3-methoxy-phenyl)-(2-methylsulfanyl-pyrimidin-4-yl)-methanone (1 g, 3.59 mmol) and hydroxylamine (50% in water, 1.5 mL) in ethanol was heated to reflux overnight. The resulting mixture was cooled to RT, diluted with EtOAc and then concentrated under reduced pressure. The residue was dissolved in THF and DBU (0.84 mL, 5.6 mmol) was added, the resulting mixture was heated to 150° C. in a microwave reactor for 30 min. The reaction mixture was then concentrated under reduced pressure and the residue was purified by flash chromatography (hexane/EtOAc, 95/5) to give 458 mg of 7-methoxy-3-(2-methylsulfanylpyrimidin-4-yl)-benzo[d]isoxazole.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:13](=[O:25])[NH:14][C:15]1[CH:19]=[CH:18][N:17]([CH2:20][C:21]([OH:24])([CH3:23])[CH3:22])[N:16]=1)[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.FC(F)(F)C(O)=O.[Cl:34]CCl>>[ClH:34].[OH:24][C:21]([CH3:23])([CH3:22])[CH2:20][N:17]1[CH:18]=[CH:19][C:15]([NH:14][C:13](=[O:25])[C@@H:8]([NH2:7])[CH2:9][CH:10]([CH3:11])[CH3:12])=[N:16]1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccn(CC(C)(C)O)n1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](N)C(=O)Nc1ccn(CC(C)(C)O)n1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of {(S)-1-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-ylcarbamoyl]-3-methyl-butyl}-carbamic acid t-butyl ester (4.15 g) in dichloromethane (8 mL) was treated with trifluoroacetic acid (8 mL) and stirred at room temperature for 1 h. At this time the mixture was concentrated in vacuo and the residue dissolved in methanol (10 mL) and treated with hydrogen chloride gas for 2 min. The mixture was concentrated in vacuo and the residue was dried under high vacuum. The solid obtained was triturated with diethyl ether which afforded (S)-2-amino-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]amide hydrochloride (3.86 g, 100%) as a white solid.