Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:36]=[CH:35][C:7]2[N:8]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:22]([NH:24][S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])=[O:23])=[CH:15][CH:14]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[CH3:37][Mg]I>O>[CH2:11]([C:9]1[N:8]([C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH:21][C:22]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:26])=[O:27])=[O:23])=[CH:17][CH:18]=2)[C:7]2[CH:35]=[CH:36][C:4]([C:1]([OH:3])([CH3:37])[CH3:2])=[CH:5][C:6]=2[N:10]=1)[CH3:12]
Reactant: C[Mg]I
Reactant: CCc1nc2cc(C(C)=O)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: O
Product: CCc1nc2cc(C(C)(C)O)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
A solution of N-[({2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide (Example 78, 100 mg, 0.19 mmol) in tetrahydrfurane (15 ml) was added MeMgI (1.2 ml, 0.99 mmol) dropwise under nitrogen at 0° C. The mixture was stirred at 0° C. for 1 h and then was stirred at rt for 30 min. The mixture was added water (10 ml) and extracted with CH2Cl2(50 ml). The organic layer was washed with brine (10 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with CH2Cl2:methanol (30:1/20:1/10:1) to afford 100 mg (97%) of the title compound as white solids.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:9]=[C:10]([NH:22][C:23]2[C:24]3[C:31]4[CH2:32][CH2:33][CH:34]([CH2:36][CH2:37]OS(C)(=O)=O)[CH2:35][C:30]=4[S:29][C:25]=3[N:26]=[CH:27][N:28]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.CCN(C(C)C)C(C)C.CO.C(Cl)Cl>C(#N)C>[Cl:7][C:8]1[CH:9]=[C:10]([NH:22][C:23]2[C:24]3[C:31]4[CH2:32][CH2:33][CH:34]([CH2:36][CH2:37][N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[CH2:35][C:30]=4[S:29][C:25]=3[N:26]=[CH:27][N:28]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CS(=O)(=O)OCCC1CCc2c(sc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Reactant: C1COCCN1
Solvent: CO
Solvent: CC#N
Solvent: ClCCl
Product: Clc1cc(Nc2ncnc3sc4c(c23)CCC(CCN2CCOCC2)C4)ccc1OCc1ccccn1
Yield: 11.9 %

Procedure:
Morpholine (0.03 mL, 26. mg, 0.30 mmol, 1.2 equiv.) was added to a suspension of Methanesulfonic acid 2-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl}-ethyl ester (135 mg, 0.25 mmol, 1 quiv.) and DIEA (0.09 mL, 0.5 mmol, 2 equiv.) in anhydrous acetonitrile (2.0 mL). The resulting mixture was stirred overnight at 80° C. at which time TLC (MeOH/DCM 5:95) indicated no more starting material left. The solvents were evaporated and residue was purified by preparative TLC (20 cm×20 cm×1 mm silica, MeOH/DCM 5:95) to give [3-Chloro-4-(pyridin-2-ylmethoxy)-phenyl]-[7-(2-morpholin-4-yl-ethyl)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl]-amine as a white solid (16 mg, 12%). 1H-NMR (CD3OD) δ 8.51 (s, 1H), 8.24 (s, 1H), 7.87 (t, 1H), 7.81 (d, J=2.4 Hz, 1H) 7.68 (d, J=7.5 Hz, 1H), 7.36 (m, 2H), 7.02 (d, J=9.2 Hz, 1H), 5.18 (s, 2H), 2.69 (t, 4H), 3.35 (s, 1H), 3.11 (m, 1H), 3.02 (m, 1H), 2.91 (m, 1H), 2.48 (m, 6H), 2.09 (m, 1H), 1.89 (m, 1H), 1.62 (m, 3H).; LCMS RT=2.25 min; [M+H]+=536.
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10]CC)=O)[C:3](OCC)=[O:4].[CH3:13][NH:14][NH:15][CH3:16].C[O-].[Na+]>CO>[OH:10][C:8]1[N:14]([CH3:13])[N:15]([CH3:16])[C:3](=[O:4])[C:2]=1[CH3:1]
Reactant: CNNC
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(O)n(C)n(C)c1=O

Procedure:
Diethyl methylmalonate and N,N'-dimethylhydrazine are heated under reflux for 170 hours in methanol in the presence of sodium methylate under an atmosphere of nitrogen. 3-Hydroxy-1,2,4-trimethyl-5-pyrazolone is obtained in the form of colorless crystals which, after recrystallization from ethyl acetate, melt at 87°-89° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([Br:16])[CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2)=O)C.CC(C[AlH]CC(C)C)C.C(C(C(C([O-])=O)O)O)([O-])=O>C(Cl)Cl>[Br:16][C:14]1[CH:15]=[C:6]([CH:4]=[O:3])[CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2
Reactant: CCOC(=O)c1cc(Br)c2ncccc2c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Solvent: ClCCl
Product: O=Cc1cc(Br)c2ncccc2c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 8-bromo-quinoline-6-carboxylic acid ethyl ester (1.0 eq) in CH2Cl2 (0.26M) at −78° C. was added dropwise DIBAL (neat; 2.0 eq). The resulting mixture was stirred 1 h at −78° C. then poured in Na/K tartrate (2N) and stirred for 2 h. The mixture was extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated to afford the desired compound along with the corresponding hydroxymethyl analog. To the mixture dissolved in EtOAc (0.45M) was added MnO2 (2.5 eq). The resulting mixture was refluxed for 1 h, cooled to room temperature, filtered on a pad of silica gel and concentrated. The residual solid was vigorously stirred in Hex/Et2O (2/1) for 2 h to afford following filtration the desired compound as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.Cl.[CH3:12][CH2:13]O>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:12][CH3:13])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Cl)n1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1cccc(Cl)n1
Temperature: 25 °C
Yield: 85 %

Procedure:
To 6-chloropicolinic acid (5.01 g, 31.8 mmol) in EtOH (100 mL) was added concentrated HCl (6 mL, 78 mmol). The reaction was heated to reflux for overnight, cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in DCM (100 mL) and NaOH (2M) aqueous solution was added until pH=8. The aqueous layer was then extracted with DCM. The combined organic extracts were combined, dried (Na2SO4) and concentrated under reduced pressure to give the desired product (85%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>FC(F)(F)C(O)=O.C([SiH](CC)CC)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCNc2cc(F)ccc21
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc2c(c1)NCCC2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 7-fluoro-2,3-dihydro-1H-quinolin-4-one obtained in Reference Example 3 (810 mg) in trifluoroacetic acid (10 ml), triethylsilane (3.9 ml) was added and stirred at room temperature for 3 days. The reaction mixture was adjusted to pH 10 to 12 by addition of 8M aqueous sodium hydroxide under ice cooling, and then extracted with chloroform. To the extracted organic layer, water and 12M aqueous hydrochloric acid were added to separate the aqueous layer. The separated aqueous layer was adjusted to pH 10 to 12 by addition of 8M aqueous sodium hydroxide, and then extracted with chloroform. The extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure to give the titled compound, i.e., 7-fluoro-1,2,3,4-tetrahydroquinoline (530 mg) as a light-yellow powder.
Reaction SMILES: [C:1]([O:4][C@@H:5]([C@@H:35]1[C@@H:39]([O:40][C:41](=[O:43])[CH3:42])[C@@H:38]([O:44][C:45](=[O:47])[CH3:46])[C@H:37]([N:48]2[CH:53]=[CH:52][C:51](=[O:54])[NH:50][C:49]2=[O:55])[O:36]1)[CH:6]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:29])[C@H:13]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH:14]C(=O)OCC1C=CC=CC=1)(=[O:3])[CH3:2]>[Pd].CO>[C:1]([O:4][C@@H:5]([C@@H:35]1[C@@H:39]([O:40][C:41](=[O:43])[CH3:42])[C@@H:38]([O:44][C:45](=[O:47])[CH3:46])[C@H:37]([N:48]2[CH:53]=[CH:52][C:51](=[O:54])[NH:50][C:49]2=[O:55])[O:36]1)[CH:6]([NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:29])[C@@H:13]([NH2:14])[CH2:25][CH:26]([CH3:27])[CH3:28])[C:30]([O:32][CH2:33][CH3:34])=[O:31])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NCCCNC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)[C@@H](OC(C)=O)[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C(NCCCNC(=O)[C@@H](N)CC(C)C)[C@@H](OC(C)=O)[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 94.8 %

Procedure:
Ethyl (5S)-12-{(R)-(acetyloxy)[(2R,3R,4R,5R)-3,4-bis(acetyloxy)-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]methyl}-5-isobutyl-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (97 mg, 0.125 mmole, obtained from Example 38) was hydrogenated using 10% palladium on carbon in methanol (2 ml) under atmospheric pressure. The catalyst was removed and the volatiles were removed in vacuo to provide ethyl (3R)-3-(acetyloxy)-2-[(3-{[(2S)-2-amino-4-methylpentanoyl]amino}propyl)amino]-3-[(2R,3R,4R,5R)-3,4-bis(acetyloxy)-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]propanoate (76 mg, 95%) as a white glassy solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][C:27]([N:30]4[C@@H:34]([CH:35]([CH3:37])[CH3:36])[CH2:33][N:32]([CH:38]5[CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39]5)[C:31]4=[O:49])=[N:26][C:25]=23)[CH:5]=[CH:6][C:7]=1[C:8]1[N:12](COCC[Si](C)(C)C)[N:11]=[CH:10][N:9]=1.C([O-])(O)=O.[Na+]>CCO>[NH:40]1[CH2:41][CH:38]([N:32]2[CH2:33][C@H:34]([CH:35]([CH3:37])[CH3:36])[N:30]([C:27]3[CH:28]=[CH:29][N:24]4[N:23]=[CH:22][C:21]([C:4]5[CH:5]=[CH:6][C:7]([C:8]6[N:9]=[CH:10][NH:11][N:12]=6)=[C:2]([F:1])[CH:3]=5)=[C:25]4[N:26]=3)[C:31]2=[O:49])[CH2:39]1
Reactant: CC(C)[C@H]1CN(C2CN(C(=O)OC(C)(C)C)C2)C(=O)N1c1ccn2ncc(-c3ccc(-c4ncnn4COCC[Si](C)(C)C)c(F)c3)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)[C@H]1CN(C2CNC2)C(=O)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)c(F)c3)c2n1
Yield: 81.3 %

Procedure:
A mixture of tert-butyl 3-((4S)-3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyl-2-oxoimidazolidin-1-yl)azetidine-1-carboxylate (22 mg, 0.032 mmol) and 1:2 EtOH/6N aqueous HCl (1 mL) was heated at reflux for 2 hours. After cooling, the reaction mixture was basified by slow addition of saturated aqueous NaHCO3 solution. The mixture was extracted with 10% MeOH in DCM. The combined extracts were washed with brine, dried and concentrated. The residue was purified by column chromatography (20% 7N ammonia in MeOH/dichloromethane) to give (S)-1-(azetidin-3-yl)-3-(3-(3-fluoro-4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropylimidazolidin-2-one (12 mg, 82%) as a pale yellow solid. LCMS (APCI+) m/z 462.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.Cl[C:14]1[N:19]=[C:18]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]2[CH3:30])[C:17]([CH3:31])=[C:16]([CH3:32])[N:15]=1>CN(C)C=O>[CH3:31][C:17]1[C:18]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]2[CH3:30])=[N:19][C:14]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[N:15][C:16]=1[CH3:32]
Reactant: COCCN
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2C)c1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCNc1nc(C)c(C)c(N2CCc3ccccc3C2C)n1
Yield: 56.3 %

Procedure:
After 2-methoxyethylamine(0.23 ml, 2.7 mmol) and triethylamine(0.38 ml, 2.7 mmol) were added to a solution of 2-chloro-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine (0.5 g, 1.74 mmol) in dimethylformamide, 320 mg of the titled compound was obtained in accordance with the same procedure as in Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)=[CH:4][CH:3]=1.[C:13](O)([CH3:16])([CH3:15])[CH3:14].S(=O)(=O)(O)O>FC(F)(F)C(O)=O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)O
Reactant: Cc1ccc(-c2nn[nH]n2)cc1
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nnn(C(C)(C)C)n2)cc1

Procedure:
A solution of 5-(4-methylphenyl)-2H-tetrazole (W. G. Finnegan, R. A. Henry, R. Lofquist J. Am. Chem. Soc. 1958, 80, 3908.) (19.9 g, 0.12 mol), t-butanol (19.5 g, 0.26 mol) and concentrated sulfuric acid (5.84 g, 0.06 mol) in trifluoroacetic acid (122 mL) was stirred at room temperature (3 h) and then diluted with ethyl acetate (250 mL). The mixture was washed sequentially with water (2×50 mL), 10% aqueous sodium hydroxide until washings were basic, water (2×30 mL), and then dried over sodium sulfate (Na2SO4) and filtered. Following removal of the solvents in vacuo, the resultant oil was purified by HPLC on silica gel eluting with 20:1 mixture of hexanes-ethyl acetate to provide 17.5 g of 5-(4-methylphenyl)-2-(1,1-dimethylethyl)-2H-tetrazole as a clear oil, bp. 120°-122° C. (0.3 mm Hg).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]CC)=[O:24])=[CH:18][C:17]=3[CH3:28])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].O>O1CCOCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=3[CH3:28])=[CH:29][CH:30]=2)=[O:10])=[CH:31][CH:32]=1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(CC(=O)O)ccc1Oc1ccc(C(=O)NCCc2ccc(Cl)cc2)cc1
Reaction time: 3 h
Yield: 85.2 %

Procedure:
Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-methylphenyl)acetate (20 mg, 0.0443 mmol) was diluted with dioxane (500 μL) followed by the addition of NaOH (0.0885 ml, 0.443 mmol) and 200 μL of water. After stirring for 3 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-methylphenyl)acetic acid (16.0 mg, 85.3% yield). 1H NMR (400 MHz, CD3Cl3, CD3OD) 7.62 (d, 2H), 7.30 (d, 2H), 7.10-7.22 (m, 4H), 6.92 (d, 1H), 6.85 (d, 2H), 3.65 (t, 2H), 3.60 (s, 2H), 2.90 (t, 2H), 2.15 (s, 3H).
Reaction SMILES: [CH2:1]([CH:3]([NH:8][NH2:9])[C:4]([CH3:7])([CH3:6])[CH3:5])[CH3:2].FC1C([O:17][C:18]([C:20]2[CH:38]=[CH:37][C:23]3[O:24][CH2:25][C@@H:26]([C:28](C)(C)[O:29][SiH2]C(C)(C)C)[O:27][C:22]=3[C:21]=2[CH3:39])=O)=C(F)C(F)=C(F)C=1F>C(OCC)(=O)C>[CH2:1]([CH:3]([NH:8][NH:9][C:18]([C:20]1[CH:38]=[CH:37][C:23]2[O:24][CH2:25][C@H:26]([CH2:28][OH:29])[O:27][C:22]=2[C:21]=1[CH3:39])=[O:17])[C:4]([CH3:7])([CH3:6])[CH3:5])[CH3:2]
Reactant: CCC(NN)C(C)(C)C
Reactant: Cc1c(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc2c1O[C@H](C(C)(C)O[SiH2]C(C)(C)C)CO2
Solvent: CCOC(C)=O
Product: CCC(NNC(=O)c1ccc2c(c1C)O[C@@H](CO)CO2)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the biphasic preparation of (1-ethyl-2,2-dimethyl-propyl)-hydrazine described above, was added a solution of approximately one gram 3(S)-(tert-butyl-dimethyl-silanyloxymethyl)-5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid pentafluorophenyl ester dissolved in 10 mL ethyl acetate. The mixture was stirred at room temperature for 2 hours, after which time the aqueous phase was withdrawn and replaced with 1 M K2CO3. The mixture was stirred overnight. The aqueous layer was separated off, and the organic layer was extracted once with 1 M K2CO3 and then once with water. The organic phase was dried. The crude product was chromatographed on silica gel using a step gradient of 10% ether in hexane followed by neat ether, yielding 3(S)-hydroxymethyl-5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid N′-(1-ethyl-2,2-dimethyl-propyl)-hydrazide. 1H NMR (500 MHz, CDCl3) δ (ppm): 7.15 (br, 1H), 6.85 (d, 1H), 6.73 (d, 1H), 4.85 (br, 1H), 4.3 (d, 1H), 4.25 (m, 1H), 4.1 (dd, 1H), 3.87 (m, 2H), 2.41 (m, 1H), 2.29 (s, 3H), 1.8 (br, 1H); 1.65 (m, 1H), 1.3 (m, 1H), 1.45 (t, 3H), 0.98 (s, 9H); TLC: Rf=0.23 (1:1 ethyl acetate:hexane).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]3)[S:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]3)[S:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C1CCN(c2nc(-c3cccc([N+](=O)[O-])c3)cs2)CC1
Agent: [Pd]
Product: CCOC(=O)C1CCN(c2nc(-c3cccc(N)c3)cs2)CC1
Reaction time: 3 h
Yield: 59.8 %

Procedure:
To a solution of the ethyl 1-[4-(3-nitrophenyl)-1,3-thiazol-2-yl]piperidine-4-carboxylate (457 mg, 1.26 mmol) in ethyl acetae (10 mL) and acetic acetic acid (1 mL) was added 10% palladium on carbon (135 mg, 0.126 mmol) and the mixture was placed under an atmosphere of H2 (balloon). The mixture was stirred for 3 hours was then filtered through celite. The filtrate was concentrated under reduced pressure. The resulting residue was purified by CombiFlash (20-60% ethyl acetate:hexanes) provided 250 mg (0.754 mmol, 60% yield) of ethyl 1-[4-(3-aminophenyl)-1,3-thiazol-2-yl]piperidine-4-carboxylate.
Reaction SMILES: [C:1]1([CH2:7][SH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[CH:19]=2)=[CH:14][N:13]=1>CN(C=O)C>[CH2:7]([S:8][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[CH:19]=2)=[CH:14][N:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)c1cccc(-c2ccc(Cl)nc2)c1
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1cccc(-c2ccc(SCc3ccccc3)nc2)c1
Reaction time: 0.25 h
Yield: 54.6 %

Procedure:
A solution of phenyl-methanethiol (0.8 mL, 5.84 mmol) in DMF (5 mL) was treated with NaH (0.140 g, 5.84 mmol) at room temperature under argon. After 15 min of stirring, the reaction mixture was treated with a solution of 2-chloro-5-(3-isopropyl-phenyl)-pyridine (0.900 g, 3.90 mmol) in DMF (15 mL). After 2 h of additional stirring at room temperature (reaction was monitored by TLC), the reaction mixture was quenched with ice cold water (20 mL), and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (2×10 mL), dried over Na2SO4, and concentrated in vacuo to obtain a crude product, which was purified over silica gel (Biotage column chromatography, gradient elution using 0-1% ethyl acetate in hexane) to furnish 2-benzylsulfanyl-5-(3-isopropyl-phenyl)-pyridine (0.680 g, 54.71%).
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[NH:33]1[CH2:38][CH2:37][CH:36]([C:39]2[S:40][C:41]3[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=3[N:43]=2)[CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[S:40]1[C:41]2[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=2[N:43]=[C:39]1[CH:36]1[CH2:35][CH2:34][N:33]([CH2:1][C@@H:3]2[C@@H:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:6][N:5]([C@H:14]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[O:16])[CH2:4]2)[CH2:38][CH2:37]1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: c1ccc2sc(C3CCNCC3)nc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(c4nc5ccccc5s4)CC3)[C@@H](c3ccccc3)C2)cc1
Temperature: 25 °C
Yield: 73.5 %

Procedure:
To a solution of 52 mg of α-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid, 4-methoxybenzyl ester (prepared above as Aldehyde 5) and 50 mg of 2-(piperidin-4-yl)benzothiazole (from Step B) in 2.5 mL of THF was added two spatula tips of 3 Å molecular sieves. After stirring at room temperature for 20 mim., 50 mg of sodium triacetoxyborohydride was added and the reaction was stirred at room temperature for 18 hours. The reaction was quenched with MeOH and diluted with EtOAc. After filtering molecular sieves, the filtrate was concentrated under reduced pressure. The residue was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous MgSO4. Concentration under reduced pressure followed by flash chromatography eluting with 20% EtOAc in hexane followed by 50% EtOAc in hexane afforded 56 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:10])[O:5][C:6]=1[C:7]([OH:9])=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][C:44]=1[CH3:45])[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[N:32]=1>CN(C)C=O.CN(C)C(=O)C>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:42]=[CH:43][C:44]([CH3:45])=[C:23]([NH:22][C:7]([C:6]5[O:5][C:4](=[O:10])[NH:3][C:2]=5[CH3:1])=[O:9])[CH:24]=4)=[N:32][N:31]3[CH:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: Cc1[nH]c(=O)oc1C(=O)O
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1oc(=O)[nH]c1C
Yield: 34.8 %

Procedure:
In the same manner as in Example 259 and using 4-methyl-2-oxo-2,3-dihydro-1,3-oxazole-5-carboxylic acid (159 mg, 1.1 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (382 μL, 4.44 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (300 mg, 0.93 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (145 mg, 35%) was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.CN(C(ON1N=NC2[CH:21]=[CH:22][CH:23]=[N:24]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CC1.CCN(CC)CC>C1COCC1.CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:24][CH:23]2[CH2:21][CH2:22]2)=[O:9])[N:6]=1
Reactant: O=C(O)c1csc(Br)n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(NC1CC1)c1csc(Br)n1
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
At RT, to a solution of 2-bromothiazole-4-carboxylic acid (Synthonix, 600 mg, 2.88 mmol) in 8 mL of THF and 2 mL of DMF was added HATU (Aldrich, 1.2 g, 3.17 mmol). The mixture was stirred for 30 min, and cyclopropanamine (0.3 mL, 4.33 mmol) was added followed by Et3N (0.4 mL, 2.88 mmol). After the reaction mixture was stirred for 1 h at RT, additional HATU (150 mg) was added and the mixture stirred for another 1 h. It was diluted with 100 mL of EtOAc, washed sequentially with 5 mL of 1 N NaOH, 5 mL of water and 5 ml of brine. The EtOAc layer was concentrated and the residue was purified on a silica gel column (25-50% EtoAc in hexanes) to give 2-bromo-N-cyclopropylthiazole-4-carboxamide (300 mg, 42% yield) as an off white crystalline solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.50 (1H, m), 8.28 (1H, s), 2.87 (1H, m), 0.67 (4H, m). MS (ESI, pos. ion) m/z: 246.9/248.9 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17]([O:19]CC)=[O:18])=[C:14]([CH3:16])[N:15]=2)[CH:9]=[C:10]([F:12])[CH:11]=1.[OH-].[Li+].Cl>C1COCC1.CO>[F:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17]([OH:19])=[O:18])=[C:14]([CH3:16])[N:15]=2)[CH:9]=[C:10]([F:12])[CH:11]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(F)cn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2c(OCc3c(F)cccc3F)cc(F)cn2c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
550 mg of ethyl 8-[(2,6-difluorobenzyl)oxy]-6-fluoro-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 13A; 1.5 mmol, 1 equivalent) were dissolved in 64 ml of THF and 12 ml of methanol, 7.5 ml of 1 N aqueous lithium hydroxide solution were added and the mixture was stirred at RT overnight. 8 ml of 1 N aqueous hydrochloric acid were then added, and the mixture was concentrated under reduced pressure. The solid formed was filtered off and washed with water. This gave 429 mg of the title compound (80% of theory).