Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[CH3:9])=[C:6]([CH2:24][CH2:25][CH3:26])[N:5]2[N:27]=[CH:28][N:29]=[C:4]2[N:3]1[CH:30]1[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]1.O1CCCC1.[BH4-].[Na+]>CO>[OH:36][C@H:33]1[CH2:34][CH2:35][C@H:30]([N:3]2[C:2](=[O:1])[C:7]([CH:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[CH3:9])=[C:6]([CH2:24][CH2:25][CH3:26])[N:5]3[N:27]=[CH:28][N:29]=[C:4]23)[CH2:31][CH2:32]1
Reactant: CCCc1c(C(C)c2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1c(C(C)c2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4′-{1-[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]ethyl}biphenyl-2-carbonitrile (1.38 g), tetrahydrofuran (15 mL) and methanol (10 mL) was added sodium borohydride (0.50 g) at 0° C., and the mixture was stirred at room temperature for 30 min. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless oil (1.24 g, 89%).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:23])[CH2:16][CH:17]([OH:22])[CH2:18][C:19]([OH:21])=[O:20])=[C:11]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:3].[OH-].[Na+:32].CC(C)=O>CO>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:23])[CH2:16][CH:17]([OH:22])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:32]
Reactant: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)O)c(-c2ccc(F)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 21 h
Yield: 60.1 %

Procedure:
Fluvastatin (3 g) was completely dissolved in MeOH (15 ml) at reflux temperature. Then, the solution was filtered to obtain a clear solution and heated to reflux again. NaOH (s) (0.29 g) was added at reflux temperature to obtain a precipitate. The slurry was cooled to room temperature to obtain a paste-like mixture. Acetone (30 g) was added dropwise at room temperature and the solution stirred at room temperature for 21 h to obtain a massive precipitate. The product was filtered under nitrogen flow, washed with acetone (2×15 ml) and dried at 50° C. in a vacuum oven for 22.5 h to obtain 1.89 g (62%) of fluvastatin sodium Form XLVIII.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:48])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[O:21][C:22]([CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[O:32][CH2:33][CH2:34][CH:35]=C)=[N:23][N:24]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:37])[C:12]=2[C@H:38]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:39]([O:41]C)=[O:40])[CH2:7][CH2:6]1)[CH:2]=C.C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCCCCCOC2C=CC(F)=CC=2CNC3=O)CC1)C(OC)=O)(C)(C)C.C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCCCCCOC2C=CC(F)=CC=2CNC3=O)CC1)C(O)=O)(C)(C)C>>[C:44]([O:43][C@@H:38]([C:12]1[C:13]([CH3:37])=[CH:14][C:15]2=[N:19][C:18]3=[CH:17][N:16]2[C:11]=1[N:8]1[CH2:7][CH2:6][C:5]([CH3:48])([O:4][CH2:1][CH2:2][CH2:35][CH2:34][CH2:33][O:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH2:25][C:22]2[O:21][C:20]3=[N:24][N:23]=2)[CH2:10][CH2:9]1)[C:39]([OH:41])=[O:40])([CH3:46])([CH3:45])[CH3:47]
Reactant: C=CCCOc1ccccc1Cc1nnc(-c2cn3c(N4CCC(C)(OCC=C)CC4)c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3n2)o1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCCCOc1ccc(F)cc1CNC3=O
Agent: Cc1cc2nc3cn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCCCOc1ccc(F)cc1CNC3=O
Product: Cc1cc2nc3cn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCCCOc1ccccc1Cc1nnc-3o1
Yield: 6 %

Procedure:
Prepared from (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(5-(2-(but-3-en-1-yloxy)benzyl)-1,3,4-oxadiazol-2-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate in 6% yield following the procedures used to prepare methyl(2S)-2-(tert-butoxy)-2-{15-fluoro-4,26-dimethyl-10-oxo-19,25-dioxa-1,7,11,31-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13(18),14,16-heptaen-3-yl}acetate and (2S)-2-(tert-butoxy)-2-{15-fluoro-4,26-dimethyl-10-oxo-19,25-dioxa-1,7,11,31-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13(18),14,16-heptaen-3-yl}acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.08-8.03 (m, 1H), 7.36-7.32 (m, 2H), 7.28-7.23 (m, 1H), 7.09-7.01 (m, 1H), 6.97-6.89 (m, 1H), 5.92-5.76 (m, 1H), 4.33-4.21 (m, 2H), 4.13-4.03 (m, 2H), 3.77-3.69 (m, 2H), 3.14-3.03 (m, 2H), 2.91-2.81 (m, 1H), 2.74-2.62 (m, 1H), 2.44-2.39 (m, 3H), 1.93-1.60 (m, 10H), 1.23-1.20 (m, 3H), 1.17 (s, 9H); LCMS (ESI, M+1): 618.5.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=O)([O-:3])=[O:2].[CH:15]1[C:20]([NH:21][NH2:22])=[CH:19][CH:18]=[C:17]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:16]=1.Cl>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[N:22][NH:21][C:20]1[CH:19]=[CH:18][C:17]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:16][CH:15]=1)([O-:3])=[O:2]
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C1=O
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc([N+](=O)[O-])cc32)cc1
Yield: 94 %

Procedure:
The title compound was prepared from 5-nitro-1H-indole-2,3-dione (Gassman, et al., Journal of Organic Chemistry 1977, 42, 1344-8) and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G in 94% yield: 1H NMR (DMSO-d6): δ 7.14 (d, J=8.6 Hz, 1H), 7.33 (s, 2H), 7.75 (d, J=8.8 Hz, 2H), 7.84 (d, J=8.8 Hz, 2H), 8.23 (dd, J=2.2, 8.6 Hz, 1H), 8.42 (d, J=2.2 Hz, 1H), 11.76 (s, 1H), 12.78 (s, 1H). Anal. Calcd for C14H11N5O5S: C, 46.54, H, 3.07; N, 19.38. Found C, 46.76, H, 3.13; N, 19.23.
Reaction SMILES: OC1O[C@@H](CO)[C@H](O)[C@H](O)[C@H]1O.[F:13][C:14]([F:25])([F:24])[C:15](=O)[CH:16](Cl)[C:17]([O:19][CH2:20][CH3:21])=[O:18].[C:26]([NH2:29])(=[S:28])[CH3:27]>>[CH3:27][C:26]1[S:28][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([C:14]([F:25])([F:24])[F:13])[N:29]=1
Reactant: CC(N)=S
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Agent: OC[C@@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O
Product: CCOC(=O)c1sc(C)nc1C(F)(F)F

Procedure:
U.S. Pat. No. 5,045,554 (Alt et al., 9/91), herein incorporated by reference, discloses the reaction of ethyl 4,4,4-trifluoro-2-chloroacetoacetate and thioacetamide to produce ethyl 2-methyl-4-(trifluoromethyl)thiazole-5-carboxylate, which was in turn used to produce fungicidal thiazolecarboxanilides. The reaction produced the thiazole in one step by refluxing the reactants in dimethylformamide, but had only a 38% isolated yield.
Reaction SMILES: Cl.Cl.[CH3:3][Si:4]([CH3:31])([CH3:30])[CH2:5][CH2:6][O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C:23]4([CH2:27][C:28]#[N:29])[CH2:26][NH:25][CH2:24]4)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1.Br[C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[C:35]([F:43])[CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(PC2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:28]([CH2:27][C:23]1([N:21]2[CH:22]=[C:18]([C:17]3[C:12]4[CH:11]=[CH:10][N:9]([CH2:8][O:7][CH2:6][CH2:5][Si:4]([CH3:30])([CH3:3])[CH3:31])[C:13]=4[N:14]=[CH:15][N:16]=3)[CH:19]=[N:20]2)[CH2:24][N:25]([C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[C:35]([F:43])[CH:34]=2)[CH2:26]1)#[N:29]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Reactant: COC(=O)c1ccc(Br)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cc1F
Temperature: 90 °C
Yield: 82.8 %

Procedure:
A mixture of {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (1.8 g, 3.7 mmol), methyl 4-bromo-2-fluorobenzoate (1.00 g, 4.29 mmol) (Combi-Blocks: Cat. #CA-4291), cesium carbonate (3.6 g, 11 mmol), palladium acetate (0.10 g, 0.44 mmol), and 9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine (0.54 g, 0.93 mmol) in dry toluene (20 mL) was de-gassed and purged several times with nitrogen, and heated at 90° C. in a sealed vial for 14 hours with stirring. Upon cooling to room temperature, the reaction mixture was filtered through a pad of celite, concentrated in-vacuo and purified by flash chromatography on a silica gel column with hexanes-ethyl acetate to afford the desired product (1.72 g, 82% yield). LCMS (M+H)+: m/z=562.2.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:10]([NH2:13])[CH2:11][CH3:12].C(N(CC)CC)C>C(O)C>[CH2:10]([NH:13][CH2:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:11][CH3:12]
Reactant: CCCN
Reactant: CCOC(=O)/C=C/CBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCNC/C=C/C(=O)OCC
Reaction time: 1.5 h

Procedure:
Ethyl 4-bromocrotonate (21.4 g) was added dropwise to a solution of n-propylamine (11.8 g) and triethylamine (20.2 g) in ethanol (80 ml) at 0° C. under stirring and taking 1.5 hours, followed by stirring for 0.5 hours at room temperature. After removing the solvent, to the residue was added ethyl acetate, and the mixture was extracted with 1N hydrochloric acid. The extract was alkalified with potassium carbonate powder and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and distilled to remove the solvent to give 13.5 of the title compound as pale yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C@@:10]3([C@@H:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=O)([CH3:26])[CH3:25])[CH2:14][C:13](=[O:30])[NH:12][C@H:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:5]2=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:52]1([S:55]([NH2:58])(=[O:57])=[O:56])[CH2:54][CH2:53]1.[H-].[Na+].Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C@@:10]3([C@@H:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH3:26])([CH3:25])[C:27]([NH:58][S:55]([CH:52]4[CH2:54][CH2:53]4)(=[O:57])=[O:56])=[O:29])[CH2:14][C:13](=[O:30])[NH:12][C@H:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1[C@@H]1NC(=O)C[C@H](c2cc(Cl)ccc2OC(C)(C)C(=O)O)[C@@]12C(=O)Nc1cc(Cl)ccc12
Reactant: NS(=O)(=O)C1CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(F)cc1[C@@H]1NC(=O)C[C@H](c2cc(Cl)ccc2OC(C)(C)C(=O)NS(=O)(=O)C2CC2)[C@@]12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
A solution of chiral (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (45 mg, 0.079 mmol) prepared in Example 12a and CDI (26 mg, 0.16 mmol) in DMF (0.5 mL) was heated at 60° C. for 2 h. Then to this solution was added a mixture of cyclopropanesulfonamide (48 mg, 0.4 mmol) and NaH (13 mg, 60%, 0.3 mmol) in DMF (1 mL), which had been stirred for 1 h at room temperature. After the resulting mixture was stirred at room temperature for 1 h, it was poured into water (5 mL) and the aqueous solution was acidified to “PH” 2-3 by addition of concentrated hydrochloride solution. After the aqueous phase was extracted with EtOAc twice, the combined extracts were dried over anhydrous Na2SO4, concentrated and the residue was purified by flash column to give the title compound as a white solid (38 mg).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[OH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[O:14][CH:13]([C:18]([OH:20])=O)[CH2:12][CH2:11]2.Cl.C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1.CCOC(C)=O>[CH2:28]([O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[O:14][CH:13]([CH2:18][OH:20])[CH2:12][CH2:11]2)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)C1CCc2cc(O)ccc2O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCC1CCc2cc(OCc3ccccc3)ccc2O1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
To a stirred suspension of LiAlH4 (0.352 g, 9.26 mmol) in THF at 10° C. was added a solution of (RS)-6-hydroxy-chroman-2-carboxylic acid (1.2 g, 6.18 mmol) in THF (25 ml) over 15 min. After allowing to warm to ambient temperature, 4N HCl (25 ml) and EtOAc (100 ml) was added and the mixture shaken. The aqueous phase was extracted with EtOAc (100 ml) and the combined organic extracts were washed with satd. NaCl (50 ml), dried with Na2SO4 and evaporated. The resulting solid was taken up in acetone (50 ml) then K2CO3 (0.94 g, 6.8 mmol) and benzyl bromide (0.81 ml, 6.8 mmol) were added and the mixture refluxed for 18 hr. The reaction mixture was filtered, evaporated to dryness and chromatographed over SiO2 (Merck 230-400 mesh) eluting with EtOAc-cyclohexane (3:7) to afford (RS)-6-benzyloxy-(chroman-2-yl)-methanol (1.0 g, 3.7 mmol, 60%) as a white solid Mp. 80-82° C., MS mn/e=270.1 (M+).
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10](=[O:18])[C:9]2=[CH:19][S:20][C:21]([CH3:22])=[C:8]12)=[O:6].[CH3:23][N:24]1[CH2:28][CH2:27][CH2:26][CH:25]1[CH2:29][CH2:30][CH2:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>C(OCC)(=O)C.C(O)C>[CH3:22][C:21]1[S:20][CH:19]=[C:9]2[C:10](=[O:18])[NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:7]([C:5]([NH:4][CH2:3][CH2:2][N:35]3[CH2:36][CH2:37][CH:32]([CH2:31][CH2:30][CH2:29][CH:25]4[CH2:26][CH2:27][CH2:28][N:24]4[CH3:23])[CH2:33][CH2:34]3)=[O:6])[C:8]=12
Reactant: CN1CCCC1CCCC1CCNCC1
Reactant: Cc1scc2c1N(C(=O)NCCBr)c1ccccc1NC2=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1scc2c1N(C(=O)NCCN1CCC(CCCC3CCCN3C)CC1)c1ccccc1NC2=O
Yield: 18 %

Procedure:
Prepared analogously to Example 109 from 4-[[[2-bromo-ethyl]amino]carbonyl]-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 4-[3-(1-methyl-pyrrolidin-2-yl)propyl]piperidine in a yield of 18% of theory. Colourless crystals, m.p. 145°-146° C. (from ethyl acetate/ethanol). RF =0.5 (TLC investigation as in Example 114).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=[C:8]([C:10]([OH:12])=O)[N:9]=1)([CH3:4])[CH3:3].[NH2:21][CH2:22][C@H:23]([N:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:37]=[C:36]([F:38])[C:33]([C:34]#[N:35])=[C:32]([Cl:39])[CH:31]=2)=[N:26]1)[CH3:24]>>[Cl:39][C:32]1[CH:31]=[C:30]([C:27]2[CH:28]=[CH:29][N:25]([C@H:23]([CH3:24])[CH2:22][NH:21][C:10]([C:8]3[N:9]=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[N:6]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=3)=[O:12])[N:26]=2)[CH:37]=[C:36]([F:38])[C:33]=1[C:34]#[N:35]
Reactant: C[C@H](CN)n1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: CC(C)(O)c1nc(C(=O)O)cn1COCC[Si](C)(C)C
Product: C[C@H](CNC(=O)c1cn(COCC[Si](C)(C)C)c(C(C)(C)O)n1)n1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 2-(2-hydroxypropan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid (1.43 mmol, 430 mg) and (R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (1.43 mmol, 400 mg). The product was purified by flash-chromatography. Yield 410 mg. LC-MS: [M+1]=561.21.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:22][O:23][CH3:24])[CH2:20]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(SCC(OC)C[NH2:45])CCCCCCCCCCCCCCC.C1(=O)NC(=O)C2=CC=CC=C12>>[CH2:1]([O:17][CH2:18][CH:19]([CH2:22][O:23][CH3:24])[CH2:20][NH2:45])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCSCC(CN)OC
Reactant: CCCCCCCCCCCCCCCCOCC(CO)COC
Agent: O=C1NC(=O)c2ccccc21
Product: CCCCCCCCCCCCCCCCOCC(CN)COC

Procedure:
3-Hexadecyloxy-2-methoxymethylpropanol Vk1 is allowed to react and worked up by the same procedure as described in (3). The phthalimide compound: m.p. 49°-51° C. The summary of the experimental condition and the physical data of the product are listed in Tables 5 and 6.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([O:15][CH3:16])[C:10]([O:13][CH3:14])=[N:11][CH:12]=2)[CH:2]=1.[Li]CCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:38])(=O)=O)=CC=1>C1COCC1.CCCCCC>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:8]([F:38])=[C:9]([O:15][CH3:16])[C:10]([O:13][CH3:14])=[N:11][CH:12]=2)[CH:2]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COc1cc(-c2cccc(-c3ccccc3)c2)cnc1OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ncc(-c2cccc(-c3ccccc3)c2)c(F)c1OC
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 29 %

Procedure:
To a solution of 5-(biphenyl-3-yl)-2,3-dimethoxypyridine (52 mg, 0.178 mmol) in THF (2 mL) at −78° C. was added n-BuLi solution in hexane (2.5 M, 0.157 mL) and then the −78° C. bath was replaced with a 0° C. cooling bath. After stirring at this temperature for 50 min, the reaction mixture was cooled down to −78° C. and then solid N-fluorobenzenesulfonimide was added to it. The reaction was quenched after 10 min by adding saturated aqueous NH4Cl solution and then partitioned between EtOAc and saturated aqueous NaHCO3 solution. Layers were separated and the aqueous solution was extracted with EtOAc (2×). Combined organic solutions were dried over Na2SO4 and concentrated. Purification by preparative HPLC (10-85% CH3CN/H2O over 20 min, 0.05% added TFA) afforded 16 mg (29%) of 5-(biphenyl-3-yl)-4-fluoro-2,3-dimethoxypyridine as a colorless viscous material. LC/MS (M+H)+ 310.2.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH:9]=[CH:10][CH2:11][CH2:12]Cl>C1C=CC=CC=1>[CH:1]1([N:7]2[CH2:12][CH:11]=[CH:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: ClC=CCCCl
Solvent: c1ccccc1
Product: C1=CCN(C2CCCCC2)C1
Temperature: 92 °C
Yield: 76 %

Procedure:
A solution of 5.19 kg (52.3 moles) of cyclohexylamine in 4.0 liters of benzene was heated to mild reflux (92° C.) and then the heating discontinued. To the solution was added, dropwise, 1,635 g (13.1 moles) of 1,4-dichlorobutene at a rate sufficient to maintain gentle reflux, 3 hours time being required. Heat was reapplied and the reactants were heated at reflux temperature for 18 hours. The mixture was cooled to about 50° C. and filtered to remove the hydrochloride. Carbon dioxide was bubbled into the filtrate to precipitate excess amine carbonate which was removed by filtration. Solvent was removed from the filtrate by distillation under reduced pressure and the reddish fluid residue slightly contaminated with benzene weighed 1,506 g (76% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([F:35])=[CH:11][C:12]([F:34])=[C:13]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:27])=[C:22]([F:26])[C:23]=3Br)[C:18](=[O:28])[C:17]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:16]2)[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn]([C:49]#[C:50][Si:51]([CH3:54])([CH3:53])[CH3:52])(CCCC)CCCC)CCC>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.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([F:35])=[CH:11][C:12]([F:34])=[C:13]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:27])=[C:22]([F:26])[C:23]=3[C:49]#[C:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[C:18](=[O:28])[C:17]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:16]2)[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Br)c(F)c(F)cc2c1=O
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(C#C[Si](C)(C)C)c(F)c(F)cc2c1=O
Yield: 74.4 %

Procedure:
Ethyl 1-(5-tert-butoxycarbonylamino-2,4-difluorophenyl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (6 g), tributylstannyltrimethylsilylacetylene (6 g) and tetrakis(triphenylphosphine)palladium (0.4 g) were added to dry toluene (30 ml). This suspension was heated under reflux overnight in a nitrogen atmosphere. After the temperature of the reaction mixture was given back to room temperature, the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with water. After an organic layer was collected and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resultant residue was subjected to column chromatography on silica gel (silica 240 cc/chloroform) to obtain the title compound (4.6 g) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:20][C:21]([CH3:24])=[N:22][N:23]=4)[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[OH:25]OS([O-])=O.[K+].O>CN(C)C=O>[F:1][C:2]1[CH:9]=[C:8]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:20][C:21]([CH3:24])=[N:22][N:23]=4)[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]([OH:25])=[O:5]
Reactant: O=S([O-])OO
Reactant: Cc1nnc(-c2ccc3occ(-c4ccc(C=O)c(F)c4)c3c2)o1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc3occ(-c4ccc(C(=O)O)c(F)c4)c3c2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
A suspension of 2-fluoro-4-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-yl]benzaldehyde (0.693 g, 2.15 mmol) and oxone (registered trade mark) (1.99 g, 3.23 mmol) in N,N-dimethylformamide (25 mL) was stirred overnight at room temperature. The reaction mixture was poured into water, and the precipitate was collected by filtration, dried and recrystallized from tetrahydrofuran to give the title compound (555 mg, yield 76%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[N:3]=1.Cl.Cl.[CH3:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C>CCO>[CH:7]1([C:4]2[N:3]=[C:2]([N:26]3[CH2:25][CH2:24][N:23]([CH2:22][CH2:21][C:20]4[CH:29]=[CH:30][C:17]([O:16][CH3:15])=[CH:18][CH:19]=4)[CH2:28][CH2:27]3)[S:6][N:5]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COc1ccc(CCN2CCNCC2)cc1
Reactant: Clc1nc(C2CCCCC2)ns1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1ccc(CCN2CCN(c3nc(C4CCCCC4)ns3)CC2)cc1
Temperature: 90 °C

Procedure:
A mixture of 5-chloro-3-cyclohexyl-1,2,4-thiadiazole (32.0 mg, 158 μmol), 1-(4-methoxyphenethyl)piperazine dihydrochloride (51.0 mg, 174 μmol) and DIPEA in EtOH was heated for 30 min at an oil bath temperature of 90° C. The mixture was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3 to yield after evaporation of the product containing fractions 13.7 mg (22%) of the title compound as light brown solid. MS (m/e): 387.3 (MH+).