Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:9]([C:11]2[CH:33]=[CH:32][C:14]3[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][C:21]=4[O:29][CH3:30])=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:42]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:43]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:9]([C:11]2[CH:33]=[CH:32][C:14]3[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:42]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:43])=[CH:22][C:21]=4[O:29][CH3:30])=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCOC(=O)Cl
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1OC)n2C)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccc4)ccc3n2C)c(OC)c1
Yield: 53 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidino-2-methoxyphenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide hydrochloride and n-pentyl chloroformate. Yield: 53% of theory, C35H42N6O6 (642.7); Rf value: 0.54 (silica gel; dichloromethane/ethanol=9:1); EKA mass spectrum: (M+H)+=643; (M+H+Na)++=333.4.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:14])([C:11]([OH:13])=[O:12])[CH2:8][CH2:7][C:6]=2[CH:15]=1.Br[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([OH:30])[C:22]=1[CH2:31][CH2:32][CH3:33].[H-].[Na+].[I-].[Na+]>CN(C)C=O>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:19][CH2:18][CH2:17][O:1][C:2]2[CH:3]=[CH:4][C:5]3[O:10][C:9]([CH3:14])([C:11]([OH:13])=[O:12])[CH2:8][CH2:7][C:6]=3[CH:15]=2)=[C:22]([CH2:31][CH2:32][CH3:33])[C:23]=1[OH:30])(=[O:29])[CH3:28]
Reactant: CC1(C(=O)O)CCc2cc(O)ccc2O1
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2ccc3c(c2)CCC(C)(C(=O)O)O3)ccc(C(C)=O)c1O
Yield: 68.9 %

Procedure:
The procedure of Example 7 was employed to alkylate 0.9 g of the ethyl ester of racemic-3,4-dihydro-6-hydroxy-2-methyl-2H-1-benzopyran-2-carboxylic acid with 4'-(3-bromopropoxy)-2'-hydroxy-3'-n-propylacetophenone (1.5 g), using sodium hydride (12.16 mmole), and sodium iodide (10 mmoles), in N,N-dimethylformamide. After saponification with lithium hydroxide monohydrate (1.5 g), the crude product was purified by chromatography on silica gel. There was obtained 1.16 g (68.9%) of racemic-6-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-2H-1-benzopyran-2-carboxylic acid as an off-white solid mp 108°-110.5° C.
Reaction SMILES: [Si]([O:8][C@@H:9]([CH3:41])[C@@H:10]([NH:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[C:33]([Cl:39])[C:32]=1[CH3:40])[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][Si](C(C)(C)C)(C)C)[CH:17]=2)=[N:14][N:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[Cl:39][C:33]1[C:32]([CH3:40])=[C:31]([NH:30][C@@H:10]([C:11]2[O:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)=[N:14][N:15]=2)[C@@H:9]([OH:8])[CH3:41])[CH:38]=[CH:37][C:34]=1[C:35]#[N:36]
Reactant: Cc1c(N[C@@H](c2nnc(-c3cccc(O[Si](C)(C)C(C)(C)C)c3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(N[C@@H](c2nnc(-c3cccc(O)c3)o2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.6 %

Procedure:
To a 25 mL round bottom flask equipped with a magnetic stirrer and a septum was added 4-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(5-(3-(tert-butyldimethyl-silyloxy)phenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-chloro-3-methylbenzonitrile (intermediate 7c) (62 mg, 0.1 mmol), which was then dissolved in anhydrous THF (3 mL) under an atmosphere of nitrogen. To this was added the tetrabutylammonium fluoride as a 1M solution in THF (0.4 mL, 0.4 mmol) producing an instant color change to yellow. This was allowed to stir at room temperature for a period of 4 h. The solvent was then removed under reduced pressure to yield a black residue. This residue was taken up in EtOAc (20 mL) and washed with water (2×10 mL), brine (1×10 mL) and dried over Na2SO4. The solution was then filtered and concentrated under reduced pressure using rotary evaporation to reveal a yellow solid. This was purified via silica gel chromatography eluted with 70% EtOAc/hexanes to provide the title compound as a white solid (31 mg, 81%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 8.88 (br s, 1H), 7.48 (m, 3H), 7.38 (m, 1H), 7.06 (m, 1H), 6.86 (d, J=8.8 Hz, 1H), 5.68 (d, J=8.5 Hz, 1H), 5.10 (dd, J=3.6, 8.5 Hz, 1H), 4.83 (br s, 1H), 4.62 (m, 1H), 2.40 (s, 3H), 1.41 (d, J=6.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[CH:11]([Mg]Br)=[CH2:12]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][NH:8][C:3]=12
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: Clc1ccnc2cc[nH]c12
Temperature: -20 °C
Reaction time: 8 h
Yield: 15.1 %

Procedure:
To a solution of 4-chloro-3-nitro-pyridine (2 g, 13 mmol) in dry THF (100 mL) under N2 at −78° C. was added excess vinyl magnesium bromide (1.0M, 40 mL, 40 mmol). The mixture was stirred at −20° C. for 8 hours before the reaction was quenched with 20% NH4Cl (75 mL). The aqueous phase was extracted with ethyl acetate (3×100 mL). The combined organic layer was dried over MgSO4, filtered and concentrated. The residue was subject to chromatography on silica gel to afford 7-Chloro-1H-pyrrolo[3,2-b]pyridine (0.3 g, 16%). 1H NMR (CD3OD, 400 Hz) δ 8.22 (d, J=5.2 Hz, 1H), 7.64 (d, J=3.2 Hz, 1H), 7.23 (d, J=5.2 Hz, 1H), 6.67 (d, J=3.2 Hz, 1H). MS (ESI+) [M+H]+ 153.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:22]([OH:23])[C:21]2[CH:25]=[CH:26][C:18]([Br:17])=[CH:19][CH:20]=2)[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)Cc2cc([N+](=O)[O-])ccc21
Reactant: O=C(O)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1C(=O)C(=C(O)c2ccc(Br)cc2)c2cc([N+](=O)[O-])ccc21

Procedure:
Prepared analogously to Example 10(a) from 1-acetyl-5-nitro-2-indolinone and 4-bromo-benzoic acid in dry DMF in the presence of TBTU, HOBT and Hunig's base (20° C., overnight) and evaporation in vacuo. A sample of the crude product obtained was purified by column chromatography on silica gel with CH2Cl2 /MeOH (20:1) as eluant.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:33]3[C:28](=[CH:29][C:30]([NH2:34])=[CH:31][CH:32]=3)[CH:27]=[CH:26]2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:34][C:30]1[CH:29]=[C:28]2[C:33](=[CH:32][CH:31]=1)[N:25]([CH:22]1[CH2:23][CH2:24][N:19]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=3)[CH2:20][CH2:21]1)[CH:26]=[CH:27]2
Reactant: Nc1ccc2c(ccn2C2CCNCC2)c1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1ccc2c(ccn2C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.9 %

Procedure:
2-(4-(Bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (3.07 mmol, 1.033 g), 1-(piperidin-4-yl)-1H-indol-5-amine (3.07 mmol, 0.66 g) and potassium carbonate (9.20 mmol, 1.271 g) were combined in acetonitrile (20 mL) and stirred at room temperature overnight. The reaction mixture was concentrated at reduced pressure. The resulting residue was taken up in dichloromethane and washed with water. The organic phase was dried over sodium sulfate and concentrated at reduced pressure. The solvent was removed and the resulting residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 3% methanol/dichloromethane) to afford the title compound (332 mg).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[S:17][C:16]=3[CH:15]=[CH:14][C:13]=2[Br:25])=[CH:8][CH:7]=1.[OH-].[K+]>O1CCCC1.CO>[Br:25][C:13]1[CH:14]=[CH:15][C:16]2[S:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[C:20]=2[C:12]=1[C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:26])=[O:2])=[CH:7][CH:8]=1
Reactant: COC(=O)COc1ccc(-c2c(Br)ccc3sc4ccccc4c23)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(-c2c(Br)ccc3sc4ccccc4c23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
To a solution of [4-(2-bromo-dibenzothiophen-1-yl)-phenoxy]-acetic acid methyl ester (0.449 g, 1.05 mmol) in tetrahydrofuran (15 mL) and methanol (5 mL) was added an aqueous solution of potassium hydroxide (1N, 1.26 mL, 1.2 eq) dropwise at room temperature. After stirring 1 hour at room temperature the solvents were removed and the residue was disolved in water (50 mL) and the reaction mixture was acidified with 10% hydrochloric acid. After stirring 15 minutes the white solid was collected on a sintered glass funnel, washed with water and dried in vacuo at 58° C. overnight to give the title compound as a white solid (0.405 g, 93%); mp 209.5-210.5° C.; NMR (DMSO, d6): δ 13.06 (broad singlet), 8.02 (d, J=8 Hz, 1H), 8.01 (dd, J=8,1 Hz, 1H), 7.82 (d, J=8 Hz, 1H), 7.40 (ddd, J=8,7,1 Hz, 1H), 7.26-7.20 (m, 2H), 7.18=7.07 (m, 3H), 6.54 (d, J=8 Hz, 1H), 4.81 (s, 2H); MS [EI] M*+ m/z=412(98%), 414(100%), 1bromine isotope pattern detected, Anal. Calc. for C20H13BrO3S: C, 58.12, H, 3.17, N, 0.00. Found: C, 57.96, H, 2.95, N, 0.03.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH2:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[S:22]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])(=[O:24])=[O:23]>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:22]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])(=[O:24])=[O:23])=[CH:6][CH:7]=1
Reactant: COC(=O)CCS(=O)(=O)Cl
Reactant: NCCOCCc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)CCS(=O)(=O)NCCOCCc1ccc(F)cc1
Yield: 85.3 %

Procedure:
The subtitle compound (8.32 g) was prepared according to the method of Example 3d) using 2-[2-(4-fluorophenyl)ethoxy]ethanamine (5.36 g), triethylamine (4.6 ml) and methyl 3-(chlorosulphonyl)propanoate (5.6 g) in diethyl ether (150 ml).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=2[C:16]#[N:17])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22]>C(OCC)(=O)C>[ClH:22].[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=2[C:16]#[N:17])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2C#N)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1C1CCNCC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(1-tertbutoxycarbonylpiperidin-4-yl)benzonitrile (1.7 g, 5.9 mmol) in ethyl acetate (˜50 ml), cooled to 0° C. was added hydrogen chloride gas, bubbled vigorously for 5 minutes. The reaction mixture was stirred for 10 minutes at 0° C., purged with argon and concentrated. Flushing with ethyl acetate×3 and concentration gave 2-(piperidin-4-yl)benzonitrile hydrochloride; 1H NMR (DMSO) d 1.98 (m, 4H), 3.07 (m, 2H), 3.21 (tt, 1H, J=12 Hz, J=3.8 Hz), 3.36 (m, 2H), 7.46 (m, 2H), 7.74 (bt, 1H, J=7.7 Hz), 7.83 (bd, 1H, J=7.0 Hz), 9.10 (bd, 2H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[C:7](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>N1C=CC=CC=1>[C:7]([O:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCC(O)CO
Solvent: c1ccncc1
Product: OCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
In 50 ml of pyridine was dissolved 4.6 g (50 mmol) of glycerol followed by addition of 13.9 g (50 mmol) of trityl chloride and the mixture was stirred at ambient temperature overnight. The reaction mixture was then concentrated under reduced pressure and the residue was diluted with water and extracted with ether. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography (silica gel/chloroform-methanol) to provide 9.5 g (59%) of 1-O-tritylglycerol.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C@@H:10]1(N2C3N=C(N)NC(=O)C=3N=C2)[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[C@H:11]1[OH:12]>>[CH3:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[N:6]([CH:7]=1)[C@@H:10]1[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[C@H:11]1[OH:12]
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]c1=O

Procedure:
A culture broth of Flavobacterium rhenanum FERM BP-1862 was prepared according to Example 1 of JP 2-23882. 5-Methyluracil and guanosine as substrates were added without removing the culture medium ingredients of the strain culture solution, and were reacted while keeping the temperature at 60° C. in the same manner as in Example 1 of the present invention. The reaction solution was cooled, filtered, decolored with activated carbon, refiltered and concentrated in vacuo. The concentrate was recooled to 5° C. The particle diameter of the obtained 5-methyluridine crystals was from 20 to 30 μm. The separation phenomenon of 5-methyluridine crystals from other crystals of nucleic acids formed as impurities was not observed. Further, the centrifugal separation took much time.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]([NH:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][C:10]=1[N:20]1[C:24]([CH2:25][O:26]CC2C=CC=CC=2)=[C:23]([C:34]([NH:36][CH:37]2[CH2:39][CH2:38]2)=[O:35])[N:22]=[N:21]1)C1C=CC=CC=1>CO.C(O)(=O)C.[C].[Pd]>[CH:37]1([NH:36][C:34]([C:23]2[N:22]=[N:21][N:20]([C:10]3[CH:11]=[CH:12][C:13]([C:15]([NH:17][CH2:18][CH3:19])=[O:16])=[CH:14][C:9]=3[OH:8])[C:24]=2[CH2:25][OH:26])=[O:35])[CH2:39][CH2:38]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COCc2ccccc2)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CO)c(O)c1
Yield: 101.6 %

Procedure:
1-{2-(Benzyloxy)-4-[(ethylamino)carbonyl]phenyl}-5-[(benzyloxy)methyl]-N-cyclopropyl-1H-1,2,3-triazole-4-carboxamide (1.50 g, 2.85 mmol) obtained in Example 316 was dissolved in methanol-acetic acid (9:1, 50 ml), and the mixture was stirred at room temperature for 68 hr in the presence of 10% palladium carbon (wet, purity 50%, 300 mg) under a hydrogen atmosphere. The reaction mixture was filtrated to remove the catalyst, the filtrate was concentrated, diluted with toluene (100 ml) and concentrated, and ethyl acetate was added to the residue. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (1.00 g, quant.). This powder (0.700 g) was crystallized from ethyl acetate, washed with ethyl acetate and diethyl ether and dried to give the title compound as a white powder (637 mg, 1.84 mmol, 64.7%).
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:6]=[CH:7][C:8](O)=[N:9][CH:10]=1)([CH3:3])[CH3:2].P(Br)(Br)([Br:14])=O>CN(C=O)C>[Br:14][C:8]1[CH:7]=[CH:6][C:5]([S:4][CH:1]([CH3:3])[CH3:2])=[CH:10][N:9]=1
Reactant: CC(C)Sc1ccc(O)nc1
Reactant: O=P(Br)(Br)Br
Solvent: CN(C)C=O
Product: CC(C)Sc1ccc(Br)nc1
Temperature: 95 °C
Reaction time: 0.17 h
Yield: 62.9 %

Procedure:
DMF (5 mL) was added slowly to a stirred mixture of 5-isopropylsulfanylpyridin-2-ol (765.8 mg, 4.525 mmol) and POBr3 (5.189 g, 18.10 mmol) at ambient temperature. After 10 minutes, the reaction mixture was warmed to 95° C. for 1 hour. The reaction mixture was cooled to ambient temperature and quenched by the slow addition of ice. The aqueous layer was extracted with EtOAc (×3) and the combined organics washed with saturated aqueous NaHCO3 (×3), brine (×1), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 80 g column, eluting with 0 to 20% EtOAc/Petroleum Ether, loaded in DCM) to give the sub-title product as an off-white solid (661 mg, 63% Yield, 65% purity). 1H NMR (400.0 MHz, DMSO) δ 1.24 (d, J=6.8 Hz, 6H), 3.58 (sept, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.78 (dd, J=2.6, 8.4 Hz, 1H) and 8.37 (d, J=2.5 Hz, 1H) ppm; MS (ES+) 231.7.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]([F:41])([F:40])[C:30]1[CH:35]=[CH:34][C:33](OB(O)O)=[CH:32][CH:31]=1.O>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].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>[C:1]([O:5][C:6](=[O:27])[C:7]([CH3:9])([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][NH:17][C:18]([C:19]2[CH:24]=[CH:23][C:22]([C:33]3[CH:34]=[CH:35][C:30]([C:29]([F:41])([F:40])[F:28])=[CH:31][CH:32]=3)=[CH:21][CH:20]=2)=[O:26])[N:15]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)Oc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CNC(=O)c2ccc(Br)cc2)cs1
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
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CNC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cs1
Yield: 86.4 %

Procedure:
Under nitrogen atmosphere, 2-[(4-{[(4-bromobenzoyl)amino]methyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (600 mg) synthesized in Example 455-1 and 4-trifluoromethylphenylboric acid (363 mg) were dissolved in dioxane (8 mL) and 2 M aqueous sodium carbonate solution (4 mL), tetrakis(triphenylphosphine)palladium (73 mg) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1 to 1:1) to give the title compound (590 mg) as a white solid.
Reaction SMILES: [CH2:1](Cl)[CH:2]=[C:3]([CH3:5])[CH3:4].[CH3:7][C:8]([CH3:10])=[O:9]>>[CH3:4][C:3]([CH3:5])=[CH:2][CH2:1][CH2:7][C:8](=[O:9])[CH3:10]
Reactant: CC(C)=CCCl
Reactant: CC(C)=O
Product: CC(=O)CCC=C(C)C

Procedure:
Process (iii): A process in which prenyl chloride obtained by the reaction of isoprene with hydrogen chloride is allowed to react with acetone in the presence of an equimolar amount of an alkali based on the prenyl chloride to give 6-methyl-5-hepten-2-one (see, e.g., U.S. Pat. Nos. 3,983,175 and 3,984,475).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)[CH3:9].[C:27]([OH:34])(=[O:33])[CH2:28][CH2:29][CH2:30][C:31]#[CH:32].C(N(CC)CC)C>COCCOC.[Cu](I)I.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>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]([NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:32]#[C:31][CH2:30][CH2:29][CH2:28][C:27]([OH:34])=[O:33])=[CH:20][CH:19]=1)=[O:26])[CH3:9]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Reactant: C#CCCCC(=O)O
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: Cc1noc(-c2ccc(C#CCCCC(=O)O)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-(2-chloro-phenyl)-ethyl ester (0.200 g, 0.46 mmol) and 5-hexynoic acid (0.06 mL, 0.55 mmol) in DME (5 mL) was added copper iodide (0.017 g, 0.09 mmol), followed by tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.05 mmol), and the mixture was purged with N2 for 5 minutes. Triethylamine (0.26 mL, 1.83 mmol) was added, and the reaction was purged with N2 for another 10 minutes and then stirred at 80° C. for 2 hours. The mixture was partitioned between EtOAc and H2O, and the aqueous layer was separated and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].CCN(C(C)C)C(C)C.[F:23][C:24]([F:28])([F:27])[CH2:25][NH2:26]>C(Cl)Cl>[F:23][C:24]([F:28])([F:27])[CH2:25][NH:26][C:2](=[O:3])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCC(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCC(F)(F)F)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 4-nitrophenyl chloroformate (4578 mg, 22715 μmol) and DIEA (2638 μL, 15143 μmol) in DCM (100 mL) at 0° C. was added 2,2,2-trifluoro-ethylamine (1500 μL, 15143 μmol). The resulting mixture was then stirred at 0° C. for 4 h and at RT for overnight. Then, the mixture was concentrated and a white precipitation was observed. The mixture was then filtered to give the title compound as a white solid, which was used in the next step without purification requirement.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:18][C@@H:19]([CH3:24])[C:20]([F:23])([F:22])[F:21])=[N:10][CH:11]=[C:12]([CH:17]=2)[C:13]([O:15]C)=[O:14])=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:18][C@@H:19]([CH3:24])[C:20]([F:23])([F:21])[F:22])=[N:10][CH:11]=[C:12]([CH:17]=2)[C:13]([OH:15])=[O:14])=[CH:6][CH:7]=1
Reactant: COC(=O)c1cnc(O[C@@H](C)C(F)(F)F)c(-c2ccc(Cl)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](Oc1ncc(C(=O)O)cc1-c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
To a solution of 0.860 g (S)-methyl 5-(4-chlorophenyl)-6-(1,1,1-trifluoropropan-2-yloxy)nicotinate in 9 mL tetrahydrofuran was added 3 mL of a 1M solution of lithium hydroxide in water and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was acidified by addition of 1M hydrochloric acid till pH=2. Ethyl acetate was added and the phases were separated. The organic phase was dried over MgSO4 and the solvent was removed to yield 830 mg (100%) of the title compound as light yellow solid, MS 344.1 (M−H)−.