Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.[CH2:9](C([Sn])=C(CCCC)CCCC)[CH2:10]CC>CN(C=O)C.C1COCC1.O.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>[CH3:8][C:5]1[N:4]=[CH:3][C:2]([CH:9]=[CH2:10])=[CH:7][N:6]=1
Reactant: Cc1ncc(Br)cn1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=Cc1cnc(C)nc1
Temperature: 120 °C

Procedure:
The title compound was prepared by following general procedure 2. 5-Bromo-2-methyl-pyrimidine (1.7 g, 9.87 mmol) was dissolved in DMF:THF (3:1 24 mL). Tributylvinyltin (3.2 mL, 10.8 mmol) and Pd(PPh3)4 (0.148 g, 0.128 mmol) was added to this solution at RT under nitrogen and was heated at 120° C. for 30 min. The reaction mixture was cooled to RT and diluted with water (60 mL) and extracted with DCM (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator below 40° C. The crude was purified through column chromatography (20% Ethyl acetate-Hexane in silica 100-200 mesh, Diameter of column—5.0 cm, Height of silica—approx. 5 inch) to provide 2-methyl-5-vinylpyrimidine a as light yellow liquid (1.1 g, 91% yield).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[N:13]=[C:14]([NH2:17])[S:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[CH3:18][N:19]=[C:20]=[S:21].C(OCC)(=O)C>C(O)C>[C:1]([NH:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[N:13]=[C:14]([NH:17][C:20]([NH:19][CH3:18])=[S:21])[S:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CN=C=S
Reactant: CC(=O)NCc1cccc(-c2csc(N)n2)n1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNC(=S)Nc1nc(-c2cccc(CNC(C)=O)n2)cs1
Temperature: 25 °C
Yield: 20.7 %

Procedure:
A mixture of 4-(6-acetylaminomethylpyridin-2-yl)2-aminothiazole (7.0 g) and methyl isothiocyanate (6.2 g) in ethanol (140 ml) was heated under reflux for 40 minutes and then the mixture was cooling to ambient temperature. To the mixture was added ethyl acetate (140 ml) and isolated precipitate was collected by filtration to give 4-(6-acetylaminomethylpyridin-2-yl)-2-(3-methylthioureido)thiazole (1.88 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([Br:8])=[CH:6][CH:7]=1.O=S(Cl)Cl.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:3]([C:9]([NH:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[F:16])=[O:11])=[N:4][C:5]([Br:8])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)nc1C(=O)O
Reactant: Nc1ccccc1F
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: Nc1ccc(Br)nc1C(=O)Nc1ccccc1F
Temperature: 130 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
A mixture of 3-amino-6-bromopicolinic acid (250 mg, 1.152 mmol) and SOCl2 (5 mL) in toluene (10 mL) was stirred at 130° C. for 2 h, then evaporated and dissolved in tetrahydrofuran (20 mL). 2-fluoro-phenylamine (256 mg, 2.3 mmol) was added dropwise maintaining the temperature at 5° C. The reaction mixture was heated to 90° C. for 15 h. The mixture was cooled to room temperature and quenched with saturated aqueous K2CO3 (10 mL) and extracted with ethyl acetate (10 mL*3), the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified with column chromatograph (PE:EtOAc=3:1) to give 3-amino-6-bromo-N-(2-fluorophenyl)picolinamide (160 mg, yield: 45%). MS (M+H)+: 311/313.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][NH:5][C:6](=[O:15])[C:7]1[CH2:8][C:9](Cl)([Cl:13])[CH:10]=[CH:11][CH:12]=1.[OH-].[Na+].[ClH:19]>>[Cl:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[Cl:19])[C:6]([NH:5][CH2:4][C:3]([OH:2])=[O:16])=[O:15]
Reactant: Cl
Reactant: COC(=O)CNC(=O)C1=CC=CC(Cl)(Cl)C1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CNC(=O)c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
(3,3-Dichlorobenzoylamino)acetic acid methyl ester (25.91 g, 100 mmol, 1.0 eq., see step (a) above) was added to the flask followed by aqueous sodium hydroxide (1 M, 198 mL, 200 mmol, 2.0 eq.). The mixture was heated to 50° C. using an oil bath for 2 hours. On cooling, a white precipitate formed. The mixture was cooled further to 5° C. using an ice/water bath. Concentrated hydrochloric acid (60 mL) was added very slowly to the cooled solution, ensuring that the temperature did not rise above 10° C. The mixture was stirred for 10 minutes and was then filtered. The white solid was air dried for 15 minutes and then dried in vacuo at 40° C. for 16 hours to give an off-white solid (19.15 g, 78%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13](F)=[C:14]([CH:17]=2)[CH:15]=[O:16])=[CH:6][CH:5]=1)[CH3:2].[SH:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([S:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:14]([CH:15]=[O:16])[CH:17]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOC(=O)CCCS
Reactant: CCOc1ccc(-c2ccc(F)c(C=O)c2)cc1
Product: CCOC(=O)CCCSc1ccc(-c2ccc(OCC)cc2)cc1C=O
Yield: 73 %

Procedure:
Ethyl 4-(4-(4-ethoxyphenyl)-2-formylphenylthio)butyrate was synthesized from 5-(4-ethoxyphenyl)-2-fluorobenzaldehyde and ethyl 4-mercaptobutyrate in the same manner as Example 2. After concentration of an extracted solution, crystallization from hexane/isopropyl ether yielded ethyl 4-(4-(4-ethoxyphenyl)-2-formylphenylthio)butyrate (Yield 73%) as yellow crystals.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].I[C:10]1[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH2:27])=[CH:21][CH:20]=1.C(O)CO.N>O.[Cu]I.C(O)(C)C>[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)[CH2:26][NH2:27])=[CH:21][CH:20]=1
Reactant: NCCc1ccc(N)cc1
Reactant: Cc1cc(C)cc(I)c1
Agent: [Cu]I
Agent: N
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)O
Solvent: OCCO
Solvent: O
Product: Cc1cc(C)cc(C(CN)c2ccc(N)cc2)c1
Temperature: 80 °C
Reaction time: 22 h
Yield: 69.5 %

Procedure:
An oven-dried resealable 15 mL Schlenk tube was charged with CuI (9.6 mg, 0.0504 mmol, 5.0 mol %), K3PO4 (440 mg, 2.07 mmol), evacuated and backfilled with argon. 5-Iodo-m-xylene (145 μL, 1.00 mmol), 2-(4-aminophenyl)ethylamine (160 μL, 1.21 mmol), ethylene glycol (115 μL, 2.06 mmol), and isopropyl alcohol (1.0 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred magnetically at 80° C. for 22 h. The resulting thick, gray-brown suspension was allowed to reach room temperature, poured into a solution of 30% aq ammonia (1 mL) in water (20 mL), and extracted with 3×15 mL of CH2Cl2. The yellow-brown organic phase was dried (Na2SO4), concentrated, and the residue was purified by flash chromatography on silica gel (2×20 cm; hexane-ethyl acetate 3:2; 15 mL fractions). Fractions 9-18 were concentrated and the residue was recrystallized from hexanes (5 mL) to give 167 mg (69% yield) of the desired product as large white needles. 1H NMR (400 MHz, CDCl3): δ 7.04−6.97 (m, 2H), 6.67−6.61 (m, 2H), 6.36 (s, 1H), 6.24 (s, 2H), 3.65−3.50 (br m, 3H), 3.30 (t, J=6.8 Hz, 2H), 2.79 (t, J=7.0 Hz, 2H), 2.23 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 148.2, 144.7, 138.8, 129.5, 129.2, 119.3, 115.3, 110.9, 45.3, 34.6, 21.5. IR (neat, cm−1): 3361, 3215, 1600, 1515, 1472, 1337, 1273, 1181, 820.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][C:8]=1[C:19]([OH:21])=O)([O-:3])=[O:2].C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C>>[N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:8]([C:19]=1[OH:21])=[CH:9][C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:11][CH:12]=2)([O-:3])=[O:2]
Reactant: O=C(O)c1cc(-c2ccccc2)ccc1N/C=C/[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1cnc2ccc(-c3ccccc3)cc2c1O

Procedure:
The title compound is prepared in analogy to Example 19b, starting from 1 g (3.518 mmol) of 4-((E)-2-nitro-vinylamino)-biphenyl-3-carboxylic acid (Example 53b), 0.418 g (4.25 mmol) potassium acetate, and 7.8 ml acetic anhydride. mp: 298° C. (dec.); MS: 265 (M+−1); HPLC: tret=8.97 min (Grad 1).
Reaction SMILES: C(OC[N:10]1[C:14]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[C:13](CO[SiH3])[N:12](C)[C:11]1([CH3:31])C(C)(C)C)C1C=CC=CC=1.C1([O:38]C)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].C(=O)([O-])O.[Na+]>[N+](C)([O-])=O.C(OCC)(=O)C.O>[Cl:22][C:18]1[CH:17]=[C:16]([S:15][C:14]2[NH:10][C:11]([CH2:31][OH:38])=[N:12][CH:13]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccccc1
Reactant: CN1C(CO[SiH3])=C(Sc2cccc(Cl)c2)N(COCc2ccccc2)C1(C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: OCc1ncc(Sc2cccc(Cl)c2)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
To a solution of 1-benzyloxymethyl-2-t-butyldimethyl-silyloxymethyl-5-(3-chlorophenylthio)imidazole (45) in nitromethane (108 ml) was added 14.7 g of (137 mmol) of anisole, and then, 18.1 g (136 mmol) of anhydrous aluminium chloride was gradually added at lower than 30° C. After completion of the addition, the mixture was stirred at room temperature for 15 minutes. The reaction mixture was cooled, and there were added water and a saturated aqueous sodium hydrogen carbonate solution to be alkaline. Ethyl acetate was added to the mixture, and the mixture was filtered on Hiflow Super Cell to separate. The organic layer was washed with water, dried over sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel chromatography (7% methanol-methylene chloride) to give 9.5 g of [5-(3-chlorophenylthio)-1H-imidazol-2-yl]methanol as oil (yield 87%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9](=[O:10])[N:8]([C:11]3[S:12][C:13]([C:17]([OH:19])=O)=[C:14]([CH3:16])[N:15]=3)[CH:7]=[N:6]2)[CH2:3][CH2:2]1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.[NH2:51][CH2:52][C:53]1[CH:58]=[CH:57][N:56]=[CH:55][CH:54]=1>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([CH2:4][N:5]2[C:9](=[O:10])[N:8]([C:11]3[S:12][C:13]([C:17]([NH:51][CH2:52][C:53]4[CH:58]=[CH:57][N:56]=[CH:55][CH:54]=4)=[O:19])=[C:14]([CH3:16])[N:15]=3)[CH:7]=[N:6]2)[CH2:2][CH2:3]1
Reactant: Cc1nc(-n2cnn(CC3CC3)c2=O)sc1C(=O)O
Reactant: NCc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-n2cnn(CC3CC3)c2=O)sc1C(=O)NCc1ccncc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49 %

Procedure:
To a solution of 2-(1-(cyclopropylmethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid (0.15 g, 0.53 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.14 g, 0.69 mmol) and N,N-diisopropylethylamine (0.09 mL, 0.69 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole (0.09 g, 0.69 mmol). The resulting mixture was stirred at ambient temperature for 15 minutes, followed by the addition of 4-aminomethylpyridine (0.07 mL, 0.69 mmol). The reaction mixture was kept stirring at ambient temperature for 20 hours, diluted with ethyl acetate (200 mL) and washed with water and brine. The organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography to afford the title compound in 49% yield (0.10 g): mp 169-170° C.; 1H NMR (300 MHz, CDCl3) δ 8.64-8.48 (m, 2H), 8.28-8.25 (m, 1H), 7.26-7.20 (m, 2H), 6.22 (t, J=5.8 Hz, 1H), 4.60 (d, J=5.8 Hz, 2H), 3.71 (d, J=7.2 Hz, 2H), 2.67 (s, 3H), 1.30-1.17 (m, 1H), 0.62-0.54 (m, 2H), 0.43-0.135 (m, 2H); MS (ES+) m/z 371.2 (M+1).
Reaction SMILES: CC[O-].[Na+].[C:5]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH2:16](Br)[CH:17]([CH3:19])[CH3:18]>CCO>[CH2:16]([CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]([O:13][CH2:14][CH3:15])=[O:12])[CH:17]([CH3:19])[CH3:18]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)CBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CC(C)C)C(=O)OCC
Yield: 87.6 %

Procedure:
To a solution of NaOEt prepared by dissolving 5.75 g (0.25 mol) of Na in 150 mL of absolute EtOH was added 39 mL (0.250 mol) of diethyl malonate with cooling in a water bath under N2. To the resulting solution was added 24 mL (0.250 mol) of isobutyl bromide. The mixture was refluxed under N2 for 14 hours. The ethanol was evaporated under reduced pressure and the residue was partitioned between CHCl3 and water. The aqueous Na2SO4 and evaporated. The residue was distilled under reduced pressure to give 47.2 g (0.219 mol, 88% of diethyl isobutylmalonate as a colorless liquid. Characteristic analytical data are as follows: bp 127°-135° C. (25 mm Hg); 1H NMR (300 MHz, CDCL3) δ4.20 (q, J=7 Hz, 4H), 3,41 (t, J=8 Hz, 1H), 1.80 (t, J=7 Hz, 2 H), 1.57 (m, 1H), 1.27 (t, J=8 Hz, 6H), 0.92 (d, J=7 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][OH:11])=[NH:9])[CH:5]=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[N:22]=[C:21]([C:29](O)=O)[N:20]=2)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[C:23]([C:25]([F:27])([F:26])[F:28])[N:22]=[C:21]([C:29]3[O:11][N:10]=[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=4)[N:9]=3)[N:20]=2)=[CH:17][CH:18]=1
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1
Reactant: N=C(NO)c1ccnc(N)c1
Product: Nc1cc(-c2noc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)n2)ccn1

Procedure:
The title compound was prepared from 2-amino-N-hydroxy-pyridine-4-carboxamidine (example C.5) (0.11 g, 0.75 mmol) and 4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.1) (0.15 g, 0.5 mmol) according to the general procedure V. Obtained as an off-white solid (0.018 g, 9%). MS (ISP) 419.0 [(M+H)+]; mp 223.5° C.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[NH2:5][C@@:6]([CH3:12])([C@H:9]([OH:11])[CH3:10])[CH2:7][OH:8].C[C@]([N+]([O-])=O)([C@H](O)C)CO>>[C:1]([OH:4])(=[O:3])[CH3:2].[NH2:5][C@@:6]([CH3:12])([C@@H:9]([OH:11])[CH3:10])[CH2:7][OH:8]
Reactant: C[C@@H](O)[C@](C)(N)CO
Agent: C[C@@H](O)[C@@](C)(CO)[N+](=O)[O-]
Solvent: CC(=O)O
Product: C[C@H](O)[C@](C)(N)CO
Yield: 93 %

Procedure:
Using the reduction procedure in 2E, (+-)(2R*,3S*)-2-methyl-2-nitro-1,3-butanediol (2A) gave (+-)(2R*,3S*)-2-amino-2-methyl-1,3-butanediol acetate (93%) (C,H,N) mp 163°-165° C.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Mg+2].[Cl-].[Cl-].[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:27])([CH3:26])[C:23](O)=[O:24])=[CH:18][CH:17]=1>C(#N)C.S(Cl)(Cl)=O>[F:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([CH3:27])([CH3:26])[C:23]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:24])=[CH:20][CH:21]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C(=O)O)c1ccc(F)cc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1ccc(F)cc1
Temperature: 0 °C
Yield: 96.3 %

Procedure:
A mixture of diethyl malonate (3 g, 16 mmol) in 50 mL ACN was stirred at 0° C., was treated with MgCl2 (2 g, 18 mmol) in one portion, and was treated dropwise with TEA (3 g, 33 mmol). The mixture was stirred at room temperature for 2.5 hours. A mixture of 2-(4-fluorophenyl)-2-methylpropanoic acid (3 g, 16 mmol) in thionyl chloride (20 mL) was refluxed for 2 hours and then concentrated in vacuo. The residue was diluted with 10 mL ACN, and was added dropwise to the above mixture. The mixture was stirred at 50° C. for 15 hours. The resulting mixture was then cooled to room temperature, diluted with 100 mL ether, washed with H2O (2×50 mL) and brine 20 mL, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-20% EtOAc/hexane to give 5 g of the product as pale yellow oil. MS m/e=325 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:20][C@H:21]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:22]2[N:23]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:25][N:26]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:12](=[O:14])(=[O:13])[N:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:10](=[O:19])[CH:9]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:20][C@H:21]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:22]2[N:23]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:39])([CH3:38])[CH3:40])[C:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:25][N:26]=2)[CH:5]=[CH:6][C:7]=1[CH:8]1[S:12](=[O:13])(=[O:14])[N:11]([C:15]([CH3:16])([CH3:17])[CH3:18])[C:10](=[O:19])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C2=CC(=O)N(C(C)(C)C)S2(=O)=O)c(Br)c1)c1ncc(-c2ccccc2)n1COCC[Si](C)(C)C
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C2CC(=O)N(C(C)(C)C)S2(=O)=O)c(Br)c1)c1ncc(-c2ccccc2)n1COCC[Si](C)(C)C
Reaction time: 0.08 h
Yield: 92.6 %

Procedure:
A solution of tert-butyl [(1S)-2-[3-bromo-4-(2-tert-butyl-1,1-dioxido-3-oxo-2,3-dihydroisothiazol-5-yl)phenyl]-1-(5-phenyl-1-[2-(trimethylsilyl)ethoxy]methyl-1H-imidazol-2-yl)ethyl]carbamate (70 mg, 92.1 μmol) and tetrahydrofuran (20 mL) was stirred at −78° C. After stirring for 5 min, 1.0 M L-selectride in tetrahydrofuran (92 μL) was added dropwise. The reaction was quenched with glacial acetic acid (0.7 mL). The reaction was diluted with water and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (65 mg, 83%). MF=C35H49BrN4O6SSi; LCMS found for C35H50BrN4O6SSi(M+H)+: m/z=761.
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[S:4].[C:6]([CH2:11][C:12](OCC)=[O:13])(=O)[CH2:7][CH2:8][CH3:9]>CO>[SH:4][C:3]1[N:5]=[C:12]([OH:13])[CH:11]=[C:6]([CH2:7][CH2:8][CH3:9])[N:2]=1
Reactant: CCCC(=O)CC(=O)OCC
Reactant: NC(N)=S
Agent: [Na]
Solvent: CO
Product: CCCc1cc(O)nc(S)n1
Temperature: 25 °C

Procedure:
Sodium (4.6 g) was added by portions at 0° C. to methanol (150 mL). The mixture was stirred at room temperature until dissolution. After cooling at 0° C., thiourea (11.0 g) was added by portions and the mixture was stirred until dissolution. Ethyl butyrylacetate (15.8 g) in methanol (200 mL) was added dropwise at 0° C. over 30 minutes. The mixture was refluxed for 9 h, then concentrated under reduced pressure. The residue was dissolved in water. After acidification with acetic acid until pH=6 and stirring for 1 h, the mixture was filtered. The precipitate was successively washed with water and isopropanol, then dried under reduced pressure to afford 2-mercapto-6-propyl-pyrimidin-4-ol (14.1) as white crystals (mp=220° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1.[CH:13]1(/[CH:19]=[C:20](\B2OC(C)(C)C(C)(C)O2)/[CH2:21][OH:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)(C)C.O.C1(P([Pd-4](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)C=CC=CC=1>[CH:13]1(/[CH:19]=[C:20](\[C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=2)/[CH2:21][OH:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CS(=O)(=O)c1ccc(Br)cc1F
Reactant: CC1(C)OB(/C(=C\C2CCCCC2)CO)OC1(C)C
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCCC2)CO)cc1F
Temperature: 25 °C
Yield: 88.6 %

Procedure:
Heat a mixture of 4-bromo-2-fluoro-l -methanesulfonyl-benzene (220 mg, 0.86 mmol), (E)-3-cyclohexyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-prop-2-en-1-ol (298 mg, 1.12 mmol), potassium carbonate (356 mg, 2.58 mmol) and tetrakis(triphenylphosphino)palladium(0) (99 mg, 86 μmol) in 40 mL toluene, 5 mL iso-propanol and 5 mL water to reflux for 2 h. After cooling to r.t. extract with ethyl acetate, wash the combined organic extracts with brine, dry them over sodium sulfate, filtrate and concentrate to obtain a brown oil. Purify the crude product by column chromatography, eluting with a gradient from 100:0 to 0:100 hexanes:ethyl acetate to obtain (E)-3-cyclohexyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-prop-2-en-1-ol (238 mg) as a pale yellow oil. MS (m/e): 295 [(M−H2O)+H].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]4[C:32]([C:37]([O:39]C(C)(C)C)=[O:38])=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:27][CH:26]=2)[CH:19]=[CH:18]3)=[O:14])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(C(C)C)C(C)C>CCCCCC.CCOC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]4[C:32]([C:37]([OH:39])=[O:38])=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:27][CH:26]=2)[CH:19]=[CH:18]3)=[O:14])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[C@H](NC(=O)c1ccc2c(ccn2Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c1)c1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1ccc2c(ccn2Cc2ccc(-c3ccccc3C(=O)O)cc2)c1)c1ccc([N+](=O)[O-])cc1
Yield: 50 %

Procedure:
A solution of (S)-tert-butyl 4′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate (23 mg, 0.04 mmol, 1 equiv) in DCM/TFA 1/1 was stirred for 30 min at room temperature. The reaction mixture was neutralized by addition of DIEA, concentrated and purified by preparative HPLC to afford a beige powder (9 mg, 0.02 mmol, 43%). ESI-MS (m/z): 520 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[C:5]1(=O)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[O:6]1>C1(C)C=CC=CC=1>[OH:4][CH2:3][CH2:2][N:1]1[C:5](=[O:6])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:14]
Reactant: NCCO
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCO
Yield: 110.6 %

Procedure:
A solution of 2-aminoethanol (41 g, 0.67 mol) and isobenzofuran-1,3-dione (100 g, 0.52 mol) in toluene (300 mL) was refluxed for 12 hours. Volatiles were distilled out to give a residue, which was purified by re-crystallization from chloroform/hexane (v/v, 1:6) to afford 126 as a white solid (110 g, 85%). (ES, m/z) [M+H]+ 192.0; 1H NMR (300 MHz, CDCl3) δ 7.84-7.90 (m, 2H), 7.71-7.77 (m, 2H), 3.87-3.93 (m, 4H), 2.10 (br, 1H).