Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([OH:15])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]1.[NH2-].[Na+].C1C=CC=CC=1>O>[CH2:28]([O:27][C:25]([N:22]1[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][O:15][C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:1])[CH2:24][CH2:23]1)=[O:26])[CH3:29]
Reactant: CC(O)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)N1CCN(CCCl)CC1
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)N1CCN(CCOC(C)(c2ccccc2)c2ccccc2)CC1
Yield: 71.8 %

Procedure:
A mixture of 1.8 g (9.1 mmole) of α-methylbenzhydrol, 2.0 g (9.1 mmole) of 1-(2-chloroethyl)-4-(ethoxycarbonyl)piperazine, 0.36 g (9.2 mmole) of sodium amide and 20 ml of benzene was heated under reflux overnight. At the end of this time, water was poured onto the reation mixture, and the mixture was extracted with ethyl acetate. The solvent was then removed from the mixture by distillation under reduced pressure, and the residue was subjected to column chromatography through silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent, to obtain 2.5 g (yield 75%) of the title compound as an oil.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH2:16][C:17]1([CH2:25]Br)[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:7][O:6][C:4]([C:3]1[C:2]2[O:1][CH2:25][C:17]3([CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19][CH2:18]3)[CH2:16][O:12][C:11]=2[C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:5]
Reactant: CC1(C)OCC(CBr)(CBr)CO1
Reactant: COC(=O)c1ccc(OC)c(O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(OC)c2c1OCC1(CO2)COC(C)(C)OC1

Procedure:
Following the general procedure, dialkylation of compound 513 (1.19 g, 6 mmol) with compound 521 (2.0 g, 6.62 mmol) in DMSO (30 mL) in the presence of K2CO3 (2.07 g, 15 mmol) afforded compound 522 as a white solid material after purification by column chromatography (30-40% EtOAc in light petroleum). LC-MS: RT=2.99 min.; m/z 339.31 (M+H)+, 361.25 (M+Na)+. 1H NMR (CDCl3): δ 7.45 (1H, d, J 8.8), 6.59 (1H, d, J 8.8), 4.22 (2H, s), 4.18 (2H, s), 3.89 (3H, s), 3.86 (7H, s), 1.43 (6H, s).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[N+:18]([C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)([O-:20])=[O:19].C(O)(=O)C.[SH:32][CH2:33][C:34](O)=[O:35]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]2[N:25]([C:24]3[CH:26]=[CH:27][C:21]([N+:18]([O-:20])=[O:19])=[CH:22][CH:23]=3)[C:34](=[O:35])[CH2:33][S:32]2)[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)CS
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(C2SCC(=O)N2c2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Reaction time: 24 h
Yield: 14.8 %

Procedure:
5 g of 3,5-di-t-butyl-4-hydroxybenzaldehyde (21 mmol) and 2.95 g of para-nitroaniline (21 mmol) are dissolved in 50 ml of anhydrous toluene. 0.5 ml of glacial acetic acid is added and the whole is taken to reflux for 24 hours. Then 1.96 g of mercaptoacetic acid (21 mmol) is added to the medium and reflux is continued for another 24 hours. After the reaction mixture has returned to ambient temperature, it is washed with water (3 times 30 ml). After decantation. the organic phase is dried over sodium sulphate and the solvent is evaporated off under reduced pressure. The residue is purified on silica gel in an ethyl acetate/heptane mixture (1/4) and 1.33 g of pure 2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-(4-nitrophenyl)-4-thiazolidinone is obtained in the form of a colourless oil (15%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:24]=1[CH:25]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O.CN(C=O)C.C(Cl)(Cl)Cl>[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:24]=1[CH2:25][NH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ccc3c(c2)C(=C2C(=O)Nc4ccccc42)OC3)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 3-(6-amino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (1 g, 3.79 mmol) and 2,4-dimethoxybenzaldehyde (0.75 g, 4.54 mmol) in 1% AcOH/DMF (30 ml), was added sodium triacetoxyborohydride (3.2 g, 15.1 mmol). The mixture was stirred at room temperature for 16 hours, diluted with CHCl3 (200 ml), washed with saturated aqueous NaHCO3 solution (200 ml) and water (2×200 ml), dried over anhydrous Na2SO4. Removal of the solvent provided the crude product. Recrystallization of the crude product from MeOH resulted in 3-[6-(2,4-dimethoxy-benzylamino)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one as a bright yellow solid (1.3 g, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]([OH:15])=O)[CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl.[CH3:17][NH:18][O:19][CH3:20].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[CH3:20][O:19][N:18]([CH3:17])[C:13]([C:8]1[CH:9]=[N:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)=[O:15]
Reactant: CNOC
Reactant: COc1ccc2cc(C(=O)O)cnc2c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2cc(C(=O)N(C)OC)cnc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of the intermediate from step D (1.5 mmol) and N,O-dimethyhydroxylamine hydrochloride (219 mg, 2.25 mmol), in dichloromethane (20 mL) was added triethyl amine (1.04 mL, 7.5 mmol) followed by bromo(trispyrrolidin-1yl)phosphonium hexafluorophosphate (840 mg, 1.8 mmol). After stirring the reaction mixture at room temperature for 3 hours, it was quenched by the addition of 1N HCl (10 mL). The resulting mixture was extracted with DCM. The organic layer was washed with saturated NaHCO3 solution, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 70% ethyl acetate-hexanes. 1H NMR (500 MHz, CDCl3): 9.15 (d, J=1.8 Hz, 1H), 8.5 (d, J=1.8 Hz, 1H), 8.0 (s, 1H), 7.7 (d, J=9.0 Hz, 1H), 7.43 (d, J=2.2 Hz, 1H), 7.24 (dd, J=2.5, 9.0 Hz, 1H), 3.96 (s, 3H), 3.57 (s, 3H), 3.43 (s, 3H). LC-MS: 1.6 min; (M+H)=247.1.
Reaction SMILES: CC1C=CC(S(N[C@H]([C@@H](N)C2C=CC=CC=2)C2C=CC=CC=2)(=O)=O)=CC=1.C(O)=O.C(N(CC)CC)C.[C:37]([O:41][C:42](=[O:56])[CH2:43][O:44][C:45]1[C:54]2[CH2:53][CH2:52][CH2:51][C:50](=[O:55])[C:49]=2[CH:48]=[CH:47][CH:46]=1)([CH3:40])([CH3:39])[CH3:38]>O>[C:37]([O:41][C:42](=[O:56])[CH2:43][O:44][C:45]1[C:54]2[CH2:53][CH2:52][CH2:51][C@H:50]([OH:55])[C:49]=2[CH:48]=[CH:47][CH:46]=1)([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)COc1cccc2c1CCCC2=O
Agent: Cc1ccc(S(=O)(=O)N[C@@H](c2ccccc2)[C@@H](N)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: O
Product: CC(C)(C)OC(=O)COc1cccc2c1CCC[C@@H]2O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a flask containing 124 mg (0.203 mmol) of di-mu-chlorobis[(p-cymene)chlororuthenium(II) ([RuCl2(C10H14)]2, Strem Chemicals, Inc., CAS No. 52462-29-0) and 153 mg (0.416 mmol) of (1S,2S)-(+)-N-p-tosyl-1,2-diphenylethylenediamine (Aldrich, CAS No. 167316-27-0) was added 50 mL of a pre-formed mixture of formic acid and triethylamine (in 5:2 molar ratio), and the resulting mixture was stirred at room temperature for 45 minutes (gas evolution was observed). Then 10 g (36.19 mmol) of (5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (V, prepared as described above) was added, and the reaction mixture was stirred at 42° C. internal temperature. Upon gas evolution and foaming, the reaction mixture was cooled to 33° C. internal temperature over 1 hour, and then stirred for an additional 24 hours at 33° C. The reaction mixture was then cooled in an ice-water bath, diluted with 50 mL of de-ionized water, and extracted with 100 mL of toluene. The organic layer was separated and washed with 1 M aqueous citric acid (50 mL), saturated aqueous sodium bicarbonate (50 mL), and water (50 mL). The organic phase was then dried over MgSO4, and concentrated azeotropically at 35° C./20 mmHg to a total volume of 30 mL. The resulting solution was co-evaporated with 2×100 mL of toluene to a total volume of 20 mL (product and toluene), which was used in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([S:11][C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[C:14](O)=O)=[CH:7][CH:8]=2)[NH:3]1.C[N:22]([C:24]([O:28]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.C1COCC1>CN(C=O)C>[CH3:14][C:13]1[C:12]([S:11][C:6]2[CH:5]=[C:4]3[C:9]([CH2:10][C:2](=[O:1])[NH:3]3)=[CH:8][CH:7]=2)=[CH:20][CH:19]=[CH:18][C:17]=1[C:24]([NH2:22])=[O:28]
Reactant: O=C1Cc2ccc(Sc3ccccc3C(=O)O)cc2N1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1c(Sc2ccc3c(c2)NC(=O)C3)cccc1C(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 31 %

Procedure:
(2-Oxo-2,3-dihydro-1H-indol-6-ylsulfanyl)-benzoic acid (as prepared in Preparation 2; 0.228 g, 0.77 mmol) was dissolved in DMF (3 mL). The resulting solution was treated with HATU (0.434 g, 1.16 mmol) and 2M MeNH2 in THF (2.68 mL, 5.36 mmol) then allowed to stir for 3 hours at room temperature. The reaction mixture was then concentrated in vacuo and the crude was re-dissolved in EtOAc (15 mL) and washed with brine (3×15 mL). The combined organics were then dried over Na2SO4, filtered and concentrated in vacuo. The crude mixture was then purified via flash silica gel chromatography (5% MeOH in CHCl3) affording the title compound as a white solid in 31% yield (71 mg, 0.239 mmol).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][CH2:4][CH2:5][CH3:6].[CH3:8][N:9]([CH:11](OC)OC)[CH3:10]>CN(C=O)C>[CH3:8][N:9]([CH3:11])/[CH:10]=[CH:1]/[C:2](=[O:7])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: COC(OC)N(C)C
Reactant: CCCCC(C)=O
Solvent: CN(C)C=O
Product: CCCCC(=O)/C=C/N(C)C
Yield: 19.3 %

Procedure:
A solution of 2-hexanone (2.0 g, 20 mmol) and DMF-DMA (2.4 g, 20 mmol) in DMF (10 mL) was stirred at 100° C. overnight. The reaction mixture was cooled, concentrated, and purified by flash column chromatography (PE/EtOAc=4:1˜2:1) to give the title compound (0.6 g, 19%) as yellow oil.
Reaction SMILES: [Br-].[F:2][C:3]([F:31])([F:30])[C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[O:32]=[C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35](=[O:42])[N:34]1[CH2:43][CH2:44][CH2:45][C:46]1[CH:47]=[C:48]([CH:51]=[CH:52][CH:53]=1)[CH:49]=O>>[F:31][C:3]([F:2])([F:30])[C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1/[CH:6]=[CH:49]/[C:48]1[CH:47]=[C:46]([CH2:45][CH2:44][CH2:43][N:34]2[C:35](=[O:42])[C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:33]2=[O:32])[CH:53]=[CH:52][CH:51]=1.[F:31][C:3]([F:2])([F:30])[C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1/[CH:6]=[CH:49]\[C:48]1[CH:47]=[C:46]([CH2:45][CH2:44][CH2:43][N:34]2[C:35](=[O:42])[C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:33]2=[O:32])[CH:53]=[CH:52][CH:51]=1
Reactant: O=Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Reactant: FC(F)(F)c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(/C=C/c2ccccc2C(F)(F)F)c1
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(/C=C\c2ccccc2C(F)(F)F)c1
Temperature: 25 °C

Procedure:
2-Trifluoromethylbenzyltriphenylphosphonium bromide was coupled with phthalimide 29 following the method used in Example 44 except that the reaction was conducted at −78° C. instead of 0° C. before warming to room temperature. Purification by flash chromatography (10 to 40% EtOAc-hexanes gradient) gave (E)-2-(3-(3-(2-trifluoromethylstyryl)phenyl)propyl)isoindoline-1,3-dione (0.0797 g, trans-/cis-isomer ratio 15.6:1) as an oil and (Z)-2-(3-(3-(2-trifluoromethylstyryl)phenyl)propyl)isoindoline-1,3-dione (0.1139 g, trans-/cis-isomer ratio 8.1:1) as an oil. Yield (0.1936 g total, 83%): Trans-isomer: 1H NMR (400 MHz, CDCl3) δ 7.69-7.73 (m, 2H), 7.68 (d, J=7.6 Hz, 1H), 7.56-7.63 (m, 3H), 7.45 (t, J=7.6 Hz, 1H), 7.34 (dq, J=16.0, 2.0 Hz, 1H), 7.21-7.28 (m, 3H), 7.14-7.19 (m, 1H), 7.05 (d, J=7.6 Hz, 1H), 6.93 (d, J=16.4 Hz, 1H), 3.69 (t, J=7.2 Hz, 2H), 2.64 (t, J=7.2 Hz, 2H), 1.95-2.04 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:9]([O:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=[C:7]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:6]=1)=[O:4].[Br:36]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:9]([O:20][C:21](=[O:28])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:8]=[C:7]([CH:29]([Br:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(Cc2ccccc2)nc(OC(=O)c2ccccc2)c1OC(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1nc(C(Br)c2ccccc2)nc(OC(=O)c2ccccc2)c1OC(=O)c1ccccc1

Procedure:
A solution of methyl-5,6-bis(benzoyloxy)-2-benzylpyrimidine-4-carboxylate (B-6) (1.0 eq.) in carbon tetrachloride was heated up to 90° C. under nitrogen; N-bromosuccinimide (1.0 eq.) and benzoyl peroxide (0.1 eq.) were added as dry powder and mixture was refluxed for 3 h. After cooling, succinimide was removed by filtration and the filtrate was concentrated and purified by flash column chromatography (SiO2, 85/15 v/v petroleum ether/ ethyl acetate as eluent) to give the title product (B-7).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][C@H:18]([NH:22][C:23](=[O:36])[C:24]4[CH:29]=[CH:28][C:27]([O:30][CH:31]([CH3:33])[CH3:32])=[C:26]([C:34]#[N:35])[CH:25]=4)[CH2:19][CH2:20][OH:21])=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:37][C:38]1[C:42](B(O)O)=[C:41]([CH3:46])[O:40][N:39]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:34]([C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[O:30][CH:31]([CH3:32])[CH3:33])[C:23]([NH:22][C@@H:18]([CH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:3]3[C:2]([C:42]4[C:38]([CH3:37])=[N:39][O:40][C:41]=4[CH3:46])=[CH:7][CH:6]=[CH:5][N:4]3[CH:8]=2)=[CH:12][CH:13]=1)[CH2:19][CH2:20][OH:21])=[O:36])#[N:35]
Reactant: CC(C)Oc1ccc(C(=O)N[C@H](CCO)Cc2ccc(-c3cn4cccc(Br)c4n3)cc2)cc1C#N
Reactant: Cc1noc(C)c1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1-c1cccn2cc(-c3ccc(C[C@@H](CCO)NC(=O)c4ccc(OC(C)C)c(C#N)c4)cc3)nc12
Temperature: 100 °C
Reaction time: 22 h
Yield: 21.8 %

Procedure:
To a solution of N-((1S)-1-{[4-(8-bromoimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-3-cyano-4-[(1-methylethyl)oxy]benzamide (200 mg, 0.366 mmol) in dry DMF (2 mL) were added 3,5-dimethyl-isoxazole-4-boronic acid (63 mg, 0.439 mmol), tetrakistriphenylphosphine palladium(0) (21 mg, 0.018 mmol) and 2.0M aqueous K2CO3 (0.46 mL) successively at rt. The reaction mixture was purged with argon and heated to 100° C., stirred for 22 h, cooled to rt, filtered and purified directly by reverse phase HPLC (MeCN/H2O with 0.1% TFA). The clean fractions were adjusted to pH ˜8 with saturated aqueous NaHCO3 and extracted with 3% MeOH/EtOAc (3×30 mL). The extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to give 45 mg (22%) of the title compound as an off-white solid. LC/MS (ES) m/e 564.2 (M+H)+.
Reaction SMILES: C([Mg]Cl)(C)C.[Li+].[Cl-].[S:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[C:13]([C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])[CH2:18][CH2:17]1)(=[O:15])[CH3:14]>C1COCC1>[OH:15][C:13]([C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])[CH2:18][CH2:17]1)([C:9]1[S:8][CH:12]=[CH:11][N:10]=1)[CH3:14]
Reactant: CCCCOC(=O)[C@H]1CC[C@H](C(C)=O)CC1
Reactant: c1cscn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCOC(=O)[C@H]1CC[C@H](C(C)(O)c2nccs2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a cooled (0° C.) flask under nitrogen containing iPrMgCl—LiCl (1.3 M in THF, 55.2 mL, 71.8 mmol) was added thiazole (5.10 mL, 71.8 mmol) keeping the internal temperature <10° C. The resulting heterogenous mixture was warmed to RT where it was stirred for 10 min then re-cooled to −20° C. Then, a solution of butyl trans-4-acetylcyclohexanecarboxylate (12.5 g, 55.2 mmol) in THF (20+5 mL) was added via syringe. The cooling bath was then removed and the reaction mixture warmed slowly to 10° C. during which time it was observed to nearly completely homogenize. After 40 min, saturated aqueous NH4Cl followed by EtOAc were added and the layers separated, the organics dried over MgSO4, filtered and concentrated in vacuo. The crude residue was absorbed on silica and purified by flash chromatography to afford butyl trans-4-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]cyclohexanecarboxylate as a light yellow oil. The enantiomers were separated by chiral SFC (Chiral Technology AZ-H, 2.1×25 cm, 5 uM, 45/55 MeOH/CO2, Flow Rate: 80 mL/min, 6 min run time, WL: 220 nm) Elution was observed at 2.98 min and 4.14 min. Pooled fractions of each peak were separately concentrated under reduced pressure.
Reaction SMILES: Cl[C:2]1[CH:34]=[CH:33][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([CH3:25])[CH3:24])[C:10]=3[OH:32])[N:8]=[C:4]2[CH:3]=1.[CH2:35]([SH:39])[CH2:36][CH2:37][CH3:38].[OH-].[K+].CN1CCCC1=O.Cl>>[CH2:35]([S:39][C:2]1[CH:34]=[CH:33][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([CH3:25])[CH3:24])[C:10]=3[OH:32])[N:8]=[C:4]2[CH:3]=1)[CH2:36][CH2:37][CH3:38]
Reactant: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Reactant: CCCCS
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CCCCSc1ccc2nn(-c3cc(C(C)(C)CC(C)(C)C)cc(C(C)(C)c4ccccc4)c3O)nc2c1
Reaction time: 5 h
Yield: 83 %

Procedure:
5-Chloro-2-(2-hydroxy-3-α-cumyl-5-tert-octylphenyl)-2H-benzotriazole (38.1 g, 0.08 mol), n-butyl mercaptan (9 g, 0.10 mol), potassium hydroxide (10.1 g, 0.18 mol) and N-methylpyrrolidone (99 g, 1.0 mol) are charged to a reactor and heated to 170°0C. The reaction mass is held at 170° C. with vigorous stirring for five hours. The reaction is judged as complete using thin layer chromatography. The temperature is reduced to 5° C. and 100 mL of aqueous 2N hydrochloric acid are then added to the reactor. The liquid is decanted and the solids are dissolved in ethyl acetate. The organic layer is washed with aqueous 2N hydrochloric acid followed by water. The ethyl acetate is stripped off and the product is crystallized from ethanol and toluene. The title compound is obtained as a yellow crystalline product in 83% yield. The structure is verified by 1Hnmr.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].[C:17](Cl)(=[O:26])[C:18]1[C:19]([O:24][CH3:25])=[CH:20][CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2]
Reactant: CCOC(=O)CNc1ncccc1[N+](=O)[O-]
Reactant: COc1ccccc1C(=O)Cl
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNc1ncccc1NC(=O)c1ccccc1OC
Reaction time: 8 h
Yield: 30.4 %

Procedure:
A solution of N-(3-nitro-2-pyridinyl)glycine ethyl ester (64.4 g, 0.286 mole) in 900 ml of tetrahydrofuran was hydrogenated in a 2-liter Parr bottle over 5% palladium on carbon (6.5 g) at room temperature for 1 hour. The reaction mixture was dried oer magnesium sulfate and filtered through a Celite pad. A 235-ml portion of the filtrate was used in this reaction. Under nitrogen atmosphere, o-anisoyl chloride (9.72 g, 0.057 mole) and triethylamine (6.33 g, 0.063 mole) were added dropwise simultaneously to the above-stirred filtrate at room temperature. The reaction mixture was allowed to stir overnight. The reaction mixture was filtered, and the filtrate was treated with Florisil® (30 g), and evaporated to a solid. The solid was recrystallized from hot tetrahydrofuran (minimum). The solid was filtered off, washed with cold tetrahydrofuran, and dried under high vacuum at room temperature to give 5.7 g of title compound, mp 111°-12° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:11]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[CH3:22])[C:12]2=[O:23])[CH:7]=[CH:8][C:9]=1F)(=O)[CH3:2].CO.O.[NH2:27][NH2:28]>C(Cl)(Cl)Cl>[CH3:2][C:1]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([N:11]3[CH2:15][CH2:14][N:13]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][C:21]=4[CH3:22])[C:12]3=[O:23])[CH:5]=2)[NH:28][N:27]=1
Reactant: NN
Reactant: CC(=O)c1cc(N2CCN(c3cnccc3C)C2=O)ccc1F
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccncc1N1CCN(c2ccc3[nH]nc(C)c3c2)C1=O
Yield: 14 %

Procedure:
1-(3-Acetyl-4-fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (160 mg, 0.513 mmol) in hydrazine hydrate (5 mL) was taken in a reaction flask and the flask was heated to reflux and maintained for 21 hours. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was partitioned between ethylacetate and water. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated. Purification by column chromatography on silica gel (3% MeOH in CHCl3), followed by preparative HPLC afforded 22 mg of the product (14% yield).
Reaction SMILES: O1CCCC1.[OH-].[Na+].[NH2:8][C:9]1[C:14]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[CH:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35]Cl)=[N:33][CH:34]=1>CN(C)C=O>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:27][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:17]3[CH:16]=[C:15]([C:14]4[C:9]([NH2:8])=[N:10][CH:11]=[CH:12][CH:13]=4)[O:19][N:18]=3)=[CH:22][CH:23]=2)=[N:33][CH:34]=1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Reactant: ClCc1ccc(Cl)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3ccc(Cl)cn3)cc2)no1
Temperature: 60 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
Tetrahydrofuran (3 mL) and a 5 N aqueous sodium hydroxide solution (22.4 μL, 0.11 mmol) were added to 4-(5-(2-amino-pyridine-3-yl)-isoxazole-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 5-1-1, which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was then concentrated under a reduced pressure to obtain a white solid. An N,N-dimethylformamide (1 mL) solution of 5-chloro-2-chloromethyl-pyridine (20 mg, 0.12 mmol) described in Manufacturing Example 63-1-2 was added to a suspension of this solid and N,N-dimethylformamide (1 mL), and stirred for 1 hour at 60° C. This mixture was cooled to room temperature and partitioned into water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (41.1 mg, 93%).