Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([I:38])=[C:34]([CH:37]=1)[CH2:35]O>CN(C=O)C>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([I:38])=[C:34]([CH:37]=1)[CH2:35][N:15]=[N+:16]=[N-:17]
Reactant: OCc1cc(Cl)ccc1I
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cc(Cl)ccc1I
Temperature: 25 °C
Yield: 107.7 %

Procedure:
DPPA (0.442 mL, 2.05 mmol) followed by DBU (0.306 mL, 2.05 mmol) were added to a stirred solution of 5-chloro-2-iodobenzyl alcohol (500 mg, 1.86 mmol) in DMF (10 mL) at 0° C. and the reaction mixture was warmed to room temperature. After 16 h the mixture was warmed to 70° C. for 2 hr. The reaction was then concentrated and the residue was partitioned between EtOAc and 10% NaHCO3. The organic layer was washed with water and brine, dried (Na2SO4) and evaporated to give 5-chloro-2-iodobenzylazide (588 mg): 1H NMR (CDCl3, 400 MHz) δ 4.43 (s, 2H), 7.03 (dd, J=2.6, 8.4 Hz, 1H), 7.39 (d, J=2.6, 1H), 7.78 (d, J=8.4 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)[CH3:2].[CH2:15](OC(=O)C(OCC)=O)C.[H-].[Na+]>>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:5](=[CH2:15])[C:4]([O:3][CH2:1][CH3:2])=[O:14])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)Cc1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Product: C=C(C(=O)OCC)c1ccc(OC)cc1

Procedure:
A process for preparing a compound of formula (6): ##STR120## characterized in that a compound of formula (1): ##STR121## is reacted with oxalic acid diethyl ester and sodium hydride to produce a compound of formula (2): ##STR122## the resulting compound of formula (2) is reacted with 3-methoxybenzenethiol represented by the formula: ##STR123## to produce a compound of formula (3): ##STR124## the resulting compound of formula (3) is reacted with hydrochloric acid to produce a compound of formula (4): ##STR125## the compound of formula formula (4) is then cyclized to produce a compound of formula (5): ##STR126## and the compound of formula (5) is reacted with methyl iodide in the presence of lithium diisopropylamide to produce the compound of formula (6).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].Cl.[CH3:13]O>>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([O:8][CH3:13])=[O:7]
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(Cl)cc1N
Reaction time: 2.5 h

Procedure:
A solution of 10.0 g (58 mmol) of 4-chloroanthranilic acid in 100 ml of methanol was heated under reflux, while gaseous hydrogen chloride was blown through the heated solution for 2.5 hrs. After the heating was terminated, methanol was distilled off. The residue was shaken with chloroform and aqueous sodium carbonate. The organic phase was taken out and dried over anhydrous sodium sulfate. Chloroform was distilled off under reduced pressure to leave 9.68 g of the desired compound as a residual pale brown crystalline product.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OCCOC)=O)=N\C(OCCOC)=O.[CH2:36]([O:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[OH:47])[C:42]#[N:43])[CH3:37].[CH2:48]([NH:50][C:51]([C:53]1[CH:54]=[N:55][C:56]([N:59]2[CH2:64][CH2:63][CH2:62][C@H:61](O)[CH2:60]2)=[N:57][CH:58]=1)=[O:52])[CH3:49]>C1COCC1.CCOCC>[C:42]([C:41]1[CH:44]=[CH:45][C:46]([O:47][C@@H:61]2[CH2:62][CH2:63][CH2:64][N:59]([C:56]3[N:57]=[CH:58][C:53]([C:51]([NH:50][CH2:48][CH3:49])=[O:52])=[CH:54][N:55]=3)[CH2:60]2)=[C:39]([O:38][CH2:36][CH3:37])[CH:40]=1)#[N:43]
Reactant: CCOc1cc(C#N)ccc1O
Reactant: CCNC(=O)c1cnc(N2CCC[C@H](O)C2)nc1
Agent: COCCOC(=O)/N=N/C(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCNC(=O)c1cnc(N2CCC[C@@H](Oc3ccc(C#N)cc3OCC)C2)nc1
Temperature: 22.5 °C
Reaction time: 16 h

Procedure:
A solution of triphenylphosphine (65 mg, 0.25 mmol) in THF (1 mL) and a solution of bis(2-methoxyethyl) (E)-diazene-1,2-dicarboxylate (56 mg, 0.24 mmol) in THF (1 mL) were added sequentially to a solution of 3-ethoxy-4-hydroxybenzonitrile (26 mg, 0.16 mmol) and (S)—N-ethyl-2-(3-hydroxypiperidin-1-yl)pyrimidine-5-carboxamide (40 mg, 0.16 mmol) in THF (2 mL) at 20-25° C. The reaction mixture was stirred at 20-25° C. for 16 hours. The mixture was diluted with ether (30 mL), and was washed sequentially with aqueous 1N NaOH solution (1 mL) and brine (1 mL). The organic phase was dried over MgSO4, filtered, and concentrated to provide a crude residue, which was purified via preparative HPLC to afford (R)-2-(3-(4-cyano-2-ethoxyphenoxy)piperidin-1-yl)-N-ethylpyrimidine-5-carboxamide. HPLC: Waters XBridge dC18 4.6×50 mm, 5 μm, 95% water/5% acetonitrile linear to 5% water/95% acetonitrile over 4.0 min, 0.03% NH4OH modifier, 2 mL/min; retention time 2.60 min. MS (ES+) 396.1 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>ClCCl>[N:4]1([CH2:3][CH2:2][NH:1][S:11]([CH3:10])(=[O:13])=[O:12])[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: CS(=O)(=O)Cl
Reactant: NCCN1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCCN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(2-aminoethyl)morpholine (0.5 g) in dichloromethane (5 ml) at 0° C. was added methane sulphonyl chloride (0.33 ml) and triethylamine (0.59 ml) The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with dichloromethane, the combined organics washed with brine, dried (MgSO4) and the solvents removed in vacuo to give a crude residue which was purified by flash chromatography to yield N-(2-morpholin-4-yl-ethyl)-methanesulfonamide (596 mg).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([N:9]2[CH:14]=[CH:13][C:12](=[O:15])[NH:11][C:10]2=[O:16])[CH:6]=[CH:7][CH:8]=1.[Si:19]([O:36][CH2:37][C@H:38](O)[CH3:39])([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[Si:19]([O:36][CH2:37][C@H:38]([N:11]1[C:12](=[O:15])[CH:13]=[CH:14][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=2)[C:10]1=[O:16])[CH3:39])([C:32]([CH3:33])([CH3:34])[CH3:35])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=c1ccn(-c2cccc(C(F)(F)F)c2)c(=O)[nH]1
Reactant: C[C@@H](O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)n1c(=O)ccn(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Yield: 60.7 %

Procedure:
To a solution of 1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 98 or 99) (740.0 mg) in tetrahydrofuran (10.0 ml) was added (R)-1-(tert-butyldiphenylsilyloxy)propane-2-ol (1.82 g), triphenylphosphine (1.5 g) and diethyl azodicarboxylate (2.7 ml:2.2 M toluene solution) and the resulting mixture was stirred at room temperature for twelve hours. To the reaction mixture was added water (50 ml), and the resulting mixture was extracted with ethyl acetate (30 ml×2) and the organic layer was washed with water (20 ml) and saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford (R)-3-[1-(tert-butyldiphenylsilyloxy)propane-2-yl]-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (969.8 mg).
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:8])=[CH:5][C:6]=1[Br:7].CCCCCC.[Li]CCCC.[CH3:20][C:21]([CH3:23])=[O:22]>CCOCC>[Br:7][C:6]1[CH:5]=[C:4]([Br:8])[S:3][C:2]=1[C:21]([OH:22])([CH3:23])[CH3:20]
Reactant: CC(C)=O
Reactant: Brc1cc(Br)c(Br)s1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(O)c1sc(Br)cc1Br
Reaction time: 0.17 h

Procedure:
A solution of 2,3,5-tribromothiophene (8.17 g, 25 mmol) in Et2O (N2 atmosphere) was cooled to −78° C. and treated with a 1.6 M hexane solution of nBuLi (15.6 mL, 25 mmol). The mixture was then stirred for 10 minutes, then treated with acetone (1.84 mL, 25 mmol). The mixture was then stirred for 30 minutes and quenched with H2O. The mixture was extracted with Et2O; the organic layers were combined, dried (MgSO4), and the solvent removed in vacuo. The residue was filtered through a plug of silica gel (gradient elution from hexanes to EtOAc) to provide the title compound.
Reaction SMILES: B.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=O)[C:12]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)=O)=[CH:3]1>O1CCCC1.CCOCC>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][CH:17]2[CH2:16][CH2:15][N:14]([CH2:12][CH2:11][C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[NH:2][CH:3]=3)[CH2:19][CH2:18]2)=[CH:26][CH:25]=1
Reactant: O=C(C(=O)N1CCC(Oc2ccc(Cl)cc2)CC1)c1c[nH]c2ccccc12
Agent: B
Solvent: CCOCC
Solvent: C1CCOC1
Product: Clc1ccc(OC2CCN(CCc3c[nH]c4ccccc34)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
60 ml. of a 1M solution of boron trihydride in tetrahydrofuran are added dropwise to a stirred solution of 7.0 g of 1-(indol-3-ylglyoxyloyl)-4-(p-chlorophenoxy)piperidine in 135 ml. of tetrahydrofuran under nitrogen. The solution is stirred at ambient temperature for 18 hours and the tetrahydrofuran is removed under reduced pressure to give a white boron complex. The complex is destroyed by refluxing in 135 ml. of methanol with a few drops of glacial acetic acid. After cooling, the methanol is removed under reduced pressure to give a yellow oil. The oil is dissolved in ether, the ether is washed with water, dried and removed under reduced pressure to give a yellow oil. After standing under vacuum for a week, the oil crystallizes to a yellow solid. The solid is recrystallized from toluene and then from an ethanol and water mixture to give white crystals of 3-{2-[4-(p-chlorophenoxy)piperidyl]ethyl}indole, m.p. 132°-133° C.
Reaction SMILES: F[B-](F)(F)F.C([O+](CC)CC)C.[C:13]([O:17][C:18](=[O:25])[NH:19][C@H:20]([C:22](=O)[NH2:23])[CH3:21])([CH3:16])([CH3:15])[CH3:14].[F:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]2[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=2)[C:30](N)=[CH:31][CH:32]=1>C(Cl)Cl>[C:13]([O:17][C:18](=[O:25])[NH:19][C@H:20]([C:22]1[N:34]([C:35]2[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=2)[C:29]2[CH:28]=[C:27]([F:26])[CH:32]=[CH:31][C:30]=2[N:23]=1)[CH3:21])([CH3:16])([CH3:15])[CH3:14]
Reactant: Cn1cc(Nc2cc(F)ccc2N)cn1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1cnn(C)c1
Yield: 85.7 %

Procedure:
Triethyloxonium tetrafluoroborate (0.35 g, 1.86 mmol) was added to a solution of ((S)-1-carbamoylethyl)carbamic acid tert-butyl ester (0.41 g, 2.22 mmol) in DCM (10 mL) at 20° C. under nitrogen and the resultant mixture stirred for 3 h then was concentrated in vacuo. The residue was dissolved in ethanol (10 mL) and 4-fluoro-N2-(1-methyl-1H-pyrazol-4-yl)-benzene-1,2-diamine (0.183 g, 0.89 mmol) added. The resultant solution was stirred at reflux for 16 h under nitrogen. The reaction mixture was concentrated in vacuo and the residue partitioned between DCM (×3) and saturated aqueous NaHCO3. The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by chromatography (SiO2, 0-5% (2M ammonia in methanol) in DCM) to give the title compound as a brown oil (0.274 g, 86%). LCMS (Method C): RT 2.77 min [M+H]+ 360.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:9][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[O:13][CH2:12][CH2:11][O:10]1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(c2ccc(Br)cc2)OCCO1

Procedure:
In 1200 milliliters of toluene in a flask equipped with a Dean-Stark tube are dissolved 100 grams of p-bromoacetophenone; and to this solution is added 140 grams of ethylene glycol and 5 grams of p-toluenesulphonic acid. This mixture is refluxed until no further water collects in the Dean-Stark tube. After distilling off 600 milliliters of toluene, the remaining solution is decanted off and evaporated to dryness in vacuo to obtain 2-methyl-2-(p-bromophenyl)-1,3-dioxolane.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[C:18]([F:35])=[C:19](/[CH:23]=[C:24](/[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[F:34])\[C:25]#[N:26])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[C:18]=2[F:35])[C:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[F:34])([C:25]#[N:26])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 71.6 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.3 g, 11 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.5 g, 8 mmol) prepared in Example 52a, AgF (0.7 g, 5.5 mmol), and triethylamine (2.9 g, 29 mmol) in dichloromethane (200 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (3 g, 64%).
Reaction SMILES: [CH3:1][C:2]([S:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[O:8]1[CH2:11][C:10](=O)[CH2:9]1>C1COCC1>[CH3:1][C:2]([S:5]([N:7]=[C:10]1[CH2:11][O:8][CH2:9]1)=[O:6])([CH3:4])[CH3:3]
Reactant: CC(C)(C)S(N)=O
Reactant: O=C1COC1
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=C1COC1
Temperature: 60 °C
Reaction time: 18 h
Yield: 47 %

Procedure:
To a solution of 2-methyl-2-propanesulfinamide (1.47 g) and 3-oxetanone (0.85 mL) in THF (24 mL) was added Ti(OEt)4 (5.34 mL) dropwise over the course of 15 minutes at room temperature. After being stirred at 60° C. for 18 h, the reaction mixture was quenched by the rapid addition into ice cooled saturated sodium bicarbonate solution. The suspension was filtered through glass fiber filter paper, washing with ethyl acetate. The filtrate was washed with saturated sodium bicarbonate solution and brine. The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (10-100% ethyl acetate in hexanes) gave the product (0.992 g, 47%). 400 M Hz 1H-NMR (CDCl3) δ: 5.80 (ddd, J=15.6 Hz, 4.1 Hz and 2.3 Hz, 1H), 5.66 (ddd, J=15.6 Hz, 4.1 Hz and 2.3 Hz, 1H), 5.52-5.41 (m, 2H), 1.27 (s, 9H).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH:12]([CH2:13][CH:14]([CH:18]([CH3:20])[CH3:19])[CH2:15][CH2:16][OH:17])[O:11][C:10]([CH3:22])([CH3:21])[N:9]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:37](Cl)(=[O:40])[CH2:38][CH3:39]>C(Cl)Cl>[CH:1]1([CH2:7][C@H:8]2[C@H:12]([CH2:13][C@@H:14]([CH:18]([CH3:19])[CH3:20])[CH2:15][CH2:16][O:17][C:37](=[O:40])[CH2:38][CH3:39])[O:11][C:10]([CH3:21])([CH3:22])[N:9]2[C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)C(CCO)CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1CC1CCCCC1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)OCC[C@@H](C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1)C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 88 %

Procedure:
1.0 g (2.43 mmol) of t-butyl 4-(cyclohexylmethyl)-5-(4-hydroxy-2-isopropylbutyl)-2,2-dimethyl-3-oxazolidinecarboxylate in 50 ml of methylene chloride is treated with 0.38 ml (2.7 mmol) of triethylamine and 0.24 ml (2.7 mmol) of propionyl chloride and stirred at room temperature for 12 hours. After the usual working-up the crude product is purified by flash chromatography on silica gel with a 1:5 mixture of ether and petroleum ether, whereby there is obtained 1.0 g (88%) of t-butyl (4S,5S)-4-(cyclohexylmethyl)-5-[(S)-2-isopropyl-4-(propionyloxy)butyl]-2,2-dimethyl-3-oxazolidinecarboxylate as an oil, MS: 452 (M-CH3)+.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=2[O:2]1.C(=O)([O-])[O-].[Na+].[Na+].[C:19]([NH:27][C:28]1[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:29]=1[C:30]([O:32]C)=[O:31])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C(=O)C>[C:19]([NH:27][C:28]1[CH:37]=[C:36]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)[CH:35]=[CH:34][C:29]=1[C:30]([OH:32])=[O:31])(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cc(-c2ccc3c(c2)OCO3)ccc1C(=O)O)c1ccccc1
Temperature: 90 °C
Reaction time: 22 h
Yield: 56.8 %

Procedure:
52 mg of 3,4-methylenedioxyphenylboronic acid, 55 mg of sodium carbonate and 30 mg of polymer supported bis(acetato)triphenylphosphine palladium(II) were added to 2.5 mL of N,N-dimethylacetamide solution containing 70 mg of methyl 2-(benzamido)-4-bromobenzoate, and stirred at 90° C. for 22 hours. After the reaction mixture was cooled to room temperature, insoluble were removed by filtration and ethyl acetate and 1.2 mol/L hydrochloric acid were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 1.0 mol/L hydrochloric acid and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. 1.0 mL of 1.0 mol/L aqueous sodium hydroxide and 2.0 mL of ethanol were added to the obtained residue and stirred at room temperature for 1 hour. 0.6 mol/L hydrochloric acid was added to the reaction mixture and a solid substance was separated by filtration to obtain 43 mg of 2-(benzamido)-4-(benzo[1,3]dioxol-5-yl)benzoic acid as white solid.
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][O:10][C:11]([NH:13][C@H:14]([C:18]([OH:20])=O)[CH:15]([CH3:17])[CH3:16])=[O:12])[N:8]=1)([CH3:3])[CH3:2].[NH2:21][C@H:22]([C@@H:30]([OH:49])[CH2:31][C@H:32]([NH:39][C:40]([O:42][CH2:43][C:44]1[S:48][CH:47]=[N:46][CH:45]=1)=[O:41])[CH2:33][C:34]1[S:38][CH:37]=[N:36][CH:35]=1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CO>C(Cl)(Cl)Cl>[CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][O:10][C:11]([NH:13][C@H:14]([C:18]([NH:21][C@H:22]([C@@H:30]([OH:49])[CH2:31][C@H:32]([NH:39][C:40]([O:42][CH2:43][C:44]2[S:48][CH:47]=[N:46][CH:45]=2)=[O:41])[CH2:33][C:34]2[S:38][CH:37]=[N:36][CH:35]=2)[CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:20])[CH:15]([CH3:16])[CH3:17])=[O:12])[N:8]=1)([CH3:2])[CH3:3]
Reactant: N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1cncs1)NC(=O)OCc1cncs1
Reactant: CC(C)c1nc(COC(=O)N[C@H](C(=O)O)C(C)C)cs1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)c1nc(COC(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](Cc2cncs2)NC(=O)OCc2cncs2)C(C)C)cs1

Procedure:
Using the procedure of Example 1U but replacing N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine with N-((2-isopropyl-4-thiazolyl)methoxycarbonyl)valine and replacing (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane with (2S,3S,5S)-2-amino-1-phenyl-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-6-(5-thiazolyl)-3-hydroxyhexane provided, after silica gel chromatography using 1% methanol in chloroform, 54 mg (66%) of the desired compound (Rf 0.6, 10% methanol in CH2Cl2). 1H NMR (DMSO-d6) δ0.69 (d, 3H), 0.74 (d, 3H), 1.31 (d, 6H), 1.47 (m, 2H), 1.85 (m, 1H), 2.75 (m, 4H), 2.95 (m, 1H), 3.57 (m, 1H), 3.80 (m, 2H), 4.08 (m, 1H), 4.95 (d, 1H), 5.03 (s, 2H), 5.19 (s, 2H), 7.12-7.29 (m), 7.45 (s, 1H), 7.47 (s, 1H). Mass spectrum: (M+H)+ =715.
Reaction SMILES: Cl[C:2]1[N:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5].[CH3:14][O:15][C:16]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:17]=1[NH2:18]>C(O)CO>[CH3:14][O:15][C:16]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:17]=1[NH:18][C:2]1[N:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5]
Reactant: C#CCNC(=O)c1cccnc1Cl
Reactant: COc1ccc(N)c(OC)c1
Solvent: OCCO
Product: C#CCNC(=O)c1cccnc1Nc1ccc(OC)cc1OC
Temperature: 140 °C

Procedure:
Compound 8 (194 mg, 1 mmol) and 2,4-dimethoxyaniline (9e, 153 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(2,4-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide 10g as pure product. To a solution of 2-(2,4-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide (10 g, 150 mg, 0.48 mmol) and 1-(azidomethyl)-4-methoxybenzene (12c, 86 mg, 0.53 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 10 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 5g (180 mg, 79%); mp: 178-180° C.; 1H NMR (500 MHz, CDCl3) δ 10.30 (s, 1H), 8.23 (m, 2H), 7.74 (dd, J=6.0, 2.0 Hz, 2H), 7.51 (s, 1H), 7.34 (brs, 1H), 7.20 (d, J=9.0 Hz, 2H), 6.86 (d, J=9.0 Hz, 2H), 6.56-6.48 (m, 3H), 5.45 (s, 2H), 4.64 (d, J=6.0 Hz, 2H), 3.87 (s, 3H), 3.79 (s, 3H), 3.79 (s, 3H); MS (ESI m/z): 475 [M+H]+. Yield: 79%
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH3:8])[C:4]([OH:6])=O)[CH3:2].N=C=N.C1C=CC2N(O)N=NC=2C=1.[CH3:22][O:23][C:24](=[O:46])[CH:25]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][C:39]=2[F:45])[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-]>C(Cl)Cl>[CH3:22][O:23][C:24](=[O:46])[CH:25]([N:32]1[CH2:33][CH2:34][N:35]([C:38]2[CH:43]=[CH:42][C:41]([NH:44][C:4](=[O:6])[CH:3]([CH2:1][CH3:2])[CH2:7][CH3:8])=[CH:40][C:39]=2[F:45])[CH2:36][CH2:37]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCC(CC)C(=O)O
Reactant: COC(=O)C(c1ccccc1)N1CCN(c2ccc(N)cc2F)CC1
Agent: N=C=N
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCC(CC)C(=O)Nc1ccc(N2CCN(C(C(=O)OC)c3ccccc3)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.9 %

Procedure:
A mixture of 2-ethylbutyric acid (32 μL, 0.22 mmol), polymer-supported carbodiimide (240 mg, 0.29 mmol), and HOBt (33 mg, 0.25 mmol) in DCM (5 mL) was stirred at rt for 15 min. A solution of [4-(4-amino-2-fluoro-phenyl)-piperazin-1-yl]-phenyl-acetic acid methyl ester (50 mg, 0.15 mmol) in DCM (1 mL) was added and the mixture was stirred for 16 h. Polymer-bound tetraalkylammonium carbonate (PB-carbonate; 250 mg, 0.77 mmol) was added and the mixture was stirred for 2 h. The resins were removed by filtration and the filtrate was concentrated to give an oil, which was purified by PTLC to give a peach solid (37 mg, 57%). MS (ESI): mass calcd. for C25H32FN3O3, 441.54; m/z found, 442.5 [M+H]+. 1H NMR (CDCl3): 7.46-7.44 (m, 3H), 7.36-7.33 (m, 3H), 7.19-7.12 (m, 1H), 7.00 (br s, 1H), 6.87 (t, J=9.0, 1H), 4.06 (s, 1H), 3.70 (s, 3H), 3.09-3.08 (m, 4H), 2.64-2.62 (m, 4H), 2.02-1.95 (m, 1H), 1.70-1.67 (m, 2H), 1.56-1.53 (m, 2H), 0.94 (t, J=7.4, 6H).