Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12]CC3C=CC=CC=3C(F)(F)F)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[CH3:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([CH2:32]Cl)=[C:27]([CH3:34])[CH:26]=1>>[C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][CH2:32][C:28]3[C:29]([CH3:31])=[CH:30][C:25]([CH3:24])=[CH:26][C:27]=3[CH3:34])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2]
Reactant: N#Cc1nc2ccc(OCc3ccccc3C(F)(F)F)cc2s1
Reactant: Cc1cc(C)c(CCl)c(C)c1
Product: Cc1cc(C)c(COc2ccc3nc(C#N)sc3c2)c(C)c1

Procedure:
This compound was synthesized in a similar way to 2-cyano-6-(2-trifluoromethylbenzyloxy)benzothiazole with α2-chloroisodurene (100 mg, 0.852 mmol). 168 mg product was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.Cl[C:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:12]>N1C=CC=CC=1>[C:11](=[O:12])([O:13][C:14]1[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=1)[O:8][CH2:7][C@@H:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC1(C)OC[C@H](CO)O1
Solvent: c1ccncc1
Product: CC1(C)OC[C@@H](COC(=O)Oc2ccc([N+](=O)[O-])cc2)O1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(4S)-2,2-Dimethyl-1,3-dioxolan-4-ylmethanol (362 mg, 2.74 mM) was dissolved in pyridine (9 ml), stirred at ambient temperature, and treated in portions with 4-nitrophenyl chloroformate (552 mg, 2.74 mM). After 6 hours, solvent was evaporated, the residue redissolved in ethyl acetate (15 ml), washed with water (15 ml), sodium bicarbonate solution (15 ml), brine (15 ml), and dried (magnesium sulfate). Removal of the solvent gave the product as an oil sufficiently pure for further use (858 mg).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].[Cl:14][C:15]1[C:20]([C:21]2([F:25])[CH2:24][CH2:23][CH2:22]2)=[CH:19][CH:18]=[C:17]([CH3:26])[N+:16]=1[O-].[OH-].[Na+]>ClCCl>[Cl:14][C:15]1[N:16]=[C:17]([CH2:26][OH:4])[CH:18]=[CH:19][C:20]=1[C:21]1([F:25])[CH2:24][CH2:23][CH2:22]1
Reactant: Cc1ccc(C2(F)CCC2)c(Cl)[n+]1[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: OCc1ccc(C2(F)CCC2)c(Cl)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.1 %

Procedure:
Trifluoroacetic anhydride (1.27 g, 840 μL, 6.04 mmol) was added under ice cooling to a solution of 2-chloro-3-(1-fluorocyclobutyl)-6-methylpyridine 1-oxide (Example 130 c, 869 mg, 4.03 mmol) in dichloromethane (10.9 mL). The mixture was stirred at ambient temperature for 72 h. Upon ice bath cooling 5 N NaOH solution (1 mL) and afterwards ice water (20 mL) were added. The mixture was extracted with dichloromethane (2×40 mL). The combined organic layers were washed with icewater/brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 50 g, heptane/EtOAc 0-40% in 120 min.) to give the title compound (279 mg, 32%) as light yellow oil, MS (ESI): m/e=216.3 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:11]([C:12]([OH:14])=O)[C:10]=2[C:18]([OH:20])=O)=[CH:5][CH:4]=1.Cl.[NH2:24][CH:25]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:26]1=[O:27]>N1C=CC=CC=1>[O:27]=[C:26]1[CH:25]([N:24]2[C:18](=[O:20])[C:10]3[C:11](=[CH:15][CH:16]=[CH:17][C:9]=3[O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:22][CH:21]=3)[C:12]2=[O:14])[CH2:31][CH2:30][C:29](=[O:32])[NH:28]1
Reactant: NC1CCC(=O)NC1=O
Reactant: COc1ccc(COc2cccc(C(=O)O)c2C(=O)O)cc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(COc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1
Yield: 40.5 %

Procedure:
A stirred mixture of 3-(4-methoxy-benzyloxy)-phthalic acid (1.5 g, 5.2 mmol), alpha-amino-glutarimide hydrochloride (0.90 g, 5.4 mmol) in pyridine was refluxed overnight. The mixture was evaporated in vacuo, and the residue was purified by flash column chromatography (Silica Gel, methanol/methylene chloride, 0% gradient to 10% 30 min) to give 2-(2,6-dioxo-piperidin-3-yl)-4-(4-methoxy-benzyloxy)-isoindole-1,3-dione as a white solid (0.83 g, 40% yield); HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 50/50 CH3CN/0.1% H3PO4, RT=4.17 min (98.6%); mp, 178-180° C.; 1HNMR (DMSO-d6) δ1.99-2.06 (m, 1H, CHH), 2.51-2.82 (m, 2H, CHHCH2), 3.76 (s, 3H, CH3), 5.08 (dd, J=6, 12 Hz, 1H, CH), 5.29 (s, 2H, CH2), 6.95-7.84 (m, 7H, Ar), 11.11 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.96, 30.91, 48.72, 55.08, 69.92, 113.88, 115.41, 116.55, 120.29, 127.93, 129.21, 133.25, 136.92, 155.57, 159.10, 165.28, 166.77, 169.90, 172.75. Anal Calcd For C21H18N2O6: C, 63.96; H, 4.60; N, 7.10. Found: C, 63.86; H, 4.30; N, 6.92.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([O:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([O:14][C:15](=[O:20])[C:16]([F:19])([F:17])[F:18])[CH2:11]2)=[CH:6][CH:5]=1
Reactant: O=C(ON1CCc2ccc([N+](=O)[O-])cc2C1)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)CN(OC(=O)C(F)(F)F)CC2
Reaction time: 2 h

Procedure:
A solution of 7-nitro-2-trifluoroacetoxy-1,2,3,4-tetrahydroisoquinoline (Stokker, Tetrahedron Letts., 1996, 37, 5453; 3.64 g, 13.3 mmol) in 100 mL EtOH at room temperature was was purged with argon and 10% palladium on carbon (300 mg) added. The mixture was then stirred under an atmosphere of hydrogen gas for 2 h. then filtered and the solvent removed in vacuo to yield a white solid which was sufficiently pure for use in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:24][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=2)=[CH:19][C:18]=1[O:32][CH3:33]>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[O:24][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=3)=[CH:19][C:18]=2[O:32][CH3:33])=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: COC(=O)c1coc(-c2ccc(N)c(OC)c2)n1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)OC)co3)cc2OC)nc1Cl
Yield: 85.6 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.13 g, 0.75 mmol), thionyl chloride (2 mL), methyl 2-(4-amino-3-methoxyphenyl)-1,3-oxazole-4-carboxylate obtained in Example (102d) (0.25 g, 1.01 mmol) and pyridine (5 mL), to obtain 0.26 g of the title compound as a colorless solid (86%).
Reaction SMILES: COC1C=CC([O:7][C:8]2[CH:9]=[C:10]([C:14]3[N:19]4[N:20]=[C:21]([NH:23][C:24]5[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]6[CH2:37][CH2:36][CH2:35][CH2:34]6)=[CH:26][CH:25]=5)[N:22]=[C:18]4[CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:12][CH:13]=2)=CC=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[N:33]1([CH2:32][CH2:31][O:30][C:27]2[CH:28]=[CH:29][C:24]([NH:23][C:21]3[N:22]=[C:18]4[CH:17]=[CH:16][CH:15]=[C:14]([C:10]5[CH:9]=[C:8]([OH:7])[CH:13]=[CH:12][CH:11]=5)[N:19]4[N:20]=3)=[CH:25][CH:26]=2)[CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: COc1ccc(Oc2cccc(-c3cccc4nc(Nc5ccc(OCCN6CCCC6)cc5)nn34)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Oc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Reaction time: 2 h

Procedure:
{5-[3-(4-Methoxy-phenoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (2.90 g, 5.41 mmol) was dissolved in dichloromethane (10 ml). Trifluoroacetic acid (10 ml) was added and the reaction mixture stirred for 2 hours. Neutralisation was performed by adding saturated aqueous sodium hydrogencarbonate. The aqueous was extracted twice with dichloromethane, then the combined organics were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the desired compound. Yield 2.01 g, 89%. 50 mg was purified by preparatory HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH:14]=[O:15].[Br:16]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:16][C:12]1[CH:11]=[C:10]([CH:14]=[O:15])[N:9]([C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:13]=1
Reactant: O=Cc1cccn1-c1c(Cl)cccc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)cn1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
In 10 ml of N,N-dimethylformamide was dissolved 0.65 g of 1-(2,6-dichlorophenyl)-1H-pyrrole-2-carbaldehyde, and then 0.53 g of N-bromosuccinimide was added thereto. The mixture was stirred at room temperature for 1 hour. Water was poured into the reaction mixture, a deposited precipitate was collected by filtration to obtain 0.85 g of 4-bromo-1-(2,6-dichlorophenyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: [C:1]([C:3](=[CH:12]OCC)[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2].[F:16][C:17]([F:26])([F:25])[C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>C(O)C>[C:1]([C:3](=[CH:12][NH:22][C:21]1[CH:23]=[CH:24][C:18]([C:17]([F:25])([F:26])[F:16])=[CH:19][CH:20]=1)[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCOC=C(C#N)C(=O)NC(=O)OCC
Solvent: CCO
Product: CCOC(=O)NC(=O)C(C#N)=CNc1ccc(C(F)(F)F)cc1
Yield: 90.8 %

Procedure:
A mixture of α-cyano-β-ethoxy-N-ethoxycarbonylacrylamide (10 g) and 45 ml of ethanol is heated to effect dissolution. Then 8.12 g of p-trifluoromethylaniline in 10 ml of ethanol is added and the mixture heated at reflux for 45 minutes. The mixture is cooled and filtered to give 14.01 g of α-cyano-β-(4-trifluoromethylanilino)-N-ethoxycarbonylacrylamide, which is added to about 60 ml of tetralin and heated at reflux for several hours. On formation of precipitate, the mixture is allowed to cool and then filtered, washed with ether, to yield 5-cyano-1-(4-trifluoromethylphenyl)uracil, m.p. 230.5°-231.5°.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:12]([F:15])([F:14])[F:13])[CH2:10][OH:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[I-].[Na+].[O:18]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(COC)OC>[C:3]1([CH:9]([C:12]([F:13])([F:14])[F:15])[CH2:10][O:11][CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:26]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: OCC(c1ccccc1)C(F)(F)F
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: FC(F)(F)C(COCc1cccc(Oc2ccccc2)c1)c1ccccc1
Temperature: 0 °C
Yield: 58.3 %

Procedure:
Sodium hydride (138 mg; 5.75 mmol) was suspended in dimethoxyethane (20 ml). There was then added in turn, with stirring, 2-phenyl-2-trifluoromethylethanol (1.0 g; 5.25 mmol), a spatula full of sodium iodide and 3-phenoxybenzyl bromide (1.39 g; 5.25 mmol). After stirring for 4 hours at room temperature, the mixture was added to ice-water, extracted with ether, the extract washed with water, dried over sodium sulphate and concentrated. After chromatogrpahy on silica gel using a mixture of hexane and toluene, there was obtained 1.14 g of product (=58.3% of theory).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:17])[CH2:11][C:10]2[C:5](=[C:6]([CH3:15])[C:7]([CH:13]=[CH2:14])=[C:8]([CH3:12])[CH:9]=2)[CH:4]1[OH:16].N1C=CN=C1.[Si:23](Cl)([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:24][CH3:25]>C(Cl)Cl.O>[CH3:17][C:3]1([CH2:2][O:1][Si:23]([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:24][CH3:25])[CH2:11][C:10]2[C:5](=[C:6]([CH3:15])[C:7]([CH:13]=[CH2:14])=[C:8]([CH3:12])[CH:9]=2)[CH:4]1[OH:16]
Reactant: C=Cc1c(C)cc2c(c1C)C(O)C(C)(CO)C2
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: C=Cc1c(C)cc2c(c1C)C(O)C(C)(CO[Si](CC)(CC)CC)C2
Reaction time: 6 h
Yield: 67 %

Procedure:
To the stirred solution of starting material 7 (0.85 g, 3.66 mmol) in dry CH2Cl2 added Imidazole (0.5 g, 7.32 mmol) and TESCl (0.6 mL, 3.66 mmol) sequentially at 0° C. under argon atmosphere and stirred the reaction mixture at same temperature for 6 h. Then reaction mixture was diluted with H2O (10 mL) followed by extraction with CH2Cl2 (50 mL), brine (25 mL), dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography (SiO2, 5 to 10% EtOAc in petroleum ether eluant) gave pure compound 8 (0.85 g, 88%) as syrup.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]([CH2:8][NH:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][CH3:13])[CH2:6][CH3:7].[Cl:18][CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23]>>[Cl:18][CH2:19][CH2:20][CH2:21][C:22]([N:9]([CH2:8][CH:5]([CH2:6][CH3:7])[CH2:4][CH2:3][CH2:2][CH3:1])[CH2:10][CH:11]([CH2:12][CH3:13])[CH2:14][CH2:15][CH2:16][CH3:17])=[O:23]
Reactant: CCCCC(CC)CNCC(CC)CCCC
Reactant: O=C(Cl)CCCCl
Product: CCCCC(CC)CN(CC(CC)CCCC)C(=O)CCCCl

Procedure:
Step A is conducted starting from 2,2′-diethylhexylamine and 4-chlorobutanoyl chloride and leads to 4-chloro-N,N-bis(2-ethylhexyl)butanamide (Yield: quantitative) for which the 1H and 13C NMR characterisations give:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[C:17]([OH:21])([CH3:20])([CH3:19])[CH3:18].C(OC(C)C)(C)C>[Zn]>[C:17]([O:21][C:3](=[O:2])[CH2:4][NH:5][C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)O
Reactant: COC(=O)CNC(=O)OCc1ccccc1
Agent: [Zn]
Solvent: CC(C)OC(C)C
Product: CC(C)(C)OC(=O)CNC(=O)OCc1ccccc1
Yield: 83.8 %

Procedure:
Under a nitrogen atmosphere, a mixture of carbobenzyloxyglycine methyl ester (3.0 mmol), t-butanol (3.6 mmol), a zinc cluster Zn4O (OCOCF3)6 (0.0375 mmol), and diisopropyl ether (5.0 ml) was refluxed for 18 hours. As a result, carbobenzyloxyglycine t-butyl ester was obtained in a yield of 83.8%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:9]=2[C:10]=1[NH2:11])=[O:5])[CH3:2].Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].C([O-])([O-])=O.[K+].[K+]>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:9]=2[C:10]=1[NH:11][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2ccc(Cl)cc2c1N
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)Nc1c(C(=O)OCC)oc2ccc(Cl)cc12
Yield: 100 %

Procedure:
To a solution of 3-amino-5-chloro-benzofuran-2-carboxylic acid ethyl ester (2.8 g, 11.7 mmol) in benzene (35 mL) was added ethyl chloroformate (1.3 mL, 14.0 mmol) followed by K2CO3 (4.5 g, 35.1 mmol). After heating at reflux for 14 h, the mixture was filtered, washing with benzene. The filtrate was concentrated to afford the desired product (100%), which was used in the next step without further purification. 1H NMR (CDCl3): 8.69 (s, 1H), 8.45 (s, 1H), 7.47-7.39 (m, 2H), 4.48 (q, J=7.1 Hz, 2H), 4.30 (q, J=7.1 Hz, 2H), 1.55 (t, J=7.1 Hz, 3H), 1.35 (t, J=7.1 Hz, 3H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]3[C@@H:22]([CH2:23][CH2:24][C@H:25]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:21](=[O:41])[N:20]3[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)(=O)=O.[P:50]([O-:55])([O:53][CH3:54])[O:51][CH3:52].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Si:34]([O:33][C@H:25]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[CH2:24][CH2:23][C@H:22]1[C:21](=[O:41])[N:20]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@@H:19]1[C:16]1[CH:15]=[CH:14][C:13]([C:9]2[CH:8]=[CH:7][CH:12]=[C:11]([P:50](=[O:55])([O:53][CH3:54])[O:51][CH3:52])[CH:10]=2)=[CH:18][CH:17]=1)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]
Reactant: COP([O-])OC
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CC[C@H]1C(=O)N(c2ccccc2)[C@@H]1c1ccc(-c2cccc(OS(=O)(=O)C(F)(F)F)c2)cc1)c1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COP(=O)(OC)c1cccc(-c2ccc([C@@H]3[C@@H](CC[C@H](O[Si](C)(C)C(C)(C)C)c4ccc(F)cc4)C(=O)N3c3ccccc3)cc2)c1
Temperature: 160 °C

Procedure:
This reaction was performed using a PersonalChemistry™ microwave instrument set at normal absorbance, fixed hold time and 30 sec pre-stirring. A 10-mL reaction vial was charged with 4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl trifluoromethanesulfonate (0.27 g, 0.38 mmol), dimethyl phosphite (0.070 mL, 0.76 mmol) and triethylamine (0.15 mL, 1.08 mmol) in toluene (4 mL). Nitrogen was bubbled through the stirred solution for 5 min, tetrakis(triphenylphosphine)palladium(0) (0.1 g) was added, and the solution was covered with a blanket of nitrogen and sealed. The reaction mixture was heated for 11 min at 160° C., then cooled to room temperature and diluted with ethyl acetate. The yellow solution was washed successively with 0.5 M hydrochloric acid (20 mL) water (3×) and brine. The organic solution was dried over sodium sulfate, filtered and the solvent was removed by rotary evaporation under reduced pressure. Pure dimethyl (4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)phosphonate was obtained as a white foam (0.26 g, 65%) by chromatography over silica gel using ethyl acetate-hexane (gradient: 5% ethyl acetate to 100%). 1H NMR (300 MHz, CDCl3) δ 8.00 (dt, J=14.2, 1.5 Hz, 1H), 7.60 (d, J=8.5 Hz, 2H), 7.40(d, J=8.5 Hz, 2H), 6.9-7.8 (m, 12H), 4.68 (t, J=5.7 Hz, 1H), 4.64 (d, J=2.4 Hz, 1H), 3.81 (d, J=0.9 Hz, 1H), 3.77 (d, J=0.9 Hz, 1H), 3.0-3.1 (m, 1H), 1.8-2.2 (m, 4H), 0.88 (s, 9H), 0.02 (s, 3H), −0.16 (s, 3H) ppm
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6]1)=[O:4].N1C=CC=CC=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([S:28]([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13][CH:5]2[C:3]([O:2][CH3:1])=[O:4])(=[O:30])=[O:29])=[CH:26][CH:27]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C1Cc2ccccc2N1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C1Cc2ccccc2N1S(=O)(=O)c1ccc(OC)cc1
Reaction time: 8 h

Procedure:
Indoline-2-carboxylic acid methyl ester (32.7 g, 151.8 mmol) was dissolved in DCM (400 ml), and pyridine (37.4 ml, 459.0 mmol) was added thereto. A solution of 4-methoxybenzenesulfonyl chloride (31.6 g, 153 mmol) dissolved in DCM (100 ml) was then added, and stirring was carried out overnight at room temperature. The mixture was diluted with DCM and washed in succession with 0.5 M KHSO4, saturated NaHCO3 solution and saturated NaCl solution. The organic phase was dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (heptane/ethyl acetate 2:1).
Reaction SMILES: [C:1]1([O:7][P:8]([O-:16])[O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([O:21][C:22](=[O:25])[CH2:23]Br)([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>ClCCl>[O:9]([P:8]([CH2:23][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:25])([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: [O-]P(Oc1ccccc1)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CP(=O)(Oc1ccccc1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of diphenylphosphite (2.25 mL) in dichloromethane at 0° C. was added t-butylbromoacetate (1.48 mL) followed by triethylamine (1.95 mL). The mixture was stirred at 0° C. for 15 min and then at rt for 1 h before being quenched with water and extracted into ethyl acetate, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate to give the title compound. 1H NMR (500 MHz, CDCl3): δ 7.40-7.18 (m, 10H); 3.22 (s, 1H); 3.18 (s, 1H); 1.50 (s, 9H).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[CH:8]1([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.O>CN(C)C(=O)C>[CH:8]1([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]4=[N:27][S:4](=[O:6])(=[O:5])[CH2:3][CH2:2][N:23]4[CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncccc1-c1ccc(OC2CCCCC2)cc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(OC4CCCCC4)cc3)C2=N1
Temperature: 60 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
A solution of 2-chloroethanesulfonyl chloride (381 mg) in N,N-dimethylacetoamide (2 mL) was added dropwise to a suspension of 3-[4-(cyclohexyloxy)phenyl]pyridin-2-amine (301 mg) in N,N-dimethylacetoamide (2 ml) and additional N,N-dimethylacetoamide (1 mL) was used to complete the addition of above solution. After being stirred at 60° C. for 3 hr, the mixture was cooled to room temperature. Water (10 mL) was added dropwise to the reaction mixture and the whole was stirred at room temperature for 0.5 hr. The precipitate was collected by filtration, washed with water (10 mL) and diisopropyl ether (3 ml), and dried in vacuo at 60° C. to give the title compound (342 mg) as an off-white powder.
Reaction SMILES: [CH:1]([Si:4]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1)([CH3:3])[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1.O.[CH2:32](O)[CH2:33][OH:34]>C1C=CC=CC=1>[O:11]1[CH2:32][CH2:33][O:34][CH:10]1[C:9]1[CH:12]=[CH:13][C:6]([O:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:14]([CH3:16])[CH3:15])[CH:17]([CH3:19])[CH3:18])=[CH:7][CH:8]=1
Reactant: OCCO
Reactant: CC(C)[Si](Oc1ccc(C=O)cc1)(C(C)C)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)[Si](Oc1ccc(C2OCCO2)cc1)(C(C)C)C(C)C

Procedure:
Heat at reflux a mixture of the aldehyde (2.1033 g, 7.55 mmol), p-TsOH.H2O (14.4 mg, 0.076 mmol), and ethylene glycol (4.2 mL, 75.5 mmol) in benzene (75 mL) overnight, while removing azeotropically the H2O formed. Cool and wash with 10% K2CO3 (2×50 mL) and brine which contains 10% K2CO3 (50 mL). Back-extract the aqueous layers with benzene and Et2O (100 mL each). Concentrate the combined organic layers after drying over Na2SO4 to afford (4-[1,3]dioxolan-2-yl-phenoxy)triisopropylsilane.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[N:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cn2)CC1
Temperature: 150 °C
Yield: 81.9 %

Procedure:
29.2 g (157 mmol) of 1,1-dimethylethyl 1-piperazine-carboxylate, 37 g (157 mmol) of 2,5-dibromopyridine and 21.7 g (157 mmol) of potassium carbonate suspended in 27 ml of dimethyl sulfoxide (DMSO) are introduced into an autoclave. The mixture is then heated at 150° C. for 21 hours. The reaction mixture is allowed to cool to room temperature, it is taken up in ethyl acetate and water and the insoluble material is then separated out by filtration. The aqueous phase is separated out and extracted twice with ethyl acetate, the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate is concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel, eluting with a 99/1 mixture of dichloromethane and methanol. 44 g of product are thus obtained in the form of a white solid.