Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[CH2:28](Br)[CH:29]=[CH2:30]>CN(C=O)C>[CH2:30]([O:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH:29]=[CH2:28]
Reactant: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 2-hydroxy-4-(1-tertbutyloxycarbonyl-4-piperidinyloxy)benzoate from Step XX of Example XX (2.50 g, 7.11 mmol) in DMF (50 mL) under N2 was added NaH (427 mg, 10.7 mmol). The reaction mixture was cooled, and allyl bromide (1.23 mL, 14.2 mmol) was added via syringe. The reaction mixture was allowed to warm to ambient temperature and stirred for 2 hours. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and aqueous NaHCO3. The ethyl acetate layer was dried (MgSO4), filtered, and evaporated under reduced pressure. The residue was purified using pressurized silica gel column chromatography using a gradient elution of 10-15% ethyl acetate in hexanes. Methyl 2-allyloxy-4-(1-tertbutyloxycarbonyl-4-piperidinyloxy)benzoate was obtained as a thick colorless oil.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([O:14][C:15](=[O:37])[CH2:16][C:17]1([CH2:20][CH2:21][CH:22]([CH2:35][OH:36])[CH2:23][CH2:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=2)[CH2:19][CH2:18]1)[CH3:13]>ClCCl>[CH2:12]([O:14][C:15](=[O:37])[CH2:16][C:17]1([CH2:20][CH2:21][CH:22]([CH:35]=[O:36])[CH2:23][CH2:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=2)[CH2:19][CH2:18]1)[CH3:13]
Reactant: CCOC(=O)CC1(CCC(CO)CCc2ccc(C(=O)OC)cc2)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)CC1(CCC(C=O)CCc2ccc(C(=O)OC)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
235.5 mg (1.09 mmol) of pyridinium chlorochromate (PCC) are added to a solution of 330 mg (0.91 mmol) of methyl 4-[5-[1-(2-ethoxy-2-oxoethyl)cyclopropyl]-3-(hydroxymethyl)pentyl]-benzoate in 30 ml of dichloromethane, and the mixture is stirred at room temperature for 12 hours.
Reaction SMILES: [NH:1]([C:7]([CH3:9])=[O:8])[C@H:2]([C:4](O)=[O:5])[CH3:3].[NH2:10][C@H:11]([C:24]([OH:26])=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].ON1C(=O)CCC1=O.[OH-].[Na+].C(N(CC)CC)C.Cl>O1CCOCC1>[NH:1]([C:7]([CH3:9])=[O:8])[C@H:2]([C:4]([NH:10][C@H:11]([C:24]([OH:26])=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[O:5])[CH3:3]
Reactant: CC(=O)N[C@@H](C)C(=O)O
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)O
Agent: Cl
Agent: O=C1CCC(=O)N1O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)O
Reaction time: 8 h

Procedure:
Ac-Ala-Lys(Boc)-OH was prepared by coupling the N-hydroxysucoinimide ester of Ac-Ala-OH, prepared by the method of Anderson et al., J. Am. Chem. Soc. 86: 1839, (1964), to H-Lys(Boc)-OH. The N-hydroxy-succinimide of Ac-Ala-OH (6.25 g, 27.4 mmoles) was dissolved in 30 mL of dioxane and was added to a solution of H-Lys(Boc)-OH (7.50 g, 30.4 mmoles) dissolved in a solution consisting of 30 mL of 1.0 N sodium hydroxide and triethylamine (2.12 mL, 15.0 mmoles). The reaction mixture was stirred overnight, then acidified with hydrochloric acid. Sufficient dry sodium chloride to nearly saturate the solution was added. The product was extracted into ethyl acetate and it was washed with 0.2 N hydrochloric acid prepared in saturated aqueous sodium chloride. The organic phase was dried over anhydrous sodium sulfate and filtered. Solvent was removed by evaporation. The product was crystallized from ethyl acetate:hexane to yield 7.3 g (mp 86°-89°).
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[CH:10][C:11]3[C:16](=[O:17])[O:15][C:14]([CH3:19])([CH3:18])[O:13][C:12]=3[CH:20]=2)=[CH:4][CH:3]=1.[CH:23]1([CH2:28][CH2:29][C:30](Cl)=[O:31])[CH2:27][CH2:26][CH2:25][CH2:24]1>>[Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]([C:8]2[CH:9]=[CH:10][C:11]3[C:16](=[O:17])[O:15][C:14]([CH3:19])([CH3:18])[O:13][C:12]=3[CH:20]=2)[C:30](=[O:31])[CH2:29][CH2:28][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: CC1(C)OC(=O)c2ccc(NCc3ccc(Br)cc3)cc2O1
Product: CC1(C)OC(=O)c2ccc(N(Cc3ccc(Br)cc3)C(=O)CCC3CCCC3)cc2O1

Procedure:
The titled compound was prepared following the procedure M using 7-[(4-bromobenzyl)amino]-2,2-dimethyl-4H-1,3-benzodioxin-4-one and 3-cyclopentylpropionyl chloride as a white powder (86%). M+ (ESI): 488.0. HPLC, Rt: 5.41 min (Purity: 99.9%).
Reaction SMILES: [C:1]([O-:10])(=[S:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Na+].Cl[CH2:13][CH2:14][CH2:15][Si:16]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([S:9][CH2:13][CH2:14][CH2:15][Si:16]([O:17][CH2:18][CH3:19])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCO[Si](CCCCl)(OCC)OCC
Reactant: CCCCCCCC([O-])=S
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: CCCCCCCC(=O)SCCC[Si](OCC)(OCC)OCC
Temperature: 25 °C

Procedure:
The aqueous solution of sodium thiooctanoate was heated to 80° C. and stirred with a mechanical stirrer throughout this procedure. To this solution was added, all at once, 4 grams of a concentrated aqueous solution of tetrabutylammonium bromide. Immediately thereafter was added a solution of 3-chloro-1-propyltriethoxysilane (120 grams, 0.5 moles). This mixture was kept at 80° C. with continued stirring for 6 hours, and then allowed to cool to ambient temperature. After cooling to ambient temperature, the organic phase was separated from the aqueous phase. Gas chromatography and mass spectrometry (GC and GCMS) revealed a product containing 93% 3-octanoylthio-1-propyltriethoxysilane. Product identity using this process confirmed by nuclear magnetic resonance spectroscopy (NMR).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][NH:8][NH2:9])[CH2:4][CH3:5])[CH3:2].Cl[C:11]1[C:24]2[C:23](=O)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3[O:26][CH3:27])[S:16][C:15]=2[C:14]([N+:28]([O-:30])=[O:29])=[CH:13][CH:12]=1>CN(C=O)C>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:6][CH2:7][N:8]1[C:11]2[CH:12]=[CH:13][C:14]([N+:28]([O-:30])=[O:29])=[C:15]3[S:16][C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([O:26][CH3:27])[C:22]=4[C:23]([C:24]=23)=[N:9]1)[CH3:2]
Reactant: CCN(CC)CCNN
Reactant: COc1cccc2sc3c([N+](=O)[O-])ccc(Cl)c3c(=O)c12
Solvent: CN(C)C=O
Product: CCN(CC)CCn1nc2c3c(c([N+](=O)[O-])ccc31)Sc1cccc(OC)c1-2
Yield: 51.7 %

Procedure:
Reaction of a mixture of 2.5 g (0.0192 mol) of 2-(diethylaminoethyl)hydrazine, 4.2 g (0.0131 mol) of 1-chloro-8-methoxy-4-nitro-9H-thioxanthen-9-one in 110 ml of DMF as described in Example 53 gave 2.7 g of product.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[N:7][C:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].[ClH:41]>CN(C=O)C.O.CCOC(C)=O.C(Cl)Cl.CCOCC>[ClH:26].[ClH:41].[CH2:1]([C:5]1[N:6]=[N:7][C:8]([O:18][CH:19]2[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]2)=[CH:9][C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:31][C:30]2[CH:33]=[CH:34][C:27]([Cl:26])=[CH:28][CH:29]=2)=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Clc1ccc(CBr)cc1
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OCc2ccc(Cl)cc2)cc1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-phenol (Example 19, 0.2 mmol, 69 mg) in dry DMF (1 mL) was added 4-chlorobenzyl bromide (0.4 mmol, 83 mg), and potassium carbonate (0.4 mmol, 56 mg). And the mixture was stirred at 80° C. over night. It was then diluted with water/EtOAc. The organic layers were combined, dried, and condensed in vacuo and the residue was purified by silica gel chromatography (DCM to DCM+10% MeOH) to give a colorless sticky solid, which was dissolved in DCM (1.0 mL), 1N HCl in ether (1.0 mL) was added, kept at room temperature for 10 min, condensed, triturated with hexanes to provide the title compound (69 mg). LCMS: m/z 467 [M+1]. 1H NMR (400 MHz, CD3OD): δ 7.44-7.47 (2H, m), 7.38-7.41 (2H, m), 7.32-7.35 (2H, m), 7.12-7.15 (2H, m), 7.02 (1H, s), 5.47-5.53 (1H, m), 5.16 (2H, s), 3.30-3.49 (4H, m), 2.91 (3H, s), 2.89-2.94 (2H, m), 2.22-2.37 (4H, m), 1.44-1.52 (2H, m), 1.18-1.26 (2H, m), 0.79 (3H, t).
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22](O)=[O:23])[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[N:34]O)[NH2:33])=[CH:28][CH:27]=1>>[CH:1]1([C:6]([N:8]2[CH2:9][CH:10]([C:22]3[O:23][N:34]=[C:32]([C:29]4[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=4)[N:33]=3)[CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:13]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Reactant: NC(=NO)c1ccc(F)cc1
Product: CCc1ccc(C2CC(c3nc(-c4ccc(F)cc4)no3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
66 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 34 mg (0.22 mmol, 1.1 eq.) of 4-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 45 mg (50% of theory)
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:9]([F:10])=[C:8]([C:11]2[CH:19]=[CH:18][C:14]3=[N:15][O:16][N:17]=[C:13]3[CH:12]=2)[N:7]=[C:6]([C:20]([O:22]C)=[O:21])[C:5]=1[Cl:24].Cl>CO>[NH2:3][C:4]1[C:9]([F:10])=[C:8]([C:11]2[CH:19]=[CH:18][C:14]3=[N:15][O:16][N:17]=[C:13]3[CH:12]=2)[N:7]=[C:6]([C:20]([OH:22])=[O:21])[C:5]=1[Cl:24]
Reactant: COC(=O)c1nc(-c2ccc3nonc3c2)c(F)c(N)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1c(F)c(-c2ccc3nonc3c2)nc(C(=O)O)c1Cl
Temperature: 23 °C
Reaction time: 72 h
Yield: 62.7 %

Procedure:
A 2M solution of aqueous sodium hydroxide (620 microliters (μL), 1.2 mmol) was added to a stirred suspension of methyl 4-amino-6-(benzo[c][1,2,5]oxadiazol-5-yl)-3-chloro-5-fluoropicolinate (200 mg, 0.62 mmol) in methanol (1.3 mL) at 23° C. The heterogeneous light brown mixture was stirred at 23° C. for 72 h. The reaction mixture was adjusted to approximately pH=4 via dropwise addition of concentrated hydrochloric acid and concentrated via rotary evaporation. The residue was slurried in water and vacuum filtered to afford the title compound (120 mg, 63% yield).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]([C:11]2([CH2:24][C:25]#[N:26])[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[N:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:25]([CH2:24][C:11]1([N:4]2[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:2]([NH:1][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[N:3]2)[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:15][CH2:16]1)#[N:26]
Reactant: COC(=O)c1cn(C2(CC#N)CCN(C(=O)OC(C)(C)C)CC2)nc1N
Reactant: Brc1ccccc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1cn(C2(CC#N)CCN(C(=O)OC(C)(C)C)CC2)nc1Nc1ccccc1
Temperature: 95 °C

Procedure:
To a microwave vessel was added tert-butyl 4-[3-amino-4-(methoxycarbonyl)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate (0.400 g, 1.10 mmol), K3PO4 (467 mg, 2.20 mmol), bromobenzene (0.13 mL, 1.2 mmol), and dioxane (5.5 mL). The mixture was degassed by bubbling argon for 5 minutes. Pd2(dba)3 (50 mg, 0.05 mmol) and X-Phos (79 mg, 0.16 mmol) were added, and the vial was sealed and heated to 95° C. for 3 hours. The reaction was then cooled to ambient temperature, diluted with EtOAc, filtered through celite, and rinsed with EtOAc. The filtrate was concentrated in vacuo, and the residue was purified by MPLC on silica gel (using a gradient elution of 0-50% EtOAc/hexanes) to afford the title compound.
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][O:9][C:8]([NH:12][C@H:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15][CH2:14]3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:22]1(B(O)O)[CH2:24][CH2:23]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.[Pd].O>[CH:22]1([C:2]2[C:11]3[CH2:10][O:9][C:8]([NH:12][C@H:13]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[CH2:15][CH2:14]4)=[N:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:24][CH2:23]1
Reactant: OB(O)C1CC1
Reactant: Brc1cccc2c1COC(N[C@@H]1CCc3ccccc31)=N2
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc2c(c1)CC[C@H]2NC1=Nc2cccc(C3CC3)c2CO1
Yield: 54.5 %

Procedure:
A stirred mixture of (5-bromo-4H-benzo[d][1,3]oxazin-2-yl) -(R)-indan-1-yl-amine (Example 10) (171.6 mg, 0.5 mmol), cyclopropylboronic acid (85.9 mg, 1.0 mmol), tricyclohexylphosphine (28 mg, 0.1 mmol), potassiumphosphate (371.5 mg, 1.75 mmol) and palladium actetate (11.2 mg, 0.05 mmol) in toluene (2 ml) and water (0.1 ml) was heated in a sealed tube at 110° C. for 17 h. The reaction mixture was poured into water (20 ml), extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with water (20 ml) and brine (20 ml), dried (MgSO4) and evaporated. Further purification by flash chromatography (ethyl acetate/heptane) on silica gel and crystallization (dichloromethane/heptane) yielded the title compound as colorless gum (83 mg, 49%). MS (ISP): m/e=305.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([SH:10])=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].[Cl:11][C:12]1[CH:13]=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:16][C:17]=1Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:3]([S:10][C:17]2[CH:16]=[CH:15][C:14]([C:19]([F:22])([F:21])[F:20])=[CH:13][C:12]=2[Cl:11])=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7]
Reactant: Nc1cc(Cl)c(S)cc1F
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Cl)c(Sc2ccc(C(F)(F)F)cc2Cl)cc1F
Reaction time: 2 h
Yield: 66 %

Procedure:
5.00 Grams of 5-chloro-2-fluoro-4-mercaptoaniline, 12.2 g of 3,4-dichlorobenzotrifluoride and 4.31 g of potassium carbonate were dissolved in 30 ml of dimethylformamide, and the resulting solution was stirred for 2 hours at a temperature of from 100° to 110° C. in an oil bath. Thereafter, the reaction solution was poured into water and extracted with three 200-ml portions of diethyl ether. The extract obtained was washed with water, dried, filtered and concentrated. The residue obtained was subjected to chromatography on silica gel to obtain 6.57 g of 5-chloro-2-fluoro-4-[2-chloro-4-(trifluoromethyl)phenylthio]aniline.
Reaction SMILES: [CH:1]1([P:7]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[I:20]C>[I-].C[P+](C1CCCCC1)(C1CCCCC1)C1CCCCC1.C1CCCCC1>[I-:20].[CH:14]1([PH+:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CI
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: C[P+](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Agent: [I-]
Solvent: C1CCCCC1
Product: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1

Procedure:
This example shows the storage stability of precatalyzed resin containing methyl tricyclohexyl phosphonium iodide catalyst. Tricyclohexyl phosphonium iodide was prepared by reacting tricyclohexylphosphine with iodomethane. 3.95 g of tricyclohexyl phosphine was charged to a 200-ml flask. 70 ml of cyclohexane was added. The resulting solution was maintained with stirring under a nitrogen blanket and condenser. 2 g of iodomethane was added to the solution, resulting in the precipitation of a white solid. The reaction mixture was vacuum filtered and dried in a vacuum oven.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]([F:24])=[C:22]3[C:17]([C:18](=[O:31])[C:19]([C:28]([OH:30])=[O:29])=[CH:20][N:21]3[CH:25]3[CH2:27][CH2:26]3)=[CH:16][C:15]=2[F:32])[CH2:10]1)=O)(C)(C)C.[ClH:33]>C(O)(=O)C>[ClH:33].[NH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]([F:24])=[C:22]3[C:17]([C:18](=[O:31])[C:19]([C:28]([OH:30])=[O:29])=[CH:20][N:21]3[CH:25]3[CH2:26][CH2:27]3)=[CH:16][C:15]=2[F:32])[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Agent: Cl
Solvent: CC(=O)O
Product: NC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Temperature: 60 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A suspension of 72.4 g (0.16 mole) of 7-[3-t-butoxycarbonylamino-1-pyrrolidinyl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 375 ml of 6 M hydrochloric acid, and 750 ml of glacial acetic acid was heated at 60° C. for four hours and the resulting solution was stirred at room temperature for 18 hours. The reaction was filtered through a fiber glass pad to clarify and the filtrate was evaporated in vacuo. The residue was triturated with 600 ml of ethanol:ether (1:1), the solid removed by filtration, washed with ethanol:ether (1:1), ether and dried in vacuo to give 63.8 g (98%) of the title compound, mp 313°-315° C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5].N1C=CN=C1.[C:14]([Si:18]([CH3:21])([CH3:20])Cl)([CH3:17])([CH3:16])[CH3:15].O>CN(C)C=O.CCCCCC>[Si:18]([O:1][CH2:2][C@H:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H](C)CO
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](C)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
A mixture of methyl (S)-(+)-3-hydroxy-2-methylpropionate (1.00 g; 8.47 mmol) and imidazole (1.15 g; 16.9 mmol) was dissolved in anhydrous dimethylformamide (10 ml), and t-butyl-dimethylchlorosilane (1.30 g; 8.62 mmol) was added thereto at room temperature, followed by stirring at room temperature for 1.5 hours. To the reaction mixture, water (10 ml) and hexane (20 ml) were added, and after separation of the organic layer, the aqueous layer was extracted with hexane (10 ml) two times. The organic layers were combined together, washed with water (5 ml) three times and dried over anhydrous magnesium sulfate. Removal of the solvent by distillation under reduced pressure gave methyl (S)-(+)-3-(t-butyldimethylsilyloxy)-2-methylpropionate (1.91 g; yield, 97%) as a colorless oil. A portion of the oil (179 mg) was distilled by Kugelrohr® to give a purified product (176 mg) (bath temperature: 120° C./14 mmHg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:15][CH2:14][NH:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][CH2:24][N:25]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[CH2:28][N:27]([CH:35]([CH3:37])[CH3:36])[S:26]1(=[O:39])=[O:38]>O.C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:15][CH2:14][N:13]([CH2:23][CH2:24][N:25]4[C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=5[CH2:28][N:27]([CH:35]([CH3:36])[CH3:37])[S:26]4(=[O:39])=[O:38])[CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(C3CCNC3)c[nH]c2c1
Reactant: CC(C)N1Cc2ccccc2N(CCCl)S1(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)N1Cc2ccccc2N(CCN2CCC(c3c[nH]c4cc(F)ccc34)C2)S1(=O)=O

Procedure:
3-{6-Fluoro-indol-3-yl}-pyrrolidine (500 mg, 2.45 mmol), potassium carbonate (1.04 g, 9.8 mmol), and 1-(2-chloroethyl)-3,4-dihydro-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide (708 mg, 2.45 mmol) were refluxed in water (15 ml) under nitrogen overnight. The solid was dissolved in ethyl acetate(2×100 ml) and washed with brine, dried, filtered and evaporated in vacuo to afford a brown oil. Column chromatography eluting with ethyl acetate gave a yellow solid, 3,4-dihydro-1-{2-[3-(6-fluoroindol-3-yl)-pyrrolidinyl]-1-ethyl}-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide, m.p.50.8-54.4° C.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][C:23]=3[O:24][CH3:25])[NH:20][CH:19]=[C:18]4[C:26](=[O:32])[C:27]([N:29]([CH3:31])[CH3:30])=[O:28])=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C[Si]([N-:39][Si](C)(C)C)(C)C.[Li+]>CN1CCCC1=O>[NH2:39][N:20]1[C:21]2[C:17](=[CH:16][C:15]([C:13]([N:10]3[CH2:11][CH2:12][CH:7]([CH2:6][C:5]4[CH:33]=[CH:34][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:8][CH2:9]3)=[O:14])=[C:23]([O:24][CH3:25])[CH:22]=2)[C:18]([C:26](=[O:32])[C:27]([N:29]([CH3:30])[CH3:31])=[O:28])=[CH:19]1
Reactant: COc1cc2[nH]cc(C(=O)C(=O)N(C)C)c2cc1C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: COc1cc2c(cc1C(=O)N1CCC(Cc3ccc(F)cc3)CC1)c(C(=O)C(=O)N(C)C)cn2N
Temperature: 25 °C
Reaction time: 6 h
Yield: 46.9 %

Procedure:
To a solution of 2-{5-[4-(4-Fluoro-benzyl)-piperidine-1-carbonyl]-6-methoxy-1H-indol-3-yl}-N,N-dimethyl-2-oxo-acetamide (620 mg, 1.33 mmol) in 1-methyl-2-pyrrolidinone (20 mL) was added lithium bis(trimethylsilyl)amide (2.1 mL, 2.1 mmol, 1.0 M in THF) at −10° C., followed by o-(diphenylphosphinyl)hydroxylamine (350 mg, 1.5 mmol). The reaction mixture was allowed to warm to RT and continually stirred for 6 h, then quenched with water (50 mL). The resulting mixture was extracted with EtOAc, washed with brine, dried (Na2SO4) and concentrated. The residue was purified by radial chromatography eluting with 2% MeOH in CH2Cl2 to give 300 mg (47%) of the desired product as a white solid. M+H+(481).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[N:5]([CH:12]([C:20]1[CH:25]=[CH:24][C:23]([O:26]CC2C=CC=CC=2)=[C:22]([O:34][CH2:35]C)[CH:21]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)CC(OC)OC)[CH3:2].[C:38](OCC)(=[O:40])C.CCCCCC>C(OCC)(=O)C.C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:37])[NH:5][CH:12]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:34][CH3:35])[CH:21]=1)[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([O:40][CH3:38])[CH:19]=1)[CH3:2]
Reactant: CCOC(=O)N(CC(OC)OC)C(Cc1ccccc1)c1ccc(OCc2ccccc2)c(OCC)c1
Reactant: CCOC(C)=O
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)NC(Cc1cccc(OC)c1)c1ccc(O)c(OC)c1
Reaction time: 15 h
Yield: 80 %

Procedure:
To a stirred solution of [1-(4-benzyloxy-3-ethoxy-phenyl)-2-phenyl-ethyl]-(2,2-dimethoxy-ethyl)-carbamic acid ethyl ester (12.0 g, 28 mmol) in ethyl acetate (120 mL) and ethanol (60 mL) solution was added 10% Pd/C (2.4 g). The mixture was hydrogenated at 1 atm for 15 hrs. The solution was filtered through a Celite® plug and evaporated to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane) afforded (2,2-dimethoxy-ethyl)-[1-(4-hydroxy-3-methoxy-phenyl)-2-(3-methoxy-phenyl)-ethyl-carbamic acid ethyl ester as a colorless oil. (10 g, 80% yield).