Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C:13](=[O:14])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:22]([Mg]Br)[CH:23]=[CH2:24]>C1COCC1>[OH:14][C@@:13]1([CH2:24][CH:23]=[CH2:22])[C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CC[C@@]1(O)CN(C(=O)OC(C)(C)C)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled solution of tert-butyl (3S)-3-(tert-butyldimethylsilyl)oxy-4-oxopyrrolidine-1-carboxylate (1.2 g) in THF (5 mL) was added dropwise a 1M solution of allylmagnesium bromide in THF (3.8 mL), and the mixture was stirred for 30 min at 0° C. The reaction was quenched with saturated aqueous NH4Cl (5 mL) and the mixture was extracted with Et2O. The extract was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified with silica gel column chromatography (eluent: hexane/EtOAc=1/0˜50/50) to give tert-butyl (3R,4S)-3-hydroxy-4-(tert-butyldimethylsilyl)oxy-3-(prop-2-en-1-yl)pyrrolidine-1-carboxylate as a pale yellow foam.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.O>[Cl:17][C:10]1[CH:9]=[C:8]([C:18](=[O:20])[CH3:19])[C:7]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: C1CNCCN1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Temperature: 65 °C
Yield: 63.5 %

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (1.1 g, 3.1 mmol, from Example 47, Step 2), piperazine (0.40 g, 4.7 mmol) and cesium carbonate (2.8 g, 8.7 mmol) in tetrahydrofuran (20 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with water, and extracted with dichloromethane. The organic phases were combined, dried over MgSO4 and concentrated. The resulting residue was purified on silica gel (eluting with 15% methanol in dichloromethane) to give the desired product (0.57 g, 63%). LCMS calculated for C15H17ClN3O (M+H)+: m/z=290.1; Found: 290.1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[Cl:12])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CC(C)=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:7][C:6]=1[Cl:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)c1ccc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc(C(C)(C)C)c(Cl)c1
Temperature: 65 °C
Yield: 100 %

Procedure:
To an acetone (5 ml) solution of 4-tert-butyl-3-chlorophenol (440 mg, 2.4 mmol) were added potassium carbonate (994 mg, 7.2 mmol) and tert-butyl bromoacetate (0.7 ml, 4.8 mmol). The stirred mixture was refluxed at 65° C. for 14 hours. The precipitate was filtered off and washed with acetone. The filtrate was concentrated under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with ethyl acetate/hexane= 1/9 to furnish 0.83 g (100% yield) of the title as a colorless oil.
Reaction SMILES: [OH-].[Na+:2].[CH2:3]([C:6]1[C:7]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:8][C:9]2[O:13][CH2:12][O:11][C:10]=2[CH:14]=1)[CH2:4][CH3:5]>C(O)C>[CH2:3]([C:6]1[C:7]([CH2:15][CH2:16][C:17]([O-:19])=[O:18])=[CH:8][C:9]2[O:13][CH2:12][O:11][C:10]=2[CH:14]=1)[CH2:4][CH3:5].[Na+:2]
Reactant: CCCc1cc2c(cc1CCC(=O)O)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1cc2c(cc1CCC(=O)[O-])OCO2

Procedure:
29.2 ml of a 1N aqueous sodium hydroxide solution and 100 ml of ethanol were added to 6.9 g of 3-(6-propyl-1,3-benzodioxole-5-yl)propionic acid to obtain a solution. The solvent was distilled off and ether was added to the residue. A precipitate thus formed was recovered by filtration and dried to obtain 7.5 g of the intended compound in the form of a colorless powder.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([CH2:9]Cl)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.[CH3:14][O:15][CH2:16][CH2:17][CH2:18][NH2:19].CS(C)=O>C(OCC)(=O)C>[CH3:14][O:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:2][CH2:3][N:4]2[N:5]=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[C:8]2[CH2:9]1
Reactant: O=[N+]([O-])c1cc(CCl)n(CCBr)n1
Reactant: COCCCN
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COCCCN1CCn2nc([N+](=O)[O-])cc2C1
Temperature: 120 °C
Yield: 66.2 %

Procedure:
A microwave vial equipped with a magnetic stirrer was charged with 1-(2-bromoethyl)-5-(chloromethyl)-3-nitro-1H-pyrazole 296c (600 mg, 2.2 mmol), 3-methoxypropan-1-amine (595 mg, 6.6 mmol), and DMSO (6 mL). It was heated at 120° C. under microwave irradiation for 0.5 h. The mixture was then cooled to room temperature and diluted with ethyl acetate (30 mL). The resulting mixture was washed with water (3×10 ml). The organic layer was dried and filtered. The filtrate was concentrated under pressure and the residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 309a (350 mg, 66%) as a yellow solid. MS-ESI: [M+H]+ 241.1
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[C:31]([F:32])=[CH:30][C:29]([F:33])=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:34])=[CH:17][N:16]=1>>[Cl:34][C:18]1[C:19]([NH:21][C:22]2[C:31]([F:32])=[CH:30][C:29]([F:33])=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:20][C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=3[CH:13]=2)=[N:16][CH:17]=1
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Reactant: CNC(=O)c1cc(F)cc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cc(F)cc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3)ncc1Cl

Procedure:
Title compound was prepared from 8-Amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3,5-difluoro-N-methyl-benzamide in an analogous manner to Example 1221d. Title compound was isolated as a beige solid (136 mg, 82%). MP=250-252 (dec), HPLC purity=93%, LCMS=473.14 (M+H), HNMR (DMSO), 9.54 (bs, 1H), 9.38 (s, 1H), 9.28 (s, 1H), 8.52 (d, J=4.4 Hz, 1H), 8.21 (s, 1H), 7.53 (dd, J=7.9 Hz, 1H), 7.36 (d, J=8.6 Hz, 1H), 7.17 (d, J=7.9 Hz, 1H), 7.04 (s, 1H), 6.97 (d, J=8.1 Hz, 1H), 2.72 (d, J=4.0 Hz, 3H), 2.59-2.56 (m, 2H), 2.09-2.03 (m, 4H).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:8]12([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2>>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][O:24][C:21]1[CH:20]=[CH:19][C:18]([C:8]23[CH2:9][CH:10]4[CH2:16][CH:14]([CH2:13][CH:12]([CH2:11]4)[CH2:17]2)[CH2:15]3)=[CH:23][CH:22]=1)[CH3:7]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Product: CCOC(=O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1

Procedure:
Analogously to the method described in Example 16, the use of ethyl bromoacetate and p-(1-adamantyl)-phenol as starting materials gives 4-(1-adamantyl)-phenoxyacetic acid ethyl ester of melting point 89°-90°C (flakes; from ether-pentane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:4]=1[CH:5]=O.[NH:15]1[CH2:21][C:19](=[O:20])[NH:18][C:16]1=[O:17].C(CN)O>O>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:4]=1[CH:5]=[C:21]1[NH:15][C:16](=[O:17])[NH:18][C:19]1=[O:20]
Reactant: O=C1CNC(=O)N1
Reactant: COc1cc(OC)c(OC)cc1C=O
Solvent: O
Solvent: NCCO
Product: COc1cc(OC)c(OC)cc1C=C1NC(=O)NC1=O
Yield: 93.3 %

Procedure:
A mixture of 2,4,5-trimethoxybenzaldehyde (2.503 g.) and hydantoin (1.275 g., 1 molar ratio) in water (15 ml) was heated to 70°. Monoethanolamine (1.17 g.) was added and the suspension was stirred and heated at 90°-92° (bath temperature) for 4 hours. Isolation in the usual manner gave the title compound as a yellow solid (3.306 g.), m.p. 276°-277° decomp. Crystallization from dioxane did not raise the melting point.
Reaction SMILES: [C:1]1(=[N:13]O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(=N[OH:22])CCCCC1.C1(=O)CCCCC1.C1(=O)CCCCCCCCCCC1.S(=O)(=O)(O)O.OS(O)(=O)=O.O=S(=O)=O>>[C:1]1(=[O:22])[NH:13][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: ON=C1CCCCC1
Reactant: ON=C1CCCCCCCCCCC1
Agent: O=C1CCCCCCCCCCC1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: O=C1CCCCC1
Product: O=C1CCCCCCCCCCCN1

Procedure:
Another industrial process is that commercially developed by Ube Industries-EMS. This process utilizes the fact that cyclohexanone oxime and caprolactam are good solvents for cyclododecanone oxime and laurolactam, respectively (for example, see Patent Reference 2). Specifically, a mixture of cyclododecanone and cyclohexanone is blended with an aqueous solution of hydroxylamine to produce oximes. Cyclohexanone oxime produced has a low melting point and is a good solvent for cyclododecanone oxime, so that the reaction can be conducted at 100° C. or lower and at an ambient pressure. Furthermore, cyclohexanone oxime is adequately hydrophilic for the oxime-forming reaction to quickly proceed, and the mixture is transferred to the rearrangement step without residual cyclohexanone or cyclododecanone. A rearrangement catalyst used is concentrated sulfuric acid or oleum. Whereas laurolactam produced has a high melting point, it is highly soluble in caprolactam having a low melting point. Therefore, the reaction can be carried out even at a temperature of 100° C. or lower. The resulting rearrangement reaction solution is neutralized with ammonia water and then extracted with an organic solvent. Caprolactam can be dissolved in water to some extent, but is extracted into an organic solvent due to salting-out effect of ammonium sulfate. Next, a large amount of water is added to the solution containing extracted laurolactam and caprolactam, and caprolactam is extracted into the aqueous phase. From the separated organic phase, the organic solvent is recovered and laurolactam is purified by distillation. The aqueous phase is concentrated and after removing impurities, caprolactam is purified.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:15][C:16]([OH:18])=[O:17]>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:15][C:16]([OH:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCOCc1ccccc1
Reactant: O=C(O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)COCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
2-(Benzyloxy)ethanol (0.75 ml) is dissolved in N,N-dimethylformamide (3 ml), and added dropwise to a solution of sodium hydride (400 mg) in N,N-dimethylformamide under ice-cooling. The mixture is stirred for 40 minutes. To the reaction solution is added chloroacetic acid (500 mg) under ice-cooling, and the mixture is stirred at room temperature for 1 day. To the reaction solution is added ice-water, and the mixture is extracted with ethyl acetate. To the aqueous layer is added 6N HCl, and the solution is adjusted to pH 2 and extracted with ethyl acetate. The organic layer is washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure to give 2-(benzyloxy)ethoxy acetic acid (895 mg). MS (m/z): 211 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH:5]=[C:6]2[CH2:9][CH2:10]O.C(Br)(Br)(Br)[Br:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:14][CH2:10][CH2:9][C:6]1[CH:7]2[CH2:8][CH:3]([CH2:4][CH:5]=1)[C:2]2([CH3:12])[CH3:1]
Reactant: BrC(Br)(Br)Br
Reactant: CC1(C)C2CC=C(CCO)C1C2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(C)C2CC=C(CCBr)C1C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
A mixture of 2-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)ethanol (0.835 g, 4.87 mmol), CBr4 (1.83 g, 5.5 mmol) and PPh3 (1.44 g, 5.5 mmol) in anhydrous CH2Cl2 (10 ml) was stirred for 2 h at room temperature. The solvent was evaporated to dryness and the residue was treated with EtOAc (10 ml) and filtered through a SiO2 bead to give the title compound (1.03 g; 90%), as colourless oil. 1H-NMR (CDCl3) 0.82 (s, 3H); 1.26 (s, 3H); 1.99-2.37 (m, 6H); 2.5 (tr, 2H, J=7.88 Hz); 3.34 (tr, 2H, J=7.27 Hz); 5.31 (broad s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][CH2:14][CH2:13][C:12]([C:16]([O-:18])=[O:17])=[CH:11][C:10]=2[CH:19]=1.[OH-].[Na+].Cl>CO.C1COCC1>[F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][CH2:14][CH2:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][C:10]=2[CH:19]=1
Reactant: O=C([O-])C1=Cc2cc(OCc3ccc(F)cc3F)ccc2CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1=Cc2cc(OCc3ccc(F)cc3F)ccc2CCC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To 2-(2,4-difluorobenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (477 mg, 1.39 mmol) dissolved in a mixed solvent of methanol (5 ml) and THF (5 ml) was added a 1N aqueous solution of sodium hydroxide (4.2 ml), and the resulting mixture was stirred at 50° C. for 2 hours. The reaction mixture was mixed with 1 N hydrochloric acid (4.2 ml) at 0° C., was concentrated under reduced pressure and was mixed with water, and an insoluble material was collected by filtration. The insoluble material was washed with water and was dried under reduced pressure to obtain 2-(2,4-difluorobenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (436 mg, 1.32 mmol, 95%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH:8]([CH:13]=[N:14][OH:15])[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][C:19](=[O:26])[C:20]([CH3:25])([CH3:24])[CH2:21][C:22]#[CH:23]>>[CH3:17][O:18][C:19](=[O:26])[C:20]([CH3:25])([CH3:24])[CH2:21][C:22]1[O:15][N:14]=[C:13]([CH:8]([NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:16])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH:23]=1
Reactant: C#CCC(C)(C)C(=O)OC
Reactant: CC(C)CC(C=NO)NC(=O)OC(C)(C)C
Product: COC(=O)C(C)(C)Cc1cc(C(CC(C)C)NC(=O)OC(C)(C)C)no1

Procedure:
Prepared from [1-(hydroxyimino-methyl)-3-methyl-butyl]-carbamic acid tert-butyl ester (71) and 2,2-dimethyl-pent-4-ynoic acid methyl ester according to the procedure outlined in example 6A. MS (Cl) m/z: 313.2 (M-tBu), 269.3 (M−99)
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[C:30]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)[CH:29]=[CH:28][C:3]=1[C:4]([NH:6][C:7]1[C:8]2[CH2:14][N:13]([S:15]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)(=[O:17])=[O:16])[C:12]([CH3:27])([CH3:26])[C:9]=2[NH:10][N:11]=1)=[O:5].C(N(CC)C(C)C)(C)C.C1C2C(COC([NH:65][C@@H:66]([CH3:70])[C:67](Cl)=[O:68])=O)C3C(=CC=CC=3)C=2C=CC=1>ClCCl>[NH2:65][C@@H:66]([CH3:70])[C:67]([NH:1][C:2]1[CH:31]=[C:30]([N:32]2[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]2)[CH:29]=[CH:28][C:3]=1[C:4]([NH:6][C:7]1[C:8]2[CH2:14][N:13]([S:15]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)(=[O:17])=[O:16])[C:12]([CH3:27])([CH3:26])[C:9]=2[NH:10][N:11]=1)=[O:5])=[O:68]
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4c3CN(S(=O)(=O)c3cc(F)cc(F)c3)C4(C)C)c(N)c2)CC1
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](N)C(=O)Nc1cc(N2CCN(C)CC2)ccc1C(=O)Nc1n[nH]c2c1CN(S(=O)(=O)c1cc(F)cc(F)c1)C2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
To a solution of 2-amino-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide (0.188 g, 0.34 mmol), N,N-diisopropylethylamine (0.59 mL, 3.4 mmol) and dichloromethane (10 mL), (S)-2-[(9H-fluoren-9-ylmethoxycarbonyl)amino]-propionyl chloride (0.448 g, 1.36 mmol, 4 eq.) was added and the reaction mixture stirred at room temperature overnight. After evaporation to dryness, the residue was treated with dichloromethane (10 mL), triethylamine (5 mL) and MeOH (5 mL) and the mixture stirred at room temperature for 72 hours. The solvent was then removed under vacuum and the residue purified by preparative HPLC/MS affording the title compound as white solid (0.105 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH2:10][CH:9]1[CH2:22][OH:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH2:10][CH:9]1[CH2:22][O:23][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(F)cc2F)CC1CO
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCC2CC(Oc3ccc(F)cc3F)CN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 75.1 %

Procedure:
To a stirred solution of 1-(tert-butoxycarbonyl)-4-(2,4-difluorophenoxy)-2-pyrrolidinylmethanol (500 mg, 1.52 mmol), methyl 4-hydroxybenzoate (277 mg, 1.82 mmol), and Ph3P (477 mg, 1.82 mmol) in THF (10 ml) was added DIAD (358 ul, 1.82 mmol), and the mixture was heated at reflux for 5 h. After cooling to room temperature, the mixture was concentrated in vacuo and the residue was chromatographed on silica gel with CHCl3-EtOAc (20:1) as eluent to give methyl 4-[1-(tert-butoxycarbonyl)-4-(2,4-difluorophenoxy)-2-pyrrolidinylmethoxy]benzoate (529 mg, 75%) as a colorless oil. 1H-NMR (CDCl3) δ1.46 (s, 9 H), 2.20-2.47 (m, 2 H), 3.64 (m, 2 H), 3.86 (s, 3 H), 4.07-4.43 (m, 3 H), 4.86 (m, 1 H), 6.74-6.87 (m, 3 H), 6.94 (d, 2 H, J=8.5 Hz), 7.95 (d, 2 H, J=8.5 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C@@H:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][OH:9])[CH3:2].C(N(C(C)C)CC)(C)C>CS(C)=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C@H:7]([CH:8]=[O:9])[NH:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH3:2]
Reactant: CCOC(=O)CC[C@H](CO)NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOC(=O)CC[C@H](C=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 102.6 %

Procedure:
Under an atmosphere of argon, to a mixed solution of (4R)-4-t-butoxycarbonylamino-5-hydroxypentanoic acid ethyl ester (1.62 g) and diisopropylethylamine (6.5 ml) in dimethylsulfoxide-ethyl acetate (1:1, 40 mL) was added sulfur trioxide pyridine complex (2.96 g) in ice bath and the mixture was stirred in ice bath for 1 hour. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with 0.5N hydrochloric acid, water and brine, dried over anhydrous magnesium sulfate and concentrated to give the title compound (1.65 g) having the following physical data.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]2[CH2:14][O:13]2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[CH3:17][NH:18][CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([N+:30]([O-:32])=[O:31])[CH:26]=2)[N:21]=1>C(O)C>[OH:13][CH:12]([CH2:14][N:18]([CH3:17])[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([N+:30]([O-:32])=[O:31])[CH:26]=2)[N:21]=1)[CH2:11][O:10][C:9]1[CH:15]=[CH:16][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Nc1ccc(OCC2CO2)cc1
Reactant: CNCc1ccc2cc([N+](=O)[O-])ccc2n1
Solvent: CCO
Product: CN(Cc1ccc2cc([N+](=O)[O-])ccc2n1)CC(O)COc1ccc(NS(C)(=O)=O)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 19.4 %

Procedure:
To a stirring solution of 2-[(4-(methanesulfonamido)phenoxy)methyl]oxirane (5.32 g, 21.89 mmol) in ethanol (140 mL) was added the 2-(methylaminomethyl)-6-nitroquinoline (4.75, 21.89 mmol) and the resulting mixture was stirred at 50° C. overnight. The reaction mixture was cooled, concentrated, and subjected to purification by HPLC (10% methanol-ethyl acetate) to afford 1.96 g of product as a yellow amorphous solid.
Reaction SMILES: Cl.C[N:3](C)[CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O.O.[NH2:16]N.[OH-].[Na+]>CO>[C:8]1([C:6]2[CH2:5][CH2:4][NH:3][N:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN(C)CCC(=O)c1ccccc1
Reactant: NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: c1ccc(C2=NNCC2)cc1
Temperature: 50 °C

Procedure:
Under N2 atmosphere, 3-dimethylamino-1-phenyl-propan-1-one hydrochloride (37.2 g) was dissolved in warm MeOH (75 mL), and slowly added to a solution of hydrazine hydrate (23 mL) and 50% aqueous NaOH (12 mL) in MeOH (30 mL) stirred at 50° C. The mixture was refluxed for 2 hours and evaporated under reduced pressure. Ice water was added to the residue and after stirring for 5 minutes the formed solid was filtered off. The residue was taken up in Et2O, dried over Na2SO4, and evaporated to dryness under reduced pressure to give 19.7 g of a yellow oil being 80% pure, which was used in subsequent steps without further purification.
Reaction SMILES: [Mg].[CH3:2]I.[CH3:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:6]=1[CH2:13]C(OC)=O.C([O:20][CH2:21][CH3:22])C>>[CH3:2][C:21]([OH:20])([CH3:22])[CH2:13][C:6]1[C:7]([CH3:12])=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=1[CH3:4]
Reactant: COC(=O)Cc1c(C)cc(C)cc1C
Reactant: CCOCC
Reactant: CI
Agent: [Mg]
Product: Cc1cc(C)c(CC(C)(C)O)c(C)c1
Yield: 79 %

Procedure:
97 g (79%) of the title compound is prepared from 38 g of magnesium and 222 g of methyl iodide in 1.2 L of diethyl ether and 116 g of methyl (2,4,6-trimethylphenyl)acetate under standard conditions in a Grignard reaction. bp15: 140° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH:16]([CH3:18])[CH3:17])(=O)=O.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][C:30]([NH2:33])([CH3:32])[CH3:31].N1C2C(=CC=CC=2)C(CC(N)(C)C)=C1>>[ClH:19].[NH:25]1[C:26]2[C:22](=[CH:21][CH:20]=[CH:28][CH:27]=2)[C:23]([CH2:29][C:30]([NH:33][CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH:16]([CH3:17])[CH3:18])([CH3:31])[CH3:32])=[CH:24]1
Reactant: CC(C)(N)Cc1c[nH]c2ccc(Cl)cc12
Reactant: CC(C)Oc1ccccc1OCCOS(C)(=O)=O
Agent: CC(C)(N)Cc1c[nH]c2ccccc12
Product: CC(C)Oc1ccccc1OCCNC(C)(C)Cc1c[nH]c2ccccc12
Product: Cl

Procedure:
Proceeding as in Example 3, but replacing 2-(cyclopropylmethyloxy)phenoxyethyl methanesulfonate with 2-[2-(prop-2-yloxy)phenoxy]ethyl methanesulfonate and [2- (5-chloro-1H-indol-3-yl)-1,1-dimethylethyl]amine with [2-(1H-indol-3-yl)-1,1-dimethylethyl]amine, gave [2-(1H-indol-3-yl)-1,1-dimethylethyl]{2- [2-(prop-2-yloxy)phenoxy]ethyl}amine hydrochloride, m.p. 164°-166° C.