Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][CH2:4][NH:3]1.[H-].[Na+].[CH2:9](Br)[C:10]#[CH:11].C(=O)(O)[O-].[Na+]>CN(C)C=O.C1(C)C=CC=CC=1>[CH2:11]([N:3]1[C:2](=[O:1])[CH2:6][S:5][CH2:4]1)[C:10]#[CH:9]
Reactant: O=C1CSCN1
Reactant: C#CCBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C#CCN1CSCC1=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of 10.3 g of 4-oxothiazolidine in 500 ml of anhydrous dimethylformamide under N2 was added 6.0 g of sodium hydride (50% in oil). After 30 min., 15 ml of a solution of 80% propargyl bromide in toluene was added and the mixture was allowed to stir for another hour. The mixture was then poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic fractions were washed twice with water, then once with brine, dried (MgSO4), filtered and concentrated. The residue was distilled at 0.1/mm Hg, 95°-98° C., to provide 9.248 g of 3-propargyl-4-oxothiazolidine as an oil which solidified upon refrigeration, mp 29°-31°.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:31]=[CH:32][CH:33]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:30])[CH2:17][S:18][CH2:19][CH2:20][N:21]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[C:22]([CH3:24])=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:34]O>C(O)(=O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:31]=[CH:32][CH:33]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:30])[CH2:17][S:18]([CH2:19][CH2:20][N:21]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[C:22]([CH3:24])=[O:23])=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)N(CCSCC(=O)NCCCOc1cccc(CN2CCCCC2)c1)c1cccs1
Reactant: OO
Solvent: CC(=O)O
Product: CC(=O)N(CCS(=O)CC(=O)NCCCOc1cccc(CN2CCCCC2)c1)c1cccs1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
There was dissolved 1.0 g (0.002 mol) of N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-[2-(2-thienylacetamino)ethylthio]acetamide in 30 ml of acetic acid and added 0.24 ml (0.0022 mol) of 30 % aqueous solution of hydrogen peroxide under cooling with ice, and the mixture was stirred for 12 hours at room temperature. The solvent was removed under reduced pressure, and then 15 the residue was purified by silica gel column chromatography (chloroform:ethanol=5:1) to give 0.72 g of the titled compound as crystals.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[C:25]([CH2:29][C:30](O)=[O:31])[CH:26]=[CH:27][CH:28]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].CC[N:35](C(C)C)C(C)C.[Cl-].[NH4+].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[C:25]([CH2:29][C:30]([NH2:35])=[O:31])[CH:26]=[CH:27][CH:28]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cccc(CC(=O)O)c3)ccc1-2
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cccc(CC(N)=O)c3)ccc1-2
Yield: 54.9 %

Procedure:
A solution of crude {3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-phenyl}-acetic acid (0.38 mmol) in 5 mL DMF was treated sequentially with DIPEA (0.33 mL, 1.92 mmol), ammonium chloride (164 mg, 3.1 mmol) and HATU (292 mg, 0.77 mmol). The reaction was monitored by LCMS. After complete conversion, the mixture was diluted with water and extracted with ethylacetate. The combined organics were washed with brine, dried over sodium sulfate and concentrated. The crude residue was purified by reverse phase HPLC to give 522 as a colorless solid (93 mg, 56%). LCMS: 446.1. 1H NMR (400 MHz, DMSO) δ 8.45 (d, J=8.3 Hz, 1H), 8.11 (s, 1H), 7.66 (s, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.54 (dd, J=8.3, 1.8 Hz, 1H), 7.49 (s, 1H), 7.44-7.35 (m, 2H), 7.27 (d, J=7.6 Hz, 1H), 6.88 (s, 1H), 5.92-5.78 (m, 1H), 4.43 (t, J=4.9 Hz, 2H), 3.47 (overlapping m, 4H), 1.57 (d, J=6.6 Hz, 6H)
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:21])([F:20])[C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[O:12][CH:13]1[CH2:16][NH:15][CH2:14]1.[CH3:22][C:23]([N:26]=[C:27]=[O:28])([CH3:25])[CH3:24].C(N(CC)CC)C.O>O1CCCC1>[CH3:22][C:23]([NH:26][C:27]([N:15]1[CH2:16][CH:13]([O:12][C:11]2[CH:17]=[CH:18][CH:19]=[C:9]([C:8]([F:7])([F:20])[F:21])[CH:10]=2)[CH2:14]1)=[O:28])([CH3:25])[CH3:24]
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Reactant: CC(C)(C)N=C=O
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reaction time: 18 h
Yield: 91.7 %

Procedure:
A stirred slurry of 6.2 g (0.02 mole) of 3-[3-(trifluoromethyl)phenoxy]azetidine oxalate in 60 ml of tetrahydrofuran was treated with 2 g (0.02 mole) of 1,1-dimethylethyl isocyanate followed in 30 min with 5 ml of triethylamine. The clear solution which developed was stirred for 18 hr. The reaction mixture was treated with 10 ml of water and after 20 min, the tetrahydrofuran portion was separated, dried over magnesium sulfate, and concentrated on a rotary evaporator. The solid residue was recrystallized from ethanol/water, yielding 5.8 g (91.7%) of fine white crystals, m.p. 105°-107° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)[N:4]=1.Cl.[CH2:21]([NH:23][CH2:24][C@H:25]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][C:36]([I:39])=[CH:35][CH:34]=1)(=[O:32])=[O:31])[C:26]([OH:28])=[O:27])[CH3:22].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CCOC(C)=O.CN(C=O)C>[CH2:21]([N:23]([C:15](=[O:17])[C:14]1[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][C:5]2[N:4]=[C:3]([NH2:2])[CH:8]=[CH:7][CH:6]=2)=[CH:19][CH:18]=1)[CH2:24][C@H:25]([NH:29][S:30]([C:33]1[CH:34]=[CH:35][C:36]([I:39])=[CH:37][CH:38]=1)(=[O:32])=[O:31])[C:26]([OH:28])=[O:27])[CH3:22]
Reactant: Nc1cccc(CCc2ccc(C(=O)O)cc2)n1
Reactant: CCNC[C@H](NS(=O)(=O)c1ccc(I)cc1)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCN(C[C@H](NS(=O)(=O)c1ccc(I)cc1)C(=O)O)C(=O)c1ccc(CCc2cccc(N)n2)cc1

Procedure:
A solution of acid 8-6 (400 mg, 1.43 mmol), amine 8-4 (686 mg, 1.57 mmol), EDC (358 mg, 1.86 mmol), HOBT (252 mg, 1.86 mmol), NMM (632 μl, 5.72 mmol) and DMF (10 ml) was stirred for ~20 h. The reaction was diluted with EtOAc and then washed with sat NaHCO3, brine, dried (MgSO4) and concentrated. Flash chromatography (silica, EtOAC→5% isopropanol/EtOAc) provided amide 8-7 as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[CH:5][C:3]=1[NH2:4].[OH-].[Na+].[C:15](Cl)(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].Cl>O.C(OC)(C)(C)C>[Br:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[CH:5][C:3]=1[NH:4][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1cc(N)c(Br)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Product: COc1cc(Br)c(NC(=O)C(C)(C)C)cc1OC
Reaction time: 1 h

Procedure:
A dry 500 mL three-necked flask was charged with 2-bromo-4,5-dimethoxyaniline (23.4 g, 0.10 mol) and t-BuOMe (200 mL), NaOH (25.3 g, 25%, 0.158 mol) was added in portions at 0° C. Then pivaloyl chloride (12.9 g, 0.106 mol) was added dropwise slowly under N2 at 0° C. After addition, the mixture was stirred for an additional 1 hour and diluted with water (100 mL), acidified by 5% HCl to pH=7 and extracted with EtOAc (100 mL×3). The combined organic layers were washed with water (100 mL×3), dried over anhydrous MgSO4, filtrated and concentrated in vacuum to afford the compound N-(2-bromo-4,5-dimethoxyphenyl)-2,2-dimethylpropanamide. MS (M+H)=316 and 318.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:5][C:6]2[O:11][CH2:10][CH2:9][O:8][C:7]=2[CH:12]=1.[C:19]([O-])(=O)/[CH:20]=[CH:21]/[C:22]([O-])=O>>[CH3:1][O:2][C:3]1[C:4]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH:20]3[CH2:6][C:7]4[C:22](=[CH:5][CH:4]=[CH:3][CH:12]=4)[CH2:21]3)[CH2:17][CH2:18]2)=[CH:5][C:6]2[O:11][CH2:10][CH2:9][O:8][C:7]=2[CH:12]=1
Reactant: COc1cc2c(cc1N1CCNCC1)OCCO2
Reactant: O=C([O-])/C=C/C(=O)[O-]
Product: COc1cc2c(cc1N1CCN(CC3Cc4ccccc4C3)CC1)OCCO2

Procedure:
Prepared as described in Example 9, starting from 4-(2,3-dihydro-7-methoxybenzo-1,4-dioxin-6-yl)piperazine (Preparation 5). The fumarate of the title compound melts at 176°-178° C. (ethanol).
Reaction SMILES: [NH2:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>C(#N)C.CO>[Cl:21][CH2:22][C:23]([NH:1][C:2]([C:6]1[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)([CH3:5])[CH2:3][OH:4])=[O:24]
Reactant: COc1ccc(C(C)(N)CO)cc1
Reactant: O=C(Cl)CCl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(C(C)(CO)NC(=O)CCl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 57.5 mmol of 2-amino-2-(4-methoxyphenyl)propan-1-ol in 190 ml of acetonitrile and 33 ml of methanol is cooled to −10° C., and 69 mmol of triethylamine and, dropwise over the course of 1 hour, 63.3 mmol of chloroacetyl chloride are successively added. The reaction mixture is warmed to room temperature and stirred for 16 hours. The mixture is evaporated, and the title compound is obtained as a colourless oil from the residue by flash chromatography (SiO2 60F). Rf=0.23 (ethyl acetate-heptane 2:1), Rt=2.88 (gradient I).
Reaction SMILES: C(NC(C)C)(C)C.[Br:8][C@H:9]([CH:13]([CH3:15])[CH3:14])[C:10](O)=[O:11].Cl.C[O:18][C:19](=[O:26])[C:20]1([CH2:25][CH2:24][CH2:23][CH2:22]1)[NH2:21]>>[Br:8][C@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([NH:21][C:20]1([C:19]([OH:26])=[O:18])[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:11]
Reactant: COC(=O)C1(N)CCCC1
Reactant: CC(C)[C@@H](Br)C(=O)O
Agent: Cl
Solvent: CC(C)NC(C)C
Product: CC(C)[C@@H](Br)C(=O)NC1(C(=O)O)CCCC1

Procedure:
The 1-[(R)-2-bromo-3-methylbutanoylamino]cyclopentanecarboxylic acid starting material is prepared essentially by methodology described in WO 99/55726 by condensation of (R)-2-bromo-3-methylbutanoic acid diisopropylamine salt (prepared from L-valine) with cycloleucine methyl ester hydrochloride.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][C:7]([F:10])([F:9])[CH2:6][N:5]1[C:11](=[O:21])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=O)[NH2:2].N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1.C(Cl)Cl>[C:1]([C@@H:4]1[CH2:8][C:7]([F:9])([F:10])[CH2:6][N:5]1[C:11](=[O:21])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])#[N:2]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CC(F)(F)C[C@H]1C(N)=O
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)N1CC(F)(F)C[C@H]1C#N
Reaction time: 1.5 h
Yield: 100 %

Procedure:
In a 50 mL round-bottomed flask (S)-tert-butyl 2-(2-carbamoyl-4,4-difluoropyrrolidin-1-yl)-2-oxoethylcarbamate (41) (0.720 g, 2.343 mmol) was dissolved in dry THF at −15° C. Then pyridine was added, followed by the dropwise addition of the solution of 2,2,2-trifluoroacetic anhydride (0.094 ml, 0.664 mmol) in 5 mL of DCM after the complete addition, the mixture was allowed to reach RT. The reaction mixture was stirred for 90 minutes. The reaction mixture was washed with 1M solution of aqueous solution of hydrochloric acid. Then the organic layer was washed three times with saturated sodium bicarbonate, brine, dried over sodium sulfate and evaporated. The crude mixture was purified using column chromatography (hexane-ethyl acetate 2-3) yielding a yellowish oil Yield: 0.678 g, 70%
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[CH:9]2.C(N(CC)CC)C.[N:25]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:2][N:3]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[CH:9]2)[C:30]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:31]
Reactant: O=C(Cl)N1CCCC1
Reactant: CNc1cccc2cc(-c3nccs3)[nH]c12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)N1CCCC1)c1cccc2cc(-c3nccs3)[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 5 %

Procedure:
To a solution of N-methyl-2-(1,3-thiazol-2-yl)-1H-indole-7-amine hydrochloride (133 mg) and triethylamine (105 μL) in tetrahydrofuran (5 mL) was added pyrrolidine-1-carbonylchloride (100 mg). The reaction mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1) to give yellow crystals (8.2 mg, yield 5%). melting point 182° C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH2:11][CH2:12][CH2:13]Cl)[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[CH2:25]([CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH2:26][CH2:27][CH3:28]>CCCCCCC.CCOC(C)=O>[CH2:25]([CH:29]1[CH2:34][CH2:33][N:32]([CH2:13][CH2:12][CH2:11][N:6]2[C:5]3[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][C:4]=3[O:9][CH2:8][C:7]2=[O:10])[CH2:31][CH2:30]1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCC1CCNCC1
Reactant: O=C1COc2cc(Cl)ccc2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCC1CCN(CCCN2C(=O)COc3cc(Cl)ccc32)CC1
Yield: 90 %

Procedure:
7-Chloro-4-(3-chloropropyl)-4H-benzo[1,4]oxazin-3-one (81MF2271b) (1.953 g, 7.49 mmol), K2CO3 (2.07 g, 14.9 mmol), NaI (2.24 g, 14.9 mmol) and 4-butylpiperidine (1.11 g, 7.86 mmol) were mixed according to GP11. CC (SiO2; Heptane/EtOAc 10:1-4) gave the title compound (81MF2271x) (2.46 g, 90%). 1H NMR (CDCl3) δ 7.08-6-96 (m, 3H), 4.57 (s, 2H), 3.95 (t, J=7.2 Hz, 2H), 2.85 (d, J=10.8 Hz, 2H), 2.35 (t, J=7.2 Hz, 2H), 1.93-1.78 (m, 4H), 1.66 (d, J=9.2 Hz, 2H), 1.31-1.18 (m, 9H), 0.88 (t, J=6.4 Hz, 3H); 13C NMR (CDCl3) δ 163.7, 146.0, 128.7, 127.7, 122.7, 117.6, 116.1, 67.7, 55.9, 54.3, 39.9, 36.5, 36.0, 32.7, 29.2, 24.8, 23.1, 14.2.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH:3]([OH:5])[CH3:4].[H-].[Na+].Cl[C:11]1[CH:12]=[CH:13][C:14]2[CH2:15][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][CH2:18][O:19][C:20]=2[N:21]=1.O>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH3:4][CH:3]([O:5][C:11]1[CH:12]=[CH:13][C:14]2[CH2:15][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][CH2:18][O:19][C:20]=2[N:21]=1)[C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: CC(O)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCOc2nc(Cl)ccc2C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(Oc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2)C(C)(C)C
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 62 %

Procedure:
To a solution of 3,3-dimethylbutan-2-ol (0.18 mL) in toluene (4 mL) was added sodium hydride (0.14 g), and the resulting mixture was stirred at 70° C. for 15 min under a nitrogen atmosphere. A mixture of tert-butyl 8-chloro-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.50 g), BINAP (0.033 g), Pd2(dba)3 (0.024 g) and toluene (4 mL) was added, and the resulting mixture was stirred at 100° C. for 2 hr under an argon atmosphere. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give tert-butyl 8-(1,2,2-trimethylpropoxy)-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.38 g, 62%) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][O:12][C:11](=[O:14])[N:10]2[C:15]([O:17]C2C=CC([N+]([O-])=O)=CC=2)=O)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:27][CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH:34]([C:37]2[CH:38]=[C:39]([NH:43][C:44](=[O:48])[CH:45]([CH3:47])[CH3:46])[CH:40]=[CH:41][CH:42]=2)[CH2:33][CH2:32]1>>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][O:12][C:11](=[O:14])[N:10]2[C:15]([NH:27][CH2:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][C:44](=[O:48])[CH:45]([CH3:46])[CH3:47])[CH:38]=3)[CH2:33][CH2:32]2)=[O:17])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C1OC[C@H](c2ccc(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)N3C(=O)OC[C@@H]3c3ccc(F)c(F)c3)CC2)c1

Procedure:
Prepared by Procedure AF and Scheme H using 4-nitrophenyl(4S)-4-(3,4-difluorophenyl)-2-oxo-1,3-oxazolidine-3-carboxylate and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 529.1 (M+H)+.
Reaction SMILES: [CH:1]([N:4]([CH3:22])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[C@H:7]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:6]1)([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[S:44]1[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[N:46]=[C:45]1[CH2:53][C:54]([O-])=[O:55].[Na+]>C1COCC1.C(Cl)Cl>[S:44]1[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[N:46]=[C:45]1[CH2:53][C:54]([NH:11][C@H:8]1[CH2:9][CH2:10][C@@H:5]([N:4]([CH:1]([CH3:3])[CH3:2])[CH3:22])[CH2:6][C@H:7]1[CH2:12][S:13]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:14])=[O:15])=[O:55]
Reactant: O=C([O-])Cc1nc2ccccc2s1
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N)[C@H](CS(=O)(=O)c2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)N(C)[C@@H]1CC[C@H](NC(=O)Cc2nc3ccccc3s2)[C@H](CS(=O)(=O)c2ccccc2)C1
Yield: 60.2 %

Procedure:
A solution of (1R,3R,4S)—N1-isopropyl-N1-methyl-3-(phenylsulfonylmethyl)-cyclohexane-1,4-diamine (see 30b) (70 mg, 0.216 mmol), EDCI (50 mg, 0.260 mmol), HOBT (35 mg, 0.260 mmol), and sodium 2-(benzo[d]thiazol-2-yl)acetate (56 mg, 0.260 mmol) in THF (5 mL) was stirred overnight at room temperature. The mixture was dilute with CH2Cl2 (25 mL) and washed with water, brine and evaporated. The residue was chromatographed on silica gel (6% NH4OH/MeOH/CH2Cl2) to give the product (65 mg). MS found: (M+1)+: 500.49.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([I:19])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH2:5][OH:6].[H-].[Na+].[CH3:22]I.[NH4+].[Cl-]>C1COCC1>[CH3:22][O:6][CH2:5][C:4]1[CH:3]=[C:2]([I:1])[C:9]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[C:8]([I:19])[CH:7]=1
Reactant: CI
Reactant: COc1ccc(Oc2c(I)cc(CO)cc2I)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCc1cc(I)c(Oc2ccc(OC)cc2)c(I)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.7 %

Procedure:
A solution of 3,5-diiodo-4-(4′-methoxyphenoxy)benzyl alcohol (9) (347 mg; 0.72 mmol) in dry THF under argon was cooled to 0° C. and treated with 60% sodium hydride in mineral oil (28 mg; 0.7 mmol). The reaction was stirred at 0° C. for 10 min, then allowed to warm to RT and stirred an additional 30 min. Methyl iodide (0.5 ml; 8.1 mmol) was added and the mixture stirred at RT for 18 h. The reaction was poured into saturated NH4Cl (20 ml) and extracted with EtOAc (20 ml). The organic layer was washed with saturated NaCl, dried over Drierite, and evaporated to a tan oil which solidified upon standing. The solid was dissolved in a minimum amount of CH2Cl2 (3 ml), applied to a silica gel column (30 g, 230-400 mesh) and eluted with EtOAc/hexanes (3:17). Product-containing fractions were combined and evaporated to give 231 mg of 3,5-diiodo-4-(4′-methoxyphenoxy)benzyl methyl ether (10) as a white solid. NMR (CDCl3) d 3.41 (s, 3H), 3.76 (s, 3H), 6.70 (m, 2H), 6.81 (m, 2H), 7.80 (s, 2H). TLC: Rf0.69 (EtOAc/hexanes, 3:7)
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:26]([CH3:34])[CH:27]=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].O>C(C(C)=O)C.C1(C)C=CC=CC=1>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH:26]([CH3:34])[CH:27]=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CCOC(=O)C=CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C=CC(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 40 °C

Procedure:
40 ml of dimethyl sulfoxide, 4.2 g of hydroquinone, 5.0 g of 2-chloro-5-trifluoromethylpyridine and 2.3 g of potassium hydroxide were reacted with stirring in a nitrogen gas stream at 150° C. for 2 hours to obtain 2.5 g of 4-(5-trifluoromethyl-2-pyridyloxy)phenol. The thus-obtained 4-(5-trifluoromethyl-2-pyridyloxy)phenol was dissolved in 20 ml of methyl ethyl ketone, and 1.7 g of anhydrous potassium carbonate was added thereto. The mixture was reacted with stirring under reflux for 1 hour, and the reaction product thusobtained was cooled to 40° C., and 2.5 g of ethyl 4-bromo-2-pentenoate was dropwise added thereto gradually. The mixture was allowed to stir for 30 minutes and then to react under reflux for 7 hours. After completion of the reaction, the reaction product was thrown into 100 ml of water, and an oily matter was extracted with methylene chloride. The extracted phase was washed with water several times, and dried over anhydrous sodium sulfate. The solvent was evaporated off to obtain a crude product which was subsequently subjected to silica gel column chromatography using toluene as an eluent to obtain 1.5 g of the object product having a refractive index, nD23, of 1.5145. This was found to have a boiling point of 148°-151° C./l mm Hg with some decomposition.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=2)[CH2:6][CH2:5][N:4]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:3]1.[H-].[Na+].[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32](F)[CH:31]=1.O>CN(C)C=O>[Cl:29][C:30]1[CH:31]=[C:32]([CH:33]=[CH:34][CH:35]=1)[O:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=2)[CH2:6][CH2:5][N:4]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:3]1
Reactant: Fc1cccc(Cl)c1
Reactant: Cc1ccc(O[C@@H]2CCN(C(=O)OCc3ccccc3)C[C@H]2O)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(O[C@@H]2CCN(C(=O)OCc3ccccc3)C[C@H]2Oc2cccc(Cl)c2)cc1C
Reaction time: 2 h

Procedure:
A solution of 15.0 g (0.04 mol) of the trans-3-hydroxy-4-(3,4-dimethyl-phenoxy)-1-carbobenzyloxy-piperidine described in Example 19 in 100 ml of dimethylformamide is introduced in the course of 30 minutes, at 30°-35°, into a suspension of 2.8 g (0.062 mol) of a 55% strength oily dispersion of sodium hydride in 50 ml of dimethylformamide. The mixture is then warmed to 50° and treated dropwise with 7.16 g (0.055 mol) of 1-chloro-3-fluorobenzene. The reaction mixture is subsequently stirred for 41/2 hours at 60°-70° and then for 15 hours at room temperature, cooled in an ice-water bath and treated with 250 ml of water. The mixture is extracted by shaking with 3 times 250 ml of ethyl acetate and the combined organic phases are washed twice with water, dried over magnesium sulphate and evaporated to dryness, first under a water pump vacuum and then under a high vacuum. The oil which remains behind is dissolved in 100 ml of toluene and the solution is filtered through a layer of silica gel. Elution with a toluene/ethyl acetate mixture (4:1) gives trans-3-(3-chlorophenoxy)-4-(3,4-dimethylphenoxy)-1-carbobenzyloxy-piperidine in the form of a pale yellow oil.