Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[O:5]1[CH:10]=[CH:9][CH2:8][CH2:7][CH2:6]1>C(Cl)Cl>[Br:1][CH2:2][CH2:3][O:4][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][O:5]1
Reactant: OCCBr
Reactant: C1=COCCC1
Solvent: ClCCl
Product: BrCCOC1CCCCO1
Reaction time: 18 h
Yield: 50.8 %

Procedure:
To a solution of 2-bromoethanol (10.00 g, 80 mmol) and 3,4-dihydro-2H-pyran (10.1 g, 120 mmol) in CH2Cl2 (400 mL) was added a spatula of Amberlyst-15 ion exchange resin and the reaction was stirred for 18 hrs. It was then filtered through Celite and concentrated. Distillation (40 mm Hg, b.p.=102° C.) afforded tetrahydro-2-(2-bromoethoxy)-2H-pyran (8.49 g).
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([O:30]CC)=O)[C:24]=2[CH:33]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F:43][CH:44]([F:47])[CH2:45][NH2:46]>>[F:43][CH:44]([F:47])[CH2:45][NH:46][C:28]([C:25]1[C:24]2[CH:33]=[C:20]([CH2:19][OH:18])[C:21]([N:35]3[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]3)=[C:22]([F:34])[C:23]=2[O:27][N:26]=1)=[O:30]
Reactant: NCC(F)F
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Product: C[C@@H]1CN(c2c(CO)cc3c(C(=O)NCC(F)F)noc3c2F)C[C@H](C)O1

Procedure:
Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and 2,2-difluoroethanamine
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5]1(=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>[Pt]>[CH:5]1([NH:3][CH2:2][CH2:1][NH2:4])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C1CCCCC1
Reactant: NCCN
Agent: [Pt]
Product: NCCNC1CCCCC1
Reaction time: 6 h

Procedure:
In this example the ratio of ethylenediamine:cyclohexanone, the reaction temperature, and the H2 :feed ratio were varied using as a catalyst 0.3 weight percent platinum (sulfided) on gamma-alumina in a non-aqueous environment. Samples were taken every 6 hours to afford the results in Table 1.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([NH:17][CH2:18][CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:24][C:25]([C:27]2[NH:28][CH:29]=[C:30]([C:32]#[N:33])[N:31]=2)=[O:26])=[CH:4][CH2:3]1.IC.[C:37]([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][C:2]1([CH3:34])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:17]([CH2:18][CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH3:37])([CH3:15])[CH3:16])[CH:11]=[CH:10][C:9]=2[NH:24][C:25]([C:27]2[NH:28][CH:29]=[C:30]([C:32]#[N:33])[N:31]=2)=[O:26])=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2cc(C(C)(C)NCCS(C)(=O)=O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(CCS(C)(=O)=O)C(C)(C)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCC(C)(C)CC2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.1 %

Procedure:
A mixture of 4-cyano-1H-imidazole-2-carboxylic acid {2-(4,4-dimethyl-cyclohex-1-enyl)-4-[1-(2-methanesulfonyl-ethylamino)-1-methyl-ethyl]-phenyl}-amide (as prepared in Example 18, 8.0 mg, 0.017 mmol), iodomethane (25 μL, 0.40 mmol) and solid NaHCO3 (25 mg, 0.30 mmol) in 1.0 mL of THF was stirred at RT for 6 h. The solvent was removed by evaporation and the residue was purified by silica gel chromatography (0-2% MeOH/DCM) to afford the title compound (5.0 mg, 61%) as a colorless oil. 1H-NMR (CDCl3; 400 MHz): δ 11.90 (s, 1H), 9.63 (s, 1H), 8.31 (d, 1H, J=8.6 Hz), 7.75 (s, 1H), 7.41 (dd, 1H, J=8.6, 2.3 Hz), 7.28 (d, 1H, J=2.3 Hz), 5.77 (m, 1H), 3.11 (t, 2H, J=7.1 Hz), 2.87 (s, 3H), 2.84 (t, 2H, J=6.0 Hz), 2.29 (m, 2H), 2.24 (s, 3H), 2.11 (m, 2H), 1.60 (t, 2H, J=6.3 Hz), 1.40 (s, 6H), 1.11 (s, 6H). Mass spectrum (ESI-neg, m/z): Calcd. for C26H35N5O3S, 496.3 (M−H). found 496.1.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17](S(C)(=O)=O)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-:35]#[N:36].[K+].O>CN(C)C=O>[C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:35]#[N:36])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Temperature: 120 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
A solution of N-(2,2-diphenylethyl)-2-(methylsulphonyl)-9-tetrahydro-2H-pyran-2-yl-9H-purin-6-amine (Preparation 4) (20.1 g, 42.1 mmol) in dry N,N-dimethylformamide (100 ml) was treated with potassium cyanide (5.5 g, 84.6 mmol) and the mixture was heated at 120° C. for 24 hours under a nitrogen atmosphere. The mixture was then cooled to room temperature, poured into water (1000 ml) and stirred for a further 1 hour. The resultant solid was slowly filtered and washed several times with water. The solid was then dissolved in dichloromethane and the resulting solution was washed with water, dried (anhydrous magnesium sulphate), filtered and evaporated under reduced pressure. The residue was azeotroped from diethyl ether twice to afford the title compound as an oil (17 g).1H-NMR (CDCl3) δ: 8.00 (1H, s), 7.40-7.20 (10H, m), 6.00-5.75 (1H, br s), 5.70 (1H, d), 4.40-4.20 (3H, m), 4.20-4.10 (1H, m), 3.80-3.70 (1H, m), 2.20-1.90 (3H, m), 1.90-1.60 (3H, m).
Reaction SMILES: [CH2:1]([N:5]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[C:12](\[CH2:18][P:19]([O:25]CC)([CH2:21][CH:22]([CH3:24])[CH3:23])=[O:20])/[C:13]([O:15]CC)=[O:14])[CH2:2][CH2:3][CH3:4].CO.O.[ClH:35]>>[ClH:35].[CH2:28]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[C:12](\[CH2:18][P:19]([OH:25])([CH2:21][CH:22]([CH3:24])[CH3:23])=[O:20])/[C:13]([OH:15])=[O:14])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCN(CCCC)CCCCC/C=C(\CP(=O)(CC(C)C)OCC)C(=O)OCC
Agent: Cl
Solvent: O
Solvent: CO
Product: CCCCN(CCCC)CCCCC/C=C(\CP(=O)(O)CC(C)C)C(=O)O
Temperature: 90 °C
Reaction time: 5.5 h
Yield: 94 %

Procedure:
Ethyl (Z)-8-dibutylamino-2-(ethoxyisobutylphosphinoyl)methyl-2-octenoate (200 mg; 0.43 millimole) was dissolved in 5 ml of concentrated hydrochloric acid, and the solution was stirred at 90° C. for 5.5 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified by medium-pressure liquid chromatography [Lobar column (a product of E. Merck & Co.), size B, Lichroprep RP-18, methanol/water (7:3)] to give 178 mg (yield 94%) of the captioned compound as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[O:14][C:15]([C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)=[C:16]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[O:14][C:15]([C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)=[C:16]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Nc1nc(-c2ccco2)c(-c2ccco2)o1
Product: O=C(Nc1nc(-c2ccco2)c(-c2ccco2)o1)c1cc(Br)ccc1O
Yield: 12.9 %

Procedure:
Using 5-bromosalicylic acid and 2-amino-4,5-bis(furan-2-yl)oxazole as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:12]2[N:13]([CH3:23])[C:14]([CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][CH3:20])=[CH:15][N:16]=2)=[CH:6][CH:5]=1.[CH3:35]I>O1CCCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH:11]([N:24]([CH3:35])[C:25](=[O:34])[O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:12]2[N:13]([CH3:23])[C:14]([CH2:17][C:18]([CH3:21])([CH3:22])[CH2:19][CH3:20])=[CH:15][N:16]=2)=[CH:8][CH:9]=1
Reactant: CCC(C)(C)Cc1cnc(C(Cc2ccc(Br)cc2)NC(=O)OCc2ccccc2)n1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C)(C)Cc1cnc(C(Cc2ccc(Br)cc2)N(C)C(=O)OCc2ccccc2)n1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60 wt % in mineral oil) (20 mg, 0.47 mmol) was added to a solution of benzyl {2-(4-bromophenyl)-1-[5-(2,2-dimethylbutyl)-1-methyl-1H-imidazol-2-yl]ethyl}carbamate (70 mg, 0.14 mmol) in tetrahydrofuran. After stirring at 0° C. for 10 min, methyl iodide (20 μL, 0.31 mmol) was added and the reaction allowed to warm to ambient temperature. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo to afford benzyl {2-(4-bromophenyl)-1-[5-(2,2-dimethylbutyl)-1-methyl-1H-imidazol-2-yl]ethyl}methylcarbamate which was used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:9]([O:12][C@@H:13]([CH2:17][CH2:18][O:19][CH3:20])[C:14](O)=[O:15])(=[O:11])[CH3:10].O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1>[C:9]([O:12][C@@H:13]([CH2:17][CH2:18][O:19][CH3:20])[C:14]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1)=[O:15])(=[O:11])[CH3:10]
Reactant: COCC[C@H](OC(C)=O)C(=O)O
Reactant: Cc1ccc(N)nc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: COCC[C@H](OC(C)=O)C(=O)Nc1ccc(C)cn1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
5-Methylpyridin-2-amine (CAS no. 1603-41-4) (460 mg, 4.26 mmol) was added to (S)-2-acetoxy-4-methoxybutanoic acid (Intermediate F3) (500 mg, 2.84 mmol), in THF (8 mL) under nitrogen. The resulting suspension was stirred at 23° C. for 30 minutes. 4-(4,6-Dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (CAS no. 3945-69-5) (1.18 g, 4.26 mmol) was added and the suspension stirred for 40 hrs. The reaction mixture was concentrated and purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane to afford (S)-4-methoxy-1-(5-methylpyridin-2-ylamino)-1-oxobutan-2-yl acetate (410 mg, 54%). 1H NMR (400 MHz, CDCl3) δ 2.13-2.28 (5H, m), 2.30 (3H, s), 3.31 (3H, s), 3.48-3.53 (2H, m), 5.37-5.40 (1H, m), 7.50-7.53 (1H, m), 8.09-8.11 (2H, m), 8.52 (1H, s); m/z (ESI+) (M+H)+=267; HPLC tR=1.22 min.
Reaction SMILES: [S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([OH:4])(=[O:3])=[O:2].[OH:12][NH:13][C:14]([NH:16][NH2:17])=[NH:15].[B]>C(OCC)(OCC)OCC>[S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([OH:4])(=[O:3])=[O:2].[OH:12][N:13]=[C:14]1[N:15]=[CH:5][N:17]=[N:16]1
Reactant: N=C(NN)NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [B]
Solvent: CCOC(OCC)OCC
Product: ON=C1N=CN=N1

Procedure:
A solution of N-hydroxy-N′-aminoguanidine tosylate (0.66 g; 2.5 mMol) in triethyl orthoformate (1.5 mL) in the presence of boron trifuloride etherate (10 mg) was stirred at room temperature during 8 h. The residue was filtered off and the product crystallised from the ethanol.
Reaction SMILES: [Li]CCCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([C:40]2[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=2)=[O:39])[CH:33]=1>C1COCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:38]([C:34]3[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=3)([C:40]3[CH:41]=[CH:42][C:43]([C:46]([F:47])([F:48])[F:49])=[CH:44][CH:45]=3)[OH:39])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: O=C(c1ccc(C(F)(F)F)cc1)c1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(C(F)(F)F)cc3)c3cccnc3)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.07 mL, 0.175 mmol) was added dropwise by syringe to a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (75.9 mg, 0.177 mmol, Intermediate 10) in dry THF (3 mL) in a dry ice-acetone bath. After 1.5 minutes, a solution of pyridin-3-yl(4-(trifluoromethyl)phenyl)methanone (48.0 mg, 0.191 mmol, Intermediate 91: step b) in dry THF (0.2 mL) was added dropwise. The reaction mixture was stirred for 5 minutes in a dry ice-acetone bath, then the reaction flask was placed into an ice-water bath. After 10 minutes, the mixture was warmed to room temperature and the reaction was quenched with methanol and water. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 10-50% EtOAc-Hexanes) to provide the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 8.51 (d, J=2.2 Hz, 1H), 8.48 (dd, J=4.8, 1.4 Hz, 1H), 8.02 (d, J=2.1 Hz, 1H), 7.83 (d, J=2.4 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.66 (d, J=1.6 Hz, 1H), 7.66-7.63 (m, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.5 Hz, 2H), 7.49 (dd, J=8.8, 2.2 Hz, 1H), 7.46 (d, J=8.3 Hz, 2H), 7.34 (d, J=8.5 Hz, 2H), 7.26-7.23 (m, 1H), 6.42 (t, J=2.1 Hz, 1H), 4.29 (s, 2H), 4.08 (s, 3H); MS m/e 602.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)C(OC(C)(C)C)=O.[C:45]1([S:51](Cl)(=[O:53])=[O:52])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:12]([CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:26][CH2:27]2)[CH2:11]1)[S:51]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)(=[O:53])=[O:52]
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](N(C)S(=O)(=O)c3ccccc3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 29, Step H in Step A and phenylsulfonyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [CH:1]([C@H:4]1[N:9]([CH2:10][C:11]([F:14])([F:13])[F:12])[C:8]2[CH:15]=[CH:16][C:17]([N+:19]([O-])=O)=[CH:18][C:7]=2[O:6][CH2:5]1)([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[NH2:19][C:17]1[CH:16]=[CH:15][C:8]2[N:9]([CH2:10][C:11]([F:14])([F:13])[F:12])[C@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][O:6][C:7]=2[CH:18]=1
Reactant: CC(C)[C@@H]1COc2cc([N+](=O)[O-])ccc2N1CC(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)[C@@H]1COc2cc(N)ccc2N1CC(F)(F)F
Yield: 90 %

Procedure:
This compound was prepared according to General Method 4 (EXAMPLE 1) from (3R)-3,4-dihydro-3-isopropyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine (0.350 g, 1.15 mmol) and 10% Pd/C (0.14 g) in 7 mL EtOAc to afford 0.284 g (90%) of (3R)-7-amino-3,4-dihydro-3-isopropyl-4-(2,2,2-trifluoroethyl)-2H-1,4benzoxazine after purification by flash chromatography (gradient elution, hexanes:EtOAc 9:1 to 3:1). Data for (3R)-7-amino-3,4-dihydro-3-isopropyl-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine: Rf 0.2 (3:1 hexanes:EtOAc); 1H NMR (400 MHz, CDCl3) δ 6.71 (d, 1H, J=8.5), 6.27 (dd, 1H, J=8.5, 2.6), 6.20 (d, 1H, J=2.5), 4.34 (dd, 1H, ABX, J=11.0, 1.5), 3.84 (dd, 1H, ABX, J=11.3, 2.2), 3.71-3.47 (m, 2H), 3.41 (broad s, 2H), 2.62 (d, 1H, J=9.8), 1.81-1.70 (m, 1H), 0.98 (d, 3H, J=6.7), 0.96 (d, 3H, J=6.7).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:17][CH:18]=[CH2:19])[CH3:16])[CH:5]=[CH:4][C:3]=1[C:20]([C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)=[O:21].[CH:29](O)=[O:30]>C(N)=O>[CH2:17]([N:15]([CH3:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([C:20](=[O:21])[C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)=[C:2]([NH:1][CH:29]=[O:30])[CH:7]=1)[CH:18]=[CH2:19]
Reactant: O=CO
Reactant: C=CCN(C)CCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)c(N)c1
Solvent: NC=O
Product: C=CCN(C)CCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)c(NC=O)c1

Procedure:
A solution of 230 mg of [2-amino-4-[6-(allyl-methyl-amino)-hexyloxy]-phenyl]-(4-bromo-phenyl)-methanone (Ex. 36) in 0.5 ml of formic acid and 2 ml of formamide is boiled at 165° C. for 5 min., concentrated at 170° C./0.1 Torr in a bulb-tube and converted into the free amine with methylene chloride/saturated sodium bicarbonate solution. After purification over silica gel with methylene chloride/methanol (2.5%) as the eluent there are obtained 30 mg of N-[5-[6-(allyl-methyl-amino)-hexyloxy]-2-(4-bromo-benzoyl)-phenyl]-formamide, MS: m/e 473 (M+H+, 1Br).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[F-].[Cs+].[N+](C1C=C(S(O[CH2:27][C@H:28]2[O:30][CH2:29]2)(=O)=O)C=CC=1)([O-])=O.O>CN(C=O)C>[O:30]1[CH2:29][C@H:28]1[CH2:27][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: Oc1cccc2ccccc12
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2c(OC[C@@H]3CO3)cccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
1-Naphthol (1.0 g) was dissolved in DMF (8 ml) under nitrogen atmosphere and the solution was cooled to 0° C. 25 Cesium fluoride (2.1 g) was added thereto and the mixture was stirred for 1 hour. Then, (S)-glycidyl m-nitrobenzenesulfonate (1.80 g, 99.3% e.e.) was added thereto and the mixture was stirred for 24 hours at the same temperature. After the reaction water was added to the mixture, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, condensed and the residue was subjected to silica gel chromatography (hexane/ethyl acetate; 6:1) to give 1.34 g of (S)-1-(2,3-epoxypropoxy)naphthalene (yield 96.5%, optical purity 99.2% e.e.) as a colorless oil.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[S:10][C:9]([OH:11])=[N:8][C:7]=1[CH3:12])(=[O:5])[CH3:4].O>C(Cl)Cl.C(O)(=O)C>[Br:1][CH2:4][C:3]([C:6]1[S:10][C:9]([OH:11])=[N:8][C:7]=1[CH3:12])=[O:5]
Reactant: BrBr
Reactant: CC(=O)c1sc(O)nc1C
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc(O)sc1C(=O)CBr
Yield: 49.8 %

Procedure:
A solution of bromine (19.2 g) in methylene chloride (10 ml) was dropwise added to a solution of 5-acetyl-2-hydroxy-4-methylthiazol (15.7 g) in a mixture of methylene chloride (300 ml) and acetic acid (50 ml) at 40° C. to 44° C. with stirring. After being stirred at the same temperature for 30 minutes, the reaction mixture was poured into water (300 ml). The separated organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 5-(2-bromoacetyl)-2-hydroxy-4-methylthiazole (11.75 g). mp 162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C(N(CC)CC)C.[CH3:17][C:18]([CH3:23])([CH3:22])[C:19](Cl)=[O:20]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:19](=[O:20])[C:18]([CH3:23])([CH3:22])[CH3:17])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cc(Cl)nc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1cc(Cl)nc(Cl)c1
Yield: 76.5 %

Procedure:
2,6-Dichloro-4-pyridinamine (10 g, 61.3 mmol) (Aldrich) and triethylamine (10.69 ml, 77 mmol) were combined in dichloromethane (DCM) (75 ml) and cooled in an ice-bath. 2,2-dimethylpropanoyl chloride (8.30 ml, 67.5 mmol) (Aldrich) in DCM (15 ml) was added drop wise and the mixture stirred whilst allowing to warm up overnight producing a clear dark orange solution. LCMS showed good conversion to product. The solution was washed with water and sat. NaHCO3 (100 ml each), dried with Na2SO4, filtered and concentrated to yield a dark orange solid. The crude product was taken up in the minimum of DCM and applied to a 320 g Companion XL silica column and eluted with 0% EtOAc in cyclohexane for 2 CVs then 0-15% EtOAc in cyclohexane over 12 CVs then held at 15% for 2 CV. Appropriate fractions were combined and evaporated to give the title compound as a yellow solid (11.59 g).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][CH2:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=1)[CH2:10][CH2:11][OH:12].C(N(CC)CC)C>C(Cl)Cl>[F:20][C:15]1[CH:14]=[C:13]([CH:9]([CH2:8][NH:7][C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:10][CH2:11][OH:12])[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: CCOC(=O)Cl
Reactant: NCC(CCO)c1ccc(F)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NCC(CCO)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
Ethyl chloroformate (3.9 mL, 40.8 mmol) was added dropwise to a stirred cooled (−40° C.) solution of 4-amino-3-(3,4-difluorophenyl)-1-butanol (7.45 g, 37 mmol) and triethylamine (5.94 mL, 42.6 mmol) in DCM (180 mL). The solution was stirred at room temperature for 30 min and at room temperature overnight. The material was washed twice with 1N HCl, twice with saturated sodium bicarbonate; dried (Na2SO4), filtered and the solvent removed to provide the title compound (8.85 g, 88%) as a yellow oil. 1H-NMR (CDCl3) δ 1.18-1.23 (t, 3H, CH) 1.72-1.98 (m, 3H) 2.96-3.00 (m, 1H, CH) 3.24-3.29 (m, 1H, CH) 3.45-4.04 (m, 3H, CH), 4.06-4.14 (m, 2H, CH) 4.66 (br. s, 1H, OH or NH) 6.91-7.37 (m, 3H, ArH). MS m/z 274 (M+H).
Reaction SMILES: C(N1CCN(NC([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)=O)CC1)(=O)C.[OH-].[Na+]>CO>[C:17]([OH:19])(=[O:18])[C:16]1[CH:21]=[CH:22][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(C(=O)NN2CCN(C(C)=O)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccccc1
Reaction time: 10 h
Yield: 241.7 %

Procedure:
To a stirred solution of methyl 4-[N-(4-acetyl-1-piperazinyl)carbamoyl]benzoate (300 mg) in methanol (9 ml) was added 1N aqueous solution of sodium hydroxide (1.2 ml) at ambient temperature and the mixture was stirred at the same temperature for 10 hours. After evaporation of solvent, the residue was diluted with water and neutralized with 1N hydrochloric acid and extracted with a mixture of ethyl acetate and tetrahydrofuran. The organic layer was dried over magnesium sulfate and concentrated. The residue was washed with tetrahydrofuran and ethyl acetate to give 4-N-(4-acetyl-1-piperazinyl)carbamoyl]benzoic acid (290 mg).
Reaction SMILES: Cl.C([O:6][C:7]([C:9]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[CH:34]=[CH:33][C:10]=1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([S:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([Cl:32])[CH:28]=3)[CH:23]=2)(=[O:21])=[O:20])[CH2:15][CH2:14]1)=[O:12])=[O:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:7]([C:9]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[CH:34]=[CH:33][C:10]=1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([S:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([Cl:32])[CH:28]=3)[CH:23]=2)(=[O:21])=[O:20])[CH2:15][CH2:14]1)=[O:12])([OH:8])=[O:6]
Reactant: CC(C)(C)OC(=O)c1cc(-c2ccncc2)ccc1C(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(-c2ccncc2)ccc1C(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 258 %

Procedure:
In dichloromethane (50 ml), 1-[2-tert-butoxycarbonyl-4-(pyridin-4-yl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride (250 mg) was dissolved, followed by the dropwise addition of trifluoroacetic acid (50 ml) under ice cooling. After stirring at room temperature for 5 hours, the solvent was distilled off. The residue was dissolved in methanol and the resulting solution was allowed to stand in a refrigerator for one day. The colorless solid so precipitated was collected by filtration and dried, whereby the title compound (550 mg, 28%) was obtained as a colorless solid.