Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2]N.C[N:5]([CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)C>CCCCO>[N:2]1[NH:5][CH2:7][CH:8]2[C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13]2
Reactant: NN
Reactant: CN(C)CC1CCCCC1=O
Solvent: CCCCO
Solvent: O
Product: C1CCC2CNN=C2C1

Procedure:
Hydrazine hydrate (28.0 mL) was dissolved in n-BuOH (200 mL) and cooled in an ice bath. A solution of 2-dimethylaminomethyl-cyclohexanone (64.0 g) in n-BuOH (50 mL) was added dropwise, the mixture was slowly warmed and refluxed for 20 hours. The solvent was evaporated under reduced pressure.
Reaction SMILES: [Mg].O1CCCC1.[C:7](Cl)([CH3:10])([CH3:9])[CH3:8].[C:12]1([Si:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(Cl)[Cl:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Cu](C#N)C#N.CCCCCC>[C:7]([Si:18]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[Cl:19])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)Cl
Reactant: Cl[Si](Cl)(c1ccccc1)c1ccccc1
Agent: N#C[Cu]C#N
Agent: [Mg]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Yield: 74.9 %

Procedure:
12.2 g (0.5 mol) magnesium was introduced into a 500 mL four-neck flask equipped with a reflux condenser, addition funnel, thermometer, and stirring rod. After drying under a nitrogen atmosphere, the tert-butyl Grignard reagent was prepared by the addition of 250 mL tetrahydrofuran and 46.3 g (0.5 mol) t-butyl chloride with stirring. To this was added 0.45 g (0.005 mol) copper cyanide at room temperature, and 126.6 g (0.5 mol) diphenyldichlorosilane was then dripped in while stirring. The system temperature rose to 50 degrees Centigrade. After heating and stirring under reflux for 5 hours, the addition of 100 mL hexane, filtration, distillation of the solvent, and continuing with distillation in vacuo gave 103 g (yield =75%) tert-butyldiphenylchlorosilane.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:20])[CH:7](OC(=O)C)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2][CH2:3][CH3:4].[C:21]1([O:27][CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>B(F)(F)F.CCOCC.C(Cl)Cl>[CH2:1]([O:5][C:6](=[O:20])[CH:7]([C:24]1[CH:25]=[CH:26][C:21]([O:27][CH3:28])=[CH:22][CH:23]=1)[NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C(NC(=O)OC(C)(C)C)OC(C)=O
Reactant: COc1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCOC(=O)C(NC(=O)OC(C)(C)C)c1ccc(OC)cc1

Procedure:
A solution of 290 mg. (1 mmol.) of N-t-butoxycarbonyl-2-acetoxyglycine n-butyl ester, 0.5 ml. of anisole and 3 drops of boron trifluoride etherate in 5 ml. of methylene chloride was stirred at 25° for 4 hours. The solvent was removed and the residue was chromatographed on silica gel and eluted with 1:1 chloroform-hexane to give the title compound.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].O>CN(C=O)C>[Si:13]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([F:3])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)n1ccc2cc(F)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
At 0° C., NaH (1.88 g, 46.2 mmol) was added to a solution of 5-fluoro-1H-indole (5.2 g, 38.5 mmol) in 40 mL DMF. After 10 min at 0° C. tert-butyldimethylsilyl chloride (6.96 g, 46.2 mmol) was added and the mixture allowed to stir at 0° C. for an additional 1 h. The mixture was warmed to room temperature and stirred overnight, then diluted by the addition of water and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated and purified by silica gel column chromatography to give the title compound (6.5 g, 67.7%)
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:12][CH2:13][CH3:14])[C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[Ar].[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:31]3[C:26](=[CH:27][C:28](I)=[CH:29][CH:30]=3)[CH:25]=[N:24]2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)CCC.[Cu]I>[F:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:31]3[C:26](=[CH:27][C:28]([O:5][C@H:4]([C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=4)[C@@H:3]([NH2:2])[CH2:12][CH2:13][CH3:14])=[CH:29][CH:30]=3)[CH:25]=[N:24]2)=[CH:21][CH:22]=1
Reactant: Fc1ccc(-n2ncc3cc(I)ccc32)cc1
Reactant: CCC[C@H](N)[C@H](O)c1ccccc1
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCCC#N
Product: CCC[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Temperature: 125 °C

Procedure:
In a vial under argon (1R,2S)-2-amino-1-phenylpentan-1-ol hydrochloride (91b, 46 mg, 0.21 mmol), 1-(4-fluorophenyl)-5-iodo-1H-indazole (87 mg, 0.26 mmol), copper(I)iodide (8.12 mg, 0.04 mmol) and cesium carbonate (278 mg, 0.85 mmol) were mixed in butyronitrile (0.6 mL). The vial was sealed and heated to 125° C. for 16 h. The mixture was filtered through celite. The celite was washed with ethyl acetate. The collected organic phases were evaporated and the crude product was purified by preparative HPLC. The pure fractions were collected, ethyl acetate and a saturated sodium carbonate were added and the mixture was shaken. The organic layer was separated and the water layer was washed twice with ethyl acetate. The combined organic layers were dried over sodium sulphate and finally evaporated to give the pure product.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.O.Cl.[NH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1>CO.O>[Cl:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[C:9]2[C:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH:17]=1
Reactant: O=C1CCNCC1
Reactant: Clc1cccc2cc[nH]c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Clc1cccc2c(C3=CCNCC3)c[nH]c12

Procedure:
Potassium hydroxide (6.89 g, 0.12 mol) was dissolved in methanol (30 mL). To the solution were added 7-chloroindole (4.65 g, 0.031 mol), 4-piperidone hydrochloride hydrate (9.48 g, 0.061 mol). The mixture was stirred at reflux temperature under nitrogen for about a day, and was cooled and diluted with 50 mL of water, added dropwise. The solid was collected, washed with water and vacuum dried. Yield 5.6 g (78%) as a yellow solid. mp 197°-201° C. FDMS m/e=232 (M+)
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:56])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:35]3[CH2:39][CH2:38][CH:37]([C:40]([O:42]CC4C=CC=CC=4)=[O:41])[CH2:36]3)=[O:34])[N:28]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:56])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:35]3[CH2:39][CH2:38][CH:37]([C:40]([OH:42])=[O:41])[CH2:36]3)=[O:34])[N:28]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC(C(=O)OCc4ccccc4)C3)n(-c3ccccc3)n2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC(C(=O)O)C3)n(-c3ccccc3)n2)CC1
Reaction time: 24 h

Procedure:
To a solution of 2.32 g 4-[(S)-2-({5-[2-(3-benzyloxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-4-tert-butoxycarbonyl-butyryl]-piperazine-1-carboxylic acid ethyl ester in 50 ml ethyl acetate was added 1.0 g Pd/C (10%) and the suspension stirred under an atmosphere of hydrogen (3 bar) for 24 h. The reaction mixture was filtrated over a plug of Celite, washed with ethyl acetate and concentrated.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](Br)[S:9][CH:10]=1)=[O:5])[CH3:2].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>O1CCOCC1>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:8]2[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CCOC(=O)c1csc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)c1csc(N2CCN(C(=O)OC(C)(C)C)CC2)n1

Procedure:
A mixture of 2-bromo-thiazole-4-carboxylic acid ethyl ester (1.4 g, 5.93 mmol), piperazine-1-carboxylic acid tert-butyl ester (1.16 g, 1.05 eq.) and DIPEA (1.15 g, 1.5 eq.) in 1,4-dioxane (20 mL) was heated to reflux overnight. After cooling, the solvent was removed in vacuo. The crude product was purified on silica gel (EtOAc:hexanes=1:4) to afford the desired product as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][N:14]1[C:21](=[O:31])[C:22]([OH:30])=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=[C:13]21)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.O>CN(C=O)C>[CH2:38]([O:30][C:22]1[C:21](=[O:31])[N:14]2[CH2:15][CH:16]3[CH2:17][CH2:18][C:12]([NH:11][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])([C:13]2=[N:24][C:23]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:20][CH2:19]3)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC1CCC2(NC(=O)OCc2ccccc2)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC1CCC2(NC(=O)OCc2ccccc2)CC1
Temperature: 50 °C
Yield: 42 %

Procedure:
To a solution of ethyl 10-(((benzyloxy)carbonyl)amino)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate (prepared according to the procedure in WO2009117540) (500 mg, 1.170 mmol) in DMF (20 mL) was added K2CO3 (323 mg, 2.339 mmol) followed by benzyl bromide (0.208 mL, 1.755 mmol) and the resulting mixture was heated at 50° C. for 16 h. After cooling to room temp, water was added and the mixture was extracted with ethyl acetate, dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel chromatography (20-100% ethyl acetate/hexane to afford the title compound (250 mg, 42% yield) as a light yellow liquid. 1H NMR (500 MHz, CDCl3) δ: 7.47 (d, 2H, J=7.02 Hz), 7.32-7.39 (m, 8H), 7.19 (brs, 1H), 5.26 (s, 2H), 5.08 (s, 2H), 4.31 (q, 2H, J=7.02 Hz), 4.13 (d, 2H, J=3.97 Hz), 2.87-2.96 (m, 2H), 2.46 (brs, 1H), 1.94-2.03 (m, 2H), 1.80-1.89 (m, 2H), 1.65-1.75 (m, 2H), 1.29 (t, 3H, J=7.32 Hz). LCMS (M+H)=518.28.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[C@H:15]([C:16](=[O:29])[NH:17][C@@H:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[F:28])[CH2:19][OH:20])[CH2:14][C@@H:13]2[C@H:11]1[CH2:12]2)=[O:9])([CH3:6])([CH3:5])[CH3:4].IC.[C:32]([O-])(O)=O.[Na+]>C1COCC1.C(Cl)Cl>[C:3]([O:7][C:8]([N:10]1[C@H:15]([C:16](=[O:29])[NH:17][C@@H:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[F:28])[CH2:19][O:20][CH3:32])[CH2:14][C@@H:13]2[C@H:11]1[CH2:12]2)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)N[C@H](CO)c1cccc(Cl)c1F
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: ClCCl
Product: COC[C@@H](NC(=O)[C@@H]1C[C@H]2C[C@H]2N1C(=O)OC(C)(C)C)c1cccc(Cl)c1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (60% in mineral oil, 25.7 mg, 0.64 mmol) in THF (3 mL) cooled at 0° C. under Argon was added (1R,3S,5R)-3-[(S)-1-(3-chloro-2-fluoro-phenyl)-2-hydroxy-ethylcarbamoyl]-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (270 mg, 0.64 mmol). The reaction mixture was stirred at 0° C. for 30 min and iodomethane (0.06 mL, 0.97 mmol) was added. After 1 h the reaction mixture was poured into saturated NaHCO3 aqueous solution. CH2Cl2 was added, the layers were separated and the aqueous one back-extracted with CH2Cl2 (×3). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 20:80) the desired compound as a colorless oil. TLC, Rf (EtOAc)=0.65; MS (UPLC/MS): 413.4/415.4 [M+H]+, 457.4/459.4 [M+HCOO]−; tR (HPLC conditions a): 3.67 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:30])[CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]([NH:27][OH:28])=[NH:26])=[CH:24][C:19]=4[O:18][C:17]3=[O:29])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:31][CH3:32].[CH:33](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:30])[CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]5[N:26]=[CH:33][O:28][N:27]=5)=[CH:24][C:19]=4[O:18][C:17]3=[O:29])[CH2:12][CH2:13]2)=[CH:4][C:3]=1[O:31][CH3:32]
Reactant: COC(OC)OC
Reactant: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(C(=N)NO)ccc43)CC2)ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(-c5ncon5)ccc43)CC2)ccc1Cl

Procedure:
A mixture 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-N-hydroxy-2-oxo-2,3-dihydro-benzooxazole-6-carboxamidine (65 mg), trimethyl orthoformate (3 ml) and p-toluenesulfonic acid (PTSA) (23 mg) was stirred at 103° C. overnight. The resultant solution was evaporated to dryness and then purified by flash chromatography to provide 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-6-[1,2,4]oxadiazol-3-yl-3H-benzooxazol-2-one (51): LCMS observed for (M+H)+: 470.5.
Reaction SMILES: C[O:2][C:3]1[CH:25]=[CH:24][C:6]([C:7]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:8])=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10]=2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:8])=[CH:24][CH:25]=1
Reactant: COc1ccc(C(=O)c2sc3ccccc3c2-c2ccccc2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(c1ccc(O)cc1)c1sc2ccccc2c1-c1ccccc1
Yield: 95.6 %

Procedure:
A mixture of 2-(4-methoxybenzoyl)-3-phenylbenzo[b]thiophene (12.0 g) and pyridine hydrochloride (35 g) was refluxed for thirty minutes. The hot reaction mixture was poured onto ice and the mixture transferred to a blender, homogenized, and the resulting crystals were collected by filtration, washed with water, and dried in vacuo at 80° C. yielding 11 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[CH:10]([CH2:15][CH2:16][Br:17])[C:11](OC)=[O:12].O>CN(C)C=O>[Br:17][CH2:16][CH2:15][CH:10]1[C:11](=[O:12])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]1
Reactant: Nc1ccccc1S
Reactant: COC(=O)C(Br)CCBr
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2SC1CCBr
Temperature: 25 °C

Procedure:
To a solution of 4.6 g of 2-aminothiophenol in 50 ml of dimethylformamide was added dropwise 9.55 g of methyl 2,4-dibromobutyrate with stirring at room temperature. After stirring one hour, the reaction mixture was poured into water to give crystals of 2-(2-bromoethyl)-2H-1,4-benzothiazin-3(4H)-one. The crystals were collected by filtration and washed with water, n-hexane and cold methanol. The yield was 6.32 g (63.3%). Recrystallization from ethyl acetate gave prisms, m.p. 151°-152° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:5](N(OC)C)=[O:6].NC1C=C(C=C([N+]([O-])=O)C=1)C(O)=O.[F:30][C:31]1[C:36]([OH:37])=[C:35]([F:38])[C:34]([F:39])=[C:33]([F:40])[C:32]=1[F:41].C1CCC(N=C=NC2CCCCC2)CC1>>[F:30][C:31]1[C:32]([F:41])=[C:33]([F:40])[C:34]([F:39])=[C:35]([F:38])[C:36]=1[O:37][C:5](=[O:6])[C:4]1[CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=[C:2]([NH2:1])[CH:3]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CON(C)C(=O)c1cc(N)cc([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1
Product: Nc1cc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Starting material (1(b)) was prepared as follows. A mixture of 3-amino-5-nitrobenzoic acid (10 g), pentafluoro-phenol (10 g) and DCCI (11.3 g) was stirred at ambient temperature for 24 hours. The reaction mixture was filtered and the filtrate poured onto a chromatography column which was then eluted with ethyl acetate/hexane (10:90) to give 3-amino-5-nitrobenzoic acid 2,3,4,5,6-pentafluorophenyl ester (1(a)) as a yellow solid (5.8 g).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.Cl.B([O-])([O-])[O-]>C1COCC1>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[B:20]([OH:25])[OH:21])(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Agent: [O-]B([O-])[O-]
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
N-tert-Butylbenzenesulfonamide (2.00 g, 12.7 mmol) was dissolved in anhydrous THF (10 mL). After being cooled to −78° C., n-BuLi (2.5 M, 6.0 mL) was injected slowly to the above solution. After being stirred at this temperature for another 1 h, triisopropyl borate (11.9 g, 63.5 mmol) was added at −78° C. The resulting mixture was then allowed to warm to room temperature slowly for 8 h. 1N HCl (10 mL) was added to hydrolyze the borate. The organic layer was dried over Na2SO4. After removal of the solvent, the residue was used for the next step without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[O:10][CH2:9][CH2:8][O:7]1)=[O:5])C.O.[OH-].[Li+]>O1CCCC1>[Br:17][C:14]1[CH:13]=[CH:12][C:11]([C:6]2([C:4]([OH:5])=[O:3])[O:7][CH2:8][CH2:9][O:10]2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)C1(c2ccc(Br)cc2)OCCO1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1(c2ccc(Br)cc2)OCCO1
Temperature: 25 °C
Reaction time: 48 h
Yield: 66 %

Procedure:
To a solution of 2-(4-Bromo-phenyl)-[1,3]dioxolane-2-carboxylic acid ethyl ester (example 346a), 300 mg) in tetrahydrofuran (2 mL) and water (2 mL) was added lithium hydroxide (41 mg) in two portions. The reaction mixture was stirred at room temperature over 2 days then concentrated in vacuo. The residue was acidified to pH=1 with aqueous hydrochloric acid solution (0.1N) extracted with ethyl acetate. The combined organic layer were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo to yield the title compound as a colorless oil (225 mg; 66%). MS (ESI): m/z=271.1 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]([CH2:13][CH:14]([F:16])[F:15])[C:9](=[O:12])OC)=[C:6]([NH2:17])[N:5]=[C:4]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[N:19]=2)[N:3]=1>O1CCCC1>[NH2:17][C:6]1[N:5]=[C:4]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[N:19]=2)[N:3]=[C:2]2[C:7]=1[N:8]([CH2:13][CH:14]([F:16])[F:15])[C:9](=[O:12])[NH:1]2
Reactant: COC(=O)N(CC(F)F)c1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Solvent: C1CCOC1
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=O)n(CC(F)F)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
132 mg (0.279 mmol) of the compound prepared in example 12A were dissolved in tetrahydrofuran (8 ml), and 0.307 ml of a 1M solution of bis(trimethylsilyl)sodium amide in tetrahydrofuran were added at 0° C. Stirring of the mixture at RT was continued overnight. This was followed by concentration and purification of the residue by means of preparative HPLC (eluent: acetonitrile/water with 0.05% formic acid, gradient). 81 mg of the title compound were obtained (62% of theory).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:27]=1[CH2:28]Cl>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:28][C:27]3[C:30]([CH3:34])=[CH:31][CH:32]=[CH:33][C:26]=3[CH3:25])[N:13]=2)=[CH:23][CH:22]=1
Reactant: Cc1cccc(C)c1CCl
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Product: Cc1cccc(C)c1Cn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2
Yield: 24.6 %

Procedure:
The title compound (0.018 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, step B; 0.2 mmol) using 2,6-dimethylbenzyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C22H24ClN3, 365.17; found, m/z 366.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.48-7.45 (m, 4H), 7.17-7.15 (br m, 1H), 7.11-7.09 (m, 2H), 5.51 (s, 2H), 3.43-3.41 (br m, 2H), 3.39-3.37 (br m, 2H), 3.31-3.29 (br m, 2H), 3.10-3.08 (br m, 2H), 2.31 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:7]=[CH:6]2)#[N:2].C(=O)(O)[O-].[Na+].Cl.[NH2:25][OH:26]>C(O)C>[OH:26][NH:25][C:1](=[NH:2])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:7]=[CH:6]2
Reactant: CCOC(=O)CCn1ncc2cc(C#N)ccc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCn1ncc2cc(C(=N)NO)ccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
Ethyl 3-(5-cyano-1H-indazol-1-yl)propanoate (D47) (1 g, 4.11 mmol) was dissolved in ethanol (30 ml) and sodium bicarbonate (1.73 g, 20.88 mmol) and hydroxylamine hydrochloride (571 mg, 8.22 mmol) were added. The reaction was left at room temperature overnight and then heated to 50° C. for 4 hours then left to cool overnight. The reaction mixture was filtered and the residue washed with ethanol. The ethanolic filtrate was evaporated to dryness in vacuo and then triturated with ether to give the title compound (764 mg) as a white solid of approximately 90% purity. MS (ES): C13H16N4O3 requires 276; found (MH+) 277.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:8][CH2:7][C@@H:6]([CH:9]([CH3:11])[CH3:10])[C@H:5]([O:12][CH2:13][CH2:14][N:15]([CH2:17][CH2:18]Cl)[CH3:16])[CH2:4]1.[C:20]1([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:2][C@@H:3]1[CH2:8][CH2:7][C@@H:6]([CH:9]([CH3:11])[CH3:10])[C@H:5]([O:12][CH2:13][CH2:14][N:15]([CH2:17][CH2:18][NH:30][CH2:29][CH2:28][CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:16])[CH2:4]1
Reactant: NCCCCc1ccccc1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OCCN(C)CCCl
Agent: Cl
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OCCN(C)CCNCCCCc1ccccc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
3.07 g of N-[2-((1R,3R,4S)-1-methyl-4-isopropylcyclohex-3-yloxy)ethyl]-N-(2-chl oroethyl)-N-methylamine hydrochloride were mixed with 8.8 g of 4-phenylbutylamine. The reaction mixture was stirred at a temperature of 45° C. for 8 hours. The reaction mixture was purified and simultaneously freed of excess 4-phenylbutylamine by chromatography on silica gel using tert.-butyl methyl ether. 3.52 g of oily N-[2-((1R,3R,4S)-1-methyl-4-isopropylcyclohex-3-yloxy)ethyl]-N-[2-(4-phenylbutylamino)ethyl]-N-methylamine were obtained.
Reaction SMILES: C(OC([N:11]1[C@@H:15]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:14]([CH:23]([OH:30])[CH2:24][NH:25][CH2:26][CH2:27][O:28][CH3:29])[O:13]C1(C)C)=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C@@H:15]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH:14]([OH:13])[CH:23]([OH:30])[CH2:24][NH:25][CH2:26][CH2:27][O:28][CH3:29]
Reactant: COCCNCC(O)C1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: COCCNCC(O)C(O)[C@@H](N)CC1CCCCC1
Yield: 100.3 %

Procedure:
44 mg of (4S,5RS)-3-benzyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-5-[(1RS)-1-hydroxy-2-(2-methoxyethylamino)ethyl]oxazolidine was dissolved in 1.5 ml of ethanol, and palladium black was added thereto. The mixture was treated in the same manner as in Example 17 to obtain 27 mg of (2RS,3RS,4S)-4-amino-5-cyclohexyl-1-(2-methoxyethylamino)-2,3-pentanediol as colorless oily substance.