Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[CH3:23][C:24]([CH3:26])=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH:24]([CH3:26])[CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: CC(C)=O
Reactant: Cn1nc(Cl)cc(Nc2ccc(C3CCNCC3)cn2)c1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)N1CCC(c2ccc(Nc3cc(Cl)nn(C)c3=O)nc2)CC1
Reaction time: 18 h
Yield: 97.3 %

Procedure:
To a solution of 6-chloro-2-methyl-4-(5-(piperidin-4-yl)pyridin-2-ylamino)pyridazin-3(2H)-one (200 mg, 625 μmol, Eq: 1.00) and acetone (799 mg, 1.01 ml, 13.8 mmol, Eq: 22) in MeOH (5 ml) was added sodium cyanoborohydride (39.3 mg, 625 μmol, Eq: 1.00) and acetic acid (656 mg, 625 μl, 10.9 mmol, Eq: 17.5). The reaction mixture stirred under N2 for 18 h. Additional acetone (1 ml) was added, followed by THF (3 ml). The reaction mixture continued stirring under N2 for 2 h. Additional sodium cyanoborohydride (19.7 mg, 313 μmol, Eq: 0.50) was added. The mixture stirred for 4 h. Concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 50% to 100% (60:10:1 DCM:MeOH:NH4OH)/DCM gradient) to give 6-chloro-4-(5-(1-isopropylpiperidin-4-yl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one (220 mg, 97%). LC/MS-ESI observed [M+H]+ 362.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([OH:17])(=[O:16])[CH2:12][C:13]([CH3:15])=O.[NH2:18]/[C:19](/[CH3:35])=[CH:20]\[C:21]([O:23][CH2:24][CH2:25][N:26]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:27])=[O:22]>C(O)(C)(C)C>[ClH:1].[CH2:28]([N:26]([CH2:25][CH2:24][O:23][C:21]([C:20]1[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([Cl:10])[C:2]=2[Cl:1])[C:12]([C:11]([OH:17])=[O:16])=[C:13]([CH3:15])[NH:18][C:19]=1[CH3:35])=[O:22])[CH3:27])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: C/C(N)=C/C(=O)OCCN(C)Cc1ccccc1
Reactant: CC(=O)CC(=O)O
Solvent: CC(C)(C)O
Product: CC1=C(C(=O)O)C(c2cccc(Cl)c2Cl)C(C(=O)OCCN(C)Cc2ccccc2)=C(C)N1
Product: Cl
Temperature: 25 °C
Yield: 38 %

Procedure:
A solution of 2,3-dichlorobenzaldehyde (0.70 g), 3-nitrooxy-2,2-bis(nitrooxymethyl)propyl ester of acetoacetic acid (1.42 g) and 2-(N-benzyl-N-methylamino)ethyl 3-aminocrotonate (0.99 g) in tert-butyl alcohol (3 ml) was heated for 2 hours at 60° C. and then refluxed for additional 5.5 hours. The resulting mixture was cooled to 25° C. and concentrated under reduced pressure. The residue obtained was subjected to column chromatography on silica gel (54 g) and eluted with a mixture of chloroform and methanol (100:1 by volume). The fractions containing the desired compound were collected and evaporated under reduced pressure to give yellow viscous oil. The oil was again subjected to column chromatography on silica gel (27 g) and eluted with a mixture of toluene and ethyl acetate (5:2 by volume). The fractions containing the desired compound were collected and evaporated under reduced pressure. The obtained residue in ethanol was treated with hydrogen chloride in ethanol. The solvent was removed by distillation under reduced pressure to give amorphous yellow powders of 3-nitrooxy-2,2-bis(nitrooxymethyl)propyl ester of 5-[2-(N-benzyl-N-methylamino)ethoxycarbonyl]-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylic acid hydrochloride (0.40 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:9](=[O:11])[NH:10][C:5]2=[N:4][CH:3]=1.B(O)(O)[C:21]1[CH:26]=[CH:25][C:24]([C:27]([NH2:29])=[O:28])=[CH:23][CH:22]=1.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O>[O:11]=[C:9]1[NH:10][C:5]2=[N:4][CH:3]=[C:2]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH2:29])=[O:28])=[CH:23][CH:22]=3)[N:7]=[C:6]2[N:8]1[CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: NC(=O)c1ccc(B(O)O)cc1
Reactant: O=c1[nH]c2ncc(Br)nc2n1CCC1CCOCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(-c2cnc3[nH]c(=O)n(CCC4CCOCC4)c3n2)cc1
Yield: 89 %

Procedure:
4-(2-oxo-3-(2-(Tetrahydro-2H-pyran-4-yl)ethyl)-2,3-dihydro-1H-imidazol-[4,5-b]pyrazin-5-yl)benzamide. 6-Bromo-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (0.400 g, 1.22 mmol), 4-carboxamide-phenylboronic acid (0.241 g, 1.46 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (0.098 g, 0.12 mmol), potassium phosphate (1.03 g, 4.88 mmol), water (2 ml) and dimethylformamide (7 mL) were reacted according to General Procedure B. The solution was condensed under reduced pressure and the product was crystallized from dichloromethane to give (0.400 g, 89% yield). 1H NMR (400 MHz, CD3OD) δ 8.54 (s, 1H) 8.40 (s, 1H), 8.09 (d, J=8.4, 2H), 7.94 (d, J=8.4, 1H), 4.08 (t, J=6.8, 2H), 3.92 (dd, J=11.2, 3.2, 2H), 3.64 (m, 2H), 1.83 (m, 4H), 1.59 (m, 1H), 1.38 (qd, J=12.8, 4.4, 2H); MS (ESI) m/z 368.4 [M+1]+; mp 233-236° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=[O:8].[H-].[Na+].[CH3:12]I.O>CN(C)C=O>[CH3:12][O:8][C:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)=[O:9]
Reactant: CI
Reactant: Cn1cccc1C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccn1C
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: The solution of 1,325 g of 1-methylpyrrole-2-carboxylic acid in 2,400 ml of dimethylformamide is added to the suspension prepared from 568.5 g of 50% sodium hydride in mineral oil and 2,400 ml of dimethylformamide, while stirring under nitrogen and cooling with ice. Thereupon 1,000 ml of dimethylformamide are added, followed by 4,316 g of methyl iodide while stirring and keeping the temperature below 88°. Stirring is continued overnight at room temperature, whereupon the mixture is cooled to 10° and combined with 10,600 ml of water. It is extracted thrice with 5,300 ml of diethyl ether, the extract washed with 5,300 ml of 10% aqueous sodium carbonate and 5,300 ml of water, dried and evaporated, to yield the 1-methylpyrrole-2-carboxylic acid methyl ester as an oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=[C:25]([C:28]4[CH:29]=[N:30][N:31]([CH2:33][CH2:34][NH:35][CH2:36][CH2:37]O)[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH2:42](N)[CH2:43]CC.NCCO>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:36]([NH:35][CH2:34][CH2:33][N:31]1[CH:32]=[C:28]([C:25]2[CH:26]=[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=2)[NH:21][CH:20]=[C:19]3[CH:16]2[CH2:17][CH2:18][N:13]([S:10]([CH2:8][CH3:9])(=[O:12])=[O:11])[CH2:14][CH2:15]2)[CH:29]=[N:30]1)[CH2:37][CH2:42][CH3:43]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCNCCO)c4)cc23)CC1
Reactant: CCCCN
Solvent: O=C(O)C(F)(F)F
Solvent: NCCO
Product: CCCCNCCn1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cn1
Yield: 26 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1H-pyrazol-4-yl)-1H-indole-7-carboxamide trifluoroacetate, substituting 1-butanamine (31 mg, 0.43 mmol) for the 2-aminoethanol to afford 7 mg of the title compound (26%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([O:7][CH2:8][CH:9]=O)=[CH:5][CH:4]=1.N1CCC[C@@H]1C(O)=O.ClN1C(=O)CCC1=O.[Br:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:41]=[N:40][C:39]([NH2:42])=[N:38][CH:37]=2)=[CH:32][C:31]=1[F:43]>C(Cl)(Cl)Cl>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[N:38][C:39]3[N:40]([C:8]([O:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=4)=[CH:9][N:42]=3)[N:41]=2)=[CH:32][C:31]=1[F:43]
Reactant: COc1ccc(OCC=O)cc1
Reactant: Nc1ncc(-c2ccc(Br)c(F)c2)nn1
Agent: O=C(O)[C@H]1CCCN1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(Oc2cnc3ncc(-c4ccc(Br)c(F)c4)nn23)cc1
Temperature: 25 °C

Procedure:
To a cooled (0° C.) mixture of (4-methoxyphenoxy)acetaldehyde (33.2 mg, 0.2 mmol) and D-proline (4.6 mg, 0.04 mmol) in chloroform (1.0 mL) was added N-chlorosuccinimide (26.7 mg, 0.2 mmol) with stirring. The mixture was stirred at 0° C. for 30 min, then gradually warmed to ambient temperature for 2 h. To the reaction mixture was added 6-(4-bromo-3-fluorophenyl)-1,2,4-triazin-3-amine (26.9 mg, 0.1 mmol). The reaction mixture was stirred for 1 h and then the solvent was removed under reduced pressure. The residue was dissolved in isopropanol (2 mL) and heated to 100° C. overnight. After cooling, the mixture was filtered and the filtrate was purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=415.0/416.9.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21]([O:23]CC)=[O:22])=[CH:15]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>O1CCOCC1.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21]([OH:23])=[O:22])=[CH:15]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2cc(NC(=O)OCc3ccccc3)ccc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1ccc2[nH]c(C(=O)O)cc2c1)OCc1ccccc1

Procedure:
Ethyl 5-Benzyloxycarbonylaminoindole-2-carboxylate, (PREPARATION 56, 0.76 g) is dissolved in 1,4-dioxane (5.6 ml) and water (0.56 ml). Crushed potassium hydroxide (0.23 g) is added and the reaction is heated to 50° for 5 hr. The reaction is neutralized by adding 4.05 ml of 1N aqueous hydrochloric acid. The reaction is extracted with THF/chloroform (10/90, 3 ×), saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title acid, NMR (300 MHz, d4-CD3OD) 7.64, 7.34-7.15, 6.98 and 5.09 δ.
Reaction SMILES: N[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[C:18]([F:21])[CH:17]=[C:16]([C:22]([NH:24][CH:25]4[CH2:27][CH2:26]4)=[O:23])[CH:15]=3)=[CH:10][CH:9]=2)=[N:5][N:4]=1.N([O-])=[O:29].[Na+].[OH-].[Na+]>C(O)(=O)C.O>[CH:25]1([NH:24][C:22]([C:16]2[CH:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:6]4[O:7][C:3]([CH2:2][OH:29])=[N:4][N:5]=4)=[CH:9][CH:10]=3)[C:19]([CH3:20])=[C:18]([F:21])[CH:17]=2)=[O:23])[CH2:26][CH2:27]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN)o2)cc1
Reactant: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CO)o2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4′-[5-(aminomethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-5-fluoro-6-methyl-1,1′-biphenyl-3-carboxamide (Example 45) (96 mg) in acetic acid/water (1:1 v/v, 7 ml) was cooled to 0° C. Sodium nitrite (206 mg) was added and the solution stirred for 30 minutes at 0° C. and then for a further 16 hours at room temperature. Concentrated sodium hydroxide solution (10 ml) was added to the reaction and the mixture extracted with ether (3×40 ml) and then chloroform (40 ml). The organic phases were combined, dried and reduced to dryness under vacuum. The residue was dissolved in 5% potassium hydroxide in methanol and stirred at room temperature for 90 minutes. The methanol was removed in vacuo, the residue partitioned between ethyl acetate/chloroform (1:1)/water and the organic phase dried and reduced to dryness under vacuum. This material was purified by chromatography on a bond-elut (silica, 2 g), eluting with an ethyl acetate/cyclohexane gradient to give after evaporation of the solvent N-cyclopropyl-5-fluoro-4′-[5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl]-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: Cl[Si](C)(C)C.Br[C:7]([F:14])([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].N1([CH2:24][NH:25][CH2:26][CH2:27][C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)C2C=CC=CC=2N=N1>O1CCCC1.[Zn]>[CH2:11]([O:10][C:8](=[O:9])[C:7]([F:14])([F:13])[CH2:24][NH:25][CH2:26][CH2:27][C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)[CH3:12]
Reactant: c1csc(CCNCn2nnc3ccccc32)c1
Reactant: CCOC(=O)C(F)(F)Br
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)CNCCc1cccs1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 28.1 %

Procedure:
To a mixture of 3.5 g (0.054 g-atom) of zinc powder (−325 mesh) and 60 mL of anhydrous tetrahydrofuran was added 5.1 mL (0.041 mole) of chlorotrimethylsilane in one portion. After stirring for 20 minutes, a solution of 5.2 mL (0.041 mole) of ethyl bromodifluoroacetate in 5 mL of tetrahydrofuran was added dropwise at a rate to keep the internal temperature below 35 degrees. The mixture was stirred for 20 minutes and then cooled to −10 to 0 degrees. A solution of 7 g (0.027 mole) of benzotriazol-1-ylmethyl-(2-thiophen-2-yl-ethyl)-amine in 20 mL of tetrahydrofuran was added dropwise at a rate to keep the internal temperature at −10 to 0 degrees. After 10 minutes the reaction mixture was warmed to room temperature and stirred for 3 hours at room temperature. The solution was cooled to −10 to 0 degrees and quenched by the addition of saturated aqueous sodium bicarbonate at a rate to maintain the internal temperature −10 to 0 degrees. Ether was added, the mixture was stirred for 15 minutes at room temperature and then filtered through Celite, washing with ether. The filtrate was extracted 3 times with ether. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Ether and hexane were added to the residue, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexane-ethyl acetate (gradient, 100:0-80:20) to give 2 g of 2,2-difluoro-3-(2-thiophen-2-yl-ethylamino)-propionic acid ethyl ester as a oil.
Reaction SMILES: [Si:1]([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:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:43][NH2:44]>C(O)C.ClCCl.[Cl-].[Na+].O>[Si:1]([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]([NH:43][NH2:44])=[O:30])[C:24]=2[CH:33]=1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
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
Reactant: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc3c(C(=O)NN)noc3c2F)C[C@H](C)O1
Yield: 72.2 %

Procedure:
Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204, 0.5 g, 0.85 mmol) in 4.5 ml ethanol was treated with anhydrous hydrazine (0.490 ml, 15.60 mmol) at room temperature for 2 hour. Reaction was diluted with dichloromethane and brine. Organic layer washed with water, dried over sodium sulfate, and concentrated. The residue purified on silica-gel column (elution 40% etoac in hexanes) to give 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carbohydrazide (0.354 g, 72.5%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[CH2:13][O:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=[N:3]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:24].[Na+].C(O)(=O)C.[C:31]([O:35][C:36]([O:38]C(OC(C)(C)C)=O)=O)([CH3:34])([CH3:33])[CH3:32].CCN(C(C)C)C(C)C>CO>[CH3:1][N:2]1[C:6]([CH:7]2[CH2:13][O:12][CH2:11][CH:10]([NH:24][C:36](=[O:38])[O:35][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:9][CH2:8]2)=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=[N:3]1
Reactant: Cn1ncc([N+](=O)[O-])c1C1CCC(=O)COC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cn1ncc([N+](=O)[O-])c1C1CCC(NC(=O)OC(C)(C)C)COC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.7 %

Procedure:
6-(2-Methyl-4-nitro-pyrazol-3-yl)oxepan-3-one (53 mg, 0.23 mmol), ammonium acetate (219 mg, 2.76 mmol), sodium cyanoborohydride (38 mg, 0.57 mmol) and a few pettets of 4A molecular seives were dissolved in methanol (2 mL). Acetic acid (35 mg, 0.57 mmol) was added and the mixture was stirred at RT under N2 atmosphere for three days. The reaction was quenched with sat. sodium bicarbonate and extracted with DCM (3×). Combined organic layers were dried (MgSO4) and the solvent removed under reduced pressure. The residue was dissolved in DCM (5 mL) and di-tert-butyl-dicarbonate (63 mg, 0.69 mmol) and DIPEA (0.067 mL, 0.38 mmol) were added. The mixture was stirred at room temperature overnight and then purified via silica gel chromatography (0-100% EtOAc/heptane) to afford tert-butyl N-[6-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-3-yl]carbamate (53 mg, 81%).
Reaction SMILES: [OH-].[Na+].FC(F)(F)C([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([S:19]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:16]=[CH:15][C:14]=2[O:32][CH3:33])[CH2:9][CH2:8]1)=O.O>CO>[CH3:33][O:32][C:14]1[CH:15]=[CH:16][C:17]([S:19]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:18][C:13]=1[N:10]1[CH2:11][CH2:12][NH:7][CH2:8][CH2:9]1
Reactant: COc1ccc(S(=O)(=O)c2cccc3ccccc23)cc1N1CCN(C(=O)C(F)(F)F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(S(=O)(=O)c2cccc3ccccc23)cc1N1CCNCC1
Yield: 68.2 %

Procedure:
A solution of 6N NaOH (0.5 mL) was added to a suspension of 2,2,2-trifluoro-1-{4-[2-methoxy-5-(naphthalene-1-sulfonyl)-phenyl]-piperazin-1-yl}-ethanone (1) (0.110 g; 0.23 mmol ) in methanol. After stirring at 80° C. for 10 min water was added (10 ml) and the mixture was extracted into ethyl acetate (20 ml). The organic phase was dried (Na2SO4) and concentrated in vacuo to give 1-[2-methoxy-5-(naphthalene-1-sulfonyl)-phenyl]-piperazine (101) as a white solid (0.060 g , 68%), MS, MH+ 383. The hydrochloride salt was prepared from ethanol-hydrogen chloride, m. p. 154-158° C.
Reaction SMILES: [CH2:1]([Zn]CC)C.C1(C)C=CC=CC=1.ClCI.[CH3:16]/[C:17](=[CH:20]/[CH:21]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[CH3:22])/[CH2:18][OH:19].S(=O)(=O)(O)O>>[CH3:16][C@:17]1([CH2:18][OH:19])[CH2:1][C@H:20]1[C@H:21]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[CH3:22]
Reactant: CC[Zn]CC
Reactant: C/C(=C/C(C)c1ccc(C)cc1)CO
Agent: ClCI
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Cc1ccc([C@H](C)[C@@H]2C[C@]2(C)CO)cc1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 68 %

Procedure:
Under a nitrogen atmosphere, a diethylzinc solution in toluene (concentration: 15% by weight, 9.4 g, 11.4 mmol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to −15° C. Chloroiodomethane (4.02 g, 22.8 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept at −15° C. After completion of the dropwise addition, the mixture was stirred at −10 to −15° C. for 20 minutes, and then cooled to −25° C. (Z)-2-Methyl-4-(4-methylphenyl)pent-2-en-1-ol (1.08 g, 5.7 mmol) was added dropwise at −20 to −25° C. over a period of 20 minutes. After completion of the dropwise addition, the stirring was continued at −15 to −25° C. for 60 minutes. Next, a 20% aqueous sulfuric acid solution (4.2 ml) was added. After stirring for 10 minutes, the aqueous layer was separated, and the organic layer was washed twice with water (10 ml). The solvent was recovered under reduced pressure to obtain a condensed residue. This residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1). [(1S*,2S*)-1-Methyl-2-((R*)-1-(4-methylphenyl)ethyl)cyclopropyl]methanol (0.79 g, 3.8 mmol, 68% yield) was obtained as the main isomer, and [(1S*,2S*)-1-methyl-2-((S*)-1-(4-methylphenyl)ethyl)cyclopropyl]methanol (0.21 g, 1.0 mmol, 18% yield) was obtained as a minor isomer. The relative configurations of the main isomer and the minor isomer were determined by NOESY measurement.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][Cl:10].C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:10][CH:9]1[CH2:8][NH:4][CH2:3][CH2:2][N:1]1[CH2:6][CH3:5]
Reactant: ClCCBr
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCNCC1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
The piperazine Example 2 (500 mg, 1.36 mmol), BrCH2CH2Cl (0.7 mL), and K2CO3 (320 mg, 2.3 mmol) were taken up in CH3CN (2 mL) and stirred at 25° C. for 18 h. The solution was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and dried (MgSO4), Filtration and concentration gave a yellow oil. The residue was purified via gradient flash chromatography (0-15% EtOAc in CH2Cl2, SiO2) which gave 357 mg (61%) of the chloro-ethyl piperazine as a yellow oil.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31].[C:32]1([C:38](Cl)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[C:38]([S:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: OCCOCCOCCOCCOCCOCCOCCCCCCCCCCCS
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: OCCOCCOCCOCCOCCOCCOCCCCCCCCCCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 49.2 %

Procedure:
To a solution of 2-{2-[2-(2-{2-[2-(11-mercapto-undecyloxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethoxy}-ethanol (3) (1.22 g, 2.6 mmol) prepared according to the method of Pale-Grosdemange et al.†, dissolved in 10 mL of THF was added triphenylmethyl chloride (1.46 g, 5.2 mmol). After stirring at room temperature for 48 hours, the reaction mixture was concentrated. The crude residue was purified by flash chromatography (gradient elution, EtOAc to 20:1 EtOAc/MeOH) to afford 910 mg (49%) of 4. 1H NMR (CDCl3, 400 MHz) d 7.36 (d, J=X Hz, 6H), 7.22 (t, J=X Hz, 6H), 7.15 (t, J=X Hz, 3H), 3.72-3.48 (br m, 24H), 3.40 (t, J=X Hz, 2H), 2.08 (t, J=X Hz, 2H), 1.52 (m, 2H), 1.4-0.9 (br, 16H). ES-MS: m/z 733.4 (M+Na+). † Pale-Grosdemange, C.; Simon, E. S.; Prime, K. L.; Whitesides, G. M. J. Am. Chem. Soc, 1991, 113, 12-20.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:17])C=1.N>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N+:6]([O-:17])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(Br)cn1
Agent: N
Solvent: ClCCl
Product: Cc1ccc(Br)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 5 -Bromo-2 -methyl-pyridine (71.35 g. 0.41 M) in dichloromethane (350 ml) was added a solution of m-chloroperbenzoic acid (78.83 g, 0.46 M) in dichloromethane (1100 ml), over a period of 2.5 hours. The reaction mixture was stirred at ambient temperature for a further 20 hours, cooled (ice/salt bath) and anhydrous ammonia bubbled into it for 1 hour during which time a white precipitate formed and the temperature of the solution was not allowed to rise above 151°. The reaction mixture was allowed to warm to room temperature, filtered and washed with dichloromethane. The filtrate and washings were combined and washed with Na2SO3 (5 %) solution (2×200 ml), water (2×150 ml), dried (phase separating paper) and evaporated to dryness in vacuo to give an off white solid. Recrystallisation from ethyl acetate gave 5 -bromo-2 -methylpyridine-N-oxide as white crystals, 65.66 g. 84 %. m.p. 116°-118°.