Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([CH3:37])[CH:36]=1)[C:6]([C:8]1[N:13]([CH2:14][CH2:15][O:16][C:17](=[O:19])[NH2:18])[C:12](=[O:20])[N:11](CC2C=CC(OC)=CC=2)[C:10](=[O:30])[C:9]=1[CH:31]([CH3:33])[CH3:32])=[O:7])#[N:2].C(O)(=O)C.O>CC#N>[C:1]([C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([CH3:37])[CH:36]=1)[C:6]([C:8]1[N:13]([CH2:14][CH2:15][O:16][C:17](=[O:19])[NH2:18])[C:12](=[O:20])[NH:11][C:10](=[O:30])[C:9]=1[CH:31]([CH3:33])[CH3:32])=[O:7])#[N:2]
Reactant: COc1ccc(Cn2c(=O)c(C(C)C)c(C(=O)c3cc(C)cc(C#N)c3)n(CCOC(N)=O)c2=O)cc1
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C#N)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2CCOC(N)=O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.2 %

Procedure:
Ceric ammonium nitrate (156 mg, 0.189 mmol, 3 eq.) was added to carbamic acid 2-[6-(3-cyano-5-methyl-benzoyl)-5-isopropyl-3-(4-methoxy-benzyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl]-ethyl ester (32 mg, 0.063 mmol, 1.0 eq.) in a mixture of MeCN (1 mL), acetic acid (0.4 mL) and water (0.2 mL). The reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture concentrated down. Ethyl acetate was added and the mixture was washed with brine. The organic layer was concentrated down and purified (silica gel, 20-80% EtOAc /hexane) to give a white solid (13.6 mg, 56%). 1H NMR (300 MHz, d6 DMSO): δ 11.52 (s, 1H), 8.43 (s, 1H), 8.22 (s, 1H), 8.09 (s, 1H), 3.92 (m, 1H), 3.81 (m, 2H), 3.22 (m, 1H), 2.44 (s, 3H), 2.08 (m, 1H), 1.04 (dd, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.[CH:11]1(O)[CH2:15][CH2:14][CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([O:8][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:7]=1
Reactant: COc1ccc(Br)cc1O
Reactant: OC1CCCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(Br)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A solution of 5-bromo-2-methoxyphenol (1 g), cyclopentanol (0.54 ml) and triphenylphosphine (1.55 g) in anhydrous tetrahydrofuran (20 ml), at 0° C., was treated with diethylazodicarboxylate (0.85 mi). The resulting yellow solution was stirred at 0° C. for 40 minutes then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of petroleum ether and ethyl acetate (19:1, v/v) to give the title compound (1.2 g) as a pale yellow oil. NMR (CDCl3): δ1.62 (m,2H), 1.78-2.20 (m,6H), 3.79 (s,3H), 4.72 (m,1H), 6.70 (d,1H), 7.00 (dd,2H). Mass spectrum (FAB): m/z 270/272 (M)+.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl.C(N(CC)CC)C.CCOC(C)=O>[C:13]([N:1]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1CCCNc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C1CCCN(C(=O)c2ccccc2)c2ccccc21
Yield: 55.7 %

Procedure:
1,2,3,4-Tetrahydro-benzo[b]azepin-5-one from Example E5.5 (480 mg, 2.98 mmol) was dissolved in a mixture of dichloromethane (30 ml) and triethylamine (1.3 ml). Benzoyl chloride (0.46 g, 3.28 mmol) was added and the reaction mixture was heated for at reflux for 2 h. The mixture was cooled and reduced in vacuo. The residue was dissolved in EtOAc and washed with 1M KHSO4 (aq), water and brine. The organic layer was dried, filtered and reduced in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 50% EtOAc: 50% hexane) to yield the title compound (440 mg, 56%).
Reaction SMILES: CO[N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH3:14])=[C:7]([OH:15])[CH:6]=1.Cl>C(O)C.[Pd]>[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH3:14])=[C:7]([OH:15])[CH:6]=1
Reactant: CCCOc1ccc(C=NOC)cc1O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCCOc1ccc(CN)cc1O
Reaction time: 3 h
Yield: 74.5 %

Procedure:
An amount of 3-hydroxy-4-propoxybenzaldehyde O-methyloxime (150 mg, 0.83 mmol) is dissolved in ethanol (4 mL). Then hydrogen chloride (0.600 mL) is added, followed by 10% Pd/C (15.0 mg). After hydrogenation at 35 psi for 3 h, the solution is filtered through Celite and evaporated to dryness. The residue is recrystallized from ethyl acetate to give 112 mg of crude product as a white solid. MS (ESI) m/z 182.3 (M+1)
Reaction SMILES: F[C:2]1C(F)=C(F)C(F)=C(F)N=1.F[C:13]1[C:18]([F:19])=[C:17]([F:20])[C:16]([F:21])=[C:15]([F:22])[N+:14]=1[O-:23].C[Mg]I.[Cl-].[NH4+]>C(OCC)C>[CH3:2][C:13]1[C:18]([F:19])=[C:17]([F:20])[C:16]([F:21])=[C:15]([F:22])[N+:14]=1[O-:23]
Reactant: [O-][n+]1c(F)c(F)c(F)c(F)c1F
Reactant: Fc1nc(F)c(F)c(F)c1F
Agent: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1c(F)c(F)c(F)c(F)[n+]1[O-]

Procedure:
2,3,4,5,6-Pentafluoropyridine (commercially available from Aldich Chemical Co.) is oxidized to the corresponding N-oxide following the procedures described in Step 6 of Example 66. The 2,3,4,5,6-pentafluoropyridine N-oxide is treated at ambient temperature with one equivalent of methylmagnesium iodide in diethyl ether as described by F. Binns and H. Suschitsky in Chemical Communications, 750-751 (1970) and J Chem Soc (C), 1223-1231 (1771). The reaction mixture is treated with aqueous ammonium chloride and extracted with diethyl ether. The ether solution is dried over anhydrous magnesium sulfate, filtered and concentated under reduced pressure and the crude product is chromatographed on silica gel to afford 2-methyl-3,4,5,6-tetrafluoropyridine N-oxide (3,4,5,6-tetrafluoro-2-picoline). The N-oxide is then reduced to afford the title compound by the procedures described in Step 8 of Example 66.
Reaction SMILES: [Br:1]Br.[CH3:3][CH:4]1[C:8]2[CH:9]=[CH:10][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:12][C:7]=2[O:6][C:5]1=[O:19].C(Cl)Cl>C(Cl)(Cl)Cl>[Br:1][C:10]1[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:12][C:7]2[O:6][C:5](=[O:19])[CH:4]([CH3:3])[C:8]=2[CH:9]=1
Reactant: CC1C(=O)Oc2cc(N3CCOCC3)ccc21
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC1C(=O)Oc2cc(N3CCOCC3)c(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 11 g (0.069 mole) of bromine in 50 ml of chloroform is added dropwise in the course of one hour, at from 0° to 5° C. while stirring, to a mixture of 15 g (0.064 mole) of 3-methyl-6-morpholinobenzofuran-2(3H)-one in 120 ml of chloroform. Subsequently the mixture is stirred at room temperature for 30 minutes. Methylene chloride is added to the reaction mixture, which is washed in succession with 10% strength sodium thiosulphate solution, dilute sodium bicarbonate solution and water. The crude product remaining after drying and concentrating by evaporation the organic phase is chromatographed over silica gel with petroleum ether/ether. Recrystallisation of the pure fractions from ether/petroleum ether yields 5-bromo-3-methyl-6-morpholinobenzofuran-2(3H)-one having a melting point of 99°-100° C.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)=[O:35].C(Cl)Cl.CO>ClCCl>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:34](=[O:35])[O:36][C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=4)=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: O=C(Cl)Oc1ccc(F)cc1
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCN1C(=O)c2cccc3cc4cccc(NC(=O)Oc5ccc(F)cc5)c4c(c23)C1=O
Temperature: 20 °C
Yield: 72.8 %

Procedure:
100 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.30 mmol) were dissolved in 6 ml of dichloromethane. 85 μl (2 molar equivalents) of triethylamine and 105 mg (2 molar equivalents) of 4-fluorophenyl chloroformate were respectively added. The reaction mixture was maintained at 20° C. for 3 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography on silica, (eluent: CH2Cl2/methanol in a 95/5 volume ratio) to provide 103 mg (yield=66%) of the desired product (formula below) as an orange powder.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([CH:15]1[O:17][CH2:16]1)[Cl:14]>>[CH2:1]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:16][O:17][CH:15]1[CH2:13][Cl:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCC1CO1
Reactant: OCCCNCc1ccccc1
Product: ClCC1OCCCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 23.7 %

Procedure:
A solution of 3-benzylamino-propan-1-ol (14 g, 88.0 mmol) and epichlorohydrin (81.4 g, 880 mmol) was heated to 40° C. After stirring for 3 h the reaction was cooled and excess epichlorohydrin was removed by evaporation in vacuo. Sulfuric acid (10 mL) was added slowly, then the reaction flask was placed in a preheated oil bath at 150° C. Stirring proceeded for 1 h, then the reaction was allowed to cool to room temperature and quenched with the addition of ice. The mixture was adjusted to a basic pH with 10% aqueous Na2CO3 solution and extracted with EtOAc (3×300 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and dried under reduced pressure. The resulting residue was purified by flash chromatography (70:28:2 hexanes/CH2Cl2/2M NH4OH aq) to afford 5 g of a light yellow oil.
Reaction SMILES: Cl.Cl.[CH3:3][C@@:4]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[O:8][C:7]2=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]2[CH2:5]1.C(N(CC)CC)C.[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([Cl:38])[CH:37]=1)[CH2:33][OH:34].[C:39](N1C=CN=C1)(N1C=CN=C1)=[O:40]>O.CN(C=O)C>[CH3:3][C@@:4]1([CH2:15][N:16]2[CH2:17][CH2:18][N:19]([C:39]([O:34][CH2:33][C:32]3[CH:31]=[C:30]([Cl:29])[CH:37]=[C:36]([Cl:38])[CH:35]=3)=[O:40])[CH2:20][CH2:21]2)[O:8][C:7]2=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]2[CH2:5]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCc1cc(Cl)cc(Cl)c1
Reactant: C[C@]1(CN2CCNCC2)Cn2cc([N+](=O)[O-])nc2O1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@]1(CN2CCN(C(=O)OCc3cc(Cl)cc(Cl)c3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.2 %

Procedure:
To a mixture of (S)-2-methyl-6-nitro-2-(piperazin-1-ylmethyl)-2,3-dihydroimidazo[2,1-b]oxazole dihydrochloride prepared in Example 408 (300 mg, 0.88 mmol) and DMF (3 ml), triethylamine (270 mg, 2.67 mmol) was added for neutralization. To the solution, a mixture of 3,5-dichlorobenzyl alcohol (180 mg, 1.02 mmol), DMF (3 ml) and 1,1′-carbonyldiimidazole (180 mg, 1.11 mmol) stirred at room temperature for 2 hours was added followed by stirring at room temperature overnight. To the reaction mixture, water was added, and the mixture was extracted with ethyl acetate twice. The organic phases were combined, washed with water twice and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to afford 3,5-dichlorobenzyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate (220 mg, yield 53%) as a white powder.
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH2:7][N:8]([CH3:10])[CH3:9])=[CH:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2.[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][C:4]1[C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=2[S:1][C:5]=1[CH2:6][CH2:7][N:8]([CH3:10])[CH3:9]
Reactant: CN(C)CCc1cc2ccccc2s1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CN(C)CCc1sc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled solution of Compound 1a (2-Benzo[b]thiophen-2-yl-ethyl) -dimethyl-amine (39 mmol) in chloroform (500 mL) was added Br2 (43 mmol) dropwise. The mixture was stirred overnight at RT and subsequently washed with sat. NaHCO3 (3×) and brine, dried (MgSO4) and concentrated in vacuo. The crude material was purified by silica gel column chromatography in EtOAc to afford [2-(3-Bromo-benzo[b]thiophen-2-yl)-ethyl]-dimethyl-amine, Compound 2a, as an oil (9.6 g, 86%); MS (MH+) 283.9.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[N:11]([CH:12]([CH3:14])[CH3:13])[C:10]([CH3:15])=[N:9][CH:8]=1)=O.Cl.[NH2:18][C:19]([NH2:21])=[NH:20].C[O-].[Na+]>C(O)CCC>[NH2:20][C:19]1[N:21]=[C:5]([C:7]2[N:11]([CH:12]([CH3:13])[CH3:14])[C:10]([CH3:15])=[N:9][CH:8]=2)[CH:4]=[CH:3][N:18]=1
Reactant: Cc1ncc(C(=O)C=CN(C)C)n1C(C)C
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: Cc1ncc(-c2ccnc(N)n2)n1C(C)C
Yield: 39.4 %

Procedure:
5-(3-Dimethylaminoprop-2-en-1-oyl)-1-isopropyl-2-methylimidazole (Method 24; 4.9 g, 22.2 mmol) and guanidine hydrochloride (5.3 g, 55.6 mmol) were suspended in 1-butanol (70 ml). NaOMe (4.8 g, 88 mmol) was added in one portion and the mixture heated under reflux, under an atmosphere of nitrogen, for 3 hours. The volatiles were removed by evaporation. Water (50 ml) was added and extracted EtOAc (3×50 ml). The organic layers were combined and dried evaporated in vacuo. The residue triturated with isohexane to give the title compound as a brown solid (1.9 g, 40%). NMR: 1.46 (d, 6H), 2.43 (s, 3H), 5.45 (m, 1H), 6.50 (brs, 1H), 6.74 (d, 1H), 7.28 (s, 1H), 8.12 (d, 1H); m/z 218
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[CH:15]1([CH:20]=[CH:21][C:22]#[N:23])[CH2:19][CH2:18][CH2:17][CH2:16]1.N12CCCN=C1CCCCC2>C(#N)C>[CH:15]1([CH:20]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:21][C:22]#[N:23])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: N#CC=CC1CCCC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC1(C)OB(c2cnn(C(CC#N)C3CCCC3)c2)OC1(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.00 g, 0.0103 mol) in acetonitrile (30 mL) was added 3-cyclopentylacrylonitrile (1.25 g, 0.0103 mol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (1.54 mL, 0.0103 mol). The resulting mixture was stirred at 60° C. overnight, then evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 50% EtOAc in hexanes, to give the desired product (2.36 g, 73%). LCMS (M+H) 316.1.
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18](/[CH:22]=[CH:23]/[C:24]2[S:25][CH:26]=[C:27]([CH:29]3[CH2:32][CH2:31][CH2:30]3)[N:28]=2)[CH:17]=1)=[O:14])C.O1CCCCC1.CO.O.[OH-].[Li+]>O>[CH:29]1([C:27]2[N:28]=[C:24](/[CH:23]=[CH:22]/[C:18]3[CH:17]=[C:16]([NH:15][C:13](=[O:14])[CH2:12][CH2:11][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[C:4]([OH:33])=[O:3])[CH:21]=[CH:20][CH:19]=3)[S:25][CH:26]=2)[CH2:32][CH2:31][CH2:30]1
Reactant: CCOC(=O)c1ccccc1CCC(=O)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOCC1
Product: O=C(CCc1ccccc1C(=O)O)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Reaction time: 20 h

Procedure:
A solution composed of 0.457 g of (E)-2-[3-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-3-oxopropyl]benzoic acid ethyl ester, 25 ml of tetrahydropyran, 8 ml of methanol, 8 ml of water and 0.282 g of lithium hydroxide monohydrate was allowed to stand at room temperature for 20 hr. The solvents were removed by rotary evaporation and the residual materials were taken up in 30 ml of water. Addition of excess acetic acid caused the precipitation of 0.42 g of (E)-2-[3-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-3-oxopropyl]benzoic acid; m.p. 238°-239° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:26])[S:16]([C:19]2[CH:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:28][NH2:29]>>[CH2:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:26])[S:16]([C:19]2[CH:20]=[N:21][C:22]([NH:28][NH2:29])=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CN([C@@H]1CC[C@H](COCc2ccccc2)C1)S(=O)(=O)c1ccc(Cl)nc1
Solvent: O
Product: CN([C@@H]1CC[C@H](COCc2ccccc2)C1)S(=O)(=O)c1ccc(NN)nc1
Yield: 86 %

Procedure:
According to process 5.2, starting with 0.58 g of N-{(1R,3S)-3-[(benzyloxy)methyl]-cyclopentyl}-6-chloro-N-methylpyridine-3-sulfonamide and 0.15 mL of hydrazine hydrate, 0.49 g of N-{(1R,3S)-3-[(benzyloxy)methyl]cyclopentyl}-6-hydrazinyl-N-methylpyridine-3-sulfonamide is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH3:13])[C:9]2=[O:12])=[CH:5][CH:4]=1.[CH2:14](OC(OCC)OCC)[CH3:15]>C(O)C>[CH3:13][C:8]1[CH2:7][C:6]2[C:10]([C:9]=1[O:12][CH2:14][CH3:15])=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2
Reactant: COc1ccc2c(c1)C(=O)C(C)C2
Reactant: CCOC(OCC)OCC
Solvent: CCO
Product: CCOC1=C(C)Cc2ccc(OC)cc21

Procedure:
6-Methoxy-2-methylindanone [1.76 g (0.01 mole)] is dissolved in 6.5 ml of absolute ethanol (containing 20% anhydrous ether). This solution is stirred with 2.4 g (0.016 mole) of triethylorthoformate and a drop of redistilled BF3C2H5OC2H5 for about 72 hours. The reaction mixture is diluted with ether poured slowly into 8.1 ml. of 5.0% sodium hydroxide solution with crushed ice with stirring. Two layers separate and the organic layer is washed with cold water until neutral followed by saturated sodium chloride solution and dried over sodium sulfate. This is then filtered and the solvent removed and the residue distilled with 1 ml of benzene solution which contains about 47.5 mg of anhydrous p-toluene sulfonic acid to obtain 2-methyl-3-ethoxy-5-methoxyindene.
Reaction SMILES: C([NH:8][C:9]1[C:10]([CH3:23])=[C:11]([CH3:22])[C:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14](=[O:19])[C:13]=2[C:20]=1[CH3:21])C1C=CC=CC=1>C(OCC)(=O)C.CCCCCC>[NH2:8][C:9]1[C:10]([CH3:23])=[C:11]([CH3:22])[C:12]2[O:16][C:15]([CH3:17])([CH3:18])[C:14](=[O:19])[C:13]=2[C:20]=1[CH3:21]
Reactant: Cc1c(C)c2c(c(C)c1NCc1ccccc1)C(=O)C(C)(C)O2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1N)C(=O)C(C)(C)O2
Yield: 88 %

Procedure:
Using 5-(benzylamino)-2,2,4,6,7-pentamethyl-1-benzofuran-3 (2H)-one obtained in Reference Example 52, the title compound was synthesized in the same manner as in Reference Example 30. Yield 88%. Melting point: 92-93° C. (ethyl acetate-hexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3([O:19][C:7]=2[C:6]([C:20]([OH:22])=[O:21])=[CH:5][CH:4]=1)[CH2:15][CH2:14][N:13](C(=O)C)[CH2:12][CH2:11]3.[Li+].[OH-].Cl.[CH3:26]O>O>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3([O:19][C:7]=2[C:6]([C:20]([O:22][CH3:26])=[O:21])=[CH:5][CH:4]=1)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3
Reactant: COc1ccc(C(=O)O)c2c1OC1(CCN(C(C)=O)CC1)O2
Reactant: CO
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1ccc(OC)c2c1OC1(CCNCC1)O2
Yield: 57 %

Procedure:
A solution of 7-methoxy-1′-acetyl-spiro[1,3-benzodioxole-2,4′-piperidine]-4-carboxylic acid (143 mg, 0.467 mmol) and LiOH (224 mg, 9.34 mmol) in water (3 mL) and MeOH (3 mL) was heated to 75° C. for five hours. At room temperature the mixture was neutralized with 2M HCl and evaporated to dryness under reduced pressure. The crude 7-methoxy-spiro[1,3-benzodioxole-2,4′-piperidine]-4-carboxylic acid [LC/MS (METHOD B): (m/z) 266.2 (MH+); RT=1.57 min; purity (UV)=82%] was refluxed overnight in 1.7 M methanolic HCl (5 mL). At room temperature water (20 mL) was added. The aqueous phase was washed with Et2O (10 mL), made basic by addition of Na2CO3 and extracted with dichloromethane (3×10 mL). The organic phase was dried over MgSO4 and evaporation under reduced pressure afforded methyl 7-methoxy-spiro[1,3-benzodioxole-2,4′-piperidine]-4-carboxylate (75 mg, 57%). 1H NMR (DMSO) δ 7.31 (d, 1H), 6.72 (d, 1H), 3.87 (s, 3H), 3.78 (s, 3H), 2.96-2.77 (m, 4H), 1.94-1.83 (m, 4H).
Reaction SMILES: [N:1]([C:4]1[C:5]([CH3:11])=[N:6][CH:7]=[C:8]([CH3:10])[N:9]=1)=[N+]=[N-].Cl.O.O.[Sn](Cl)(Cl)(Cl)Cl>CO.C(OCC)(=O)C>[NH2:1][C:4]1[C:5]([CH3:11])=[N:6][CH:7]=[C:8]([CH3:10])[N:9]=1
Reactant: Cc1cnc(C)c(N=[N+]=[N-])n1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cnc(C)c(N)n1
Temperature: 60 °C
Reaction time: 12 h
Yield: 38 %

Procedure:
To a stirred solution of 3-azido-2,5-dimethyl pyrazine (100 mg; 0.66 mmol) in methanol (800 μL) was added 12N HCl (100 μL) and tin chloride dihydrate (149 mg; 0.66 mmol). The reaction was heated to 60° C. and stirred for 12 hours. The reaction was cooled to room temperature, diluted with 50 mL of ethyl acetate and washed with aqueous 10% sodium carbonate (1×50 mL), brine (50 mL), then dried (MgSO4) and filtered. The material was purified using a biotage 12i cartridge eluting with ethyl acetate to yield an off white solid (38% yield).
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[I:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20](O)=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>>[I:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:1][CH:2]3[CH:7]4[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]4)[CH2:3]3)=[CH:19][CH:18]=2)=[CH:15][CH:16]=1
Reactant: OC1CN2CCC1CC2
Reactant: Oc1ccc(-c2ccc(I)cc2)cc1
Product: Ic1ccc(-c2ccc(OC3CN4CCC3CC4)cc2)cc1

Procedure:
3-Hydroxy quinuclidine (Aldrich, 508 mg, 4 mmol) was coupled with 4′-iodo-1,1′-biphenyl-4-ol (Avacado, 592 mg, 2 mmol) according to the procedure of Example 5A. The title product was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.30) as solid (480 mg, yield, 59%). 1H NMR (MeOH-d4, 300 MHz) δ 1.43-1.57 (m, 1H), 1.62-1.88 (m, 2H), 1.97-2.12 (m, 1H), 2.14-2.21 (m, 1H), 2.72-3.00 (m, 5H), 3.31-3.43 (m, 1H), 4.51-4.60 (m, 1H), 6.98 (d, J=8.8 Hz, 2H), 7.35 (d, J=8.5 Hz, 2H), 7.53 (d, J=8.8 Hz, 2H), 7.74 (d, J=8.5 Hz, 2H) ppm. MS (DCl/NH3) m/z 406 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]([F:18])([F:17])[F:16])[CH2:3][CH2:2]1.Cl.[NH2:20][C:21]([CH2:28][CH3:29])([CH2:26][CH3:27])[C:22]([O:24][CH3:25])=[O:23]>>[CH3:25][O:24][C:22](=[O:23])[C:21]([NH:20][C:12]([C:10]1[CH:9]=[CH:8][C:7]([C:15]([F:18])([F:17])[F:16])=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH2:28][CH3:29])[CH2:26][CH3:27]
Reactant: CCC(N)(CC)C(=O)OC
Reactant: O=C(O)c1ccc(C(F)(F)F)c(OCC2CC2)n1
Agent: Cl
Product: CCC(CC)(NC(=O)c1ccc(C(F)(F)F)c(OCC2CC2)n1)C(=O)OC

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Example 113 d) and methyl 2-amino-2-ethylbutanoate hydrochloride (CAN 92398-54-4) as starting materials. MS (EI): m/e=389.0 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH2:14][CH2:13][C:12]4([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[C:11]3=[O:20])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C(O)(=O)C.[Na].[C:26]1([CH2:32][CH2:33][CH:34]=O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.O>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH2:14][CH2:13][C:12]4([CH2:19][CH2:18][N:17]([CH2:34][CH2:33][CH2:32][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH2:16][CH2:15]4)[C:11]3=[O:20])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=CCCc1ccccc1
Reactant: O=C1N(c2ccc(C3CC3)cc2)CCC12CCNCC2
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: O=C1N(c2ccc(C3CC3)cc2)CCC12CCN(CCCc1ccccc1)CC2
Temperature: 25 °C
Yield: 25 %

Procedure:
A mixture of 20 mg (0.074 mmol) 2-(4-Cyclopropyl-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, 42 uL acetic acid, 44 mg (0.148 mmol) sodium triacetyoxyborohydride and excess 3-phenyl-propionaldehyde in 2 mL THF was stirred for at room temperature over night. Water was added, the mixture was extracted with ethyl acetate and the combined organic layers were evaporated to dryness. The residue was taken up in methanol and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 7.1 mg (25%) of the title compound. MS m/e: 389.4 [M+H]+.