Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH:11]([C:12]2[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=2)[CH2:10][CH:9]2[CH2:19][CH:6]1[CH2:7][CH2:8]2)[CH3:3].[CH3:20][C:21]([CH3:26])([CH3:25])[C:22](Cl)=[O:23].C(N(CC)CC)C>C(Cl)Cl>[CH3:3][N:2]([CH2:4][CH:5]1[CH:11]([C:12]2[CH:13]=[C:14]([O:18][C:22](=[O:23])[C:21]([CH3:26])([CH3:25])[CH3:20])[CH:15]=[CH:16][CH:17]=2)[CH2:10][CH:9]2[CH2:19][CH:6]1[CH2:7][CH2:8]2)[CH3:1]
Reactant: CN(C)CC1C2CCC(C2)CC1c1cccc(O)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CC1C2CCC(C2)CC1c1cccc(OC(=O)C(C)(C)C)c1
Yield: 81.8 %

Procedure:
Stir a mixture of 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-phenol (200 mg, 0.772 mmol), 2,2-dimethyl-propionyl chloride (111.6 mg, 0.927 mmol) and triethyl amine (234 mg, 2.316 mmol) in CH2Cl2 (40 mL) at ambient temperature for 12 hours. Concentrate the mixture under reduced pressure, and purify the residue by preparative TLC to afford 2,2-dimethyl-propionic acid 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-phenyl ester as white solid (217 mg, Yield: 81.9%). MS (m/z): 344 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.36-7.40 (t, J=13.6, 1H), 7.19-7.21 (d, J=7.2, 1H), 7.03 (s, 1H), 6.92-6.94 (d, J=8.0, 1H), 2.97-3.03 (t, J=23.6, 1H), 2.49-2.68 (m, 6H), 2.40-2.44 (d, J=13.2, 1H), 2.35 (s, 2H), 2.17-2.21 (m, 2H), 1.60-1.84 (m, 8H), 1.37 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH:9]2[CH2:15][O:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[CH:4][CH:3]=1.[ClH:23]>C(O)(C)C>[ClH:23].[ClH:23].[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH:9]2[CH2:15][O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(CC2COCCN(C(=O)OC(C)(C)C)C2)n1
Agent: Cl
Solvent: CC(C)O
Product: Cc1cccc(CC2CNCCOC2)n1
Yield: 85.7 %

Procedure:
tert-Butyl 6-[(6-methylpyridin-2-yl)methyl]-1,4-oxazepane-4-carboxylate (Preparation 83, 42.5 g, 0.14 mol, 1 eq) was dissolved in isopropanol (250 mL), concentrated hydrogen chloride (38 mL, 0.42 mol, 3 eq) was added under stirring, and the mixture was refluxed for 2 h. The reaction mixture was then evaporated, and the residue was coevaporated twice with isopropanol. The product was crystallized from isopropanol, and the crystals were washed with diethylether/isopropanol (3:1) mixture and ether and finally vacuum-dried to give title compound as white crystals (32.3 g, 0.12 mol, 82%).
Reaction SMILES: [CH:1]1[C:6](N=C=S)=[CH:5][C:4]2[C:10]([O:12][C:13]3([C:23]4[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=4[O:21][C:15]4[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]3=4)[C:3]=2[CH:2]=1)=[O:11].CCN(C(C)C)C(C)C>CN(C=O)C>[CH:1]1[CH:6]=[CH:5][C:4]([C:10]([OH:12])=[O:11])=[C:3]([C:13]2[C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[O:21][C:22]3[C:23]=2[CH:24]=[CH:25][C:26]([CH:27]=3)=[O:28])[CH:2]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Reaction time: 1.5 h
Yield: 52.9 %

Procedure:
The amine (11.3 mg, 23 μmol) was combined with fluorescein isothiocyanate (10.4 mg, 35 μmol) and DIEA (12 μL, 69 μmol) in DMF (400 μL). The solution was stirred 1.5 h and concentrated. The product was purified using HPLC (gradient 50-70% ACN/H2O) to yield 11 as an orange solid (16.2 mg, 18.5 μmol) in 80% yield. 1H (300 MHz, CD3OD): δ 8.11 (s, 1H), 7.70 (d, 1H, J=8.1 Hz), 7.51 (d, 2H, J=7.8 Hz), 7.20 (s, 4H), 7.15 (d, 2H, J=8.5 Hz), 7.08 (d, 1H, J=8.2 Hz), 6.71 (d, 2H, J=8.5 Hz), 6.68 (d, 2H, J=2.1 Hz), 6.54 (dd, 2H, J=8.8, 2.4 Hz), 4.66 (dd, 1H, J=8.4, 5.0 Hz), 3.53 (m, 2H), 3.30 (dd, 1H, J=14.4, 5.0 Hz), 3.05 (dd, 1H, J=14.0, 8.2 Hz), 2.56 (t, 2H, J=7.8 Hz), 1.60-1.57 (m, 4H), 1.31 (br s, 8H); 13C (75 mHz, CD3OD): δ 182.5, 173.4, 170.4, 170.1, 154.6, 136.5, 133.6, 131.8, 130.5, 129.6, 129.3, 126.9, 126.0, 114.1, 144.0, 103.2, 60.4, 60.3, 37.7, 36.3, 32.1, 30.1, 30.0, 29.8, 29.6, 27.6; LC/MS (ESI) (m/z) [M+H]+ calcd 875.3. found 875.3.
Reaction SMILES: [CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([C@@H:11]([C:19]2[S:20][CH:21]=[C:22](Br)[CH:23]=2)[C:12]2[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=2)[C@@H:6]([CH3:25])[CH2:5]1)[CH:2]=[CH2:3].C([Li])CCC>>[CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([C@@H:11]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[C:12]2[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=2)[C@@H:6]([CH3:25])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1C[C@H](C)N([C@H](c2cccc(O)c2)c2cc(Br)cs2)C[C@H]1C
Agent: [Li]CCCC
Product: C=CCN1C[C@H](C)N([C@H](c2cccc(O)c2)c2cccs2)C[C@H]1C
Yield: 74.1 %

Procedure:
(-)-3-((R)-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)(4-bromo-2-thienyl)methyl)phenol (0.53 g, 1.3 mmol, Example 66) was debrominated with n-butyllithium as in Example 9. The crude product was recrystallized from acetonitrile to give 0.33 g (77%) of (-)-3-((R)-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)(2-thienyl)methyl)phenol as beige crystals, mp 176°-178° C., [α]D20 =-23.30° (ethyl acetate, c=1.5). HPLC on β-cyclodextrin with methanol:0.1M aqueous ammonium acetate/1:1 gave one peak at tR =8.5 min. Calc. for C20H26BrN2OS 0.25 H2O: C, 69.23; H, 7.70; N, 8.07; S, 9.24. Found: C, 68.86; H, 7.47; N, 8.27; S, 9.06. The product (0.30 g, 0.87 mmol) was treated with ethanolic hydrogen chloride as in Example 42 to give 0.201 g (61%) of the monohydrochloride salt. Calc. for C20H26BrN2OS HCl 0.75 H2O: C, 61.21; H, 7.32: N, 7.12; S, 8.17; Cl, 9.03. Found: C, 61,35; H, 7.01; N,7.30; S, 8.16; Cl, 9.11. [α]D20 =-11.9° (ethanol, c=1.05).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11].[CH3:24][O:25][C:26]([C:28]1[O:29][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:31][CH:32]=1)=[O:27]>C(Cl)Cl>[CH3:24][O:25][C:26]([C:28]1[O:29][C:30]([S:33]([N:20]2[CH2:21][CH2:22][CH:17]([NH:16][C:15]([O:14][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:23])[CH2:18][CH2:19]2)(=[O:35])=[O:34])=[CH:31][CH:32]=1)=[O:27]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)o1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(S(=O)(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
Diisopropylethylamine (0.75 ml, 4.45 mmol) was added in one portion to a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (0.45 g, 2.26 mmol) in DCM (5 ml) at room temperature. To this mixture was added 5-chlorosulfonyl-furan-2-carboxylic acid methyl ester (0.5 g, 2.26 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the mixture was diluted with DCM (100 ml) and washed sequentially with HCl (1M solution, 50 ml), NaOH (1M solution, 50 ml) and brine (50 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting solid was collected by filtration, washed with diethyl ether and dried under vacuum to give the title compound (0.76 g, 88% yield) as an off-white solid. Tr=1.98 min, m/z (ES+) (M+Na)+ 411.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]2[CH2:11][CH2:12][C:13]3[C:18]([C:9]=2[N:8]([CH3:20])[CH:7]=1)=[N:17][C:16]([NH2:19])=[N:15][CH:14]=3)=[O:5])C.[OH-].[K+]>CCO>[NH2:19][C:16]1[N:17]=[C:18]2[C:13]([CH2:12][CH2:11][C:10]3[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]([CH3:20])[C:9]=32)=[CH:14][N:15]=1
Reactant: CCOC(=O)c1cn(C)c2c1CCc1cnc(N)nc1-2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cn1cc(C(=O)O)c2c1-c1nc(N)ncc1CC2
Yield: 75 %

Procedure:
To a solution of 8-amino-1-methyl-4,5-dihydro-1H-1,7,9-triaza -cyclopenta[a]naphthalene-3-carboxylic acid ethyl ester M1 (0.51 mmol) in 95% EtOH (10 mL), KOH (1.54 mmol) was added. The mixture was heated to reflux for 10 h then cooled and evaporated to dryness. The residue was dissolved in 30 mL of water, acidified with glacial AcOH and the precipitate was filtered and washed with water. The product was dried affording the title compound (75% yield). ESI (+) MS: m/z 245 (MH+). 1H NMR: 2.65 (t, J=7.80, 2H), 2.92 (t, J=7.80, 2H), 4.15 (s, 3H), 6.39 (bs, 2H), 7.78 (s, 1H), 8.01 (s, 1H), 12.30 (bs, 1H).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:13])[C@H:8]([CH:10]([CH3:12])[CH3:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].CN1CCOCC1.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1>ClCCl>[C:2]([O:6][C:7](=[O:13])[C@@H:8]([NH:9][S:34]([C:31]1[CH:30]=[CH:29][C:28]([C:25]2[CH:26]=[CH:27][C:22]([Br:21])=[CH:23][CH:24]=2)=[CH:33][CH:32]=1)(=[O:35])=[O:36])[CH:10]([CH3:11])[CH3:12])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(Br)cc2)cc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(Br)cc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.3 %

Procedure:
To a solution of L-valine-tert-butyl ester hydrochloride (15.7 g, 0.075 mol) and N-methylmorpholine (15.2 g, 0.15 mol) in dichloromethane (250 mL) was added in one portion 4'-bromobiphenyl-4-sulfonyl chloride (25 g, 0.075 mol). The solution was stirred at room temperature for 16 hours, filtered, and the filtrate was concentrated in vacuo. The residue was diluted with ethyl acetate (250 mL) and washed with HCl (1N), saturated sodium chloride, and dried over magnesium sulfate. The drying agent was filtered, and the filtrate was concentrated in vacuo leaving a cream-colored solid. The crude product was purified using silica gel chromatography (elution with chloroform) to give the title compound (21.2 g, 60%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24]Br)[CH:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:24][C:20]3[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=3)[C:17]([OH:26])=[O:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: Oc1ccc(-c2ccc(Cl)cc2)cc1
Product: O=C(O)c1cccc(COc2ccc(-c3ccc(Cl)cc3)cc2)c1

Procedure:
3-(4′-Chloro-biphenyl-4-yloxymethyl)-benzoic acid was prepared using general procedure A from 4-chloro-4′-hydroxybiphenyl (available from TCI America, Portland, Oreg.) and 3-(bromomethyl)benzoic acid methyl ester (available from Lancaster Synthesis Ltd., Morcambe, Lancashire, UK). Yield: 80 mg. Mass spectrum (ES) MH+=339.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[O:15][C:14]([NH2:16])=[N:13][N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[F:17][C:18]([F:41])([F:40])[C:19]1[CH:39]=[CH:38][C:22]([CH2:23][C@H:24]2[CH2:28]OS(=O)(=O)[N:25]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[O:15][C:14]([NH:16][CH2:28][C@@H:24]([NH:25][C:31](=[O:32])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:23][C:22]4[CH:38]=[CH:39][C:19]([C:18]([F:41])([F:40])[F:17])=[CH:20][CH:21]=4)=[N:13][N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Nc1nnc(-c2ccc3cnccc3c2)o1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(C(F)(F)F)cc2)COS1(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CNc1nnc(-c2ccc3cnccc3c2)o1)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 20 %

Procedure:
5-(Isoquinolin-6-yl)-1,3,4-oxadiazol-2-amine (0.083 g, 0.39 mmol) was mixed with (S)-tert-Butyl 4-(4-(trifluoromethyl)benzyl)-1,2,3-oxathiazolidine-3-carboxylate-2,2-dioxide (0.15 g, 0.39 mmol) and Cs2CO3 (0.381 g, 1.17 mmol) in 2 mL DMF. The mixture was stirred at room temperature for 3 hours, then at 60° C. for 1 hour. After removing the DMF at a reduced pressure, the remaining residue was treated with 1N HCl for 30 minutes. It was then partitioned between EtOAc and saturated aqueous ammonium chloride. The EtOAc solution was washed twice with saturated aqueous ammonium chloride and dried over sodium sulfate. After removing the EtOAc, the remaining residue was subjected to a silica gel column using 70% EtOAc in hexane as the eluant. A white solid was obtained as the desired product (0.040 g, 20%). LCMS (API-ES) m/z (%): 514.0 (100%, M++H).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1.[CH3:24][C:25]1([CH3:31])[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]1>CN(C)C=O>[CH3:24][C:25]1([CH3:31])[CH2:30][CH2:29][CH2:28][N:27]([CH2:2][C:3]2[O:7][N:6]=[C:5]([C:8]3[N:9]=[CH:10][N:11]4[C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=5[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=34)[N:4]=2)[CH2:26]1
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccccc2C1=O
Reactant: CC1(C)CCCNC1
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3noc(CN4CCCC(C)(C)C4)n3)ncn2-c2ccccc2C1=O
Yield: 92.8 %

Procedure:
1.15 g (3.5 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at room temperature for 1 hour with 1 g (8.8 mmol) of 3,3-dimethylpiperidine and 10 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate/ethanol 9/1 there were obtained 1.32 g (92%) of 3-[5-(3,3-dimethylpiperidin-1-yl)methyl-1,2,4-oxadiazol-3-yl]-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 167°-168°, which was converted into the hydrochloride.
Reaction SMILES: [H-].[Na+].CC(C)(OC([NH:9][C:10]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=O)C.I[CH:26]([CH3:28])[CH3:27]>CN(C)C=O>[CH3:27][CH:26]([NH:9][C:10]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:28]
Reactant: CC(C)I
Reactant: CCOC(=O)c1cccc([N+](=O)[O-])c1NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc([N+](=O)[O-])c1NC(C)C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
4.8 g (0.12 mol) of a 60% sodium hydride solution are added, at 0° C., under argon, and in portions, to a solution of 34 g (0.11 mol) of ethyl 2-[[(1,1-dimethylethoxy)carbonyl]amino]-3-nitrobenzoate in 100 ml of dimethylformamide. The mixture is left stirring for 20 minutes at 0° C. 55.9 g (0.33 mol) of 2-iodopropane are then added and the mixture is heated at 80° C. for 4 hours and then at room temperature for 48 hours. Hydrolysis is carried out by adding water and extraction is carried out 3 times with ethyl acetate. The organic phase is collected and washed successively with water and with a saturated sodium chloride solution. It is dried and evaporated.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:7].[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:29][C:30]([CH:32]4[CH2:33][CH2:34]4)=[O:31])[CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:18]2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: O=C(CCCCCl)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Product: O=C(CCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-(4-nitrophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 450.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[C:4]([O:24][CH3:25])[CH:3]=1.[C:26]([O:30][C:31](SC1N=C(C)C=C(C)N=1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>O1CCCC1>[C:26]([O:30][C:31]([NH:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][CH2:15]2)=[C:4]([O:24][CH3:25])[CH:3]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: Cc1cc(C)nc(SC(=O)OC(C)(C)C)n1
Reactant: COc1cc(N)ccc1OCCCN1CCN(c2ccccc2)CC1
Solvent: C1CCOC1
Product: COc1cc(NC(=O)OC(C)(C)C)ccc1OCCCN1CCN(c2ccccc2)CC1
Yield: 101.3 %

Procedure:
A mixture of 1 g of 1-[3-(4-amino-2-methoxyphenoxy)-n-propyl]-4-phenyl-piperazine, 1.06 g of 2-(t-butoxycarbonylthio)-4,6-dimethylpyrimidine and 15 ml of anhydrous tetrahydrofuran is refluxed for 65 hours. After the reaction, the mixture is evaporated under reduced pressure to remove tetrahydrofuran. Methylene chloride is added to the residue, and the mixture is washed with an aqueous 10% sodium hydroxide solution and water, successively. Said mixture is dried and then evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel chromatography (Solvent; 1.5% methanol/chloroform), and then recrystallized from a mixture of benzene and n-hexane. 1.31 g of 1-[3-(4-t-butoxycarbonylamino-2-methoxyphenoxy)-n-propyl]-4-phenyl-piperazine are thereby obtained as colorless needles. Yield: 85%
Reaction SMILES: [Mg].[Br-].C(OCC)C.[CH2:8](Br)[CH:9]=[CH2:10].[CH3:12][C:13]1([CH3:23])[CH2:19][CH2:18][CH2:17][CH2:16][C:15]([CH3:21])([CH3:20])[C:14]1=[O:22]>>[CH2:10]([C:14]1([OH:22])[C:15]([CH3:21])([CH3:20])[CH2:16][CH2:17][CH2:18][CH2:19][C:13]1([CH3:23])[CH3:12])[CH:9]=[CH2:8]
Reactant: CC1(C)CCCCC(C)(C)C1=O
Reactant: C=CCBr
Agent: [Br-]
Agent: [Mg]
Solvent: CCOCC
Product: C=CCC1(O)C(C)(C)CCCCC1(C)C
Yield: 74.5 %

Procedure:
Magnesium (5.37 g, 0.221 moles) was added to 500 ml four-necked flask equipped with a mechanical stirrer, a dropping funnel, a thermometer, a reflux condenser and a nitrogen gas inlet tube, into which nitrogen gas was passed to remove moisture from the flask. Thereafter, a small amount of a mixed solution of ally bromide (1.5 g, 0.0124 moles)/dried diethyl ether (7.5 ml) was dropped while stirring, followed by dropping a mixed solution of allyl bromide (21.29 g, 0.176 moles)/2,2,7,7-tetramethylcycloheptanone (24.68 g, 0.147 moles)/dried diethyl ether (75 ml) in 2 hours while cooling to 15° C. or below on an iced water bath. The resulting mixture was stirred for 1 hour while keeping at 15° C. or below. Thereafter, the reaction mixture was treated in the same manner as in Example 1, thereby obtaining 23.03 g (yield 74.5%) of the captioned compound. This compound was a colorless transparent liquid having a woody, green, earthy and patchuli oil-like odor.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.O=[C:12]([CH:18]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)C)C(OCC)=O>>[O:4]=[C:2]([CH2:12][CH2:18][C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)[C:1]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)C(=O)C(C)c1cccs1
Product: CCOC(=O)C(=O)CCc1cccs1

Procedure:
A mixture of phosphorous tribromide (18.95 g) and pyridine (3.76 cc) in 10 ml of benzene is chilled to -5° C. and treated with a solution of 2-(2-thienyl)-ethanol (25 g) in 10 ml of benzene containing 1.25 cc of pyridine at such a rate that the reaction temperature never exceeds 0° C. The mixture is then allowed to come to room temperature while stirring overnight. The reaction mixture is then concentrated on a water pump at 30°-40° C. to remove solvent and other volatiles, and the residue Claisen-distilled under water pump vacuum to yield 21 g of crude bromide (b.p. 115°-119° C.). This material is then fractionally distilled at 0.3 mm to provide 19 g of pure 2-(2-thienyl)-ethyl bromide (b.p. 50°-51° C.; 99.9% by gc). This bromide is dissolved in 40 ml of dry tetrahydrofuran and added, dropwise, to a stirred mixture of magnesium turnings (2.4 g) and 15 ml of dry tetrahydrofuran under nitrogen atmosphere. The mixture is then stirred and refluxed for 1 hour, cooled to room temperature, and added, dropwise under nitrogen, to a stirred mixture of diethyl oxalate (17.5 g) in 25 ml of dry tetrahydrofuran in a -15° C. bath. After completion the reaction mixture is stirred at -10° C. for 15 minutes, then allowed to warm to 10° C. and treated with 60 ml of saturated ammonium chloride solution. The aqueous layer is extracted twice with toluene; the combined organic layers dried over magnesium sulfate and concentrated in vacuo to provide 16.7 g of a mixture containing by gc analysis: solvent (26%); diethyl oxalate (10.5%); and ethyl 2-oxo-(2-thienyl)-butyrate (63.4%). The nmr spectrum (CDCl3) is consistent for this mixture, showing the presence of two specific types of ethyl esters, and the mass spectrum exhibits a peak at m/e=212 for the molecular ion of one keto-ester along with a fragmentation pattern consistent with structure.
Reaction SMILES: [CH3:1][C:2]1([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[CH:20]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH:41]([C:44](O)=[O:45])[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH:41]([C:44]([N:28]2[CH2:29][CH2:30][N:25]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([C:16]4[N:17]=[C:18]5[C:10]([C:8]([C:2]6([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]6)=[O:9])=[CH:11][NH:12][C:13]5=[N:14][CH:15]=4)[CH:20]=3)[CH2:26][CH2:27]2)=[O:45])[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CC1(C(=O)c2c[nH]c3ncc(-c4cccc(N5CCNCC5)c4)nc23)CCCCC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(c3cccc(-c4cnc5[nH]cc(C(=O)C6(C)CCCCC6)c5n4)c3)CC2)CC1

Procedure:
4-(4-{3-[7-(1-Methyl-cyclohexanecarbonyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-phenyl}-piperazine-1-carbonyl)-piperidine-1-carboxylic acid tert-butyl ester was prepared starting from (1-methyl-cyclohexyl)-[2-(3-piperazin-1-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone and piperidine-1,4-dicarboxylic acid mono-tert-butyl ester following general procedures as described in these Examples. M+H=615.
Reaction SMILES: P(=[S:5])([O-])([O-])[O-].[Na+].[Na+].[Na+].Cl.[CH3:10][O:11][N:12]=[C:13]1[CH2:17][CH2:16][N:15]([C:18](=[NH:21])[CH2:19][Cl:20])[CH2:14]1.Cl>O>[ClH:20].[CH3:10][O:11][N:12]=[C:13]1[CH2:17][CH2:16][N:15]([C:18](=[NH:21])[CH2:19][SH:5])[CH2:14]1
Reactant: [O-]P([O-])([O-])=S
Reactant: CON=C1CCN(C(=N)CCl)C1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CON=C1CCN(C(=N)CS)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
1.77 g of trisodium phosphorothioate were added to an ice-cooled solution of 2.1 g of 2-(3-methoxyiminopyrrolidin-1-yl)-2-iminoethylchloride hydrochloride in 12 ml of water, and the mixture was stirred at room temperature for about one hour. 9.8 ml of 1N hydrochloric acid were then added, and the mixture was heated at 65° C. for 30 minutes. The resulting solution was concentrated under reduced pressure, the concentrate was mixed with 9.8 ml of isopropanol, insolubles were filtered off, and the filtrate was concentrated under reduced pressure. Ether was added to the concentrate, and the crystals which separated out were collected by filtration and reprecipitated from a mixture of ethanol and ether, giving 1.6 g of 2-(3-methoxyiminopyrrolidin-1-yl)-2-iminoethylmercaptan hydrochloride.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:15][C:16]1[CH:17]=[CH:18][C:19](O)=[C:20]([CH:24]=1)[C:21]([NH2:23])=[O:22].N1CCCC1>CO>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([NH:23][C:21](=[O:22])[C:20]3[CH:24]=[C:16]([Br:15])[CH:17]=[CH:18][C:19]=3[O:14]2)[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: NC(=O)c1cc(Br)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC2(C1)NC(=O)c1cc(Br)ccc1O2
Temperature: 70 °C
Yield: 68.4 %

Procedure:
1-BOC-piperidin-3-one (4.0 g, 20 mmol) was added to a mixture of 5-bromo-2-hydroxybenzamide (2.0 g, 9.2 mmol) and pyrrolidine (0.76 ml, 9.2 mmol) in MeOH (7.5 ml), and the reaction mixture was heated to 70° C. by MW (closed vessel) for 5 h. The solution was then concentrated under vacuum and the crude mixture was purified by column chromatography on silica gel (eluent: DCM/EtOAc 7:3) to give (±)-6-bromo-3,4-dihydro-4-oxo-spiro-[2H-(1,3)-benzoxazine-2,3′-piperidine]-1′-carboxylic acid tert-butyl ester (2.50 g) as a yellow solid.