Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:13](O)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:1][CH:2]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)[CH2:13][OH:14]
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC(CO)Cc1c[nH]c2ccccc12
Reaction time: 72 h

Procedure:
L Tryptophan (10.2 g) was cautiously added in portions to a stirred solution of lithium aluminium hydride in tetrahydrofuran (1M, 150 ml). The reaction was stirred for 72 hours and then heated to reflux for 1 hour. The reaction mixture was cooled and then quenched carefully with 2N sodium hydroxide (150 ml). Ethyl acetate (500 ml) was added and the mixture was filtered through a pad of Celite. The organic phase was washed with water, dried (MgSO4) and evaporated to yield the crude title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[CH3:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[CH:28]=O)[N:25]=1.OOS([O-])=O.[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C.O>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:28]1[C:27]1[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=1[C:24]1[N:25]=[C:21]([CH3:20])[S:22][CH:23]=1)([CH3:16])([CH3:18])[CH3:17]
Reactant: Cc1nc(-c2ccccc2C=O)cs1
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Agent: O=S([O-])([O-])=S
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2ccccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)cs1
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To a solution of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (50 mg, 0.19 mmol) in DMF (5 mL) is added 2-(2-methyl-thiazol-4-yl)-benzaldehyde (59 mg, 0.29 mmol) at room temperature. Oxone (119 mg, 0.19 mmol) in H2O (1 mL) is added and the solution is stirred for 1 hour. Saturated sodium thiosulfate solution (5 mL) is added and the mixture is extracted with EtOAc (3×10 mL) and H2O (10 mL). The combined organic layer is dried (MgSO4), filtered and concentrated and the residue is purified by silica gel flash column chromatography eluting with 10% MeOH in CH2Cl2 to afford the title compound (71 mg, 83%) as a pale brown solid. LCMS (ESMS): m/z 441.20 (M++1)
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]2)=[C:18]([CH:21]=1)[C:19]#[N:20]>>[C:19]([C:18]1[CH:21]=[C:14]([NH:13][C:6]([C:5]2[S:1][C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[CH:4]=2)=[O:8])[CH:15]=[CH:16][C:17]=1[N:22]1[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][OH:30])[CH2:26][CH2:27]1)#[N:20]
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: N#Cc1cc(N)ccc1N1CCN(CCO)CC1
Product: N#Cc1cc(NC(=O)c2cc3ccccc3s2)ccc1N1CCN(CCO)CC1
Yield: 40.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using benzo[b]thiophene-2-carboxylic acid (1 g) and 5-amino-2-[4-(2-hydroxyethyl)piperazin-1-yl]benzonitrile (1.2 g), the title compound (0.8 g) was obtained. melting point: 238-239° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]3[CH2:17][CH2:16]S[CH2:14][CH2:13]3)[C:7](=[O:18])[C:6]3([CH3:23])[CH2:19][O:20][CH2:21][CH2:22][N:5]3[C:4]=2[N:3]=1.O[O:25][S:26]([O-:28])=O.[K+]>CO.O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]3[CH2:13][CH2:14][S:26](=[O:28])(=[O:25])[CH2:16][CH2:17]3)[C:7](=[O:18])[C:6]3([CH3:23])[CH2:19][O:20][CH2:21][CH2:22][N:5]3[C:4]=2[N:3]=1
Reactant: O=S([O-])OO
Reactant: CC12COCCN1c1nc(Cl)ncc1N(C1CCSCC1)C2=O
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC12COCCN1c1nc(Cl)ncc1N(C1CCS(=O)(=O)CC1)C2=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.4 %

Procedure:
To a solution of 2-chloro-6a-methyl-5-(tetrahydro-2H-thiopyran-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (9.4 mg, 0.026 mmol) in MeOH (1 ml) at 0° C. was added dropwise a solution of oxone (40.7 mg, 0.066 mmol) in water (1 ml), and the reaction mixture was stirred at room temperature for 16 h, followed by solvent removal in vacuo. The residue was partitioned between EtOAc and water. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were dried and concentrated in vacuo to give 2-chloro-5-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-6a-methyl-6a,7,9,10-tetrahydro[1,4]oxazino[3,4-h]pteridin-6(5H)-one (6.5 mg, 0.017 mmol, 63% yield) as a white solid. This was used in the next step without further purification. MS [M+H] found 387.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2.Cl[CH2:45][C:46]1[N:50]=[CH:49][O:48][N:47]=1.BrCC1OC(C(F)(F)F)=CC=1>>[O:48]1[CH:49]=[N:50][C:46]([CH2:45][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:13]4=[CH:14][C:15]5[O:19][CH2:18][O:17][C:16]=5[CH:20]=[C:12]4[O:11][CH2:10]3)[C:2]2=[O:21])=[N:47]1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: ClCc1ncon1
Agent: FC(F)(F)c1ccc(CBr)o1
Agent: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Product: O=C1N(Cc2ncon2)c2ccccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 3-(chloromethyl)-1,2,4-oxadiazole to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (36%)) as a colorless solid: mp 160-162° C.; 1H NMR (300 MHz, CDCl3) δ 7.39 (dt, 1H), 7.20-7.13 (m, 3H), 7.05 (d, 1H), 6.50 (s, 1H), 6.12 (s, 1H), 5.86 (dd, 2H), 4.78 (ABq, 2H), 4.68 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 176.7, 156.0, 149.3, 142.5, 139.6, 131.6, 129.4, 124.8, 124.5, 118.4, 113.6, 108.7, 103.0, 101.7, 93.7, 80.3, 58.2, 29.7, 28.0; MS (ES+) m/z 365.2 (M+1).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[O:22][C:23]([C@@H:26]3[CH2:32][CH2:31][C@@H:30]4[CH2:33][N:27]3[C:28](=[O:39])[N:29]4[O:34][S:35]([OH:38])(=[O:37])=[O:36])=[N:24][N:25]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl.CCOCC>[S:35]([OH:38])([O:34][N:29]1[C:28](=[O:39])[N:27]2[CH2:33][C@H:30]1[CH2:31][CH2:32][C@H:26]2[C:23]1[O:22][C:21]([N:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)=[N:25][N:24]=1)(=[O:36])=[O:37]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OS(=O)(=O)O)o2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: O=C1N2C[C@@H](CC[C@H]2c2nnc(N3CCNCC3)o2)N1OS(=O)(=O)O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 35.6 %

Procedure:
TFA (0.30 mL) was added to a 0° C. mixture of tetrabutylammonium tert-butyl 4-(5-((2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)piperazine-1-carboxylate (21 mg, 0.03 mmol) in dry DCM (0.80 mL). The reaction mixture was stirred at 0° C. for 2-3 hrs then diluted with ether (−15 mL). The precipitate was collected via centrifugation, washed with ether (3×) and dried under high vacuum to afford (2S,5R)-7-oxo-2-(5-(piperazin-1-yl)-1,3,4-oxadiazol-2-yl)-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate (4 mg, 35%) as a light yellow solid after prep-HPLC purification using ammonium formate buffer. ESI-MS (EI+, m/z): 375.2. 1H NMR (300 MHz, D2O) δ 4.65 (d, J=6.6 Hz, 1H), 4.19 (br s, 1H), 3.80-3.65 (m, 2H), 3.38-3.28 (m, 2H), 3.20-3.16 (m, 1H), 2.99-2.95 (m, 1H), 2.32-1.88 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[CH:15]([NH:16][C:17]([C:19]4([NH2:22])[CH2:21][CH2:20]4)=[O:18])[CH2:14][S:13][C:12]=3[CH:23]=2)[CH:7]=1.[O:31]1[C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=[N:32]1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[CH:15]([NH:16][C:17]([C:19]4([NH:22][C:36]([C:35]5[O:31][N:32]=[CH:33][CH:34]=5)=[O:37])[CH2:21][CH2:20]4)=[O:18])[CH2:14][S:13][C:12]=3[CH:23]=2)[CH:7]=1
Reactant: Cn1nnc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)SCC3NC(=O)C2(N)CC2)n1
Reactant: O=C(O)c1ccno1
Product: Cn1nnc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)SCC3NC(=O)C2(NC(=O)c3ccno3)CC2)n1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-6-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-phenyl]-2,3-dihydro-benzo[b]thiophen-3-yl}-amide (example 61) has been coupled with isoxazole-5-carboxylic acid to yield the title compound as light yellow oil. MS: 540.1 (MH+, 1Cl).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])=[CH:21][CH:20]=1)[CH3:18]>>[F:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH:17]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])=[CH:21][CH:20]=3)[CH3:18])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: CC(=O)NCc1ccc(C(C)Cl)cc1
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: Cl
Product: CC(=O)NCc1ccc(C(C)N2CCN(c3ccc(F)cc3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using 1-(4-fluorophenyl)piperazine dihydrochloride instead of phenylpiperazine and N-(4-(1-chloroethyl)phenylmethyl)acetamide instead of N-(4-chloromethylphenylmethyl) acetamide, the title compound was obtained as white crystals, m.p.=128-130° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH3:13])[C:7]([CH:11]=[O:12])=[C:8](I)[N:9]=1)[CH2:2][CH2:3][CH3:4].CC([O-])=O.[K+]>CO.[Pd]>[CH2:1]([C:5]1[N:6]([CH3:13])[C:7]([CH:11]=[O:12])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(I)c(C=O)n1C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Product: CCCCc1ncc(C=O)n1C
Reaction time: 3 h

Procedure:
2-n-Butyl-4-iodo-1-methyl-1H-imidazole-5-carbaldehyde (1.93 g, 6.6 mmol) dissolved in MeOH (100 ml) buffered with KOAc (850 mg) was treated with 10% Pd/C and shaken under 50 psi of H2 for 3 h. The catalyst was removed by filtration and the MeOH removed under reduced pressure. The residue was partitioned between CH2Cl2 and 5% NaHCO3 solution. The layers were separated and the aqueous portion further extracted with CH2Cl2 (2x). The combined organic portions were dried (MgSO4 anhydrous), filtered, and evaporated to give the title compound as a bright yellow oil. (1.86 g, 99% )
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[NH:8][C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([F:29])=[CH:11][N:10]=2)=[O:5])[CH3:2].Br[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34]>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[N:8]([CH2:32][C:33](=[O:34])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([F:29])=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(F)cnc2[nH]c1=O
Reactant: O=C(CBr)c1ccccc1
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(F)cnc2n(CC(=O)c2ccccc2)c1=O

Procedure:
This compound was prepared from 6-fluoro-2-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (80) and 2-bromoacetophenone according to General Procedure B. Yield 293 mg (38%), MP 262° C.; 1H-NMR (DMSO-d6): δ 1.29 (t, J=7.2 Hz, 3H), 3.19 (m, 4H), 3.92 (m, 4H), 4.32 (q, J=7.2 Hz, 2H), 5.88 (s, 2H), 7.16 (dd, J=3.6, 4.8 Hz, 1H), 7.47 (dd, J=1.2, 3.6 Hz, 1H), 7.61 (m, 2H), 7.72 (m, 1H), 7.81 (d, J=4.8 Hz, 1H), 8.11 (m, 2H), 8.18 (dd, J=2.8, 8.8 Hz, 1H), 8.65 (d, J=2.8 Hz, 1H); EIMS: 549 (M+1). Anal. (C28H25FN4O5S) C, H, N.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][CH2:8][CH:7]2[CH:5]([O:6]2)[CH2:4][O:3]1.O.[NH3:12]>>[CH3:1][C:2]1([CH3:10])[O:9][CH2:8][C@@H:7]([NH2:12])[C@H:5]([OH:6])[CH2:4][O:3]1
Reactant: CC1(C)OCC2OC2CO1
Reactant: N
Solvent: O
Product: CC1(C)OC[C@@H](N)[C@H](O)CO1
Temperature: -70 °C
Yield: 87 %

Procedure:
A steel bomb was charged with liquid ammonia (60 ml) with cooling in an isopropanol-dry ice bath maintained at -70° C. The epoxide (III) (21.46 g, 0.15 mole) was added to it, followed by water (2.70 ml, 0.15 mole). The bomb was sealed and, then, heated in an oil bath at 120° for 4 hr. The bomb was cooled, opened and the ammonia was allowed to evaporate. The crude residue was triturated with ether, chilled, and the crystalline product was isolated by filtration. The amine (IV) was obtained as white prisms. (18.78 g, yield 87%). m.p. 81.5°-82.5°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[F-].[Cs+].C(OCC)(=O)C>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:14][C:15]1[CH:16]=[C:17]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: Brc1cccc(I)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2cccc(Br)c2)cc1

Procedure:
4-(Methoxycarbonyl)phenylboronic acid (1.55 g, 8.63 mmol), 1-bromo-3-iodobenzene (2.22 g, 7.84 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.29 g, 0.392 mmol), and CsF (2.38 g, 15.7 mmol) in dioxane (40 mL) were stirred at 80° C. for 8 hours. The reaction was cooled, poured into ethyl acetate, washed twice with water and brine, and the combined organic layers were concentrated. The residue was chromatographed on silica gel using 2-20% ethyl acetate in hexanes afford the title compound.
Reaction SMILES: C(O)CC=C.C=CC=C.C([O-])(=O)C=CC=C.[C:17](SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(O)(=O)OP(O)(=O)OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1OP(O)(O)=O)(=[O:22])[CH2:18][C:19]([OH:21])=[O:20].[C:71]([S:74][CH2:75][CH2:76][NH:77][C:78](=[O:121])[CH2:79][CH2:80][NH:81][C:82](=[O:120])[C@H:83]([OH:119])[C:84]([CH3:118])([CH3:117])[CH2:85][O:86][P:87]([OH:116])(=[O:115])[O:88][P:89]([OH:114])(=[O:113])[O:90][CH2:91][C@H:92]1[O:96][C@@H:95]([N:97]2[C:106]3[N:105]=[CH:104][N:103]=[C:101]([NH2:102])[C:100]=3[N:99]=[CH:98]2)[C@H:94]([OH:107])[C@@H:93]1[O:108][P:109]([OH:112])([OH:111])=[O:110])(=[O:73])[CH3:72]>>[O:22]=[C:17]([CH2:18][C:19]([OH:21])=[O:20])[CH2:72][C:71]([S:74][CH2:75][CH2:76][NH:77][C:78](=[O:121])[CH2:79][CH2:80][NH:81][C:82](=[O:120])[C@H:83]([OH:119])[C:84]([CH3:117])([CH3:118])[CH2:85][O:86][P:87]([OH:116])(=[O:115])[O:88][P:89]([OH:114])(=[O:113])[O:90][CH2:91][C@H:92]1[O:96][C@@H:95]([N:97]2[C:106]3[N:105]=[CH:104][N:103]=[C:101]([NH2:102])[C:100]=3[N:99]=[CH:98]2)[C@H:94]([OH:107])[C@@H:93]1[O:108][P:109]([OH:112])([OH:111])=[O:110])=[O:73]
Reactant: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)CC(=O)O
Reactant: CC(=O)SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O
Agent: C=CC=C
Agent: C=CC=CC(=O)[O-]
Agent: C=CCCO
Product: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)CC(=O)CC(=O)O

Procedure:
Pathways to 3-butene-1-ol, butadiene and 2,4-pentadienoate from malonyl-CoA and acetyl-CoA are shown in FIG. 21. In these pathways, malonyl-CoA and acetyl-CoA are joined by a thiolase to form 3-oxoglutaryl-CoA. This intermediate can then be converted to 3,5-dihydroxypentanoate by several alternate routes (Steps B/C/D, Steps B/G, Steps H/I/J, Steps H/L/D, K/J). Once formed, 3,5-dihydroxypentanoate can be decarboxylated by a 3-hydroxyacid decarboxylase to form 3-butene-1-ol (Step M). Subsequent dehydration by a 3-butene-1-ol dehydrogenase or a chemical catalyst yields butadiene (Step O). Alternately, 3,5-dihydroxypentanoate can be dehydrated to 5-hydroxypent-2-enoate as shown in Step E. This intermediate can then be decarboxylated to 3-butene-1-ol (Step N) or further dehydrated to 2,4-pentadienoate (Step F).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][C@@H:21]([CH3:23])[N:20]([CH:24]4[CH2:27][O:26][CH2:25]4)[CH2:19][C@@H:18]3[CH3:28])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:29]([O:32][CH2:33][C:34]1[C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][C:37]([F:49])=[CH:36][C:35]=1[N:50]1[CH2:62][CH2:61][N:53]2[C:54]3[CH2:55][CH2:56][CH2:57][CH2:58][C:59]=3[CH:60]=[C:52]2[C:51]1=[O:63])(=[O:31])[CH3:30]>>[C:29]([O:32][CH2:33][C:34]1[C:35]([N:50]2[CH2:62][CH2:61][N:53]3[C:54]4[CH2:55][CH2:56][CH2:57][CH2:58][C:59]=4[CH:60]=[C:52]3[C:51]2=[O:63])=[CH:36][C:37]([F:49])=[CH:38][C:39]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][C@@H:21]([CH3:23])[N:20]([CH:24]4[CH2:25][O:26][CH2:27]4)[CH2:19][C@@H:18]3[CH3:28])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: C[C@@H]1CN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4C[C@@H](C)N(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 69.1 %

Procedure:
Following the procedures as described for compound 108f, reaction of 104e (268 mg, 0.60 mmol) and 104o (289 mg, 0.60 mmol) afforded 104p as a yellow solid (300 mg, 85%). LCMS: [M+H]+ 724
Reaction SMILES: [C:1]1([N:7]2[CH2:13][CH2:12][C:11](O[Si](C)(C)C)=[C:10](O[Si](C)(C)C)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.Br.[NH2:26][CH2:27][C:28]([NH2:30])=[NH:29].[OH-].[Na+]>[Cu].II.CC(O)=O.CO>[NH2:30][C:28]1[CH:27]=[N:26][C:11]2[CH2:12][CH2:13][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9][C:10]=2[N:29]=1
Reactant: C[Si](C)(C)OC1=C(O[Si](C)(C)C)CCN(c2ccccc2)CC1
Reactant: N=C(N)CN
Agent: [Cu]
Agent: Br
Agent: II
Solvent: CC(=O)O
Solvent: CO
Product: Nc1cnc2c(n1)CCN(c1ccccc1)CC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 35 gm (0.1 mol) of 1-phenyl-2,3,6,7-tetrahydro-4,5-bis(trimethylsilyloxy)-azepine and 750 ml of methanol was boiled for 2 hours. Thereafter, 60 gm (0.3 mol) of copper-II-acetate was added, and the mixture was boiled for 60 minutes more. Subsequently, the reaction mixture was filtered, the filtrate was evaporated, and the residue was extracted with boiling cyclohexane. The cyclohexane extract solution was evaporated, and the residue was dissolved in 250 ml of methanol, and the solution was admixed with 500 gm of ice and 20.6 gm (0.08 mol) of 2-amino-acetamidine dihydrobromide. 2N sodium hydroxide was then added dropwise to the mixture until a constant pH of 5 was reached, and the mixture was allowed to stand overnight in the refrigerator, then concentrated by evaporation, and the residue was made alkaline and extracted with methylene chloride. The dried and concentrated extract solution was chromatographed on silicagel with ethyl acetate as the mobile phase.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[C:10]([N:18]1[CH2:27][CH2:26][C@H:25]2[C@H:20]([CH2:21][CH2:22][C:23](=[O:28])[CH2:24]2)[CH2:19]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OCC)(=O)C>C1COCC1>[C:10]([N:18]1[CH2:27][CH2:26][C@H:25]2[C@H:20]([CH2:21][CH2:22][C:23]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)([OH:28])[CH2:24]2)[CH2:19]1)(=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: O=C1CC[C@@H]2CN(C(=O)c3ccccc3)CC[C@@H]2C1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1ccccc1)N1CC[C@@H]2CC(O)(c3ccc(F)cc3)CC[C@@H]2C1

Procedure:
Following the general procedure described in Example 25, a solution of p-fluorophenyl magnesium bromide in THF (1.0M, 2.61 mL, 2.61 mmol) was reacted with cis-2-benzoyl-6-oxodecahydroisoquinoline (670 mg, 2.61 mmol) in anhydrous THF at -78° C. Column chromatography (ethyl acetate) afforded the product, a solid (478 mg):mp 84°-85° C.; NMR (CDCl3, 200 MHz): 7.5-7.35 (m, 7H), 7.0 (t, 2H, J=8), 4.65-4.35 (m, 1H), 3.8-3.6 (m, 1H), 3.3-3.1 (m, 1H), 3.1-2.8 (m, 1H), 2.65-2.35 (m, 1H), 2.1-1.4 (m, 10 H); Anal. Calcd for C22H24FNO2 : C, 74.76, H, 6.84, N, 3.96, F, 5.38; Found: C, 74.59, H, 6.93, N, 3.79, F, 5.53.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CC(C)=O.C1(O)C=CC=CC=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([Cl:28])[C:26]=1[OH:27])[CH2:22][OH:23].Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37]([O:39][CH3:40])=[O:38]>>[Cl:18][C:19]1[CH:20]=[C:21]([CH2:22][OH:23])[CH:24]=[C:25]([Cl:28])[C:26]=1[O:27][CH:36]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:30]=1)[C:37]([O:39][CH3:40])=[O:38]
Reactant: COC(=O)Cc1ccccc1Br
Reactant: OCc1cc(Cl)c(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Oc1ccccc1
Product: COC(=O)C(Oc1c(Cl)cc(CO)cc1Cl)c1ccccc1
Yield: 20.4 %

Procedure:
Using the K2CO3 /acetone conditions for phenol alkylation described in Step A of Example 30, 0.400 g (2.07 mmol) of the product of Step C was alkylated with 0.522 g (2.28 mmol) of methyl 2-bromophenylacetate to afford 0.144 g (20%) of the title compound.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:6][N:5]=1)[CH3:2].C(OCC)(=O)C>CCOCC>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:8]2[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:6][N:5]=[C:4]2[S:3][CH2:1][CH3:2])=[CH:11][CH:12]=1
Reactant: CCSc1nnc(-c2ccccc2)n1Cc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCSc1nnc(-c2ccccc2)n1Cc1ccc(N)cc1
Yield: 82 %

Procedure:
Following the procedure of Example, 1, Part E, 3-ethylthio-4-(4-nitrobenzyl)-5-phenyl-4H-1,2,4triazole was reduced with stannous chloride to give (after multiple extractions with ethyl acetate in addition to ether) an 82% yield of the amine as a solid, mp 126.5°-127° C., homogeneous by TLC in 9:1 CH2Cl2 --MeOH, mass spectrum (FAB) m/e 311 (M+1)+.
Reaction SMILES: [NH2:1][C@H:2]([CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:7][CH2:6]1)=O.Cl>C1(C)C=CC=CC=1.O.C(OCC)C>[CH:20]1([CH2:19][C@@H:2]([NH2:1])[CH2:3][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])[CH2:7][CH2:6]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COc1ccccc1N1CCN(C(=O)[C@H](N)CC2CCCCC2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccccc1N1CCN(C[C@H](N)CC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
The above-described desired (R)-2-amino-3-cyclohexyl-1-[4-(2-methoxyphenyl)-piperazin-1-yl]-propan-1-one (0.83 g, 2.25 mmol) was dissolved in 20 ml of dry toluene and placed in a flame-dried flask under a nitrogen atmosphere. The mixture was heated to reflux and a solution of 0.45 mL of 10M borane-dimethylsulfide complex in 15 mL of dry toluene was added dropwise over ten minutes as reflux was maintained. After complete addition, the reaction mixture was refluxed an additional two hours. The reaction was then cooled to room temperature and 30 mL of 1N aq. HCl was added and the mixture stirred for one hour. Stirring was halted, the mixture was diluted with 20 mL of water and 20 mL of diethyl ether, and the layers were separated. The aqueous layer was washed with an additional 30 mL portion of diethyl ether and then made basic by addition of 50% aq. sodium hydroxide solution. The basic aqueous mixture was then extracted with three 50 mL portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to yield the desired {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-amine (0.74 g, 93% yield) as a yellow oil, which was pure enough to use in subsequent experiments; MS (+) ESI m/z=(M+H)+.