Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3]Br.[CH3:5][O:6][C:7](=[O:23])[C@H:8]([CH2:17][C:18]1[N:22]=[CH:21][NH:20][CH:19]=1)[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:13]([O:12][C:10]([NH:9][C@@H:8]([CH2:17][C:18]1[N:22]=[CH:21][N:20]([CH2:1][CH2:2][CH3:3])[CH:19]=1)[C:7]([O:6][CH3:5])=[O:23])=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: CCCBr
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCn1cnc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)c1

Procedure:
n-propyl bromide (0.17 ml, 1.85 mmol) was added to a mixture of Nα-Boc-L-histidine methyl ester (500 mg, 1.85 mmol) and potassium carbonate (200 mg, 1.85 mmol) in acetonitrile (20 ml), and the mixture was heated under reflux for 18 hours. TLC analysis showed starting material remaining, so additional n-propyl bromide (0.17 ml, 1.85 mmol) and potassium carbonate (200 mg, 1.85 mmol) were added, and the mixture was heated for a further 8 hours. The cooled mixture was concentrated under reduced pressure. The residue was dissolved in water and the solution was extracted with ethyl acetate (3×20 ml). The combined organic extracts were washed with brine (3×20 ml), dried (Na2SO4) and evaporated under reduced pressure. The residual orange oil was purified by column chromatography on silica gel using an elution gradient of hexane:ethyl acetate (100:0 to 0:100) to afford the title compound as a colourless oil, 200 mg. 1H-NMR (CDCl3, 300 MHz) δ: 0.90 (t, 3H), 1.42 (s, 9H), 1.78 (m, 2H), 3.03 (m, 2H), 3.68 (s, 3H), 3.80 (t, 2H), 4.56 (m, 1H), 5.92 (m, 1H), 7.37 (s, 1H). LRMS: m/z (TSP+) 312.2 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=C[C:19](C(O)=O)=[CH:18][N:17]=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7]2=[O:33].[N:34]1C=CN=CC=1N>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=[N:34][CH:19]=[CH:18][N:17]=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)[C:7]2=[O:33]
Reactant: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(C(=O)O)cn1
Reactant: Nc1cnccn1
Product: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1cnccn1

Procedure:
The product from Example 11, Part D (100 mg, 0.3 mmol) and pyrazin-2-ylamine (43 mg, 0.45 mmol) were converted to the title compound in a manner analogous to the method described in Example 7, Part E, using CH2Cl2 in place of THF in the reaction and EtOAc in the workup, and without crystallization (8 mg, 7%). 1H NMR (300 MHz, CDCl3) δ 9.42 (s, 1H), 8.31 (d, J=3 Hz, 1H), 8.15 (m, 1H), 7.83 (s, 1H), 7.68 (d, J=8 Hz, 1H), 7.46 (m, 1H), 7.32 (m, 2H), 7.20 (t, J=9, 1H), 7.02 (t, J=7 Hz, 2H), 5.25 (d, J=15 Hz, 1H), 4.71 (m, 1H), 4.25 (d, J=15 Hz, 1H), 2.61 (m, 1H), 2.52 (m, 1H), 2.00 (m, 2H). MS: m/z (MH+) 409.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17]CC)=[O:16])=[CH:10][C:9]=2[CH3:20])=[O:7])=[CH:4][CH:3]=1.C(I)CCCCC>>[CH2:14]([C:11]1[N:12]([CH3:13])[C:8]([C:6](=[O:7])[C:5]2[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:9]([CH3:20])[CH:10]=1)[CH3:15].[CH2:11]([CH2:14][C:15]([O-:17])=[O:16])[CH2:10][CH2:9][CH2:8][CH2:6][CH3:5]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Solvent: CCCCCCI
Product: CCCCCCCC(=O)[O-]
Product: CCc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C

Procedure:
The alkylation procedure of Example 77A is performed upon ethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example 84), using an equivalent quantity of n-hexyl iodide instead of methyl iodide used in Example 77A to yield ethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)acetate.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])C=CC=CC=1.[CH2:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH2:13][N:12]1[C:20]([NH:22][C:23]1[N:28]=[N:27][C:26]([C:29]([OH:31])=O)=[CH:25][CH:24]=1)=[O:21].C1C2C(=CC=CC=2)CN1[C:41](NC1C=CC(C(O)=O)=CC=1)=[O:42]>>[O:42]1[CH2:1][CH2:7][CH:8]([CH2:9][NH:10][C:29]([C:26]2[N:27]=[N:28][C:23]([NH:22][C:20]([N:12]3[CH2:11][C:19]4[CH:18]=[CH:17][N:16]=[CH:15][C:14]=4[CH2:13]3)=[O:21])=[CH:24][CH:25]=2)=[O:31])[CH2:41]1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccncc3C2)nn1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Reactant: NCCCc1ccccc1
Product: O=C(NCC1CCOC1)c1ccc(NC(=O)N2Cc3ccncc3C2)nn1

Procedure:
The title compound was prepared as described in Example 1C, substituting tetrahydrofuran-3-ylmethamine for 3-phenylpropan-1-amine and 6-(2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carboxamido)pyridazine-3-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ 10.05 (s, 1H), 9.13 (t, J=6.1 Hz, 1H), 8.62 (s, 1H), 8.51 (d, J=5.0 Hz, 1H), 8.30 (d, J=9.3 Hz, 1H), 8.12 (d, J=9.3 Hz, 1H), 7.44 (d, J=5.1 Hz, 1H), 5.05-4.76 (m, 4H), 3.80-3.57 (m, 4H), 3.48 (dd, J=12.1, 6.8 Hz, 1H), 3.37-3.31 (m, 1H), 2.62-2.52 (m, 1H), 2.01-1.80 (m, 1H), 1.71-1.56 (m, 1H); MS (ESI(+)) m/e 369 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH2:12][C:13]#N)[CH:7]=[N:8][C:9]=1[CH2:10][CH3:11])[CH:2]=[CH2:3].Cl.[O:16]1CCOC[CH2:17]1.C([O-])(O)=[O:23].[Na+]>CO>[CH3:17][O:16][C:13](=[O:23])[CH2:12][C:6]1[CH:7]=[N:8][C:9]([CH2:10][CH3:11])=[C:4]([CH2:1][CH:2]=[CH2:3])[CH:5]=1
Reactant: C=CCc1cc(CC#N)cnc1CC
Reactant: O=C([O-])O
Reactant: C1COCCO1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCc1cc(CC(=O)OC)cnc1CC
Reaction time: 8 h
Yield: 79 %

Procedure:
A solution of 5-allyl-6-ethyl-pyridin-3-yl-acetonitrile (1.30 g, 6.98 mmol) and 4.0 M HCl/dioxane (6.9 mL, 28 mmol) in anhydrous methanol (16 mL, 0.4 M) is warmed to a gentle reflux and stirred overnight under nitrogen. After cooling, the mixture is added to saturated aq NaHCO3 (30 mL), extracted with ethyl acetate (2×30 mL) and dried over Na2SO4. The product is purified by MPLC (25-90% ethyl acetate in n-heptane) to provide 5-allyl-6-ethyl-pyridin-3-yl-acetic acid methyl ester as a clear oil (1.21 g, 79%): Rf 0.39 (50% ethyl acetate in n-heptane), 1H NMR (CDCl3, 300 MHz) δ 8.32 (d, J=2.2 Hz, 1 H), 7.38 (d, J=2.2 Hz, 1 H), 5.93 (ddt, J1=16.8 Hz, J2=10.2 Hz, J3=6.2 Hz, 1 H), 5.12 (dd, J1=10.2 Hz, J2=1.6 Hz, 1H), 5.02 (dd, J1=16.8 Hz, J2=1.6 Hz, 1H), 3.70 (s, 3 H), 3.40 (d, J=6.2 Hz, 2 H), 2.81 (q, J=7.5 Hz, 2 H), 1.28 (t, J=7.5 Hz, 3 H). ESI-LCMS m/z calcd for C13H17NO2: 219.1; found 220.0 (M+1)+.
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH2:7][CH2:8][C@H:9]([OH:14])[C:10]([CH3:13])([OH:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].O.[C:18]1(C)[CH:23]=CC(S(O)(=O)=O)=C[CH:19]=1>COC(OC)(C)C>[C:1]([Si:5]([CH3:15])([CH3:16])[O:6][CH2:7][CH2:8][C@H:9]1[C:10]([CH3:11])([CH3:13])[O:12][C:18]([CH3:23])([CH3:19])[O:14]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(O)[C@@H](O)CCO[Si](C)(C)C(C)(C)C
Solvent: O
Solvent: COC(C)(C)OC
Product: CC1(C)O[C@@H](CCO[Si](C)(C)C(C)(C)C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1503.3 %

Procedure:
Step E To a suspension of (S)-5-(tert-butyl-dimethyl-silanyloxy)-2-methyl-pentane-2,3-diol (6.8 g, 27 mmol) in 2,2-dimethoxypropane (35 mL) was added p-toluenesulfonic acid monohydrate (0.2 g). The reaction mixture was stirred at room temperature for 30 min. The mixture was partitioned between water and dichloromethane. The organic layer was separated, the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:20) to give tert-butyl-dimethyl-[2-((S)-2,2,5,5-tetramethyl-[1,3]dioxolan-4-yl)-ethoxy]-silane as a yellow oil (4.56 g, 58%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[N:6][CH:5]=[CH:4][N:3]=1.CC#N.N1C=CC=CC=1.[C:18]1([O:24][C:25](Cl)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH3:8][C:7]1[C:2]([NH:1][C:25](=[O:26])[O:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1nccnc1N
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1nccnc1NC(=O)Oc1ccccc1
Reaction time: 18 h

Procedure:
A solution of 2-amino-3-methyl-pyrazine (1.50 g, 1.37 mmol) in a mix of 1:2 THF:MeCN (30 mL), and pyridine (0.664 g, 1.44 mmol) was treated dropwise with phenylchloroformate (1.3 g, 1.44 mmol) in THF (10 mL). After stirring for 18 h, the reaction mixture was concentrated in vacuo to a solid and was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:18]=[CH:19]/[CH:20]=[CH:21]/[C:22]([OH:24])=O)[CH:6]=[C:7]([O:16][CH3:17])[C:8]=1[O:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15].C(N(CC)CC)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:47][CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][CH:53]([C:56]2[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[NH:58][CH:57]=2)[CH2:52][CH2:51]1>CN(C)C=O>[CH3:17][O:16][C:7]1[CH:6]=[C:5](/[CH:18]=[CH:19]/[CH:20]=[CH:21]/[C:22]([NH:47][CH2:48][CH2:49][N:50]2[CH2:51][CH2:52][CH:53]([C:56]3[C:64]4[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=4)[NH:58][CH:57]=3)[CH2:54][CH2:55]2)=[O:24])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: COCCOCOc1c(OC)cc(/C=C/C=C/C(=O)O)cc1OC
Reactant: NCCN1CCC(c2c[nH]c3ccccc23)CC1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCOCOc1c(OC)cc(/C=C/C=C/C(=O)NCCN2CCC(c3c[nH]c4ccccc34)CC2)cc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To a stirred mixture of 5-[3,5-dimethoxy-4-{(2-methoxyethoxy)methoxy}phenyl]-(2E,4E)-2,4-pentadienoic acid (1.35 g) and triethylamine (1.17 ml) in dry N,N-dimethylformamide (8 ml) was added slowly diphenyl phosphinic chloride (0.97 g) at -10° to -15° C. under an inert atmosphere. After being stirred for 1 hour, a solution of 1-(2-aminoethyl)-4-(3-indolyl)piperidine (0.97 g) in dry N,N-dimethylformamide (8 ml) was added slowly to the reaction mixture at the same temperature. After being stirred for 40 minutes at the same temperature, the reaction mixture was poured into ice-water (160 ml) and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried over magnesium sulfate. The solvent was evaporated to give syrup of 1-[2-[5-[3,5-dimethoxy-4-{(2-methoxyethoxy)methoxy}phenyl]-(2E,4E)-2,4-pentadienoylamino]ethyl]-4-(3-indolyl)piperidine (1.97 g).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33].C(#N)C>O.CO>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC#N
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
Fluvastatin methyl ester (3.0 g) was added to a solution of NaOH (1 eq.) in water (0.75 ml) and methanol (7.5 ml). The mixture was stirred at about 60° C. for 4 hr, after which the starting material was no longer detectable by HPLC. Then, acetonitrile (58 ml) was dripped into the solution over 1.5 h. Turbidity appeared in the solution which as it was allowed to cool slowly to room temperature. The mixture was stirred overnight. The product was isolated by filtration under nitrogen, washed with acetonitrile (50 ml) and dried at 50° C. in a vacuum oven for 24 h to obtain 2.23 g (73%) of fluvastatin sodium Form VI.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=O.C([O-])(O)=O.[Na+]>CO.O>[CH2:16]([C:13]1[CH:14]=[CH:15][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH2:10][C:9]=2[CH:12]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCCCc1ccc2c(c1)CCNCC2
Yield: 98.4 %

Procedure:
To a solution of the product of Step D (0.17 g, 0.47 mmol) in a mixture of MeOH and H2O (10 ml: 1 ml), NaHCO3 (0.3 g, 3.6 mmol) was added and the reaction mixture was stirred at reflux for 2 h. The solvents were evaporated and the residue was diluted to 20 ml with EtOAc and washed with H2O, dried over MgSO4, filtered and the filtrate evaporated to dryness to give the title compound (0.12 g; 100%), as pale oil. 1H-NMR (CDCl3) 0.86 (tr, 3H, J=6.93 Hz); 1.25-1.28 (m, 12H), 1.45-1.6 (m, 2H); 2.52 (tr, 2H, J=7.71 Hz); 2.85-2.93 (m, 8H); 6.85-6.92 (m, 2H); 6.97-7.0 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:23][O:24][CH2:25][CH2:26][OH:27]>>[CH3:23][O:24][CH2:25][CH2:26][O:27][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][C:13]=2[Cl:22])[CH:9]=[CH:10][C:2]=1[Cl:1]
Reactant: COCCO
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Cl
Product: COCCOC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Cl
Yield: 87 %

Procedure:
In 20 ml methyl cellosolve was heated 2.0 g (0.0054 mol) of 2-chloro-5-(2-chloro-4-trifluoromethylphenoxy)benzoyl chloride to temperatures of 80°-120° C. for 3 hours with stirring. After methyl cellosolve was distilled off, the residue was extracted with benzene. The extract was washed with a dilute aqueous solution of caustic soda and with water, and then dehydrated by adding sodium sulfate. By vacuum concentration thereof 2.2 g (0.0047 mol) of the intended product was obtained as a viscous oily substance; yield 87.0%, nD25 1.5321.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[CH:7]=[C:8]([C:10]([O:12]CC)=[O:11])[O:9][C:5]=2[CH:4]=1.CO.[Li+].[OH-]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[CH:7]=[C:8]([C:10]([OH:12])=[O:11])[O:9][C:5]=2[CH:4]=1
Reactant: CCOC(=O)c1cc2ccc(OC)cc2o1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2cc(C(=O)O)oc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
To a stirred solution of Product of Step B (0.25 g, 1.21 mmol) in a mixture of THF, MeOH and H2O (5 ml:2 ml:1 ml), LiOH (0.145 g, 6 mmol) in H2O (0.5 ml) was added and the mixture was stirred for 3 h at room temp. The solvents were distilled off and the residue was portioned between EtOAc (20 ml) and 1M HCl (2 ml). The organic layer was washed with H2O, dried over MgSO4 and filtered. The filtrate was evaporated to dryness to give the title compound (0.21 g, 91%), as a colourless solid. 1H-NMR (DMSO-d6) 7.61 (d, 1H, J=8.67 Hz); 7.54 (s, 1H); 7.24 (d, 1H, J=1.59 Hz); 6.93 (dd, 1H, J=8.67, 2.4 Hz); 3.8 (s, 3H).
Reaction SMILES: CN(S(F)(F)[F:5])C.[CH:8]([C@H:21]1[N:26]2[CH2:27][C@H:28](O)[CH2:29][C@H:25]2[CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)=O.CC(C)=O.[Cl:45]CCl>>[ClH:45].[ClH:45].[CH:8]([C@H:21]1[N:26]2[CH2:27][C@@H:28]([F:5])[CH2:29][C@H:25]2[CH2:24][NH:23][CH2:22]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClCCl
Reactant: CN(C)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H](O)CN2[C@H](C(c2ccccc2)c2ccccc2)C1
Agent: O=C=O
Solvent: CC(C)=O
Product: Cl
Product: F[C@H]1C[C@H]2CNC[C@@H](C(c3ccccc3)c3ccccc3)N2C1
Temperature: -50 °C
Reaction time: 0.33 h

Procedure:
(Dimethylamino)sulfur trifluoride (0.068 ml) was added dropwise to a solution of tert-butyl (4R,7R,8aS)-4-benzhydryl-7-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (115 mg) in dichloromethane (2 ml) under cooling with dry ice-acetone. The mixture was stirred for 20 minutes at the same temperature (−50° C.), followed by room temperature for 2 hours. The mixture was poured into ice-water and the dichloromethane layer was separated, dried over magnesium sulfate, and evaporated under reduced pressure. The syrup was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (2:1). The fractions containing the objective compound were collected and evaporated under reduced pressure. The resulting syrup was treated with 4N hydrogen chloride in ethyl acetate (2 ml) and evaporated under reduced pressure to give (4R,7S,8aS)-4-benzhydryl-7-fluorooctahydropyrrolo[1,2-a]pyrazine dihydrochloride (75 mg).
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].[CH2:5]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[NH4+].Cl>O1CCCC1>[CH2:5]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]([OH:15])[CH:1]=[CH2:2])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=Cc1ccccc1Cc1ccccc1
Reactant: C=C[Mg]Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1ccccc1Cc1ccccc1

Procedure:
30 ml of a 1.6 molar solution of vinyl-magnesium chloride in tetrahydrofuran are introduced into 100 ml of absolute tetrahydrofuran at 0° C. 9.8 g (0.05 mole) of 2-benzylbenzaldehyde in 100 ml of absolute tetrahydrofuran are added dropwise whilst stirring and excluding moisture. The reaction mixture is stirred for 3 hours at 25° C. and is then cautiously decomposed by adding a cold saturated ammonium chloride solution and a few milliliters of 10% strength hydrochloric acid until the precipitate dissolves. The mixture is then extracted by shaking three times with ether and the combined ether phases are washed with sodium bisulfite solution, sodium bicarbonate solution and water, dried over sodium sulfate and concentrated under reduced pressure. 9.4 g of a yellowish oil, which is sufficiently pure for the further reactions, are obtained; nD21 =1.5855.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.[CH3:11][CH:12]1[O:17][CH:16]([CH3:18])[CH2:15][NH:14][CH2:13]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:18][C@H:16]1[O:17][C@@H:12]([CH3:11])[CH2:13][N:14]([C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=2)[CH2:15]1.[CH3:18][C@H:16]1[O:17][C@H:12]([CH3:11])[CH2:13][N:14]([C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=2)[CH2:15]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC1CNCC(C)O1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(c2ccc(N)cc2)C[C@@H](C)O1
Product: C[C@@H]1CN(c2ccc(N)cc2)C[C@H](C)O1

Procedure:
4-Fluoronitrobenzene and 2,6-dimethylmorpholine were allowed to undergo the reaction in DMF in the presence of diisopropylethylamine, and then cis and trans isomers were separated and purified by a silica gel column chromatography and respectively subjected to catalytic hydrogenation in the same manner as shown in Reference Example 3 to obtain cis-4-(2,6-dimethylmorpholin-4-yl)aniline (Reference Example 7; F: 207) and trans-4-(2,6-dimethylmorpholin-4-yl)aniline (Reference Example 8; F: 207).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:18])=[C:13]([C:15](=O)[CH3:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:18][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:15]([CH3:16])[C:13]=2[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1cc(OCc2ccccc2)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1oc2ccc(OCc3ccccc3)cc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
To a solution (200 mL) of 1-[5-(benzyloxy)-2-hydroxyphenyl]ethanone (15.3 g) synthesized in Example A82(1) in N,N-dimethylformamide were added potassium carbonate (13.1 g) and ethyl bromoacetate (7.7 mL) at room temperature, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure, the obtained residue was dissolved in N,N-dimethylformamide (100 mL) again, and 1,8-diazabicyclo[5.4.0]undec-7-ene (12.2 mL) was added to the solution. The reaction mixture was stirred at 80° C. overnight. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure and the obtained solid was washed with ethanol-isopropyl ether to give the title object compound (3.3 g, 17%) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([OH:27])=O)[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:28][C@@H:29]1[CH2:53][CH2:52][C@@:51]2([CH3:54])[CH:31]([CH2:32][CH2:33][C@@H:34]3[C@@H:50]2[CH2:49][CH2:48][C@@:47]2([CH3:55])[C@H:35]3[CH2:36][CH2:37][C@@H:38]2[C@H:39]([CH3:46])[CH2:40][CH2:41][CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:30]1>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([NH:28][C@@H:29]1[CH2:53][CH2:52][C@@:51]2([CH3:54])[CH:31]([CH2:32][CH2:33][C@@H:34]3[C@@H:50]2[CH2:49][CH2:48][C@@:47]2([CH3:55])[C@H:35]3[CH2:36][CH2:37][C@@H:38]2[C@H:39]([CH3:46])[CH2:40][CH2:41][CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:30]1)=[O:27])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](N)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](NC(=O)[C@H](CCCCNC(=O)OCc5ccccc5)NC(=O)OC(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
By using Nα-tert-butyloxycarbonyl-Nε-benzyloxycarbonyl-L-lysine (760 mg, 2.00 mmol) and 3α-aminocholestane (853 mg, 2.20 mmol), the title compound was obtained in the same manner as in Synthetic Example BB 1 (1.57 g, quantitative).
Reaction SMILES: C1(C#C)C=CC=CC=1.[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)#[CH:10].[N:17]([C:20]1[S:21][C:22]([C:26]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])=[C:23]([CH3:25])[N:24]=1)=[N+:18]=[N-:19]>>[CH2:29]([NH:28][C:26]([C:22]1[S:21][C:20]([N:17]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[N:19]=[N:18]2)=[N:24][C:23]=1[CH3:25])=[O:27])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: C#Cc1cccnc1
Reactant: Cc1nc(N=[N+]=[N-])sc1C(=O)NCc1ccccc1
Solvent: C#Cc1ccccc1
Product: Cc1nc(-n2cc(-c3cccnc3)nn2)sc1C(=O)NCc1ccccc1
Yield: 13 %

Procedure:
Following the procedure as described in Example 10, making variations as necessary to replace phenylacetylene with 3-ethynylpyridine to react with 2-azido-N-benzyl-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 13% yield: mp 117-119° C. (methanol/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 9.65 (s, 1H), 9.04 (t, J=3.0 Hz, 1H), 8.42 (d, J=6.0 Hz, 1H), 7.71 (d, J=6.0 Hz, 1H), 7.39-7.27 (m, 7H), 4.48 (d, J=6.0 Hz, 2H), 2.66 (s, 3H); MS (ES+) m/z 377.3 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2)([O-])=O.I[CH2:15][CH2:16][CH3:17].[CH3:18][CH2:19][OH:20]>>[CH2:15]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[NH:1][C:19](=[O:20])[CH3:18])[CH2:9]1)[CH2:16][CH3:17]
Reactant: CCCI
Reactant: CCO
Reactant: O=[N+]([O-])c1cccc2cnccc12
Product: CCCN1CCc2c(cccc2NC(C)=O)C1

Procedure:
A solution of 5-nitroisoquinoline (25 g, 0.144 mol) and iodopropane (36.7 g, 0.216 mol) in 500 mL of EtOH was converted to the title compound by the procedures described in Example 1. The crude title compound was purified by chromatography (silica gel, 95:5 EtOAc:EtOH). The purified product was recrystallized from iPr2O/THF to give the title compound as a white solid (3.33 g, 18%), mp=123° C.