Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:20](I)=[CH:19][C:5]([O:6][C:7]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([Cl:22])[CH:3]=1.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>C(N(CC)CC)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:1][C:2]1[C:20]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])=[CH:19][C:5]([O:6][C:7]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([Cl:22])[CH:3]=1
Reactant: CCOC(=O)c1ccc(F)cc1Oc1cc(I)c(N)cc1Cl
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(F)cc1Oc1cc(C#C[Si](C)(C)C)c(N)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of EXAMPLE 242B (3.0 g), bis(triphenylphosphine)palladium(II) dichloride (242 mg), CuI (66 mg) in triethylamine (30 mL) was added trimethylsilylacetylene (2.2 g). The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (200 mL) and washed with aqueous NH4Cl, water, brine and dried over Na2SO4. The mixture was filtered, and the solvent was evaporated and the residue was loaded on a column and eluted with 10% ethyl acetate in hexane to give the pure product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:33]=[CH:34][CH:35]=1)[CH2:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[N:10]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:9]=1)([O-])=O.Cl>CO.[Pd]>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([CH2:7][C:6]4[CH:5]=[C:4]([NH2:1])[CH:35]=[CH:34][CH:33]=4)=[CH:9][N:10]([S:23]([C:26]4[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=4)(=[O:25])=[O:24])[C:11]3=[N:12][CH:13]=2)[CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(Cc3cccc([N+](=O)[O-])c3)c3cc(-c4cccnc4)cnc32)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2cc(Cc3cccc(N)c3)c3cc(-c4cccnc4)cnc32)cc1
Reaction time: 8 h

Procedure:
To 3-(3-nitro-benzyl)-5-pyridin-3-yl-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (552, 230 mg, 0.14 mmol) in methanol (5 mL) was added 10% palladium on carbon (10 mg) and few drops of concentrated aqueous hydrochloric acid. The resulting mixture was stirred under an atmosphere of hydrogen overnight, and the catalyst was filtered out through a bed of celite. The filtrate was concentrated and purified by silica gel column chromatography eluting with 90% ethyl acetate in hexane to give the compound (553, 88 mg, 41%). MS (ESI) [M+H+]+=455.3.
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10]3[N:18]4[C:13]([CH:14]=NC(O)=[N:17]4)=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[CH:20]([N:23](CC)C(C)C)(C)C.[N-](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[NH2:44][C:45]1[C:59]([O:60][CH3:61])=[CH:58][C:48]2[CH2:49][CH2:50][N:51]([CH2:54][C@H:55]([OH:57])[CH3:56])[CH2:52][CH2:53][C:47]=2[CH:46]=1>CN(C=O)C>[O:1]1[C:5]2[C:6]([C:10]3[N:18]4[C:13]([CH:14]=[CH:20][N:23]([NH:44][C:45]5[C:59]([O:60][CH3:61])=[CH:58][C:48]6[CH2:49][CH2:50][N:51]([CH2:54][C@H:55]([OH:57])[CH3:56])[CH2:52][CH2:53][C:47]=6[CH:46]=5)[NH:17]4)=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: COc1cc2c(cc1N)CCN(C[C@@H](C)O)CC2
Reactant: Oc1ncc2ccc(-c3cccc4c3OCC4)n2n1
Reactant: CCN(C(C)C)C(C)C
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1cc2c(cc1NN1C=Cc3ccc(-c4cccc5c4OCC5)n3N1)CCN(C[C@@H](C)O)CC2
Temperature: 70 °C
Yield: 10 %

Procedure:
To a mixture of 7-(2,3-Dihydro-benzofuran-7-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol (0.100 g, 0.395 mmol, 1.05 eqv) and N,N-Diisopropylethylamine (0.28 mL, 4.22 eqv) in anhydrous DMF (1 mL) in a 10 mL sealed tube was added N-Phenylbis(trifluoromethane-sulfonimide (0.148 g, 1.105 eqv.). The mixture was stirred at room temperature for 1 h and to it (R)-1-(7-amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-propan-2-ol (0.094 mg, 0.38 mmol, 1.00 eqv.) was added. The reaction mixture was heated at 70° C. for 2 h, concentrated in vacuo and purified via prepTLC (silica gel; eluant: 6% methanol in methylene chloride) to afford (R)-1-{7-[7-(2,3-Dihydro-benzofuran-7-yl)-pyrrolo[2,1-f]triazin-2-ylamino]-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl}-propan-2-ol as a dark brown solid (0.018 g, 10%). MP>200° C. (decomp.). LCMS (E/I+) 486.16 (M+H). 1H NMR (CDCl3) δ 8.80 (s, 1H), 8.30 (d, 2H, J=6.50 Hz), 7.45 (s, 1H), 7.30 (s, 2H), 7.00 (dd, 1H, J=6.00H, 6.00 Hz), 6.80 (d, 1H, J=6.00 Hz), 6.65 (s, 1H), 4.80 (t, 2H, J=6.00 Hz), 3.90 (broad, 1H), 3.80 (s, 3H), 3.30 (t, 2H, J=6.00 Hz), 2.90-2.10 (overlapping m, 11H), 1.10 (d, 3H, J=6.00 Hz).
Reaction SMILES: [CH2:1]([C@H:8]([NH:37][C:38](=[O:48])[O:39][C@@H:40]1[C@H:47]2[C@H:43]([O:44][CH2:45][CH2:46]2)[O:42][CH2:41]1)[C@H:9]([OH:36])[CH2:10][N:11]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28]CC2C=CC=CC=2)=[CH:24][CH:23]=1)(=[O:21])=[O:20])[O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[CH2:1]([C@H:8]([NH:37][C:38](=[O:48])[O:39][C@@H:40]1[C@H:47]2[C@H:43]([O:44][CH2:45][CH2:46]2)[O:42][CH2:41]1)[C@H:9]([OH:36])[CH2:10][N:11]([O:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)[S:19]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCCC1)S(=O)(=O)c1ccc(OCc2ccccc2)cc1)O[C@H]1CO[C@H]2OCC[C@H]21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCCC1)S(=O)(=O)c1ccc(O)cc1)O[C@H]1CO[C@H]2OCC[C@H]21
Reaction time: 16 h
Yield: 87.1 %

Procedure:
A solution of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[{[4-(benzyloxy)phenyl]sulfonyl}(cyclohexyloxy)amino]-2-hydroxypropylcarbamate (140 mg, 0.206 mmol) in ethyl acetate (5 mL) was combined with Palladium on carbon (10 wt %, 28 mg) and reduced under an atmosphere of Hydrogen gas. After stirring for 16 hours, the reaction mixture was filtered and evaporated in vacuo to a residue. The residue was purified on a preparative TLC plate (20×20 cm, 500 μM) eluting with 3:2 ethyl acetate:hexane. The product band was removed, eluted with 4:1 methylene chloride:methanol, filtered, and evaporated in vacuo. The residue was triturated with water, filtered and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-{(cyclohexyloxy)[(4-hydroxyphenyl)sulfonyl]amino}-2-hydroxypropylcarbamate (106 mg, 87%) as a white solid. H1-NMR (chloroform-D3): 1.27 (m, 6H), 1.67 (m, 5H), 2.05 (m, 2H), 2.93 (m, 4H), 3.11 (b, 1H), 3.68 (m, 2H), 3.90 (m, 4H), 4.19 (m, IH), 4.81 (d, 1H), 4.99 (m, 1H), 5.65 (d, 1H), 6.24 (b, 1H), 6.92 (d, 2H), 7.22 (m, 5H), 7.67 (d, 2H). MS(ESI): 613(M+Na).
Reaction SMILES: [C:1](OCC)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH3:9][CH:10]([CH2:13][CH2:14][CH3:15])[CH:11]=[O:12].CC(C1OC(=O)CC1)CCC>>[CH3:4][CH:3]1[CH:11]([CH:10]([CH2:13][CH2:14][CH3:15])[CH3:9])[O:12][C:1](=[O:5])[CH2:2]1
Reactant: C/C=C/C(=O)OCC
Reactant: CCCC(C)C=O
Agent: CCCC(C)C1CCC(=O)O1
Product: CCCC(C)C1OC(=O)CC1C

Procedure:
Ethyl crotonate (6.7% by weight) and 2-methylpentanal (5.9% by weight) were reacted electrochemically by a method analogous to example 3 (all % by weight are based on the total aqueous reaction electrolyte). A yield of 4-(2-pentyl)butyrolactone of 66.7% and a yield of the corresponding ethyl γ-hydroxycarboxylate of 26.6% were achieved. This corresponded to a total yield of target products of 93.2% of the theoretical yield.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[CH:12][C:13]([NH:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)=[O:14].[N+:27]([CH2:30]C(C1C=CC=CC=1)CC(NC1C=CC(C(OCC)=O)=CC=1)=O)([O-:29])=[O:28]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([CH2:30][N+:27]([O-:29])=[O:28])[CH2:12][C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=1)=[O:14]
Reactant: CCOC(=O)c1ccc(NC(=O)C=Cc2ccc3ccccc3c2)cc1
Reactant: CCOC(=O)c1ccc(NC(=O)CC(C[N+](=O)[O-])c2ccccc2)cc1
Product: CCOC(=O)c1ccc(NC(=O)CC(C[N+](=O)[O-])c2ccc3ccccc3c2)cc1
Yield: 70 %

Procedure:
This was prepared from corresponding amide 42 (0.995 g, 2.88 mmol) in a similar manner as described for preparation of 47. Chromatography on silica gel performed using a FlashMaster 3 purification station (75:25 hexanes/ethyl acetate, Rf 0.20) afforded 48 (0.819 g, 2.017 mmol, 70%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 1.26 (3H, t, J 7.6 Hz), 2.85-2.93 (2H, m), 4.10 (1H, quint, J 8.0 Hz), 4.23 (1H, q, J 7.2 Hz), 5.02-5.10 (2H, m), 7.45-7.48 (2H, m), 7.54 (1H, dd, J 1.6, 8.8 Hz), 7.62 (2H, d, J 8.8 Hz), 7.82-7.87 (6H, m). 13C NMR (400 MHz, CDCl3) δ 14.52, 40.75, 40.79, 61.21, 79.48, 119.21, 124.97, 126.43, 126.65, 126.78, 126.87, 127.92, 128.04, 129.37, 130.94, 133.11, 133.59, 135.89, 141.68, 166.37, 168.54. MS (API-ES): m/z found 407 [M+H]+ (100%), HRMS (API-ES) m/z 407.1607 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:7][CH2:8][NH2:9])[S:5][CH:6]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:7][CH2:8][NH:9][C:10](=[O:12])[CH3:11])[S:5][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1csc(CCN)c1
Product: CC(=O)NCCc1cc(C)cs1
Yield: 95 %

Procedure:
In close analogy to the procedure described above, 2-(4-Methyl-thiophen-2-yl)-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[NH:19][C:14]3=[CH:15][N:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:20]([O:24][C:25](=[O:31])[NH:26][CH2:27][CH2:28][O:29][NH2:30])([CH3:23])([CH3:22])[CH3:21].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[N:30][O:29][CH2:28][CH2:27][NH:26][C:25](=[O:31])[O:24][C:20]([CH3:22])([CH3:21])[CH3:23])[C:11]2[NH:19][C:14]3=[CH:15][N:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)NCCON
Reactant: O=C(c1ccc(Cl)c(Cl)c1)c1cc2ccncc2[nH]1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCON=C(c1ccc(Cl)c(Cl)c1)c1cc2ccncc2[nH]1
Yield: 51.5 %

Procedure:
(3,4-Dichlorophenyl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (Example 127) (92 mg, 0.32 mmol) and tert-butyl[2-(aminooxy)ethyl]carbamate (58 mg, 0.33 mmol) were combined in ethanol (5 mL). The pH was adjusted to ca. 4 using 1 M ethereal hydrogen chloride and the react ion mixture was refluxed for 14 h. The solvent was removed under vacuum. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution and then brine, dried over sodium sulfate, and concentrated to a solid. Purification by Biotage chromatography (silica gel, 97:3 CH2Cl2:CH3OH) produced tert-butyl 2-[[[(3,4-dichlorophenyl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]ethylcarbamate (74 mg, 51%) as a yellow foam: 1H NMR (300 MHz CD3OD) δ 1.39 (9H, s), 3.50-3.54 (2H, m), 4.26-4.39 (2H, m), 6.35 (0.35H, s), 6.62 (0.65H, s), 7.38-7.77 (4H, m), 8.04-8.11 (1H, m), 8.72 (0.35H, s), 8.93 (0.65H, s); ESI MS m/z 449 [C21H22Cl2N4O3+H]+.
Reaction SMILES: C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(F)=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)C.[C:49]([O:53][C@@H:54]([C:59]1[C:88]([CH3:89])=[C:87]([Br:90])[C:86]2=[N:91][C:83]3=[C:84]([Br:92])[N:85]2[C:60]=1[N:61]1[CH2:98][CH2:97][C:64]([CH3:99])([O:65][CH2:66][CH2:67][CH2:68][CH2:69][C@H:70]([CH3:96])[O:71][C:72]2[CH:73]=[C:74](C)[C:75]([F:94])=[CH:76][C:77]=2[C:78]2[CH:93]=[C:82]3[CH:81]=[CH:80][CH:79]=2)[CH2:63][CH2:62]1)[C:55]([O:57][CH3:58])=[O:56])([CH3:52])([CH3:51])[CH3:50]>>[C:49]([O:53][C@@H:54]([C:59]1[C:88]([CH3:89])=[C:87]([Br:90])[C:86]2=[N:91][C:83]3=[C:84]([Br:92])[N:85]2[C:60]=1[N:61]1[CH2:62][CH2:63][C:64]([CH3:99])([O:65][CH2:66][CH2:67][CH2:68][CH2:69][C@H:70]([CH3:96])[O:71][C:72]2[CH:73]=[CH:74][C:75]([F:94])=[CH:76][C:77]=2[C:78]2[CH:93]=[C:82]3[CH:81]=[CH:80][CH:79]=2)[CH2:97][CH2:98]1)[C:55]([O:57][CH3:58])=[O:56])([CH3:52])([CH3:50])[CH3:51]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(Br)c2nc3c(Br)n2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(C)c(F)cc1-c1cccc-3c1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(Br)c2nc3c(Br)n2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Yield: 73 %

Procedure:
Prepared in 73% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for methyl(2S)-2-(tert-butoxy)-2-[(22S)-5,8-dibromo-17-fluoro-4,18,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate. LCMS (ESI, M+1): 816.05.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].[CH3:13][NH:14][CH3:15]>C(O)C>[CH3:13][N:14]([CH3:15])[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6]
Reactant: N#Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: CNC
Solvent: CCO
Product: CN(C)c1cc(C#N)ccc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
The mixture of 16.7 g (100 mmol) of 3-fluoro-4-nitrobenzonitrile and 100 mL of the solution of dimethylamine in ethanol (5 M) was refluxed overnight. The resulting dark red solution was then poured in to 100 mL of ice-water. The precipitate was collected by filtration and washed by H2O (50 mL×2) and ethanol (50 mL×2) to give 16.9 g of a organe needle crystal as the desired product. MS ESI (m/z) 192 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].[N:10]([O-])=O.[Na+].O.O.[Cl:16][Sn]Cl.[OH-].[Na+].CCOCC>Cl.O>[ClH:16].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([NH:7][NH2:10])[CH:8]=1
Reactant: O=N[O-]
Reactant: Cc1ccc(Br)cc1N
Reactant: Cl[Sn]Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(Br)cc1NN
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a suspension of 5-bromo-2-methylaniline (4.80 g, 25.8 mmol) in concentrated HCl (16 mL) was added dropwise a solution of sodium nitrite (1.96 g, 28.4 mmol) in water (10 mL) over 30 minutes at 0° C. To the mixture was added dropwise a solution of SnCl2.2H2O (17.46 g, 77.4 mmol) in concentrated HCl (15 mL) over 50 minutes. After stirring for 1 hour at 0° C., the reaction mixture was basified with 50% NaOH (30 mL). The mixture was further diluted with water (20 mL) and treated with another 50% NaOH (10 mL) and then crushed ice (100 g). The reaction mixture was extracted with ether (3×100 mL) and the combined organic phases were washed with brine, dried over Na2SO4, and filtered. The filtrate was acidified by adding an anhydrous solution of HCl in ether (1 N in ether, 31 mL, 31 mmol). The precipitate was collected and dried under reduced pressure to give 4.57 g (75%) of title compound as a white amorphous solid. 1H NMR (DMSO): 300 MHz δ 10.31 (bs, 3H), 8.11 (bs, 1H), 7.12 (s, 1H), 7.06 (m, 2H), 2.14 (s, 3H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[C:13]#[N:14])[CH:2]1[O:4][CH2:3]1.[CH3:15][C:16]([NH2:27])([CH3:26])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>>[ClH:12].[OH:4][CH:2]([CH2:1][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[C:13]#[N:14])[CH2:3][NH:27][C:16]([CH3:26])([CH3:15])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1
Reactant: COc1ccc(CC(C)(C)N)cc1
Reactant: N#Cc1c(Cl)cccc1OCC1CO1
Product: COc1ccc(CC(C)(C)NCC(O)COc2cccc(Cl)c2C#N)cc1
Product: Cl
Yield: 143.2 %

Procedure:
Using the method of Example 6, supra, 3-chloro-2-cyanophenyl glycidyl ether (0.093 g, 0.44 mmol) and 1,1-dimethyl-(4-methoxyphenyl)ethylamine (0.095 g, 0.53 mmol) were used to prepare 134 mg of the title compound as a white solid: 1H-NMR (CDCl3) ∂ 9.68 (1H, br s), 8.2 (1H, br s), 7.4 (1H, t), 7.15 (2H, d), 7.03 (1H, d), 6.95 (1H, d), 6.8 (2H, d), 5.7 (1H, br s), 4.8 (1H, m), 4.3 (2H, d), 3.75 (3H, s), 3.4 (2H, m), 3.13 (2H, dd), 1.44 (3H, s), 1.40 (3H, s)
Reaction SMILES: [CH:1]([CH2:3][CH2:4][CH2:5][C:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18])=O.Cl.[CH:20]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[CH:20]1([N:29]2[CH2:34][CH2:33][N:32]([CH2:1][CH2:3][CH2:4][CH2:5][C:6]34[CH2:17][CH2:16][CH2:15][C:13]5[C:14]3=[C:9]([CH:10]=[CH:11][CH:12]=5)[NH:8][C:7]4=[O:18])[CH2:31][CH2:30]2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1
Reactant: c1ccc2c(c1)CCC2N1CCNCC1
Reactant: O=CCCCC12CCCc3cccc(c31)NC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: O=C1Nc2cccc3c2C1(CCCCN1CCN(C2CCc4ccccc42)CC1)CCC3

Procedure:
2a-(3-Formylpropyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (210 mg, 0.90 mmol), 1-(1-indanyl)piperazine hydrochloride (270 mg, 1.0 mmol), acetic acid (540 mg, 9.0 mmol) and sodium triacetoxyborohydride (380 mg, 1.8 mmol) were stirred at room temperature for 20 hours in 1,2-dichloroethane (3 ml). The reaction solution was mixed with ethyl acetate (80 ml), washed with sodium hydroxide aqueous solution (1 N) and saturated brine and dried with anhydrous sodium sulfate, the solvent was removed by evaporation under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 430 mg (1.0 mmol, 100% in yield) of the title compound.
Reaction SMILES: Cl.[CH3:2][NH:3][C@H:4]([C:22]([OH:24])=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[O:20][CH3:21])=[CH:8][CH:7]=1.[Li+].[OH-:26].CO.[CH2:29]1[CH2:33][O:32][CH2:31][CH2:30]1>O>[CH:17]1[C:30]2[CH:29]([CH2:33][O:32][C:2]([NH:3][C@H:4]([C:22]([OH:24])=[O:23])[CH2:5][C:6]3[CH:7]=[CH:8][C:9]([C:12]4[C:13]([O:20][CH3:21])=[CH:14][CH:15]=[CH:16][C:17]=4[O:18][CH3:19])=[CH:10][CH:11]=3)=[O:26])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:31]=2[CH:14]=[CH:13][CH:12]=1
Reactant: CN[C@@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)C(=O)O
Reactant: C1CCOC1
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Product: COc1cccc(OC)c1-c1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reaction time: 0.67 h
Yield: 100 %

Procedure:
Methyl 4-(2,6-dimethoxyphenyl)-L-phenylalanine hydrochloride (3.53 g, 10 mmol) obtained in step 3 in Example 50 was dissolved in methanol/THF. A solution of LiOH (927 mg) in water (10 ml) was added to the obtained solution. After stirring for 40 minutes, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure and then subjected to the azeotropic distillation with ethanol twice. The obtained solid was dissolved in acetone/water (20 ml/20 ml). Sodium hydrogencarbonate (1.68 g) and Fmoc-Osu (3.37 g) were added to the obtained solution, and they were stirred for 19 hours. The reaction solution was adjusted to pH 2 with concentrated hydrochloric acid. After the extraction with a solvent mixture of isopropanol/dichloromethane (1/1), the extract was concentrated under reduced pressure. The product was purified by the silica gel column chromatography (hexane, hexane/ethyl acetate, 2/1, 3/2) to obtain 5.74 g (100%) of the intended compound.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)=[N:10][CH:9]=[CH:8][N:7]=2)[CH2:3]1.Cl[C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1.[C:31]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([C:11]2[C:6]([CH:4]3[CH2:5][N:2]([C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[C:24]([CH3:31])[CH:25]=[CH:26][CH:27]=5)[N:22]=4)[CH2:3]3)=[N:7][CH:8]=[CH:9][N:10]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(-c2nccnc2C2CNC2)c1
Reactant: Clc1ccc2ccccc2n1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(-c2nccnc2C2CN(c3ccc4cccc(C)c4n3)C2)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of 2-azetidin-3-yl-3-(3-methoxy-phenyl)-pyrazine hydrochloride (138 mg, 0.50 mmol) and 2-chloro-quinoline (84 mg, 0.50 mmol) in DMF (6 mL) was added Cs2CO3 (325 mg, 1.0 mmol). The reaction mixture was stirred at 110° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (30 mL×2). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 40% EtOAc in petroleum ether) to give 2-{3-[3-(3-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-8-methyl-quinoline (118 mg, 0.31 mmol, 63.35%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:17][Mg]Br>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)([OH:9])[CH3:17])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cccc(F)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)(c1ccc(Cl)cc1)c1cccc(F)c1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a stirred solution of (4-chlorophenyl)-(3-fluorophenyl)-methanone (200 mg, 0.717 mmol) in THF (6 mL) was added 1.4 M of methylmagnesium bromide in THF (1.8 mL, 2.5 mmol) at −78° C. The reaction was stirred at −78° C. for 4 h. The reaction was quenched with sat. aq. NaHCO3 at −78° C. The crude material was extracted with DCM and concentrated in vacuo to afford the title compound as a colorless oil which was used for next step without further purification.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]([OH:16])[CH2:14][N:15]=2)=[CH:6][CH:5]=1)[CH3:2].[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCCl>[CH2:1]([S:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:11][CH:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]([O:16][C:30](=[O:31])[NH:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][N:15]=2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: O=C=Nc1ccccc1
Reactant: CCSc1ccc(C2=NCC(O)C(c3ccccc3)O2)cc1
Solvent: ClCCCl
Product: CCSc1ccc(C2=NCC(OC(=O)Nc3ccccc3)C(c3ccccc3)O2)cc1
Temperature: 80 °C
Yield: 12.3 %

Procedure:
A mixture of (5RS, 6SR)-2-[4-(ethylthio)phenyl]-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (6.5 g) and phenylisocyanate (2.6 g) in 1,2-dichloroethane (100 cc) is heated to a temperature in the region of 80° C. for 5 hours. After being cooled, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue obtained is purified by chromatography on silica (0.063-0.2 mm; 150 g) contained in a column 3.5 cm in diameter eluting in 20-cc fractions with an ethylacetate/cyclohexane mixture (50:50 by volume). Fractions 5 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is further purified by chromatography on silica (0.063-0.2 mm; 100 g) contained in a column 3.5 cm in diameter, eluting in 25-cc fractions with a methylene chloride/methanol mixture (99:1 by volume). Fractions 10 to 18 are combined and concentrated to dryness under reduced pressure. (5RS, 6SR)-2-[4-(Ethylthio)phenyl]-6-phenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (1.1 g), m.p. 70° C., is thereby obtained.