Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH2:11][CH2:12][C:13]([N:15]1[C@@H:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:18]([C:26]([O:28][CH3:29])=[O:27])[S:17][C@H:16]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:14]>O1CCCC1>[CH3:29][O:28][C:26]([C@@H:18]1[S:17][C@@H:16]([C:30]([O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:31])[N:15]([C:13](=[O:14])[CH2:12][NH:11][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[O:10])[C@H:19]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:27]
Reactant: COC(=O)[C@@H]1S[C@@H](C(=O)OC(C)(C)C)N(C(=O)CN)[C@H]1c1ccccc1
Reactant: Cc1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1S[C@@H](C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc2cccc(C)c2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
50 μl of 3-methylphenyl isocyanate are added to a round-bottomed flask containing 0.14 g of tert-butyl (2S,4S,5R)-3-(2-aminoacetyl)-5-methoxycarbonyl-4-phenyl-2-thiazolidinecarboxylate dissolved in 10 ml of tetrahydrofuran. The reaction mixture is stirred for 12 hours at a temperature in the region of 25° C. and then concentrated to dryness under reduced pressure at 35° C. The crude product is purified by chromatography on silica [eluent: ethyl acetate/cyclohexane (40/60 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40° C. 0.13 g of tert-butyl (2S,4S,5R)-5-methoxycarbonyl-3-{2-[3-(3-methylphenyl)ureido]acetyl}-4-phenyl-2-thiazolidinecarboxylate is thus obtained in the form of a white foam, [α]D25 =-9.5°±0.8° (c=1.0; CH3OH), 1H NMR: (200 MHz, (CD3)2SO with addition of a few drops of CD3COOD, at a temperature of 373 K, δ in ppm): 1.51 (s, 9H: CH3 of the tert-butyl); 2.28 (s, 3H: ArCH3); 3.69 and 4.05 (broad d and d respectively, J=17 Hz, 1H each: COCH2N); 3.78 (s, 3H: COOCH3); 4.31 (d, J=3.5 Hz, 1H: at C5 of the ring); 5.75 (s, 1H: H at C2 of the ring); 5.86 (d, J=3.5 Hz, 1H: H at C4 of the ring); 6.76 (broad d, J=7.5 Hz, 1H: aromatic H (H ortho to the CH3)); 7.10 (t, J=7.5 Hz, 1H: aromatic H (H meta to the CH3) ); from 7.10 to 7.50 (mt, 5H: aromatic H); 7.73 (mt, 2H: H ortho to the phenyl).
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].CN(C1C=CC=CN=1)C.[CH:25]1([CH2:28][O:29][C:30]2[CH:31]=[C:32]([C:36]3[C:44]4[C:39](=[CH:40][CH:41]=[C:42](O)[CH:43]=4)[N:38]([CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[C:49]([O:53][CH3:54])[CH:48]=4)[C:37]=3[C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH:33]=[CH:34][CH:35]=2)[CH2:27][CH2:26]1>ClCCl.N1C=CC=CC=1.C(OCC)(=O)C>[CH:25]1([CH2:28][O:29][C:30]2[CH:31]=[C:32]([C:36]3[C:44]4[C:39](=[CH:40][CH:41]=[C:42]([O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])[CH:43]=4)[N:38]([CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[C:49]([O:53][CH3:54])[CH:48]=4)[C:37]=3[C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH:33]=[CH:34][CH:35]=2)[CH2:27][CH2:26]1
Reactant: CCOC(=O)c1c(-c2cccc(OCC3CC3)c2)c2cc(O)ccc2n1Cc1cccc(OC)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-c2cccc(OCC3CC3)c2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2n1Cc1cccc(OC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
Triflic anhydride (0.84 mL, 1.4 g, 5.0 mmol) and dimethylaminopyridine (25 mg, 0.20 mmol) were added to a cooled (0° C.) and stirred solution of ethyl 3-[3-(cyclopropylmethoxy)phenyl]-5-hydroxy-1-(3-methoxybenzyl)-1H-indole-2-carboxylate (Example 66, 1.00 g, 2.12 mmol) in dichloromethane (10 mL) and pyridine (2 mL). The reaction was warmed to rt and then stirred an additional 2 h. The solution was diluted with ethyl acetate (100 mL), washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Flash chromatography of the residue over silica gel using 15% ethyl acetate/hexane afforded 1.14 g (89%) of desired product. The product had: 1H NMR (300 MHz, acetone-D6) δ 7.73 (d, 1 H), 7.54 (d, 1 H), 7.35-7.42 (m, 3 H), 7.20 (dd, 1 H), 7.00-7.07 (m, 2 H), 6.68-6.83 (m, 3 H), 5.88 (s, 2 H), 4.16 (q, 2 H), 3.91 (d, 2 H), 3.72 (s, 3 H), 1.25-1.35 (m, 1 H), 10.5 (t, 3 H), 0.55-0.65 (m, 2 H), 0.32-0.42 (m, 2 H); mass spectroscopy gave M+=603.1 (exact mass calc'd for C20H28F3NO7S=603.15).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[CH2:15][O:14][C@@H:13]([CH2:16][OH:17])[O:12]2)=[C:4](Cl)[N:3]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[CH2:15][O:14][C@@H:13]([CH2:16][OH:17])[O:12]2)=[C:4]([NH:22][CH:19]2[CH2:21][CH2:20]2)[N:3]=1
Reactant: NC1CC1
Reactant: Nc1nc(Cl)c2ncn([C@H]3CO[C@@H](CO)O3)c2n1
Solvent: CCO
Product: Nc1nc(NC2CC2)c2ncn([C@H]3CO[C@@H](CO)O3)c2n1
Temperature: 0 °C
Yield: 76 %

Procedure:
[4(R)-(2-Amino-6-chloro-purin-9-yl)-[1,3]dioxolan-2(R)-yl]-methanol (1.2 kg, 4.5 moles), ethanol (15.2 L) and cyclopropylamine (756 g) were refluxed under nitrogen for 16 hours. The reaction was monitored for completion by HPLC. Once completed the reaction mixture was hot-filtered and allowed to cool to 0° C. slowly. The solids were filtered and subsequently recrystallized from ethanol to give [4(R)-(2-Amino-6-cyclopropylamino-purin-9-yl)-[1,3]dioxolan-2(R)-yl]-methanol (1.0 kg, 77%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([C:28]([OH:30])=O)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:32][O:33][NH:34][CH3:35].N=C=N.C(N(CC)CC)C.C1C=NC2N(O)N=NC=2C=1>ClCCCl>[CH3:32][O:33][N:34]([CH3:35])[C:28]([C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([S:15](=[O:17])(=[O:16])[NH:14][CH:11]2[CH2:10][CH2:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:13][CH2:12]2)=[CH:19][CH:20]=1)=[O:30]
Reactant: O=C(O)c1ccc(S(=O)(=O)NC2CCN(Cc3ccccc3)CC2)c2ccccc12
Reactant: CNOC
Agent: Cl
Agent: N=C=N
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(S(=O)(=O)NC2CCN(Cc3ccccc3)CC2)c2ccccc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-benzyl-piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid 34 (212 mg, 0.5 mmol) in DCE (5 mL), was added O,N-dimethyl-hydroxylamine hydrochloride (59 ul, 0.6 mmol), PS-carbodiimide (1.9 g, 2.5 mmol), triethyl amine (140 uL, 1 mmol) and HOAt (102 mg, 0.75 mmol). After stirring at 50° C. overnight, the resultant solution was filtered and concentrated in vacuo to give the crude product 4-(1-benzyl-piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid methoxy-methyl-amide 35. LCMS showed m/z: 468 (M+H)+. This material was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[N:11]1([CH2:10][CH2:9][O:8][C:7]2[CH:17]=[CH:18][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(OCCN2CCOCC2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(OCCN2CCOCC2)cc1
Yield: 72 %

Procedure:
A mixture of 4-[2-(4-nitro-phenoxy)-ethyl]-morpholine (3.2 g, 13 mmol) and 5% Pd—C (0.3 g) in ethyl acetate (70 mL) was hydrogenated under 50 psi hydrogen for 20 hours. The mixture was filtered through Celite, and the filtrate was evaporated in vacuo, providing 2.0 g, in 72% yield; 1H NMR (CDCl3) δ 2.57 (t, J=4.6 Hz, 4H), 2.77 (t, J=5.8 Hz, 2H), 3.74 (t, J=4.6 Hz, 4H), 4.04 (t, J=5.8 Hz, 2H), 6.63 (d, J=8.8 Hz, 2H), 6.75 (d, J=8.8 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[C:16]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])#[N:17]>Cl.O1CCOCC1>[O:6]=[C:4]1[C:3]2[C:2](=[CH:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=2)[N:1]=[C:16]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[NH:17]1
Reactant: N#CC(=O)OCc1ccccc1
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(=O)[nH]c(C(=O)OCc3ccccc3)nc2c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
To a solution of dimethyl 2-aminoterephthalate (1.70 g, 8.1 mmol) in 4.0 M hydrochloric acid in 1,4-dioxane (20 mL) was added benzyl cyanoformate (2.0 mL, 14 mmol). The reaction mixture was heated to 50° C. and stirred for 3 h. The mixture was then cooled to rt, concentrated and the residue was twice co-evaporated with toluene. Diethyl ether was added and the solid was filtered to afford 2-benzyl 7-methyl 4-oxo-3,4-dihydroquinazoline-2,7-dicarboxylate (2.7 g, 98%). LC-MS: (FA) ES+ 339.
Reaction SMILES: [CH2:1]([C:5]1[CH:14]=[N:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)[CH:2]([CH3:4])[CH3:3]>C1(C)C=CC=CC=1>[CH2:1]([C@H:5]1[CH2:14][NH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1cnc2ccccc2n1
Solvent: Cc1ccccc1
Product: CC(C)C[C@H]1CNc2ccccc2N1
Temperature: 40 °C
Reaction time: 31 h
Yield: 81.9 %

Procedure:
To an argon-purged pressure-resistant glass vessel (100 mL) equipped with a magnetic stir bar, RuCl[(R)-daipena][(R)-dm-segphos] (2.4 mg, 2.0 μmol) and KO(t-Bu) (11.9 mg, 0.106 mmol) were added, and the vessel was purged with argon again. To this vessel, a toluene (2.0 mL) solution containing 2-isobutylquinoxaline (378.3 mg, 2.03 mmol) and being degassed by the freeze-pump-thaw technique in advance was added by pressure transfer using a cannula. An operation in which hydrogen was introduced into the pressure-resistant vessel up to 0.8 MPa and then released was repeated 10 times to completely substitute the inside with hydrogen. Then, hydrogen was introduced up to 2.0 MPa, and the vessel was stirred in a water bath at 40° C. for 31 hours. After hydrogen was released, the solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1 to 4:1 to 1:1) to obtain (S)-1,2,3,4-tetrahydro-2-isobutylquinoxaline (316.4 mg, 82%). A result of an analysis was conducted by high performance liquid chromatography (column: CHIRALCEL OD-H, mobile phase: hexane:IPA=80:20, 1 mL/min) showed that the optical purity of this product was 97% ee.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([SH:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)=[CH:21][C:20]=1[N+:30]([O-:32])=[O:31]>CN(C=O)C>[N:25]1([C:22]2[CH:23]=[CH:24][C:19]([S:11][C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH:4]=[CH:3][N:2]=[CH:1]4)=[C:20]([N+:30]([O-:32])=[O:31])[CH:21]=2)[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: Sc1cccc2cnccc12
Reactant: O=[N+]([O-])c1cc(-n2ccnc2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(-n2ccnc2)ccc1Sc1cccc2cnccc12
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 97.6 %

Procedure:
According to the method in Example 10, a mixture of 5-isoquinolinethiol 360 mg (2.2 mmol), DMF 9 ml, potassium carbonate 600 mg (4.3 mmol) and 1-(4-chloro-3-nitrophenyl)-1H-imidazole 420 mg (2.0 mmol) was stirred at 100° C. for 2.5 hours, and 5-[4-(1H-1-imidazolyl)-2-nitrophenylsulfanyl)isoquinoline 680 mg (97.6%) was obtained.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[CH2:8][CH:7]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]1=[O:18])[CH2:2][CH2:3][CH3:4].NC1C(=O)N(C2C=CC=CC=2)C(=O)C1>>[CH2:1]([N:5]1[C:9](=[O:10])[CH:8]=[C:7]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]1=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)CC(Nc2ccccc2)C1=O
Agent: NC1CC(=O)N(c2ccccc2)C1=O
Product: CCCCN1C(=O)C=C(Nc2ccccc2)C1=O
Yield: 93 %

Procedure:
Utilizing the procedure above and substituting N-butylanilinosuccinimide for the 3-amino-N-phenylsuccinimide yields 93% of N-butylanilinomaleimide which upon crystallization from isopropyl alcohol has a m.p. of 128°-130° C. Anal. Calcd. for C14H16N20 2: 68.85; H, 6.56; N, 11.48. Found: C, 68.58; H, 6.45; N, 11.38.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[CH2:5][N:6]([CH3:8])[CH3:7].Br[C:14]1[CH:23]=[N:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]>>[CH3:7][N:6]([CH2:5][C:4]1[CH:9]=[CH:10][CH:11]=[CH:12][C:3]=1[CH2:2][NH:1][C:20]1[CH:21]=[N:22][CH:23]=[CH:14][C:15]=1[C:16]([O:18][CH3:19])=[O:17])[CH3:8]
Reactant: CN(C)Cc1ccccc1CN
Reactant: COC(=O)c1ccncc1Br
Product: COC(=O)c1ccncc1NCc1ccccc1CN(C)C
Yield: 65 %

Procedure:
The title compound was prepared in 65% yield from N-[2-(aminomethyl)benzyl]-N,N-dimethylamine and methyl 3-bromoisonicotinate according to the procedure for Preparation 4A. 1H NMR (400 MHz, CDCl3): δ 8.27 (s, 1H), 7.88 (d, 1H, J=5.1 Hz), 7.82 (br s, 1H), 7.61 (d, 1H, J=5.1 Hz), 7.20-7.36 (m, 4H), 4.68 (d, 2H, J=5.8 Hz), 3.87 (s, 3H), 3.46 (s, 2H), 2.22 (s, 6H). [M+H] calc'd for C17H21N3O2, 300; found 300.
Reaction SMILES: [CH2:1]([C:8]1[C:12]([C:13]2[CH:14]=[C:15](SC)[C:16]3[N:17]([C:19]([CH3:22])=[N:20][N:21]=3)[N:18]=2)=[CH:11][N:10]([CH3:25])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:29])(=O)=O>C(Cl)(Cl)Cl>[CH2:1]([C:8]1[C:12]([C:13]2[CH:14]=[C:15]([Cl:29])[C:16]3[N:17]([C:19]([CH3:22])=[N:20][N:21]=3)[N:18]=2)=[CH:11][N:10]([CH3:25])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CSc1cc(-c2cn(C)nc2Cc2ccccc2)nn2c(C)nnc12
Solvent: ClC(Cl)Cl
Product: Cc1nnc2c(Cl)cc(-c3cn(C)nc3Cc3ccccc3)nn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-benzyl-1-methyl-4-[3-methyl-8-(methylsulfanyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-1H-pyrazole (32 mg; 0.09 mmol) was dissolved in 1 ml chloroform and was treated with sulfurylchlorid (44 μl; 0.54 mmol). The reaction mixture is stirred for 18 h at 25° C.
Reaction SMILES: N=C=N.[NH:4](C(OCC1C=CC=CC=1)=O)[C@H:5]([C:10](O)=[O:11])[C@H:6]([CH2:8][CH3:9])[CH3:7].[NH2:23][C@H:24]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[NH2:4][C@H:5]([C:10]([NH:23][C@H:24]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:11])[C@H:6]([CH2:8][CH3:9])[CH3:7]
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: N=C=N
Product: CC[C@H](C)[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Yield: 90 %

Procedure:
In accordance with the carbodiimide method indicated Z-Ile-OH (4) was linked with H-Phe-OtBu (5). By means of subsequent catalytic diacylation of the intermediate benzyloxy-carbonyl-dipeptide ester (4-5a) it was possible to isolate H-Ile-Phe-OtBu (4-5b) with a yield of above 90 %.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[F:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[C:14](=[O:29])[CH2:15][C:16]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)=[N:17]2.FC1C=C2C(C(=O)CC(C3C=CC(C)=CC=3)=N2)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[C:14]([O:29][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4])=[CH:15][C:16]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)=[N:17]2
Reactant: O=C(CBr)N1CCOCC1
Reactant: Cc1ccc(C2=Nc3cccc(F)c3C(=O)C2)cc1
Agent: Cc1ccc(C2=Nc3cc(F)ccc3C(=O)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1ccc(-c2cc(OCC(=O)N3CCOCC3)c3c(F)cccc3n2)cc1
Temperature: 20 °C
Yield: 18 %

Procedure:
4-(2-Bromoacetyl)morpholine (7.3 g) in 2 butanone (50 cc) is added to a stirred suspension of a mixture (11.2 g of 5-fluoro-2-(4-methylphenyl)-4-quinolone and 7-fluoro-2-(4-methylphenyl)-4-quinolone and anhydrous potassium carbonate (11.3 g) in 2-butanone (250 cc). The mixture is heated to reflux for 15 hours and cooled to room temperature (approximately 20° C.), the insoluble matter is removed by filtration and the 2-butanone is evaporated off under reduced pressure. The residue is taken up with water (200 cc) and the aqueous phase is extracted with methylene chloride (3×100 cc). The organic phase is separated after settling has taken place, dried and evaporated under reduced pressure. After chromatography of the residue on silica gel by means of cyclohexane/ethyl acetate mixture (70:30 by volume) as eluant, the solid obtained is ground in 40°-60° C. petroleum ether (100 cc). 4-≡[5-fluoro-2-(4-methylphenyl-4-quinolyl]oxyacetyl}morpholine (2.4 g), m.p. 142°-4° C., is thereby obtained.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[C:9]([CH:10]=O)[C:8]([OH:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][C:22](=[O:24])[CH3:23]>C(#N)C>[C:22]([C:23]1[O:13][C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:12][C:9]=2[CH:10]=1)(=[O:24])[CH3:21]
Reactant: CC(=O)CCl
Reactant: CC(C)(C)c1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1cc2cc(C(C)(C)C)ccc2o1
Temperature: 25 °C
Yield: 60.9 %

Procedure:
5-tert-Butylsalicylaldehyde (163 g) was dissolved in 1.5 liters of acetonitrile, 252.5 g of anhydrous potassium carbonate was added and 84.6 g of chloroacetone was dropped into the mixture with stirring at room temperature. After completion of the dropping, the reaction mixture was stirred for 8 hours and then insoluble matters were filtered off. The filtrate was concentrated in vacuo and the residue was dissolved in ethyl acetate followed by washing with water twice. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was crystallized by adding isopropyl ether thereto followed by filtering to give 120.5 g of crystals. M.p. 99°-101° C.
Reaction SMILES: [CH2:1]([N:8]([C:37](=[O:52])[CH2:38][CH2:39][CH2:40][NH:41]C(OCC1C=CC=CC=1)=O)[NH:9][C:10](=[O:36])[C@@H:11]([C@@H:16]([C:26](=[O:35])[NH:27][O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1)[CH2:17][CH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[NH2:41][CH2:40][CH2:39][CH2:38][C:37]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[NH:9][C:10](=[O:36])[C@@H:11]([C@@H:16]([C:26](=[O:35])[NH:27][O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1)[CH2:17][CH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:52]
Reactant: [H][H]
Reactant: CC(C)C[C@@H](C(=O)NN(Cc1ccccc1)C(=O)CCCNC(=O)OCc1ccccc1)[C@H](CCCC1CCCCC1)C(=O)NOC1CCCCO1
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(Cc1ccccc1)C(=O)CCCN)[C@H](CCCC1CCCCC1)C(=O)NOC1CCCCO1

Procedure:
A solution of 2′-benzyl-2′-(4-benzyloxycarbonylaminobutyryl)-2(R)-[4-cyclohexyl-1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]butyl]-4-methylvalerohydrazide in methanol was shaken in an atmosphere of hydrogen in the presence of 10% palladium-on-charcoal catalyst for 3 hours. The catalyst was filtered off and the methanol evaporated to give 2′-(4-aminobutyryl)-2′-benzyl-2(R)-[4-cyclohexyl-1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]butyl]-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][C:8]([CH3:15])([CH:13]=[CH2:14])[CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.Cl.[CH2:19](O)[CH3:20]>>[CH2:19]([O:11][C:10](=[O:12])[CH2:9][C:8]([CH2:7][C:6]1[CH:16]=[CH:17][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)([CH3:15])[CH:13]=[CH2:14])[CH3:20]
Reactant: C=CC(C)(CC(=O)O)Cc1ccc(OC)cc1
Reactant: CCO
Agent: Cl
Product: C=CC(C)(CC(=O)OCC)Cc1ccc(OC)cc1

Procedure:
A solution of product prepared in STEP 3 (5.6 g), saturated hydrochloric acid/ethanol (70 ml) was stirred at room temperature overnight. Solvent was removed. The crude product was purified on a silica gel column, eluting with 0.5% ethyl acetate/hexane to afford colorless oil (3.3 g). The 1H NMR was consistent with the proposed structure.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1)([CH3:3])[CH3:2].[CH3:12][N:13]1[C@H:27]2[C@@H:17]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:28]=3[C:25]([CH2:26]2)=[CH:24][NH:23]4)[CH2:16][C:15](=O)[CH2:14]1>[Pd]>[CH3:12][N:13]1[C@H:27]2[C@@H:17]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:28]=3[C:25]([CH2:26]2)=[CH:24][NH:23]4)[CH2:16][CH:15]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[N:6][CH:7]=2)[CH2:14]1
Reactant: CN1CC(=O)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: CC(C)Oc1ccc(N)cn1
Agent: [Pd]
Product: CC(C)Oc1ccc(NC2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cn1

Procedure:
The following compounds (isomers Ia and Ib) are obtained in a manner analogous to that described in Example 3, from 2-isopropoxy-5-aminopyridine and 6-methyl-8-oxo-ergoline in the presence of palladium:
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[F:24][C:25]([F:35])([F:34])[C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1.O>COCCOC>[O:1]=[C:2]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)[CH:3]([CH2:30][C:29]1[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:34])[F:35])=[CH:33][CH:32]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(=O)c1ccc(Oc2ccccc2)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of ethyl 3-oxo-3-(4-phenoxyphenyl)propionate (12 g, 42.2 mmol) in 1,2-dimethoxyethane (80 ml) was added sodium hydride (60% in oil, 1.69 g, 42.2 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 4-trifluoromethylbenzyl bromide (10.1 g, 42.2 mmol) in 1,2-dimethoxyethane (50 ml), and the reaction solution was stirred at room temperature for 4 hrs. The reaction solution was poured into water (200 ml), and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give ethyl 3-oxo-3-(4-phenoxyphenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionate (14.0 g, 75%).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:38][CH3:39])[C:7]([NH:28][CH:29]2[CH2:34][CH2:33][CH:32]([C:35](O)=[O:36])[CH2:31][CH2:30]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[C:13]([C:24]([F:27])([F:26])[F:25])[CH:12]=1)(=[O:3])[NH2:2].[CH3:40][O:41][C:42]1[C:43]([NH2:48])=[CH:44][CH:45]=[CH:46][CH:47]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:38]([C:6]1[N:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:9]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[C:13]([C:24]([F:25])([F:26])[F:27])[CH:12]=2)=[N:8][C:7]=1[NH:28][CH:29]1[CH2:34][CH2:33][CH:32]([C:35](=[O:36])[NH:48][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[O:41][CH3:40])[CH2:31][CH2:30]1)[CH3:39]
Reactant: COc1ccccc1N
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)c(C(F)(F)F)c2)nc1NC1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)c(C(F)(F)F)c2)nc1NC1CCC(C(=O)Nc2ccccc2OC)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 44.7 %

Procedure:
To a mixture of 4-[(5-carbamoyl-3-ethyl-6-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)amino]cyclohexanecarboxylic acid (Example 436) (62 mg), o-anisidine (42 mg) and DMF (2 mL), 1-hydroxy-1H-benzotriazole monohydrate (46 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (65 mg) were added and stirred at room temperature for 7 hours. The reaction liquid was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride sequentially and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol) to give 6-ethyl-5-({4-[(2-methoxy-phenyl)carbamoyl]cyclohexyl}amino)-3-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}pyrazine-2-carboxamide (33 mg) as a yellow powder.