Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]=[C:14]=S)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(N=C=NC(C)C)(C)C.[NH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][C:27]=1[NH:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>O1CCCC1>[C:44]([O:43][C:41]([NH:40][CH2:39][CH2:38][CH2:37][N:36]1[C:27]2[CH:28]=[C:29]([C:30]([O:32][CH3:33])=[O:31])[CH:34]=[CH:35][C:26]=2[N:25]=[C:14]1[NH:13][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=1)=[O:42])([CH3:46])([CH3:47])[CH3:45]
Reactant: COC(=O)c1ccc(N)c(NCCCNC(=O)OC(C)(C)C)c1
Reactant: COc1cc(N=C=S)cc(OC)c1OC
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc2nc(Nc3cc(OC)c(OC)c(OC)c3)n(CCCNC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C

Procedure:
3,4,5-trimethoxyphenyl isothiocyanate (6.6 g, 1.2 eq) and diisopropylcarbodiimide (9.1 g, 3 eq) are successively added to a solution of methyl 4-amino-3-({3-[(tert-butoxycarbonyl)amino]propyl}amino)benzoate (7.75 g, 1 eq) in tetrahydrofuran (130 ml). The mixture is heated under reflux for 16 hours then cooled down to ambient temperature and concentrated under reduced pressure at 40° C. Water (100 ml) and dichloromethane (200 ml) are added to the residue obtained. After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: heptane/ethyl acetate 8:2 to 3:7) produces the expected compound in the form of a solid which is washed with ether (4.4 g, 36% 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[OH:11].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:22])[C:20]=1[F:21])[CH:16]=O.[C:23]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])#[N:24].N1CCCCC1>C(O)C.O>[CH2:29]([O:28][C:26]([C:25]1[CH:16]([C:15]2[CH:14]=[C:13]([F:12])[C:20]([F:21])=[C:19]([F:22])[CH:18]=2)[C:3]2[C:2](=[CH:1][C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[CH:4]=2)[O:11][C:23]=1[NH2:24])=[O:27])[CH3:30]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: Oc1ccc2ccccc2c1
Reactant: CCOC(=O)CC#N
Solvent: C1CCNCC1
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1=C(N)Oc2cc3ccccc3cc2C1c1cc(F)c(F)c(F)c1
Temperature: 80 °C

Procedure:
2-Naphthol (170 mg, 1.2 mmol), 3,4,5-trifluorobenzaldehyde (160 mg, 1 mmol) and ethyl cyanoacetate (113 mg, 1 mmol) were taken in 7 ml ethanol at room temperature, charged with piperidine (50 μL) and then stirred at 80° C. under LC-MS control till the reaction was complete. The reaction mixture was cooled down to room temperature, diluted with water to about 15 ml, stirred for 1 h, solids were collected by filtration, washed with 60% aq ethanol and dried (346 mg, 0.86 mmol, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13](NC2C=CN(C)N=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[CH:42]([N:45]1[CH:49]=[CH:48][C:47]([NH2:50])=[N:46]1)([CH3:44])[CH3:43]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:50][C:47]2[CH:48]=[CH:49][N:45]([CH:42]([CH3:44])[CH3:43])[N:46]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CC(C)n1ccc(N)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)n1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.9 %

Procedure:
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 302 mg, 0.91 mmol) was suspended in methylene chloride (4.5 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (456 μL, 0.91 mmol) was added and the reaction stirred at 25° C. for 10 min. The solution was chilled to 0° C. and 2,6-lutidine (212 μL, 1.82 mmol) was added. The reaction continued to stir at 0° C. for 15 min. 1-Isopropyl-1H-pyrazol-3-ylamine (114 mg, 0.91 mmol) was dissolved in methylene chloride (4.5 mL) and added dropwise to the reaction. The ice bath was removed and the reaction continued to stir at 25° C. for 30 min. The reaction was diluted with ethyl acetate (50 mL), washed with water (2×15 mL), 1.0 M aqueous hydrochloric acid solution (10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate and concentrated in vacuo to an orange foam. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% ethyl acetate/methylene chloride to 20% ethyl acetate/methylene chloride) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-isopropyl-1H-pyrazol-3-yl)-propionamide (183 mg, 46%) as a white foam: ESI-LRMS m/e calcd for C21H28ClN3O3S [M+] 437.15, found 438.3 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.08-1.22 (m, 2H, CH2), 1.46 (d, J=6.6 Hz, 6H, 2×CH3), 1.44-1.94 (m, 8H, CH), 4×CH2), 2.11-2.32 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.53 (t, J=7.5 Hz, 1H, CH), 4.33 (sept, J=6.6 Hz, 1H, NCH), 6.64 (d, Jo=2.3, 1H, Ar), 7.30 (d, Jo=2.3, 1H, Ar), 7.46 (dd, Jo=8.2, Jm=1.6 Hz. 1H, Ar), 7.60 (d, Jm=1.6 Hz, 1H, Ar), 7.86 (s, 1H, NH), 8.09 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][C:11]([F:14])([F:13])[F:12])[CH:3]=1.[H][H]>C(O)C.C(O)(=O)C.[Pd]>[CH3:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][C:4]=1[O:10][C:11]([F:12])([F:13])[F:14]
Reactant: O=Cc1ccc(O)cc1OC(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(O)cc1OC(F)(F)F
Reaction time: 22 h

Procedure:
A solution of 4-hydroxy-2-(trifluoromethoxy)benzaldehyde (210 g, 1 equiv) in ethanol: acetic acid 3:1 (1050 Lt) was treated with Pd/C 5% catalyst-50% wet (21 g) and stirred at 800 rpm under 5 bar of hydrogen for 2.5 hrs. A second aliquot of Pd/C 5% catalyst-50% wet (33.6 g) was then added and the mixture subjected to the same hydrogenation conditions until reaching 22 hrs in total. The reaction mixture was filtered on a charcoal cartridge and washed with ethanol (525 mL). The resulting clear solution was concentrated to ca. 420 mL and the residue diluted with ethyl acetate (1050 Lt) and an aqueous 10% solution of ammonium chloride (525 mL). The phases were allowed separating and the organic one washed with water (2×525 mL), dried over sodium sulfate, filtered and concentrated to dryness. The title compound was obtained as colorless oil (196 g).
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32]Cl)[CH3:28].C[O-].[Na+]>C1(C)C=CC=CC=1.CO>[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)(=[O:11])=[O:10])=[CH:7][CH:8]=1)[CH3:28]
Reactant: CCN(CC)CCCCl
Reactant: O=S(=O)(c1ccc(O)cc1)c1c(-c2ccccc2)oc2ccccc12
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCN(CC)CCCOc1ccc(S(=O)(=O)c2c(-c3ccccc3)oc3ccccc23)cc1

Procedure:
A solution of 0.14 g. (0.006 g.-atom) of sodium in 20 ml. of methanol was added to a solution of 1.1 g. (0.003 mol.) of 3-(4-hydroxyphenylsulfonyl)-2-phenylbenzofuran in 25 ml. of dry methanol and the mixture was refluxed for 0.5 hour. The solvent was evaporated and 25 ml. of toluene and 3 ml. of dimethylformamide were added to the residue. A solution of 0.86 g. (0.006 mol.) of 3-diethylaminopropyl chloride in 10 ml. of toluene was added dropwise and the mixture was refluxed for 2.5 hours. An additional 0.162 g. (0.003 mol.) of sodium methoxide and 0.43 g. (0.003 mol.) of 3-diethylaminopropyl chloride were added and the mixture was refluxed for ca. 16 hours. The mixture was filtered, water and methylene chloride were added and the layers were separated. The aqueous phase was extracted with methylene chloride and the organic phase was extracted with water and saturated sodium chloride solution. The organic layers were combined, dried (MgSO4) and evaporated to dryness to give the title compound.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20].[CH3:34][O:35][CH2:36][C@@H:37](O)[CH3:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:27]([O:26][C:24]1[CH:23]=[C:18]([CH:17]=[C:16]([O:15][C@H:37]([CH3:38])[CH2:36][O:35][CH3:34])[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC[C@H](C)O
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC[C@@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 20 h
Yield: 67.2 %

Procedure:
DIAD (4.6 g, 0.029 mol) was added dropwise to a solution of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (6 g, 0.023 mol), (S)-(+)-1-methoxy-2-propanol (2.59 g, 0.029 mol) and triphenylphosphine (7.53 g, 0.029 mol) in THF (100 mL), under argon, at 0° C. The reaction was stirred at 0° C. for 1 hour and at RT for 20 hours. The volatiles were removed in vacuo and isohexane/ethyl acetate 2:1 added followed by stirring for 1 hour. A white solid was removed by filtration and the filtrate was evaporated to a residue which was chromatographed on silica, eluting with a gradient of 0-20% ethyl acetate in isohexane, to give the desired compound (5.11 g).
Reaction SMILES: [O:1]1[C:6]([C:7](=[N:11][O:12][CH3:13])[C:8]([OH:10])=O)=[CH:5][S:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.[NH2:19][CH:20]1[C:31](=[O:32])[N:22]2[C:23]([C:28]([OH:30])=[O:29])=[CH:24][CH:25]([CH3:27])[S:26][C@H:21]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.CN(C)C=O>[O:1]1[C:6]([C:7](=[N:11][O:12][CH3:13])[C:8]([NH:19][CH:20]2[C:31](=[O:32])[N:22]3[C:23]([C:28]([OH:30])=[O:29])=[CH:24][CH:25]([CH3:27])[S:26][C@H:21]23)=[O:10])=[CH:5][S:4][CH2:3][CH2:2]1
Reactant: CC1C=C(C(=O)O)N2C(=O)C(N)[C@H]2S1
Reactant: CON=C(C(=O)O)C1=CSCCO1
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)C1=CSCCO1
Yield: 57.6 %

Procedure:
A solution of 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetic acid (syn isomer, 1.4 g.), dry N,N-dimethylformamide (0.59 ml.) and phosphoryl chloride (1.17 g.) in dry ethyl acetate (12.3 ml.), and a solution of 7-amino-2-methyl-3-cephem-4-carboxylic acid (1.35 g.) and trimethylsilylacetamide (5.75 g.) in ethyl acetate (40 ml.) were treated in a similar manner to that of Example 14 to give 7-[2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer, 1.45 g.)
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:11][C:10]=1[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[C:23]([Cl:30])[CH:22]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:31][C:32]#[N:33].[Na+]>>[CH2:1]([N:8]1[C:9]2[C:10](=[CH:11][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:13][CH:14]=2)[C:19]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[C:23]([Cl:30])[CH:22]=2)=[N:33][C:32]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCOc1ccc(NCc2ccccc2)c(C(=O)c2ccc(C(C)C)c(Cl)c2)c1
Reactant: N#C[O-]
Agent: [Na+]
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)c(Cl)c1)nc(=O)n2Cc1ccccc1

Procedure:
The title compound is prepared from (2-benzylamino-5-prop-2-ynyloxy-phenyl)-(3-chloro-4-isopropylphenyl)-methanone (hydrochloric acid salt) by cyclisation with sodium cyanate analogously to the method described for the preparation of example 62.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([O:19]CC)=O)=[CH:4][CH:3]=1.[NH3:22].C>CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:22])=[O:19])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Reactant: N
Agent: C
Solvent: CO
Product: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a solution of 600 mg of ethyl 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate in 62 mL of a 3N solution of ammonia in methanol are added 11 mL of 22% aqueous ammonia solution. The reaction mixture is stirred for 20 hours in an autoclave at 80° C. (12 bar) and then concentrated under reduced pressure. The residue obtained is diluted in 100 mL of methanol, treated with carbon black and refluxed for 30 minutes. The mixture is filtered while hot through Celite and then rinsed with 2×10 mL of methanol. The filtrate is concentrated under reduced pressure to give 490 mg of 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide in the form of a foam, the characteristics of which are as follows:
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[NH2:24][C:25](=[O:39])[C@@H:26]([NH:28][C:29]1[N:34]=[C:33](Cl)[N:32]=[C:31]([C:36]([NH2:38])=[O:37])[CH:30]=1)[CH3:27].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.O.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>[NH2:24][C:25](=[O:39])[C@@H:26]([NH:28][C:29]1[N:34]=[C:33]([C:10]2[CH:9]=[N:8][C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:23][CH:22]=3)=[CH:12][CH:11]=2)[N:32]=[C:31]([C:36]([NH2:38])=[O:37])[CH:30]=1)[CH3:27]
Reactant: C[C@H](Nc1cc(C(N)=O)nc(Cl)n1)C(N)=O
Reactant: CC1(C)OB(c2ccc(Oc3ccc(F)cc3)nc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: C[C@H](Nc1cc(C(N)=O)nc(-c2ccc(Oc3ccc(F)cc3)nc2)n1)C(N)=O
Temperature: 100 °C
Reaction time: 14 h
Yield: 50.5 %

Procedure:
A mixture of 2-(4-fluorophenoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine (158 mg, 0.5 mmol), (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-chloropyrimidine-4-carboxamide (121 mg, 0.5 mmol), Na2CO3 (2 M, 1 mL, 2 mmol) and Pd(PPh3)2Cl2 (20 mg, 0.025 mmol) in DME/EtOH/H2O (2 mL/1 mL/2 mL) was purged with Ar for one minute, then stirred at 100° C. for 14 hrs. The reaction mixture was then worked up with DCM. The DCM was isolated, dried over MgSO4, and removed under vacuum. The residue was subjected to silica gel flash chromatography using dichloromethane/methanol as the eluent to give (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(6-(4-fluorophenoxy)pyridin-3-yl)pyrimidine-4-carboxamide as a gray solid (100 mg, yield 50%). NMR (DMSO-d6): 9.3 (1H, s), 8.9 (1H, m), 8.3 (1H, s), 8.05 (1H, m), 7.75 (1H, s), 7.5 (1H, s), 7.2-7.4 (4H, m), 6.95-7.15 (2H, m), 6.80 (1H, s), 4.5 (1H, m), 1.35 (3H, d, J=7.0 Hz). LC/MS: m/z=398 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]#[N:6].[N-:34]=[N+:35]=[N-:36].[Na+].[Cl-].[NH4+].C(Cl)(Cl)Cl>CN(C)C=O>[CH3:1][CH:2]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)[CH2:3][CH2:4][C:5]1[NH:36][N:35]=[N:34][N:6]=1
Reactant: CC(CCC#N)Cc1ccc(OCc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(CCc1nnn[nH]1)Cc1ccc(OCc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Temperature: 135 °C

Procedure:
A mixture of 4-methyl-5(4-(4-(2-quinolinylmethyloxy)benzyloxy)phenyl)valeronitrile (1.5 g.), sodium azide (3 g), ammonium chloride (1.9 g) in dimethylformamide (20 ml) is stirred and heated at 135° C. for 18 hours. After cooling, the reaction mixture is poured into ice water and the insoluble material is taken up by chloroform. The residue from the evaporation of chloroform is purified by silica gel dry column (5% methanol chloroform as eluant) to yield 5-(3-methyl-4-(4-(4-(2-quinolinylmethyloxy)benzyloxy)-phenyl)butyl)tetrazole.
Reaction SMILES: C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[CH3:16][O:17][C:18]1[CH:19]=[C:20](/[CH:30]=[CH:31]/[C:32]([OH:34])=O)[CH:21]=[CH:22][C:23]=1[N:24]1[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]1.[NH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH:38]([C:42]2[CH:47]=[CH:46][C:45]([Br:48])=[CH:44][CH:43]=2)[C:37]1=[O:49].O>CN(C=O)C.C(OCC)(=O)C>[Br:48][C:45]1[CH:44]=[CH:43][C:42]([CH:38]2[CH2:39][CH2:40][CH2:41][N:36]([NH:35][C:32](=[O:34])/[CH:31]=[CH:30]/[C:20]3[CH:21]=[CH:22][C:23]([N:24]4[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]4)=[C:18]([O:17][CH3:16])[CH:19]=3)[C:37]2=[O:49])=[CH:47][CH:46]=1
Reactant: NN1CCCC(c2ccc(Br)cc2)C1=O
Reactant: COc1cc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/C(=O)NN2CCCC(c3ccc(Br)cc3)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
BOPCl (1.18 g) was added to a suspension of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (800 mg), 1-amino-3-(4-bromophenyl)piperidin-2-one (898 mg) and TEA (0.9 mL) in DMF (20 mL), and the reaction solution was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture and the organic layer was separated. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate-methanol system) to obtain 1.484 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:17]([C:18]4[N:19](S(C5C=CC(C)=CC=5)(=O)=O)[N:20]=[CH:21][CH:22]=4)=[CH:16][N:15](S(C4C=CC(C)=CC=4)(=O)=O)[C:12]3=[N:13][CH:14]=2)O1.Br[C:45]1[CH:46]=[N:47][CH:48]=[C:49]([CH:53]=1)[C:50]([NH2:52])=[O:51].ClCCl>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].C(#N)C>[N:20]1[NH:19][C:18]([C:17]2[C:11]3[C:12](=[N:13][CH:14]=[C:9]([C:45]4[CH:46]=[N:47][CH:48]=[C:49]([CH:53]=4)[C:50]([NH2:52])=[O:51])[CH:10]=3)[NH:15][CH:16]=2)=[CH:22][CH:21]=1
Reactant: NC(=O)c1cncc(Br)c1
Reactant: Cc1ccc(S(=O)(=O)n2nccc2-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(B4OC(C)(C)C(C)(C)O4)cc23)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CC#N
Solvent: ClCCl
Product: NC(=O)c1cncc(-c2cnc3[nH]cc(-c4ccn[nH]4)c3c2)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 2.9 %

Procedure:
To a solution of 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-3-[2-(toluene-4-sulfonyl)-2H-pyrazol-3-yl]-1H-pyrrolo[2,3-b]pyridine (56 mg, 0.09 mmol) in a 1:1 acetonitrile/saturated aqueous NaHCO3 solution (2 mL total) in a microwave vial was added 5-bromonicotinamide (20 mg, 0.10 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (1:1) (3.7 mg, 0.004 mmol). The vial was capped, flushed with N2, evacuated under vacuum, and heated in a microwave at 90° C. for 1800 seconds. The product was extracted into ethyl acetate and the organic layer was dried over Na2SO4. The solution was filtered and concentrated under vacuum. The residue was redissolved in a 1:1 MeOH/acetone solution (2 mL total) and treated with 200 uL of 50% KOH (aq) solution and stirred at ambient temperature for 1 hour. Citric acid (1 M) was added dropwise until pH=7 and the product was extracted into ethyl acetate. The organic layer was dried over Na2SO4, filtered, and adsorbed onto silica gel. The material was purified by flash chromatography using a gradient of ethyl acetate (containing 10% MeOH) and hexane then concentrated under vacuum. The residue was titrated with diethyl ether to afford the title compound as a beige solid (0.8 mg, 3% yield). 1H NMR (500 MHz, d6-DMSO) δ 12.67 (s, 1H), 11.87 (s, 1H), 8.95 (s, 1H), 8.62 (s, 1H), 8.50 (s, 1H), 8.25 (s, 1H), 7.89 (s, 1H), 7.63 (s, 1H), 7.41 (d, J=7.5 Hz, 1H), 7.05 (d, J=7.5 Hz, 1H). MS: m/z 305.0 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[Cl-].[Ca+2].[Cl-].[C:8](#N)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([C:8]2[O:4][CH2:3][CH2:2][N:1]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#Cc1ccccc1
Reactant: NCCO
Agent: [Ca+2]
Agent: [Cl-]
Product: c1ccc(C2=NCCO2)cc1

Procedure:
The methods (1) to (6) will be described more specifically. For example, as the method (1), potassium hydroxide or acetic anhydride is reacted to 2-chloroethylformamide to provide 2-oxazoline, and the case where 2-bromoethylbenzamide is used provides 2-phenyl-2-oxazoline (see, for example Non-patent Document 1). As the method (2), thionyl chloride is reacted to 2-formamide ethanol to provide 2-oxazoline, and N-(2-hydroxyethyl)benzamide is heated with phosphorous pentoxide to provide 2-phenyl-2-oxazoline (see, for example, Non-patent Document 2). As the method (3), benzoic acid and 2-aminoethanol are heated with alumina to provide 2-phenyl-2-oxazoline (see, for example, Non-patent Document 3). As the method (4), benzonitrile and 2-aminoethanol are heated with calcium chloride at 110 to 120° C. to provide 2-phenyl-2-oxazoline (see, for example, Non-patent Document 4 and Patent Document 1). As the method (5), methyl benzimidate and 2-aminoethanol are heated with alumina to provide 2-phenyl-2-oxazoline (see, for example, Non-patent Document 5). Vinylbenzamide is simply heated to provide 2-phenyl-2-oxazoline. As the method (6), N-allylbenzamide is heated with sulfuric acid to provide 5-methyl-2-phenyl-2-oxazoline (see, for example, Non-patent Document 6).
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([C:20]1[N:25]=[CH:24][C:23]([Br:26])=[CH:22][N:21]=1)[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1F.[CH2:36]([O:38]C(=O)NCC)[CH3:37].[H-].[Na+].O>O1CCCC1.C(OCC)(=O)C>[F:32][C:30]([F:33])([F:31])[C:28]1[CH:27]=[C:5]([CH:4]=[C:3]([C:15]([F:18])([F:17])[F:16])[CH:29]=1)[CH2:6][N:7]([C:20]1[N:25]=[CH:24][C:23]([Br:26])=[CH:22][N:21]=1)[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:16])([F:18])[F:17])[CH:12]=[CH:11][C:10]=1[O:38][CH2:36][CH3:37]
Reactant: CCNC(=O)OCC
Reactant: Fc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Temperature: 120 °C
Reaction time: 1 h
Yield: 140.3 %

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-(2-fluoro-5-trifluoromethyl-benzyl)-amine (300 mg) is dissolved in tetrahydrofuran (3 ml) and thereto are added ethyl-carbamic ethyl ester (67 mg) and sodium hydride (60%) (23 mg) and the mixture is stirred at 120° C. under a condition of 192 W by a microwave instrument for 1 hour and thereto are added ethyl-carbamic ethyl ester (134 mg) and sodium hydride (60%) (46 mg) and the mixture is stirred at 120° C. under a condition of 192 W by a microwave instrument for an additional 1 hour. To the reaction solution are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=1:0→9:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-(2-ethoxy-5-trifluoromethyl-benzyl)-amine (220 mg). MS (m/z): 602/604 [M+H]+