Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][C@@H:9]1[CH2:11][C@H:10]1[C:12]1[C:13]2[C:17]([CH:18]=[CH:19][C:20]=1[F:21])=[N:16][N:15]([CH3:22])[CH:14]=2)([CH3:4])([CH3:3])[CH3:2].CC(NCCC#N)CC1C=CC=CC=1.Cl.CCCCCC.CC(O)C>CCCCCC.CC(O)C>[C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][C@H:9]1[CH2:11][C@@H:10]1[C:12]1[C:13]2[C:17]([CH:18]=[CH:19][C:20]=1[F:21])=[N:16][N:15]([CH3:22])[CH:14]=2)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cn1cc2c([C@@H]3C[C@H]3CNC(=O)OC(C)(C)C)c(F)ccc2n1
Agent: CC(Cc1ccccc1)NCCC#N
Agent: Cl
Solvent: CC(C)O
Solvent: CCCCCC
Product: Cn1cc2c([C@H]3C[C@@H]3CNC(=O)OC(C)(C)C)c(F)ccc2n1
Yield: 48 %

Procedure:
Trans-tert-butyl{[2-(5-fluoro-2-methyl-2H-indazol-4-yl)cyclopropyl]methyl}carbamate (735 mg) was fractionated by high performance liquid chromatography (instrument: K-Prep (manufactured by YMC), column: CHIRALPAK AS (50 mm ID×500 mm L, manufactured by Dicel Chemical Industries, Ltd.), mobile phase: A) hexane 100%, B) 2-propanol 100%, mixing ratio: A/B=900/100, flow rate: 80 mL/min, column temperature: 25° C., sample concentration: 21 mg/mL (hexane/2-propanol=900/100), injection amount: 735 mg). A fraction solution containing an optically active compound having a longer retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give the title compound (353 mg, 99.9% ee). Enantiomer excess (ee) was measured by high performance liquid chromatography (column: CHIRALPAK AS (4.6 mm ID×250 mm L, manufactured by Dicel Chemical Industries, Ltd.), mobile phase: hexane/2-propanol=90/10, flow rate: 1.0 mL/min, column temperature: 30° C., sample concentration: 0.5 mg/mL (hexane/2-propanol=90/10), injection volume: 10 μL).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]2[O:14][CH2:13][C:12](=O)[N:11]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10]2)=[CH:4][C:3]=1[Cl:20].B.CSC>>[ClH:8].[NH2:1][C:2]1[C:3]([Cl:20])=[CH:4][C:5]([CH:9]2[O:14][CH2:13][CH2:12][N:11]([C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:10]2)=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)N1CC(c2cc(Cl)c(N)c(Cl)c2)OCC1=O
Agent: B
Solvent: CSC
Product: CC(C)(C)N1CCOC(c2cc(Cl)c(N)c(Cl)c2)C1
Product: Cl

Procedure:
The title compound, m.p. 283°-4° C. (d) (methanol-ethyl acetate), was prepared from 2-[4-amino-3,5-dichlorophenyl]-4-[1,1-dimethylethyl]-5-oxo morpholine and borane-methyl sulphide by an analogous procedure to that described in Example 1.
Reaction SMILES: Br[C:2](Br)=[CH:3][CH:4]1[CH2:8][CH:7]([O:9][CH3:10])[O:6][CH:5]1[O:11][CH3:12].C([Li])CCC.[CH2:19]([Sn:23](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22].[NH4+].[Cl-]>CCOCC>[CH3:12][O:11][CH:5]1[CH:4]([C:3]#[C:2][Sn:23]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:8][CH:7]([O:9][CH3:10])[O:6]1
Reactant: COC1CC(C=C(Br)Br)C(OC)O1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CCCC[Sn](C#CC1CC(OC)OC1OC)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To solution of crude 3-(2,2-dibromoethenyl)-2,5-dimethoxy-tetrahydrofuran (1.78 g, 5.64 mmol) in ether (30 mL) at −78° C. was added n-butyllithium (9.02 mL of 1.25 M in hex). After 1 hour at −78° C., tributyltin chloride (1.68 mL, 6.20 mmol) was added, and the mixture was allowed to warm to ambient temperature. After 16 hours, ether (35 mL) and saturated aqueous NH4Cl (30 mL) were added. The organic layer was separated, washed with saturated aqueous NH4Cl (30 mL), H2O (25 mL), and saturated aqueous NaHCO3 (25 mL), dried over K2CO3, and evaporated to give an orange oil, which was purified via flash column chromatography with 2% MTBE/hex to furnish 1.92 g (77%) of 2,5-dimethoxy-3-(2-tributylstannylethynyl)-tetrahydrofuran as a colorless oil. A mixture of diastereomers was evident in the 1H NMR spectrum, which was used immediately without further purification. IR: 2923, 1456, 1374, 1215, 1105, 1017, 967 cm−1. Anal. Calculated for C20H38O3Sn: C, 53.96; H, 8.60. Found: C, 54.21; H, 8.66.
Reaction SMILES: [Na].[CH3:2][C:3]([OH:9])([CH3:8])[CH:4]([OH:7])[CH2:5][OH:6].[C:10]1([CH3:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[CH2:16]([O:6][CH2:5][CH:4]([O:7][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([CH3:8])([OH:9])[CH3:2])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:16]([O:6][CH2:5][CH:4]([OH:7])[C:3]([CH3:8])([OH:9])[CH3:2])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(O)C(O)CO
Reactant: Cc1ccccc1
Agent: [Na]
Solvent: CCO
Product: CC(C)(O)C(COCc1ccccc1)OCc1ccccc1
Product: CC(C)(O)C(O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 0.460 g of sodium in 10 ml of ethanol is treated with 2.4 g of (RS)-3-methyl-1,2,3-butanetriol. 20 ml of toluene are added thereto and, with the simultaneous dropwise addition of 60 ml of toluene, solvent is distilled off slowly until the distillate amounts to 75 ml. The residual suspension is suction filtered, the residue is washed with ether and dried at room temperature/11 Torr. The salt is suspended in 10 ml of tetrahydrofuran, then 0.740 g of tetrabutylammonium iodide and 4.0 ml of benzyl bromide are added and the mixture is stirred at room temperature for 3 days. The mixture is diluted with benzene and concentrated at 30°/11 Torr. The residue is chromatographed on 30 g of silica gel with hexane/ether (4:1). There are thus obtained, besides 0.616 g of (RS)-1,2-dibenzyloxy-3-methyl-3-butanol, as the polar fraction 1.15 g of the desired product as a colourless oil of boiling point 150°/2 Torr (bulb-tube).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[N:9]=[C:8]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:7]=[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[N:5]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.O>CC(N(C)C)=O>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([C:6]2[N:5]=[C:4]([CH2:3][CH2:2][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:9]=[C:8]([NH:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[CH:7]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: C1COCCN1
Reactant: COc1cccc(-c2cc(Nc3cccnc3)nc(CCBr)n2)c1
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cccc(-c2cc(Nc3cccnc3)nc(CCN3CCOCC3)n2)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Compound 15 (1 eq) is dissolved in 3 ml of dimethyl acetamide and morpholine (5 eq) is added. The reaction mixture is stirred at 60° C. for 4 h, then cooled down to room temperature. Water is added to the mixture and the crash out is filtered off, washed with water and purified by reverse phase preparatory HPLC, obtaining [6-(3-methoxyphenyl)-2-(morpholin-4-ylethyl)pyrimidin-4-yl]-3-pyridylamine 16.
Reaction SMILES: [CH2:1]1[O:10][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18]>C(O)C>[CH2:17]([NH:18][CH2:1][CH:2]([OH:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][CH2:1][CH:2]([OH:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: NCCCCCCN
Reactant: CCCCCCCC1CO1
Solvent: CCO
Product: CCCCCCCC(O)CNCCCCCCNCC(O)CCCCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-nonene oxide (97.4 g.) and hexamethylenediamine (39.8 g.) and recrystallization of the resulting product (67g.) from ethanol afforded N,N'-(1,6-hexylene)-bis[2-hydroxynonylamine] (I: R= CH3 (CH2)6, R' = H, X= (CH2)6, Z= H) (67 g., m.p. 122°-129.2° C.).
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:3]1.O[CH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]1>>[F:19][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=2)[C:8]([O:10][CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:9])[CH2:3]1
Reactant: O=C(O)[C@](O)(c1ccc(Br)cc1)[C@@H]1CCC(F)(F)C1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Product: O=C(OCCC1CCNCC1)[C@](O)(c1ccc(Br)cc1)[C@@H]1CCC(F)(F)C1

Procedure:
Using (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)acetic acid and t-butyl 4-(2-hydroxyethyl)tetrahydropyridine-1(2H)-carboxylate, the title compound was prepared by a method similar to steps 2 and 3 of Referential Example 12.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](OCC)=O)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[ClH:28]>O1CCCC1>[Cl:28][CH2:13][C:9]1[CH:10]=[N:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: CCOC(=O)c1cnoc1-c1ccc(C)cc1
Reactant: Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2oncc2CCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of ethyl 5-(4-methylphenyl)isoxazole-4-carboxylate (7.70 g) in tetrahydrofuran (100 ml) was gently added diisobutylaluminum hydride (1.0 M toluene solution, 83 ml) at 0° C. and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was dissolved in toluene (100 ml) and thionyl chloride (5.94 g) was added dropwise at 0° C., after which the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, saturated aqueous sodium hydrogencarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 4-chloromethyl-5-(4-methylphenyl)isoxazole (6.49 g, yield 94%) was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:9, volume ratio). NMR (CDCl3) δ: 2.44 (3H, s), 4.62 (2H, s), 7.34 (2H, d, J=8 Hz), 7.67 (2H, d, J=8 Hz), 8.35 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:10])[C:5](=[CH:7][C:8]=1[Cl:9])[OH:6].[C:11](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][C:5]([OH:6])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(Cl)c(Cl)cc1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1cc(Cl)c(Cl)cc1O
Temperature: 130 °C
Reaction time: 20 h
Yield: 45.2 %

Procedure:
A suspension of 4,5-dichlorocatechol (1 g, 5.62 mmol), potassium carbonate (780 mg, 5.62 mmol), and methyl iodide (0.34 mL, 5.62 mmol) in N,N-dimethylformamide (20 mL) was stirred rapidly at 130° C. for 20 hours, under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature before diluting with ethyl acetate (50 mL). The mixture was washed with water (50 mL), saturated aqueous sodium bicarbonate (50 mL), and saturated brine solution (50 mL). The organic layer was separated and dried over sodium sulphate, and evaporated under reduced pressure to a deep brown solid. The crude material was purified by flash chromatography (eluting with 1:1 heptane/dichloromethane) to afford 4,5-dichloro-2-methoxyphenol as a white solid (490 mg, 45%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N:11]([C:21]([C:23]2[CH:50]=[CH:49][C:26]([C:27]([N:29]3[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[NH:33][C:32](=[O:40])[C@@H:31]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:30]3)=[O:28])=[CH:25][CH:24]=2)=[O:22])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:51][C:52]1[CH:53]=[C:54]2[C:59](=[CH:60][CH:61]=1)[C:58]([CH2:62]Cl)=[C:57]([O:64][CH3:65])[CH:56]=[CH:55]2.[C:66](=[O:69])([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Br:51][C:52]1[CH:53]=[C:54]2[C:59](=[CH:60][CH:61]=1)[C:58]([CH2:62][N:33]1[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[N:29]([C:27](=[O:28])[C:26]3[CH:25]=[CH:24][C:23]([C:21]([N:11]4[C:12]5[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=5[N:14]([CH2:62][C:58]5[C:59]6[C:54](=[CH:53][C:52]([Br:51])=[CH:61][CH:60]=6)[CH:55]=[CH:56][C:57]=5[O:69][CH3:66])[C:15](=[O:16])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10]4)=[O:22])=[CH:50][CH:49]=3)[CH2:30][C@H:31]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:32]1=[O:40])=[C:57]([O:64][CH3:65])[CH:56]=[CH:55]2
Reactant: COc1ccc2cc(Br)ccc2c1CCl
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)c2ccc(C(=O)N3C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc4ccccc43)cc2)c2ccccc2NC1=O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CN(C(=O)c2ccc(C(=O)N3C[C@H](NC(=O)OC(C)(C)C)C(=O)N(Cc4c(OC)ccc5cc(Br)ccc45)c4ccccc43)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
tert-Butyl N-[(3S)-5-[4-[(3S)-3-(tert-butoxycarbonylamino)-2-oxo-3,4-dihydro-1H-1,5-benzodiazepine-5-carbonyl]benzoyl]-2-oxo-3,4-dihydro-1H-1,5-benzodiazepin-3-yl]carbamate (27.6 mg, 0.0403 mmol), 6-bromo-1-(chloromethyl)-2-methoxynaphthalene (25.3 mg, 0.0887 mmol), and cesium carbonate (39.4 mg, 0.121 mmol) where combined in DMF (2 mL) and stirred at room temperature for 16 h. The mixture was diluted with ethyl acetate, washed with water, brine and dried over anhydrous magnesium sulfate. Concentration gave an oil that was chromatographed over silica gel to give tert-butyl N-[(3S)-5-[(6-bromo-2-methoxy-1-naphthyl)methyl]-1-[4-[(3S)-5-[(6-bromo-2-methoxy-1-naphthyl)methyl]-3-(tert-butoxycarbonylamino)-4-oxo-2,3-dihydro-1,5-benzodiazepine-1-carbonyl]benzoyl]-4-oxo-2,3-dihydro-1,5-benzodiazepin-3-yl]carbamate (31 mg, 65%) as a white foam.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[CH:12]1([N:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[C:16]2=[O:31])[CH2:14][CH2:13]1.[H-].[Na+]>CN(C=O)C.CO>[CH:12]1([N:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:2]4[N:6]([CH3:7])[C:5]5[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=5[N:3]=4)=[CH:26][CH:25]=3)[C:16]2=[O:31])[CH2:14][CH2:13]1
Reactant: Cn1c(Cl)nc2ccccc21
Reactant: O=c1n(-c2ccc(O)cc2)c2ncccc2n1C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1c(Oc2ccc(-n3c(=O)n(C4CC4)c4cccnc43)cc2)nc2ccccc21
Temperature: 180 °C
Yield: 14 %

Procedure:
2-Chloro-1-methyl-1H-benzimidazole (15 mg) was added to a solution of 1-cyclopropyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (24.06 mg) and NaH (5.40 mg) in DMF (1 mL) at 100° C. The mixture was heated at 180° C. for 1 h under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 1-cyclopropyl-3-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (5.0 mg) as white crystals.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)(O)=[O:6]>>[ClH:3].[Cl:3][C:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)=[O:6]
Reactant: O=C(O)c1cn(-c2ccnc3ccccc23)c2ccccc12
Reactant: O=S(Cl)Cl
Product: Cl
Product: O=C(Cl)c1cn(-c2ccnc3ccccc23)c2ccccc12

Procedure:
25 cm3 of thionyl chloride are added at 25° C. under an argon atmosphere to 0.85 g (2.6 mmol) of 3-carboxy-1-(quinol-4-yl)-1H-indole. After stirring at reflux for 3 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), successively triturated twice with 10 cm3 of dimethoxyethane and then concentrated to dryness under reduced pressure (2.7 kPa) to give 0.9 g of 3-chlorocarbonyl-1-(quinol-4-yl)-1H-indole hydrochloride in the form of a yellow solid which is used directly in the following step.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16]3[O:20][C:19]([C:21]([O:23]C)=[O:22])=[CH:18][CH:17]=3)[C:13](=[O:25])[N:12]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[C:11]([CH3:36])=[C:10]2[C:37]([C:39]2[O:40][CH:41]=[CH:42][CH:43]=2)=[O:38])=[CH:5][CH:4]=1)#[N:2].[OH-].[Li+].Cl.CO>O1CCCC1.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16]3[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=3)[C:13](=[O:25])[N:12]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[C:11]([CH3:36])=[C:10]2[C:37]([C:39]2[O:40][CH:41]=[CH:42][CH:43]=2)=[O:38])=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc(CN2C(=O)N(c3cccc(C(F)(F)F)c3)C(C)=C(C(=O)c3ccco3)C2c2ccc(C#N)cc2)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1=C(C(=O)c2ccco2)C(c2ccc(C#N)cc2)N(Cc2ccc(C(=O)O)o2)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of methyl 5-{[6-(4-cyanophenyl)-5-(2-furoyl)-4-methyl-2-oxo-3-[3-(trifluoro-methyl)-phenyl]-3,6-dihydropyrimidin-1(2H)-yl]methyl}-2-furoate (Example 51) (30 mg, 0.51 mmol) in tetrahydrofuran (1.5 ml) is added a solution of lithium hydroxide (2.4 mg, 0.10 mmol) in water (1.5 ml). The reaction is stirred at room temperature overnight (16 h), then acidified with 1 N hydrochloric acid. A precipitate is obtained. Methanol (7 ml) is added, and the crude product is purified by preparative HPLC(RP18 column; eluent: acetonitrile/0.1% aq. formic acid 30:70→90:10).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:15]([CH:18](C(OC)=O)[C:19]([O:21][CH3:22])=[O:20])([O-])=[O:16]>C1(C)C=C(C)C=C(C)C=1>[C:1]1([C:7]2[C:18]([C:19]([O:21][CH3:22])=[O:20])=[N:15][O:16][C:8]=2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C(#Cc1ccccc1)c1ccccc1
Reactant: COC(=O)C(C(=O)OC)[N+](=O)[O-]
Solvent: Cc1cc(C)cc(C)c1
Product: COC(=O)c1noc(-c2ccccc2)c1-c1ccccc1
Temperature: 150 °C
Yield: 14 %

Procedure:
A mixture of 1,2-diphenylethyne (1.53 g, 8.6 mmol) and dimethyl 2-nitromalonate (1.05 mL, 7.83 mmol) in mesitylene (11 ml) was heated to 150° C. for 18 hr. The volatiles were removed in vacuo and the residue was chromatographed on a 5×12 cm silica gel column eluting with 0-10% EtOAc/hexanes. The essentially pure fractions containing product were concentrated to afford methyl 4,5-diphenylisoxazole-3-carboxylate (307 mg, 1.1 mmol, 14.04% yield) as a light yellow solid. HPLC retention time=1.85 minutes (YMC Combi 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1 TFA a 2 minute gradient.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[C:7]1[CH2:27][CH2:26][C:10]2([CH2:15][CH2:14][N:13](C(OCC3C=CC=CC=3)=O)[CH2:12][CH2:11]2)[CH:9]=[CH:8]1)=[O:5])[CH3:2].[H][H]>C(O)C>[CH2:15]1[C:10]2([CH2:26][CH2:27][CH:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:8][CH2:9]2)[CH2:11][CH2:12][NH:13][CH2:14]1
Reactant: [H][H]
Reactant: CCOC(=O)C=C1C=CC2(CC1)CCN(C(=O)OCc1ccccc1)CC2
Solvent: CCO
Product: CCOC(=O)CC1CCC2(CCNCC2)CC1

Procedure:
9.6 g (26.0 mmol) of the protected Spiro compound from Step B were dissolved in 400 ml ethanol, and the solution was filled into a hydrogenation vessel followed by 2 g Pd(II) hydroxide on charcoal. The reaction was carried out at 40° C. and 1 atm hydrogen, and it was complete after about 40 hours. The catalyst was removed by filtration through silica gel, and the filtrate was concentrated under reduced pressure. The remaining oil was treated with dry ether, filtered, and the filtrate was acidified with ethereal hydrochloric acid. The hydrochloride of the title compound was collected by filtration, washed two times with ether, dissolved in water, and the solution was made alkaline with 2 N aqueous sodium hydroxide solution. After extraction with dichloromethane the organic layer was dried over sodium sulfate and concentrated in vacuo.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2[NH:17][C:18]([CH:20]([C:22]3[N:23]([CH3:34])[C:24]4[CH:30]=[C:29]([C:31](O)=[O:32])[CH:28]=[CH:27][C:25]=4[N:26]=3)[CH3:21])=[N:19][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:35][CH2:36][CH2:37][O:38][C:39]1[CH:48]=[CH:47][CH:46]=[CH:45][C:40]=1[C:41]([O:43][CH3:44])=[O:42].C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>C(Cl)CCl.CN(C=O)C>[CH3:44][O:43][C:41]([C:40]1[CH:45]=[CH:46][CH:47]=[CH:48][C:39]=1[O:38][CH2:37][CH2:36][NH:35][C:31]([C:29]1[CH:28]=[CH:27][C:25]2[N:26]=[C:22]([CH:20]([C:18]3[NH:17][C:14]4[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[O:10])[CH2:12][C:13]=4[N:19]=3)[CH3:21])[N:23]([CH3:34])[C:24]=2[CH:30]=1)=[O:32])=[O:42]
Reactant: CC(c1nc2c([nH]1)CCN(C(=O)OCc1ccccc1)C2)c1nc2ccc(C(=O)O)cc2n1C
Reactant: COC(=O)c1ccccc1OCCN
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccccc1OCCNC(=O)c1ccc2nc(C(C)c3nc4c([nH]3)CCN(C(=O)OCc3ccccc3)C4)n(C)c2c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 67.7 %

Procedure:
A mixture comprising 2-[1-(5-benzyloxycarbonyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)ethyl]-3-methyl-3H-benzoimidazole-5-carboxylic acid (0.75 g, 1.6 mmol), DMF (6.5 mL), methyl 2-(2-aminoethoxy)benzoate (0.38 g, 1.6 mmol) and HOBT (0.22 g, 1.6 mmol) was cooled under nitrogen to −40° C., treated with EDC (0.32 g, 1.6 mmol) and N,N-diisopropylethylamine (0.29 mL, 1.6 mmol) and 15 minutes later with additional N,N-diisopropylethylamine (0.29 mL), allowed to warm to 20° C. and stirred for 16 hours. The mixture then was cooled to −40° C., treated with additional EDC (0.080 g) and N,N-diisopropylethylamine (0.050 mL), stirred for 15 minutes at −40° C. and 2 hours at 20° C. and concentrated by shortpath distillation. The residue was partitioned between chloroform and sodium bicarbonate and the organic layer was washed with sodium chloride, 0.5M potassium sulfate and sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (CHCl3/MeOH/AcOH: 95/5/1) to provide benzyl 2-(1-{6-[2-(2-methoxycarbonylphenoxy)ethylcarbamoyl]-1-methyl-1H-benzoimidazol-2-yl}ethyl)-1,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-carboxylate (0.69 g, 66%) as a glassy brown foam; 1H-NMR (300 MHz, DMSO-d6) d ppm: 11.92 (s, 1H), 8.49 (t, 1H, J=5.0 Hz), 8.02 (s, 1H), 7.69 (d, 1H, J=9.9 Hz), 7.60 (m, 2H), 7.50 (t, 1H, J=8.3 Hz), 7.30 (m, 5H), 7.19 (d, 1H, J=9.9 Hz), 6.99 (t, 1H, J=8.3 Hz), 5.04 (s, 2H), 4.61 (q, 1H, J=8.8 Hz), 4.30 (br s, 2H), 4.20 (t, 2H, J=5.0 Hz), 3.74 (s, 3H), 3.68 (s, 3H), 3.63 (m, 4H), 2.55 (br s, 2H), 1.67 (d, 3H, J=8.8 Hz).
Reaction SMILES: COC1C=C(OC)C=CC=1C(Cl)=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.[CH3:36][O:37][C:38]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:39]=1[C:46]([N:48]=[C:49]=[S:50])=[O:47]>C1(C)C=CC=CC=1.C(O)C>[CH3:36][O:37][C:38]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:39]=1[C:46]([N:48]=[C:49]=[S:50])=[O:47].[CH3:36][O:37][C:38]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:39]=1[C:46]([NH:48][C:49]([NH:33][C:32]1[CH:34]=[CH:35][C:29]([O:28][C:19]2[C:18]3[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=3)[N:22]=[CH:21][CH:20]=2)=[CH:30][CH:31]=1)=[S:50])=[O:47]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: COc1ccc(C(=O)Cl)c(OC)c1
Agent: COc1ccc(C(=O)N=C=S)c(OC)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
2,4-Dimethoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-dimethoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2,4-dimethoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (42 mg, yield 48%).