Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:23]([C:26]1[CH:27]=[CH:28][C:29]([O:35][CH3:36])=[C:30](B(O)O)[CH:31]=1)([CH3:25])[CH3:24]>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:30]4[CH:31]=[C:26]([CH:23]([CH3:25])[CH3:24])[CH:27]=[CH:28][C:29]=4[O:35][CH3:36])[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: COc1ccc(C(C)C)cc1B(O)O
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: COc1ccc(C(C)C)cc1-c1cc(-c2cnc3c(F)c(C(C)(C)O)ccn23)ccc1F
Yield: 6 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 5-isopropyl-2-methoxybenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[8-fluoro-3-(2-fluoro-5′-isopropyl-2′-methoxybiphenyl-5-yl)imidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (8 mg, 6%): m/z (ES+) 437 [MH+].
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:5]([C:10]([F:13])([F:12])[F:11])[C:6]=1[C:7]([NH2:9])=[O:8].ClC(Cl)(Cl)[C:22]([N:24]=C=O)=[O:23].N>O1CCCC1.CO>[NH2:24][C:22]([NH:1][C:2]1[S:3][C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:5]([C:10]([F:11])([F:13])[F:12])[C:6]=1[C:7]([NH2:9])=[O:8])=[O:23]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: NC(=O)c1c(N)sc(-c2ccccc2)c1C(F)(F)F
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)Nc1sc(-c2ccccc2)c(C(F)(F)F)c1C(N)=O
Reaction time: 0.08 h
Yield: 36.1 %

Procedure:
2-Amino-4-trifluoromethyl-5-phenyl-3-thiophenecarboxamide (0.35 g) was suspended in tetrahydrofuran (10 ml) and trichloroacetylisocyanate (0.19 g) was added dropwise with stirring over 5 minutes. Stirring was continued for 1 h at room temperature and then a 2M solution of ammonia in methanol (10 ml) was added and stirring continued for a further 12 h. A precipitate formed and was filtered off and washed with ethyl acetate (5 ml) to give the title urea (0.12 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:15][C@H:14]3[N:11]([C:12](=[O:23])[C@@H:13]3[C@H:16]([O:18][Si](C)(C)C)[CH3:17])[C:10]=2[C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])[CH:6]=[CH:7][CH:8]=1.Cl.C(=O)([O-])O.[Na+]>C1COCC1.O.[Cl-].[Na+].O>[OH:18][C@@H:16]([C@H:13]1[C:12](=[O:23])[N:11]2[C@@H:14]1[CH2:15][C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[C:10]2[C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])[CH3:17]
Reactant: C=CCOC(=O)C1=C(c2cccc(OC)c2)C[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)C1=C(c2cccc(OC)c2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reaction time: 0.25 h
Yield: 97.6 %

Procedure:
Allyl (5R,6S)-3-(3-methoxyphenyl)-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1.70 g, 4.09 mmol) prepared by step c) was dissolved in THF (40 ml) and water (20 ml), and the mixture was cooled in a water bath and thereto was gradually dropped 1N hydrochloric acid using a pH meter so as to become pH=2.5. After 15 minutes, thereto were added an aqueous saturated sodium hydrogencarbonate solution (50 ml) and saturated brine (50 ml), and the mixture was extracted with chloroform (50 ml×3 times). The organic layers were combined and dried over magnesium sulfate, filtered, and concentrated to give allyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(3-methoxyphenyl)-7-oxo1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1.37 g, 3.99 mmol, yield 98%) as a pale yellow oil.
Reaction SMILES: C(O[C:4]1([CH2:12][C:13]([O:15]CC)=O)[CH2:8][C:7](=[O:9])[NH:6][C:5]1=C=O)C.[OH-:18].[Na+].Cl>>[CH2:5]([N:6]1[C:13](=[O:15])[CH2:12][C:4]2([CH2:8][C:7](=[O:9])[NH:6][CH2:5]2)[C:7]1=[O:18])[CH3:4]
Reactant: [OH-]
Reactant: CCOC(=O)CC1(OCC)CC(=O)NC1=C=O
Agent: Cl
Agent: [Na+]
Product: CCN1C(=O)CC2(CNC(=O)C2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 24.3 g (0.10 mmole) 3-ethoxy-carbonyl-5-oxo-3-pyrrolidineacetic acid, ethyl ester in an excess of 2 N sodium hydroxide, was stirred three hours at room temperature, acidified with dilute hydrochloric acid, and evaporated to dryness in vacuo. The product, 3-carboxy-5-oxo3-pyrrolidineacetic acid, was taken up in isopropyl alcohol, separated from insoluble sodium chloride by filtration, concentrated to a syrup and dissolved in 100 ml 70% ethylamine. The solution was gradually heated in an oil bath up to 230° C. allowing volatiles to distill and then maintained at 230°-240° C. for ten minutes. After cooling, the product was crystallized from isopropyl alcohol to afford 10.1 g of 2-ethyl-2,7-diazaspiro[4.4]nonane-1,3,8-trione, mp 168°-169° C.
Reaction SMILES: Cl[C:2]1[C:7]2=[CH:8][CH:9]=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[OH:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:21][C:2]1[C:7]2=[CH:8][CH:9]=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Clc1ncnn2cccc12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ncnn3cccc23)c(F)c1
Temperature: 25 °C
Yield: 57.4 %

Procedure:
4-Chloropyrrolo[2,1-f][1,2,4]triazine (4.1g, 27 mmol), 2-fluoro-4-nitrophenol (5.0 g, 32 mmol), and potassium carbonate (7.4 g, 53 mmol) in 100 mL of dimethylformamide was stirred at 60° C. for 15 h. After cooling to room temperature, the reaction mixture was filtered through a plug of silica gel with EtOAc. The filtrate was concentrated in vacuo and the resulting crude product was purified by flash chromatography on silica gel (SiO2, EtOAc/Hexane 1:4) to give the title compound (4.25 g, 58%) as a white solid. 1H NMR (CDCl3) δ 8.09 (m, 2H), 7.88 (s, 1H), 7.77 (dd, 1H, J=2.6, 1.2 Hz), 7.46 (t, 1H, J=7.6 Hz), 6.98 (dd, 1H, J=4.6, 1.4 Hz), 6.84 (dd, 1H, J=4.5, 2.6 Hz); 13C NMR (CDCl3) δ 160.6, 154.3 (J=254 Hz), 146.5, 145.8, 144.8 (J=12.9 Hz), 125.0, 121.7, 120.7, 114.5, 113.9, 113.6 (J=23.2 Hz), 103.6.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4](C(OCC2C=CC=CC=2)=O)[CH2:3]1.[C:16]([O:20][C:21]1[N:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(C)C=CC=CC=1>C1COCC1>[NH:4]1[CH2:3][CH:2]([O:1][C:24]2[CH:23]=[CH:22][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:26][CH:25]=2)[CH2:5]1
Reactant: CC(C)(C)Oc1ccc(O)cn1
Reactant: O=C(OCc1ccccc1)N1CC(O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)Oc1ccc(OC2CNC2)cn1
Temperature: 55 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
Benzyl 3-hydroxyazetidine-1-carboxylate (2.3 g) and 6-tert-butoxypyridin-3-ol (1.5 g) were mixed with THF (25 ml), and triphenylphosphine (4 g) was added thereto. A 1.9 M DIAD/toluene solution (8 ml) was added dropwise thereto, followed by stirring at 55° C. overnight. The reaction mixture was concentrated under reduced pressure. The obtained residue was mixed with ethanol (25 ml), and 10% palladium carbon (800 mg) were added thereto, followed by stirring at room temperature for 5 hours under hydrogen atmosphere. The reaction mixture was filtered using Celite as a filtration adjuvant, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 5-(azetidin-3-yloxy)-2-tert-butoxypyridine (595 mg).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[N:20]=[C:19]([CH:21]=[O:22])[C:18]([Cl:23])=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:23][C:18]1[CH:17]=[CH:16][C:15]([C:6]2[CH:7]=[N:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[N:20][C:19]=1[CH:21]=[O:22]
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Reactant: O=Cc1nc(Br)ccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=Cc1nc(-c2ccc(C(F)(F)F)nc2)ccc1Cl
Temperature: 75 °C
Yield: 57.5 %

Procedure:
Nitrogen was bubbled through a mixture of 6-(trifluoromethyl)pyridin-3-ylboronic acid (828 mg, 4.34 mmol), 6-bromo-3-chloropicolinaldehyde (956 mg, 4.34 mmol), Na2CO3 (919 mg, 8.67 mmol), DME (20 mL) and water (10 mL) for 35 minutes, followed by the addition of Pd(Ph3P)4 (75 mg, 0.065 mmol). Nitrogen for bubbled through the mixture for 10 minutes. The reaction mixture was heated overnight at 75° C., after which it was cooled to room temperature, followed by the addition of 200 mL EtOAc and washing with 200 mL water and 200 mL brine. The organic phase was separated, dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on a Grace Reveleris 40 g column, eluted with 0-50% EtOAc in Heptane (25 mL/min) to provide the title compound (715 mg, 2.494 mmol, 57.5% yield) as a yellow solid. MS (ESI+) m/z 319.0 (M+H+MeOH); 1H NMR (300 MHz, DMSO-d6) δ 10.21 (s, 1H), 9.52 (d, J=1.9, 1H), 8.82 (dd, J=8.3, 1.8, 1H), 8.48 (d, J=8.5, 1H), 8.34 (d, J=8.6, 1H), 8.11 (d, J=8.3, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][C:8](=O)[N:7]([CH3:12])[C:6]=2[C:5]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:8]1[N:7]([CH3:12])[C:6]2[C:5]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCC(CC)c1ccc(Cl)c2[nH]c(=O)n(C)c12
Product: CCC(CC)c1ccc(Cl)c2nc(Cl)n(C)c12
Temperature: 90 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
A mixture of 4-chloro-7-(1-ethylpropyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (1.17 g, 4.63 mmol) in phosphorous oxychloride (28 g) was stirred at 90° C. for 3 h. The reaction was allowed to cool to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was subjected to chromatography on silica gel (n-hexane/ethyl acetate=10:1-1:1) and crystallized from ethyl acetate-hexane to afford the title compound as colorless crystals (1.03 g, 82%). mp 94-95° C.
Reaction SMILES: [C:1]([O:7][C:8]1[CH:16]=[CH:15][C:14]([Br:17])=[C:13]([CH3:18])[C:9]=1[C:10]([OH:12])=O)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH3:31])[CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCl>[Br:17][C:14]1[CH:15]=[CH:16][C:8]([O:7][C:1](=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5])=[C:9]([C:13]=1[CH3:18])[C:10]([C:22]1[C:23]([CH3:31])=[CH:24][C:25]([O:29][CH3:30])=[C:26]([O:27][CH3:28])[C:21]=1[O:20][CH3:19])=[O:12]
Reactant: COc1cc(C)cc(OC)c1OC
Reactant: Cc1c(Br)ccc(OC(=O)C(C)(C)C)c1C(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: COc1cc(C)c(C(=O)c2c(OC(=O)C(C)(C)C)ccc(Br)c2C)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 50A (6.3 g, 20 mmol), 3,4,5-trimethoxytoluene (3.83 g; 21 mmol), P2O5 (12.0 g) and dichloromethane (100 ml) is stirred at room temperature for 16 hours. Subsequently, the dichloromethane is distilled off and the residue is diluted with water and ethyl acetate. The organic phase is washed with water and concentrated. The residue is purified by flash chromatography with petrol ethers/ethyl acetate (9:1 v/v) as eluent yielding the pure product as white crystals, 5.58 g, (58.2%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C@H:11]([NH:15][C:16]([O:18][CH2:19][CH:20]1[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[C:12](O)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.CN1CCOCC1.[BH4-].[Na+]>O1CCCC1.O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C@H:11]([NH:15][C:16]([O:18][CH2:19][CH:20]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=2[C:27]2[C:32]1=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:17])[CH2:12][OH:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC[C@@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: -15 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
(S)-4-tert-Butoxycarbonylamino-2-(9H-fluoren-9-ylmethoxycarbonylamino)butyric acid (493 mg, 1.12 mmol) was dissolved in tetrahydrofuran (1 ml), and then isobutyl chloroformate (0.15 ml, 1.14 mmol) and N-methylmorpholine (0.125 ml, 1.15 mmol) were added thereto at −15° C. After stirring for one hour, the precipitate was filtrated and washed with tetrahydrofuran (7 ml). The filtrate was cooled to −15° C., and an aqueous solution (4 ml) of sodium borohydride (127 mg, 3.36 mmol) was dropwise added thereto. After stirring for 30 minutes, water (25 ml) was added to the solution and extracted three times with ethyl acetate (20 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: dichloromethane:methanol=50:1) to yield [(S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-hydroxybutyl]carbamic acid tert-butyl ester (411 mg) as a colorless oily material.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(N(CC)CC)C.O>ClCCl>[CH2:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][C:3]([CH2:2][NH:1][C:22]([O:24][CH2:25][CH3:26])=[O:23])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:4][CH2:5]1)=[O:10])[CH3:13]
Reactant: CCOC(=O)N1CCC(CN)(c2ccccc2C)CC1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)NCC1(c2ccccc2C)CCN(C(=O)OCC)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
Subsequently, the obtained 4-aminomethyl-1-(ethoxycarbonyl)-4-(2-methylphenyl)piperidine was dissolved in dichloromethane (10 ml), added with ethyl chloroformate (0.18 ml) and triethylamine (0.26 ml) and stirred at room temperature for 30 minutes. The reaction mixture was added with water (10 ml), and the layers were separated. Then, the aqueous layer was further extracted with dichloromethane (10 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=2:1) to obtain 372 mg of the title compound. Yield: 51% (for the two steps).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:21]=1[C:22](O)=[O:23].ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>O1CCCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:22](=[O:23])[C:21]2[CH:25]=[C:26]([C:29]([F:31])([F:32])[F:30])[CH:27]=[CH:28][C:20]=2[O:19][CH3:18])[N:7]([CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(F)(F)F)cc1C(=O)O
Reactant: CC(C)(C)c1cc(N)n(CC2CCCCO2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C(F)(F)F)cc1C(=O)Nc1cc(C(C)(C)C)nn1CC1CCCCO1
Temperature: 60 °C
Reaction time: 16 h
Yield: 14.7 %

Procedure:
To a solution of Example 63C (0.73 g, 3.1 mmol) in tetrahydrofuran (20 mL) were added 2-methoxy-5-(trifluoromethyl)benzoic acid (0.68 g, 3.1 mmol, JRD Fluorochemicals), 1-hydroxybenzotriazole (0.47 g, 3.1 mmol, Aldrich), N-(3-dimethylaminopropyl)-N-ethylcarbodimide hydrochloride (0.59 g, 3.1 mmol) and triethylamine (1.3 mL, 9.2 mmol). After stirring at 60° C. for 16 h, the reaction mixture was cooled and quenched with saturated NaHCO3 (20 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% ethyl acetate in hexanes) to provide 0.2 g of the title compound. MS (ESI+) m/z 440 (M+H)+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH:12]=[C:11]([C:13]3[CH:36]=[CH:35][C:16]4[N:17]([C:20]5[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[O:28])[CH:23]=[CH:24][CH:25]=5)[CH:18]=[N:19][C:15]=4[CH:14]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.[O:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[C:42](O)=[O:43]>>[O:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[C:42]([N:2]1[CH2:3][CH2:4][CH:5]([N:8]2[CH:12]=[C:11]([C:13]3[CH:36]=[CH:35][C:16]4[N:17]([C:20]5[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:33])([F:32])[F:34])=[O:28])[CH:23]=[CH:24][CH:25]=5)[CH:18]=[N:19][C:15]=4[CH:14]=3)[CH:10]=[N:9]2)[CH2:6][CH2:7]1)=[O:43]
Reactant: O=C(O)C1CCCO1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cnn(C5CCNCC5)c4)ccc32)c1
Agent: Cl
Product: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cnn(C5CCN(C(=O)C6CCCO6)CC5)c4)ccc32)c1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 1 (Step 6) starting from N-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea HCl salt and 2-tetrahydro-furancarboxylic acid, (Aldrich, Cat. No. 341517), LCMS (M+H)+: m/z=582.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH3:20])[NH:10][C:9]1=S)([CH3:4])([CH3:3])[CH3:2].O.[NH2:24][NH2:25]>CO>[C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH3:20])[NH:10][C:9]1=[N:24][NH2:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: C[C@H]1NC(=S)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1c1ccccc1
Solvent: CO
Solvent: O
Product: C[C@H]1NC(=NN)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1c1ccccc1
Reaction time: 1.25 h

Procedure:
To as solution of tert-butyl[(3S,5S,6R)-6-methyl-5-phenyl-2-thioxopiperidin-3-yl]carbamate (100 mg, 0.31 mmol) in methanol (3.1 mL) was added hydrazine hydrate (55%, 833 μL, 9.36 mmol). The mixture was stirred 75 min, and then concentrated. Saturated aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate (×3). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the crude title compound, MS 319.4 (M+1).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:2]1=[O:3].[H][H]>CO.C(O)(=O)C.CN1CCCC1=O.[OH-].[Pd+2].[OH-]>[NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:2]1=[O:3]
Reactant: O=c1ccc2ccccc2[nH]1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: O=C1CCc2ccccc2N1

Procedure:
A carbostyril of Formula 14 is hydrogenated, e.g., in a mixture of methanol/acetic acid, or preferably in N-methylpyrrolidinone, with a palladium hydroxide catalyst at elevated temperature (e.g., 40° to 80° C.) and under a source of hydrogen for 24 to 48 hours, preferably about 36 hours. The catalyst is removed to give the 3,4-dihydrocarbostyril compound of Formula 5c.
Reaction SMILES: C(OC)(=O)C1C(=CC=CC=1)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C(N=NC(N(C)C)=O)=O.C([NH:62][C:63]1[S:64][CH:65]=[C:66]([CH2:68][CH2:69][O:70][C:71]2[CH:80]=[CH:79][CH:78]=[CH:77][C:72]=2[C:73]([O:75][CH3:76])=[O:74])[N:67]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>C1COCC1.CO>[NH2:62][C:63]1[S:64][CH:65]=[C:66]([CH2:68][CH2:69][O:70][C:71]2[CH:80]=[CH:79][CH:78]=[CH:77][C:72]=2[C:73]([O:75][CH3:76])=[O:74])[N:67]=1
Reactant: COC(=O)c1ccccc1OCCc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: COC(=O)c1ccccc1O
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1OCCc1csc(N)n1
Reaction time: 8 h

Procedure:
Ethyl 2-aminothiazole-4-acetate (931 mg, 5.0 mmol) was dissolved in DCM (10 mL) and TEA (0.765 mL, 5.5 mmol). Trityl chloride (1.53 g, 5.5 mmol) was added in portions. The mixture was left overnight at room temp and filtered. The filtrate was evaporated and the product purified by flash-chromatography on silica gel using 20% ethyl acetate/toluene as eluent: 1H NMR (CDCl3) δ 7.2-7.4 (m), 6.6 (s, 1H), 6.15 (s, 1H), 4.2 (q, 2H), 3.5 (s, 2H), 1.3 (t, 3H). A solution of the tritylated ethylester (5 mmol) in THF (18 mL) was added to lithium aluminiumborohydride (1.00 g, 26 mmol) in THF (100 mL) under cooling in ice. The mixture was stirred overnight at room temperature and then cooled in ice. Aqueous sodium hydroxide (10%, 15 mL) was added carefully. The solution was separated from the precipitate. The precipitate was washed with THF and ethyl acetate. The combined solutions were evaporated and the residue dissolved in ethyl acetate (80 mL) and washed with brine. Evaporation and chromatography on silica gel with 20% and 50% ethyl acetate in toluene gave 1.22 g product, 63% yield: 1H NMR (CDCl3) δ 7.2-7.4 (m), 6.4 (s, 1H), 6.0 (s, 1H), 3.75 (t, 2H), 2.7 (t 2H). This material (386 mg, 1.0 mmol), methyl salicylate (183 mg, 1.2 mmol) and triphenylphosphine (314 mg, 1.2 mmol) were dissolved in THF (5 mL). N,N,N′,N′-tetramethylazo-dicarboxamide (206 mg, 1.2 mmol) was added and the solution was left overnight. The mixture was filtered and the filtrate was purified by flash-chromatography on silica gel using toluene and ethyl acetate/toluene as eluent. Yield 418 mg, 80%: 1H NMR (CDCl3) δ 7.74 (d, 1H), 7.4 (m, 1H), 7.18-7.38 (m), 6.95 (m, 2H), 6.5 (s, 1H), 6.15 (s, 1H), 4.2 (q, 2H), 3.8 (s, 3H), 3.0 (t, 2H). MS-ES (pos) m/z 521.2. Methyl 2-{2-[2-(tritylamino)-1,3-thiazol-4-yl]ethoxy}benzoate (343 mg, 0.656 mmol) was mixed with methanol: conc. HCl 9:1 (50 mL) and heated to 60° C. for 24 h. The mixture was concentrated to 10 mL, filtered and the filtrate was made alkaline with aqueous sodium carbonate (1 M). The solution was extracted with chloroform. Evaporation gave a product that was purified by flash-chromatography on silica gel using 0-2% methanol/DCM as eluent. Yield 128 mg, 70% (partially crystalline): 1H NMR (CDCl3) δ 7.75 (d, 1H), 7.42 (t, 1H), 6.96 (m, 2H), 6.35 (s, 1H), 4.29 (t, 2H), 3.85 (s, 3H), 3.05 (t, 2H). MS-ES (pos) m/z 279.3.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:23][C@@H:24]([C:32]([O:34][CH3:35])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.ClC(OCC(C)C)=O>>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([NH:23][C@@H:24]([C:32]([O:34][CH3:35])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@H](N)Cc1ccccc1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Product: COC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Yield: 66 %

Procedure:
Condensation of ZPheOH (7.5 g.) and HDPheOMe (5.4 g.) by the mixed anhydride method using isobutyl chloroformate gave ZPhe-DPheOMe in 66% yield. Debenzyloxycarbonylation of ZPhe-DPheOMe (6.9 g.) by hydrogenation with palladium catalyst gave HPhe-DPheOMe in 100% yield. Condensation of BocProOH (3.23 g.) and HPhe-DPheOMe (4.9 g.) by the mixed anhydride method using isobutyl chloroformate gave BocPro-Phe-DPheOMe in 70% yield. Hydrazinolysis of BocPro-Phe-DPheOMe (5.0 g.) gave BocPro-Phe-DPheNHNH2 in 84% yield.