Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][O:38][C:39]3[C:44]([Cl:45])=[CH:43][C:42]([CH3:46])=[CH:41][C:40]=3[Cl:47])=[CH:31][CH:30]=2)[CH2:19][NH:20]C(=O)OC(C)(C)C)=[C:14]([CH3:48])[CH:13]=1)(=[O:3])[CH3:2].Cl>CCOCC.CCOC(C)=O>[ClH:45].[C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][O:38][C:39]3[C:40]([Cl:47])=[CH:41][C:42]([CH3:46])=[CH:43][C:44]=3[Cl:45])=[CH:31][CH:30]=2)[CH2:19][NH2:20])=[C:14]([CH3:48])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1ccccc1-c1ccc(C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)c(C)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(=O)NCc1ccccc1-c1ccc(C(CN)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)c(C)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 2, step 5 using tert-butyl (2-{2′-[(acetylamino)methyl]-3-methylbiphenyl-4-yl}-3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}propyl)carbamate from step 1 as starting materials. Following flash chromatography the desired material (colorless oil) was dissolved in CH2Cl2/Et2O (1/1). HCl (4M in dioxane) was added in excess and the resulting suspension was triturated with Et2O to afford after filtration the title compounds as an off-white solid. 1H NMR (500 MHz, CD3OD): δ 7.45 (d, 1H), 7.41-7.33 (m, 3H), 7.24 (d, 2H), 7.21 (s, 2H), 7.07 (s, 1H), 6.99 (d, 2H), 6.83 (d, 2H), 4.35-4.29 (m, 6H), 4.23 (d, 1H), 3.68-3.50 (m, 1H), 3.41-3.34 (m, 1H), 3.02 (dd, 1H), 2.87 (dd, 1H), 2.30 (s, 3H), 2.14 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3]O.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>O1CCCC1>[CH2:7]([O:6][CH2:5][C@@H:2]1[CH2:3][CH2:21][S:22](=[O:24])(=[O:23])[NH:1]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: N[C@@H](CO)COCc1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=S1(=O)CC[C@@H](COCc2ccccc2)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-2-amino-3-benzyloxy-1-propanol (5.0 g) and triethylamine (7.9 mL) was dissolved in tetrahydrofuran (40 mL), methanesulfonyl chloride (4.4 mL) was added under ice-cooling, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was dissolved in N,N-dimethylformamide (10 mL), sodium chloride (3.2 g) was added, and the mixture was stirred at 80° C. for 5 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. A mixture of the obtained residue and 1,10-phenanthroline (28 mg) was dissolved in tetrahydrofuran (80 mL), diisopropylamine (3.9 mL) was added at −70° C., and n-butyllithium (38 mL) was further added. The reaction mixture was heated to room temperature, and stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (4.49 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N+:15]([O-:17])[CH3:16])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1.[C:18]1([NH:24][CH2:25][CH:26]=[CH2:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:9][N:10]3[CH:14]=[CH:13][N:12]=[CH:11]3)[CH2:27][CH:26]([CH2:25][NH:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:17][N:15]2[CH3:16])=[CH:4][CH:3]=1
Reactant: C=CCNc1ccccc1
Reactant: C[N+]([O-])=C(Cn1ccnc1)c1ccc(Cl)cc1
Product: CN1OC(CNc2ccccc2)CC1(Cn1ccnc1)c1ccc(Cl)cc1

Procedure:
Derivative 3 (R1 =4-Cl, R2 =R3 =H) is obtained by a procedure similar to that described in Example 1 by reacting 1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)-N-methylethanimine N-oxide (1: R1 =4-Cl) with N-phenyl-2-propen-1-amine (2: R2 =R3 =H). The product cis-/trans-diastereometric mixture is flash-chromatographed on neutral silica gel using chloroform-methanol (97:3 by volume) as eluent. Isomer A has a melting point of 159°-160° C. (ethyl acetate). Anal. Calcd for C21H23ClN4O: C, 65.87; H, 6.05; N, 14.63; Cl, 9.26. Found: C, 65.77; H, 6.20; N, 14.42; Cl, 9.48. Isomer B has a melting point of 172°-173° C. (ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:29])=[C:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][C:16]([O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:17][CH:18]=4)[NH:13][C:12]=3[C:11]([C:26]([NH2:28])=[O:27])=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([CH:40]=O)=[C:35]([CH:39]=1)[C:36]([OH:38])=[O:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C.O1CCCC1>[C:26]([C:11]1[C:12]2[NH:13][C:14]3[C:19]([C:20]=2[C:8]([C:4]2[C:3]([CH3:29])=[C:2]([NH:1][CH2:40][C:34]4[CH:33]=[CH:32][C:31]([Cl:30])=[CH:39][C:35]=4[C:36]([OH:38])=[O:37])[CH:7]=[CH:6][CH:5]=2)=[CH:9][N:10]=1)=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23][O:24][CH3:25])[CH:15]=3)(=[O:27])[NH2:28]
Reactant: O=Cc1ccc(Cl)cc1C(=O)O
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(N)c3C)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(NCc4ccc(Cl)cc4C(=O)O)c3C)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.4 %

Procedure:
A mixture of 4-(3-amino-2-methylphenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxamide (60.0 mg, 0.154 mmol), 5-chloro-2-formylbenzoic acid (70.9 mg, 0.384 mmol), sodium triacetoxyborohydride (98 mg, 0.461 mmol), and acetic acid (0.018 mL, 0.307 mmol) in dichloroethane (3 mL) and tetrahydrofuran (2 mL) was stirred at room temperature for 16 hr and then quenched with water (3 mL). The resulting mixture was diluted with ethyl acetate (50 mL) and washed with water (25 mL). The aqueous solution was extracted with ethyl acetate (2×30 mL). The combined extract was washed with brine (25 mL) and dried over anhydrous MgSO4. The organic solution was concentrated under vacuum to dryness. The residue was dissolved with minimum amount of DMF, diluted with MeOH (3 mL), divided into 2 portions, and purified by prep. reverse phase HPLC. The correct fractions were combined, concentrated under vacuum, and lyophilized to afford the desired product (TFA salt) (38 mg, 0.056 mmol, 36.7% yield) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15])=[CH:6][CH:5]=1)([O-])=O.[O:18]1[C:23](=[O:24])[CH2:22][CH2:21][CH2:20][C:19]1=[O:25]>O1CCCC1>[O:17]=[C:12]([CH2:13][C:14](=[O:16])[CH3:15])[CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([NH:1][C:23]([CH2:22][CH2:21][CH2:20][C:19]([OH:25])=[O:18])=[O:24])=[CH:5][CH:6]=1
Reactant: O=C1CCCC(=O)O1
Reactant: CC(=O)CC(=O)CCc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)CCc1ccc(NC(=O)CCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.7 %

Procedure:
200 mL tetrahydrofuran, 6-(4-nitro-phenyl)-hexane-2,4-dione (8.0 g, 34.0 mmol) and dihydro-pyran-2,6-dione (3.88 g, 34.0 mmol) were added to a reaction vessel. The reaction vessel was purged three times with argon. Approximately 200 mg palladium (10 wt % on activated carbon) was added. The reaction vessel was purged again with argon and excess hydrogen introduced via a balloon. Solution stirred 16 hours at room temperature. Hydrogen removed under reduced pressure and catalyst removed by filtration through celite. Tetrahydrofuran removed under reduced pressure to afford title compound (10.5 g, 97%, yellow solid).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:19]1[C:24](Br)=[CH:23][CH:22]=[CH:21][N:20]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)(C)(C)C.C([Sn](CCCC)(CCCC)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)CCC.[ClH:46]>O1CCOCC1.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>[ClH:46].[ClH:46].[N:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:24]1[C:19]([C@H:8]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:13][CH:14]=2)[NH2:7])=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CC(C)(C)OC(=O)N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1-c1ccccn1
Temperature: 125 °C
Reaction time: 2 h

Procedure:
A mixture of (S)-tert-butyl(3-bromopyridin-2-yl)(4-(trifluoromethyl)-phenyl)methylcarbamate (Intermediate 40, Step 5) (0.711 g, 1.649 mmol), 2-(tributylstannyl)pyridine (0.910 g, 2.473 mmol), and (Ph3P)4Pd (0.381 g, 0.330 mmol) in 1,4-dioxane (10 mL) was heated by microwave at 125° C. for 30 min. The reaction mixture was then cooled, concentrated, and purified by ISCO (silica gel, 0-60% EtOAc/hexanes). The residue was dissolved in DCM (3 mL) and hydrogen chloride (3.30 mL, 13.19 mmol, 4.0 M in 1,4-dioxane) was added. After stirring for 2 h, the mixture was concentrated to dryness to give the title compound. MS (ESI pos. ion) m/z: 330.0 (M+H).
Reaction SMILES: C([NH:4][C@:5]1([C:22](NC(C)(C)C)=[O:23])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17]C(C)(C)C(C)(C)[O:14]2)[CH2:8][NH:7][CH2:6]1)(=O)C.C([NH:36][CH:37]1[CH2:41][CH2:40][CH2:39][C:38]1=O)(OC(C)(C)C)=O.S([O-])([O-])(=O)=[O:44].[Na+].[Na+].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[NH2:4][C@:5]1([C:22]([OH:23])=[O:44])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17])[CH2:8][N:7]([CH:38]2[CH2:39][CH2:40][CH2:41][CH:37]2[NH2:36])[CH2:6]1
Reactant: O=S(=O)([O-])[O-]
Reactant: CC(C)(C)OC(=O)NC1CCCC1=O
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: NC1CCCC1N1C[C@H](CCCB(O)O)[C@](N)(C(=O)O)C1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 77.5 %

Procedure:
A stirred solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) and 2-(N-BOC-amino)cyclopentane-1-one (0.199 g, 1.0 mmol) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (1 g) and glacial acetic acid (30 mg, 0.5 mmol), stirred at 40° C. for 1.5 h, then cooled to room temperature and treated with sodium triacetoxyborohydride (276 mg, 1.3 mmol) and stirred for 18 h. Aqueous sodium carbonate (10%, 5 mL) was added and the mixture stirred for a few minutes and extracted with ethyl acetate (30 mL, then 2×10 mL). The combined organic solution was washed with water and brine (20 mL each), dried (MgSO4), and concentrated in vacuo. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-1-(2-aminocyclopentyl)-4-(3-boronopropyl)pyrrolidine-3-carboxylic acid (116 mg, 57%) as a white powder. NMR (D2O) δ 3.85-4.05 (m, 4 H), 3.77 (d, J=12.5 Hz, 1 H), 3.42 (dt, J1=11.5 Hz, J2=4 Hz, 1 H), 2.50-2.65 (m, 1 H), 2.10-2.35 (m, 2 H), 1.75-1.95 (m, 4 H), 1.55-1.65 (m, 1 H), 1.15-1.40 (m, 3 H), 0.63-0.73 (m, 2 H). MS (m+1): 300.0; MS (m−H2O+1): 281.9.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[CH:9]1[CH2:13][CH:12]=[CH:11][CH:10]=1.[Mg].O1CCCC1>O>[C:10]12[CH2:9][C:13](=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]2=1
Reactant: Brc1ccccc1I
Reactant: C1=CCC=C1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: C1=C2CC(=C1)c1ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Bromo-2-iodobenzene (1 ml) was combined with cyclopentadiene (1.5 ml) and added dropwise to a mixture of magnesium (0.25 g) and tetrahydrofuran (25 ml) which had been heated to reflux. After the addition, heating was continued for 1 hour. The mixture was cooled to room temperature, treated with water (50 ml), and extracted with ether (3×30 ml). The combined organic layers were dried over magnesium sulfate and the solvents removed on a rotary evaporator. The residue was distilled on a Kugelrohr apparatus (40° C. at 0.1 mm Hg) to provide the product as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])(=[O:20])=[O:19])O[C:10]=1[C:28]([OH:30])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S(C(N)C2[N:46](C)[C:45](C(O)=O)=C(OCC3C=CC=CC=3)C(=O)C=2)(=O)=O)C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])(=[O:20])=[O:19])[N:46]([CH3:45])[C:10]=1[C:28]([OH:30])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1oc(CNS(=O)(=O)c2ccccc2Cl)cc(=O)c1OCc1ccccc1
Reactant: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(OCc2ccccc2)c1C(=O)O
Product: Cn1c(CNS(=O)(=O)c2ccccc2Cl)cc(=O)c(OCc2ccccc2)c1C(=O)O
Yield: 77.6 %

Procedure:
3-Benzyloxy-6-[(2-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-03) (1.7 g, 77.6%) was synthesized as a white solid from 3-benzyloxy-6-[(2-chloro-benzenesulfonylamino)-methyl]-4-oxo-4H-pyran-2-carboxylic acid (12-03) (2.0 g, 4.45 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-01).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH:20]1([CH:23]([NH2:30])[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:22][CH2:21]1>>[CH:20]1([CH:23]([NH:30][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:21][CH2:22]1
Reactant: NC(c1cccnc1)C1CC1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)NC(c3cccnc3)C3CC3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and (cyclopropyl-pyridin-3-yl-methyl)-amine to afford the title compound. MS: m/e=389 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH:15]=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[C:24](=O)([O-])[OH:25].[K+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([CH:24]=[O:25])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH:9]([O:8][CH:1]([CH3:2])[CH3:24])([CH3:14])[CH3:10]
Reactant: Cc1cn2cccc(OCc3ccccc3)c2n1
Reactant: O=C([O-])O
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)OC(C)C
Product: Cc1nc2c(OCc3ccccc3)cccn2c1C=O
Temperature: 0 °C

Procedure:
4.77 g of 8-benzyloxy-2-methylimidazo[1,2-a]pyridine are stirred in a Vilsmeier mixture of 20 ml of dimethylformamide and 2.3 ml of phosphoryl chloride for 2.5 h at 60° C., and are worked up mit ice/water and potassium hydrogen carbonate in a usual manner. 8-Benzyloxy-2-methylimidazo[1,2-a]pyridine-3-carboxaldehyde of m.p. 105°-106° C. (from diisopropylether) is obtained, which is debenzylated according to Kaminski et al., J. Med. Chem. 28, 876 (1985), method H, to yield 3-formyl-8-hydroxy-2-methylimidazo[1,2-a]pyridine of m.p. 251°-252° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(=O)=O.[C:15]1([C:21]23[CH2:26][CH:25]2[CH2:24][NH:23][CH2:22]3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([N:23]2[CH2:24][CH:25]3[C:21]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)([CH2:26]3)[CH2:22]2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: c1ccc(C23CNCC2C3)cc1
Agent: O=C=O
Solvent: C1CCOC1
Product: O=C(Cc1ccc(F)cc1)N1CC2CC2(c2ccccc2)C1
Reaction time: 1 h

Procedure:
To a solution of 6.2 g. of p-fluorophenylacetic acid in 60 ml. of dry tetrahydrofuran is added 6.8 g. of N,N'-carbonyl diimidazole. The resultant mixture is allowed to stand 1 hour, at which time the evolution of carbon dioxide has ceased. To this solution is added 6.4 g. of 1-phenyl-3-azabicyclo[3.1.0]hexane and the reaction solution is allowed to stand 1/2 hour and then warmed on a steam bath for 1/2 hour. After removal of the solvent, the residue is poured into ice-water and the mixture is extracted with chloroform. The extracts are dried and evaporated to give the product as an amber oil; IR 6.04μ.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7])#[CH:2].C[OH:13].N1[CH:19]=[CH:18]C=CC=1>ClCCl.CCCCCC>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([O:13][CH2:18][CH3:19])=[O:7])#[CH:2]
Reactant: CO
Reactant: c1ccncc1
Reactant: C#Cc1cccc(C(=O)Cl)c1
Solvent: ClCCl
Solvent: CCCCCC
Product: C#Cc1cccc(C(=O)OCC)c1

Procedure:
Air in a 20 ml Schlenk tube was replaced by Ar gas and 1.02 g (7 mmol) of m-ethynylbenzoic acid and 5 g (42 mmol) of thionyl chloride were added to the tube and the mixture was stirred at 50° C. for 2 hours and then excess thionyl chloride was removed by distillation under reduced pressure to obtain m-ethynylbenzoyl chloride. To the m-ethynylbenzoyl chloride obtained was added a solution having 298 μl (7.35 mmol) of methanol and 3.4 ml (42 mmol) of pyridine dissolved in 7 ml of dichloromethane under ice-cooling and then the resultant mixture was stirred at room temperature for one hour. After completion of the stirring, dichloromethane was removed by distillation under reduced pressure and 35 ml of water was added to the resultant residue and extracted with 35 ml of diethyl ether. The ether layer was dried over magnesium sulfate and the solvent was removed by distillation under reduced pressure using an evaporator. The resultant crude reaction product was dissolved in 15 ml of hexane at 70° C., insoluble matter was removed by filtration and the filtrate was cooled to obtain 0.74 g of ethyl 3-ethynylbenzoate which is a desired product as yellow solid. (Yield: 66E)
Reaction SMILES: N[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([NH:5][CH3:6])=[O:4].O.C([O-])([O-])=O.[Na+].[Na+].[Cl:20]CC(Cl)=O>CC(C)=O>[Cl:20][CH2:2][C:3]([NH2:5])=[O:4].[CH3:6][NH:5][C:3](=[O:4])[CH2:2][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CNC(=O)C(N)c1ccccc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CNC(=O)Cc1ccccc1
Product: NC(=O)CCl
Reaction time: 1.5 h
Yield: 83.55 %

Procedure:
Compound (II) obtained in the previous example (395.0 g, 2.405 mol) and acetone (1074 mL) were placed in a 5 L glass reactor and deionised water (1303 mL) was added to the slightly cloudy resulting solution, with a slight exothermic reaction of 6° C. being observed. Then, Na2CO3 (153.0 g, 1.443 mol) was added, with a slight exothermic reaction of 2° C. being observed. The resulting whitish suspension was cooled with an ice water bath at 0°-5° C. and, for approximately 1 hour without exceeding 5° C., a solution made up of chloroacetyl chloride (III) (201.0 mL, 285.3 g, 2.526 mol) in acetone (735 mL) was slowly added. The addition created vapours and a slight release of gases. The resulting milky suspension was stirred at 0°-5° C. and, after 1.5 hours, Na2CO3 (30.6 g, 0.289 mol) and a solution made up of chloroacetyl chloride (38.3 mL, 54.3 g, 0.481 mol) in acetone (140 mL) was added. After a further 1.5 hours, the suspension was concentrated at reduced pressure to a volume of approximately 1.0 L, with approximately 3.0 L having been distilled. The white thick suspension was cooled to 18°±2° C. and was filtered, with the filter being washed with deionised water (300 mL). A white solid was obtained that was dried at 60° C. and at reduced pressure and, which corresponded to the title product (I), having a melting point of 192-194° C. (483.7 g, 83.55% yield).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([OH:18])=O.[NH2:19][C@H:20]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:22]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:21]1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([NH:19][C@H:20]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[C@H:22]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:21]1)=[O:18]
Reactant: CC(C)(C)OC(=O)N1C[C@H](N)C[C@H]1COCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCCN1c1nc2ccccc2o1
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)[C@@H]2CCCCN2c2nc3ccccc3o2)C[C@H]1COCc1ccccc1

Procedure:
The title compound was prepared by a similar method to Example 1 from (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylic acid [see Preparation 3] and tert-butyl (2S,4R)-4-amino-2-[(benzyloxy)methyl]pyrrolidine-1-carboxylate [see Preparation 34]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 70:30 changing to 50:50, by volume, hexane: ethyl acetate to afford tert-butyl (2S,4R)-4-([(2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinyl]carbonylamino)-2-[(benzyloxy)methyl]pyrrolidine-1-carboxylate as a foam.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:17])[C:5](I)=[CH:6][NH:7]2.C1(C)C=CC=CC=1.[O:25]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26]1.C(=O)([O-])[O-].[Na+].[Na+]>O.CO>[F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:17])[C:5]([C:27]1[CH:28]=[CH:29][O:25][CH:26]=1)=[CH:6][NH:7]2
Reactant: OB(O)c1ccoc1
Reactant: CCCOc1ccc(F)c2c(=O)c(I)c[nH]c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccoc3)c[nH]c12
Temperature: 110 °C
Reaction time: 20 h
Yield: 28 %

Procedure:
5-Fluoro-3-iodo-8-propoxy-1H-quinolin-4-one (780 mg, 2.24 mmol) was suspended in a mixed solvent of toluene (10 ml) and methanol (1.6 ml), and furan-3-boronic acid (752 mg), tetrakis triphenylphosphine palladium (130 mg, 0.11 mmol), and a 2N sodium carbonate aqueous solution (2.25 ml) were added thereto in that order. The mixture was stirred under a nitrogen atmosphere at 110° C. for 20 hours. After the reaction mixture was cooled to room temperature, water was added, and the resulting mixture was extracted with dichloromethane. The organic layer was concentrated under reduced pressure, the residue was then purified by silica gel column chromatography (dichloromethane:methanol=60:1→50:1). The purified product was concentrated under reduced pressure and was recrystallized from ethanol to thereby obtain 180 mg of powdery pale yellow 5-fluoro-3-furan-3-yl-8-propoxy-1H-quinolin-4-one (yield: 58%).