Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]2[N:12]([CH3:17])[C:13](=[O:16])[NH:14][N:15]=2)=[CH:4][CH:3]=1.[O:18]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:33](=[O:36])([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:17][N:12]1[C:11]([CH2:10][CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:28][C:27]3[CH:30]=[CH:31][CH:32]=[C:25]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:26]=3)=[CH:7][CH:6]=2)=[N:15][N:14]([CH2:28][C:27]2[CH:26]=[CH:25][CH:32]=[C:31]([O:36][C:33]3[CH:21]=[CH:20][CH:19]=[CH:24][CH:23]=3)[CH:30]=2)[C:13]1=[O:16]
Reactant: Cn1c(CCCc2ccc(O)cc2)n[nH]c1=O
Reactant: O=C([O-])[O-]
Reactant: ClCc1cccc(Oc2ccccc2)c1
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(CCCc2ccc(OCc3cccc(Oc4ccccc4)c3)cc2)nn(Cc2cccc(Oc3ccccc3)c2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of 5-[3-(4-hydroxyphenyl)propyl]-4-methyl-2,4-dihydro-[1,2,4]triazol-3-one (Example 1, step C) (0.350 g, 1.50 mmol) in DMF (5 mL), was added 3-phenoxybenzyl chloride (0.94 g, 4.29 mmol) followed by potassium carbonate powder (0.74 g, 5.35 mmol). The mixture was stirred at rt under nitrogen overnight. The reaction mixture was partitioned between ethyl acetate (20 mL) and water (20 mL). The organic phase was dried over MgSO4 and filtered. Evaporation of solvent gave a crude product, which was purified on a silica gel column (125 mL SiO2) eluting with 50% EtOAc/hexanes to give the titled compound as colorless oil (0.0.78 g, 87%). 400 MHz 1H NMR (CDCl3) δ 7.32 (q, J=7.6 Hz, 4H), 7.30−7.25 (m, 3H), 7.20−6.90 (m, 10H), 6.97 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 5.01 (s, 2H), 4.91 (s, 2H), 3.16 (s, 3H), 2.63 (t, J=7.2 Hz, 2H), 2.46 (t, J=7.6 Hz, 2H), 1.94 (quintet, J=7.6 Hz, 2H); Mass (M+H+)=598.4.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.CCN(C(C)C)C(C)C.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>ClCCl>[C:9]([O:8][C:7]([NH:6][C@H:3]1[CH2:4][CH2:5][N:1]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:2]1)=[O:13])([CH3:10])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a solution of (S)-tert-butyl pyrrolidin-3-ylcarbamate (6.0 g, 32.2 mmol) and DIEA (12.5 g, 16.8 mL, 96.6 mmol) in dichloromethane (60 mL) cooled to 0° C. on an ice-bath was added benzyl chloroformate (8.7 g, 7.2 mL, 48.3 mmol), and the resulting mixture stirred at 0° C. for 2 hours. The mixture was diluted with dichloromethane (30 mL) and washed successively with cold aqueous 10% HCl, water, saturated sodium bicarbonate solution and brine. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography silica gel (Biotage, 65M; 20% ethyl acetate/hexanes) to afford (S)-benzyl 3-(tert-butoxycarbonylamino)pyrrolidine-1-carboxylate (10 g, 97%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]([O:11][C:12](=[O:26])[CH:13]([CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14](=O)[CH3:15])[CH3:10].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[CH:17]=[C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:5]([C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([Br:1])[CH:3]=2)[C:14]=1[CH3:15])=[O:26])[CH3:10]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Reactant: Nc1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccc(Br)c2)c1C

Procedure:
m-Bromoaniline (5 mmol, 0.9 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The named product was recrystallized from ethanol (m.p. 111° C.-112.7° C.)
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]([C@H:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19](C(=O)C2C=C(C(F)(F)F)C=C(C(F)(F)F)C=2)[C@@H:18]([CH3:42])[CH2:17]1)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:7])(=O)C.[OH-].[K+].Cl>C(O)C.O>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([N:8]([C@H:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][C@@H:18]([CH3:42])[CH2:17]2)[C:6](=[O:7])[CH2:5][OH:4])=[CH:14][CH:13]=1
Reactant: CC(=O)OCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@H]1C[C@@H](N(C(=O)CO)c2ccc(Cl)cc2)c2ccccc2N1
Temperature: 70 °C

Procedure:
To a solution of 2-[{(2S,4R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl}(4-chlorophenyl)amino]-2-oxoethyl acetate (500 mg, 0.82 mmol, 1 equ.) in ethanol (6 mL) and water (1 mL) was added potassium hydroxide (229 mg, 4.1 mmol, 5 equ.). The mixture was heated to 70° C. for 4 h. The mixture was neutralized with 1N aqueous HCl and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate and twice with brine, dried over sodium sulfate, filtered and concentrated to give crude N-(4-chlorophenyl)-2-hydroxy-N-[(2S,4R)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide used as such in the next step.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:27]1([CH2:33][O:34][CH2:35][CH2:36][Br:37])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC#N>[Br-:37].[OH:10][C:9]([C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:36][CH2:35][O:34][CH2:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: BrCCOCc1ccccc1
Reactant: COc1ccc(C(O)(c2ccc(OC)cc2)C23CCN(CC2)CC3)cc1
Solvent: CC#N
Product: COc1ccc(C(O)(c2ccc(OC)cc2)C23CC[N+](CCOCc4ccccc4)(CC2)CC3)cc1
Product: [Br-]
Yield: 46.7 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl{bis[4-(methyloxy)phenyl]}methanol (0.0498 g, 0.141 mmol) and 2-bromoethyl phenylmethyl ether (0.0334 mL, 0.211 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0374 g, 46.7%). EI-MS m/z 488 (M+) Rt (1.94 min).
Reaction SMILES: [CH2:1]([N:5]([CH2:23][CH2:24][CH2:25][CH3:26])[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([CH:14]=[CH:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[C:8]([O:21][CH3:22])[CH:7]=1)[CH2:2][CH2:3][CH3:4].C([Li])CCC.CN(C)[CH:34]=[O:35].C(Cl)(Cl)Cl>O1CCCC1>[CH2:23]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:7]=[C:8]([O:21][CH3:22])[C:9]([CH:14]=[CH:15][C:16]2[S:17][C:18]([CH:34]=[O:35])=[CH:19][CH:20]=2)=[C:10]([O:12][CH3:13])[CH:11]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCN(CCCC)c1cc(OC)c(C=Cc2cccs2)c(OC)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1cc(OC)c(C=Cc2ccc(C=O)s2)c(OC)c1
Temperature: 0 °C
Yield: 100 %

Procedure:
In a stream of argon, in 10 ml of tetrahydrofuran was dissolved 0.75 g (2.00 mmol) of 2-[2-(4-dibutylamino-2,6-dimethoxyphenyl)vinyl]thiophene, and 1.27 ml of n-butyllithium (1.6 M solution in hexane) (2.03 mmol) was added dropwise thereto under cooling. The mixture was stirred for hour. To this mixture, 0.20 ml (1.20 mmol) of N,N-dimethylformamide was added dropwise and reacted. The temperature was then allowed to rise gradually, and the mixture was allowed to react at room temperature for 12 hours. After the mixture was poured into 100 ml of ice water, extraction with 200 ml of chloroform, washing with a saturated saline solution, drying over anhydrous magnesium sulfate, and concentration were performed. The residue was purified by silica gel chromatography to give 482 mg (yield: 60%) of 5-[2-(4-dibutylamino-2,6-dimethoxyphenyl)vinyl]thiophene-2-carboaldehyde as a dark purple crystal (mp: 105-106° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11](O)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)/C=C/c1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCCc1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
(2E)-3-(3,4-Dichlorophenyl)acrylic acid (800 mg, 3.69 mmol) was dissolved in tetrahydrofuran (80 mL), and the resulting solution was cooled to 0° C. Then, lithium aluminum hydride (280 mg, 7.38 mmol) was added thereto, and the temperature of the resulting mixture was raised to room temperature, and the mixture was stirred for 8 hours. Water was added to the reaction solution, and the organic matter was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 70:30 (v/v)), whereby the objective title compound was obtained as a yellow oily substance (229 mg, yield: 30%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.CN(C)[CH:13]=[C:14]([N:20]=[CH:21]N(C)C)[C:15]([O:17][CH2:18][CH3:19])=[O:16].FC(F)(F)C(O)=O>C(O)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:20]=[CH:21][C:9]=2[CH:8]=[CH:7]1
Reactant: CCOC(=O)C(=CN(C)C)N=CN(C)C
Reactant: COCCCn1cccc1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc2c(ccn2CCCOC)cn1
Yield: 64.8 %

Procedure:
A solution of 1-(3-methoxypropyl)-1H-pyrrole (3.92 g), ethyl 3-dimethylamino-2-(dimethylaminomethyleneamino)acrylate (7.20 g) (ref. Liebigs Ann. Chem. 1980, 344-357) and trifluoroacetic acid (8.33 mL) in acetic acid (32 mL) was stirred at room temperature for 18 hours, and then heated to reflux for 3 hours. After cooling, the reaction solution was concentrated under reduced pressure. To the resulting residue was added aqueous saturated sodium hydrogen carbonate solution under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1→AcOEt) to give ethyl 1-(3-methoxypropyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylate [REx(105.2)] (4.79 g) as a brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH3:11][O:12][CH2:13][CH2:14]Br.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:14][CH2:13][O:12][CH3:11])[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(C=O)cc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 30 %

Procedure:
An amount of 3,4-dihydroxybenzaldehyde (5.0 g, 36.2 mmol) in 20 mL of N,N′-dimethylformamide is added 2-bromoethyl methyl ether (3.4 mL, 36.2 mmol), and sodium carbonate (5.0 g, 72.4 mmol). The reaction mixture is stirred at room temperature for 3 days. After removal solids by filtration, the solution is subsequently evaporated under high-pressure vacuum to dark brown liquid. The residue is added water and acidified with 12 N HCl solution to pH˜2, then extracted 4×100 mL of EtOAc. The combined organic layer is washed with brine, dried over Mg2SO4, stirred in darko, filtered and evaporated to give yellow liquid. Purification is performed by column chromatography over silica gel using 40% EtOAc/Hex as eluent to give 2.13 g of colorless solid: mp 74-75° C.; MS (ESI) m/z 195.1 (M+H)−1
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:19][C:20]1[CH:50]=[CH:49][C:23]2[N:24]3[C:28]([CH2:29][N:30]([CH:32]4[CH2:36][CH2:35][NH:34][CH2:33]4)[CH2:31][C:22]=2[CH:21]=1)=[N:27][N:26]=[C:25]3[CH:37]1[CH2:42][CH2:41][N:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=2)[CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>ClCCl>[ClH:19].[ClH:19].[ClH:19].[Cl:19][C:20]1[CH:50]=[CH:49][C:23]2[N:24]3[C:28]([CH2:29][N:30]([CH:32]4[CH2:36][CH2:35][N:34]([CH:2]([CH3:4])[CH3:1])[CH2:33]4)[CH2:31][C:22]=2[CH:21]=1)=[N:27][N:26]=[C:25]3[CH:37]1[CH2:38][CH2:39][N:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=2)[CH2:41][CH2:42]1
Reactant: CC(C)=O
Reactant: Clc1ccc2c(c1)CN(C1CCNC1)Cc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)N1CCC(N2Cc3cc(Cl)ccc3-n3c(nnc3C3CCN(c4ccccn4)CC3)C2)C1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Acetone (0.1 ml) and sodium triacetoxyborohydride (47 mg, 0.22 mmol) were added to a solution of the amine from example 56 (100 mg, 0.22 mmol) in dichloromethane (5 ml), and the reaction mixture was stirred at room temperature for 16 hours. Saturated aqueous sodium bicarbonate solution (10 ml) was added, the mixture was stirred vigorously for 10 minutes, and the layers were separated. The organic layer was evaporated under reduced pressure and the residue purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (95:5:0.5) as eluant. The product was treated with ethereal hydrochloric acid to afford the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[N:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.[F-].[K+].CC[N:29](C(C)C)[CH:30]([CH3:32])[CH3:31].CC(N)C>CS(C)=O.O>[CH:30]([NH:29][C:2]1[N:7]=[C:6]2[CH:8]=[N:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)([CH3:32])[CH3:31]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3ccncc3nc2Cl)CC1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(C)N
Solvent: O
Product: CC(C)Nc1nc2cnccc2nc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 23 °C
Reaction time: 22 h
Yield: 59 %

Procedure:
To a flask charged with tert-butyl 4-(3-chloropyrido[3,4-b]pyrazin-2-yl)piperazine-1-carboxylate (3.35 g, 9.58 mmol) and potassium fluoride (0.723 g, 12.45 mmol) in DMSO (25 mL) was added DIPEA (3.34 mL, 19.15 mmol) and propan-2-amine (2.468 mL, 28.7 mmol) at 23° C. The reaction was stirred at 23° C. for 22 hr and diluted with water (100 mL) to furnish an orange, oily sludge. The mixture was cooled to 0° C. to furnish a yellow-orange suspension. The resulting solid was filtered, rinsed with water, and dried in vacuo. The crude material was dissolved in EtOAc, adsorbed on NH silica gel (11 g), and purified via medium pressure chromatography using a gradient of 10% to 100% EtOAc in heptane on an NH 60 μM size 400 column (Shoko Scientific Purif-Pack™) to give the title compound (2.105 g, 59.0%) as a light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.26 (d, J=6.8 Hz, 6H), 1.43 (s, 9H), 3.30-3.33 (m, 4H), 3.52-3.60 (m, 4H), 4.32-4.42 (m, 1H), 6.54 (d, J=7.8 Hz, 1H), 7.43-7.46 (m, 1H), 8.29 (d, J=5.4 Hz, 1H), 8.78 (s, 1H); ESI-MS m/z [M+F]+ 373.0.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[O:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][C@@H:17]1[CH2:26][NH2:27]>>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:27]([CH2:26][C@H:17]2[CH2:18][CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:16]2)[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: NC[C@H]1CCc2ccccc2O1
Agent: Cl
Product: N=c1c(C(N)=O)cc(Cl)cn1C[C@H]1CCc2ccccc2O1

Procedure:
According to the method of Example 160, 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide was reacted with 1-[(2R)-3,4-dihydro-2H-chromen-2-yl]methanamine hydrochloride to give the title compound.
Reaction SMILES: [O-][CH2:2][CH3:3].[Na+].C(O[C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])C.C(O[C:19](=[O:33])[C:20](=[C:30]([NH2:32])[CH3:31])[CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)C>C(O)C>[CH2:13]([O:12][C:10]([C:9]1[C:8](=[O:15])[N:32]([CH2:2][CH3:3])[C:30]([CH3:31])=[C:20]([CH2:21][CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:19]=1[OH:33])=[O:11])[CH3:14]
Reactant: CC[O-]
Reactant: CCOC(=O)C(CCCc1ccccc1)=C(C)N
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(O)c(CCCc2ccccc2)c(C)n(CC)c1=O

Procedure:
Sodium ethoxide in ethanol (27.5 ml; 0.0738 mol) was stirred and refluxed. Malonic acid diethyl ester (11.8 ml; 0.0738 mol) was added dropwise. A solution of intermediate 23 (8.3 g; 0.0335 mol) in ethanol (30 ml) was added dropwise. The mixture was stirred and refluxed for 15 hours. Three-quarters of EtOH were evaporated. The mixture was poured out in ice, acidified with HCl 3N and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated The residue (19.5 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/NH4OH 96/4/0.1; 15–35 μm). Two fractions were collected and the solvent was evaporated and dried to yield 0.43 g (4%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:24][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=2)=[CH:19][C:18]=1[O:32][CH3:33]>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[O:24][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=3)=[CH:19][C:18]=2[O:32][CH3:33])=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: COC(=O)c1coc(-c2ccc(N)c(OC)c2)n1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)OC)co3)cc2OC)nc1Cl
Yield: 85.6 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.13 g, 0.75 mmol), thionyl chloride (2 mL), methyl 2-(4-amino-3-methoxyphenyl)-1,3-oxazole-4-carboxylate obtained in Example (102d) (0.25 g, 1.01 mmol) and pyridine (5 mL), to obtain 0.26 g of the title compound as a colorless solid (86%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.C([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)(OC(C)(C)C)=O.N1CCCC1>C1(C)C(C)=CC=CC=1>[Cl-:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[O:11][C:22]1([CH2:23][CH2:24][NH2+:19][CH2:20][CH2:21]1)[CH2:9][CH2:8]2
Reactant: CC(=O)c1cccc(Cl)c1O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: C1CCNC1
Solvent: Cc1ccccc1C
Product: Clc1cccc2c1OC1(CC[NH2+]CC1)CC2
Product: [Cl-]
Temperature: 100 °C

Procedure:
tert-Butyl 8-chloro-4-oxo-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxylate A mixture of 1-(3-chloro-2-hydroxyphenyl)ethanone (500 mg, 2.93 mmol), 1-boc-4-piperidone (584 mg, 2.93 mmol) and pyrrolidine (61 pt, 0.738 mmol) in Xylene (4 mL) was heated to 100° C. for 20 h. The reaction mixture was purified by column chromatography on SiO2 (40 g, gradient from 0 to 40% EtOAc/hexanes) to afford the title compound as a white solid. LC-MS: m/z=376.1, 374.1 (M+Na).
Reaction SMILES: [OH:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:15]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[CH3:15][O:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cccc([N+](=O)[O-])c1OC
Temperature: 45 °C
Reaction time: 5 h
Yield: 98.9 %

Procedure:
To a solution of methyl 2-hydroxy-3-nitrobenzoate (26.8 g, 136 mmol) in DMF (200 mL) was added K2CO3 (61 g, 440 mmol). Then iodomethane (62 g, 436 mmol) was added dropwise to the mixture at rt. The mixture was stirred at 45° C. for 5 h. Then the mixture was cooled to rt and water was added. The reaction mixture was extracted with EtOAc (500 mL×2). The combined organic layers were washed with water successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound of Step B (28.4 g, 98.8% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.10 (dd, J=1.8 Hz, 8.4 Hz, 1H), 8.00 (dd, J=1.3 Hz, 8.2 Hz, 1H), 7.40 (dd, J=8.2 Hz, 8.4 Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: [I:1][C:2]1[N:3]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:4]=[C:5]([C:7](O)=[O:8])[N:6]=1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[NH2:48][C@H:49]([C:56]([O:58][CH3:59])=[O:57])[CH2:50][CH2:51][C:52]([O:54][CH3:55])=[O:53]>O1CCCC1>[I:1][C:2]1[N:3]([C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:4]=[C:5]([C:7]([NH:48][C@H:49]([C:56]([O:58][CH3:59])=[O:57])[CH2:50][CH2:51][C:52]([O:54][CH3:55])=[O:53])=[O:8])[N:6]=1
Reactant: O=C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(I)n1
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)CC[C@H](NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(I)n1)C(=O)OC
Yield: 75.3 %

Procedure:
2-Iodo-1-triphenylmethylimidazole-4-carboxylic acid (1.443 g, 3.0 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (553 mg, 3.15 mmol), 4-methylmorpholine (0.614 mL, 6.6 mmol), dimethyl L-glutamate hydrochloride (698 mg, 3.3 mmol), and tetrahydrofuran (20 mL) were then allowed to react in the manner described in Example 15 to yield dimethyl N-(2-iodo-1-triphenylmethylimidazol-4-ylcarbonyl)--L-glutamate (1.44 g, 75%, mp 86-88° C.): 1H N (CDCl3) δ 7.47 (s, 1H), 7.44 (d, 1H, J=8.6 Hz), 7.32-7.26 (m, 9H), 7.21-7.05 (m, 6H), 4.72 (m, 1H), 3.71 (s, 3H), 3.62 (s, 3H), 2.41 (m, 2H), 2.27 (m, 1H), 1,99 (m, 1H). HRMS calcd for C30H28IN3O5 637.1074, found 637.1054. Anal. Calcd for C30H28IN3O5 : C, 56.52; H, 4.43; N, 6.59. Found: C, 56.36; H, 4.45, N, 6.57.
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].N1C=CC=CC=1.[CH3:12][O:13][C:14]([CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)=[O:15]>CCOCC>[CH3:12][O:13][C:14]([CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([O:5][CH2:4][CH:2]2[O:3][CH2:1]2)=[O:22])=[CH:19][CH:18]=1)=[O:15]
Reactant: OCC1CO1
Reactant: COC(=O)Cc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: COC(=O)Cc1ccc(C(=O)OCC2CO2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture containing 14.8 g (0.2 mole) of glycidol, 150 ml of anhydrous ether, 16 g (0.4 mole of pyridine and 43 g (0.2 mole) of 4-[(methoxycarbonyl)methyl]benzoyl chloride is stirred at room temperature for two hours. The mixture is filtered and the ether evaporated to leave an oil. This oil is distilled to give a colorless oil.