Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-:1].[K+].CS(O[CH:8]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]1)(=O)=O>CS(C)=O.C(OCC)C.O>[I:1][CH:8]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]1
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(I)C1
Temperature: 140 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
Potassium iodide (51.0 g, 307 mind) was added to a solution of tert-butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate described in Production Example 26-2 (7.72 g, 30.7 mmol) in dimethylsulfoxide (80 mL) under nitrogen atmosphere at room temperature, and the mixture was stirred at 140° C. for 2 hours. The reaction liquid was diluted with diethyl ether and water. The aqueous layer was extracted with diethyl ether. The combined organic layer was washed serially with an aqueous sodium pyrosulfite solution and a saturated saline solution and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the resultant was concentrated under vacuum. The residue was purified with silica gel column chromatography (n-heptane:ethyl acetate 9:1-1:1) to obtain the title compound (5.91 g, 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[N:10]O)=[CH:5][CH:4]=1.C([O-])(=O)C.[NH4+].C(OCC)(=O)C>N.C(O)C.[Zn]>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH:9]([NH2:10])[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(C(=NO)c2ccc(OC)cc2)cc1
Agent: CC(=O)[O-]
Agent: N
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(C(N)c2ccc(OC)cc2)cc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Bis-(4-methoxy-phenyl)-methanone oxime (20 g, 77.82 mmol) is suspended in ammonia 0.880(450 ml) and ethanol (90 ml). Ammonium acetate (3.00 g, 38.91 mmol) is added followed by the portionwise addition of zinc dust (25.29 g, 389.10 mmol). Once the addition is complete the reaction mixture is slowly heated to 50° C. When the effervescence has ceased the reaction mixture is refluxed. The reaction is shown to be complete by TLC after 4 hours. The reaction mixture is allowed to cool and ethyl acetate is added (250 ml). The reaction mixture is filtered through Celite™ and the phases are separated. The organic layer dried is over MgSO4, filtered and the solvent removed in vacuo to give the title compound. 1H nmr (CDCl3, 400 MHz); 7.25 (d, 4H), 6.80(d, 4H), 5.10(s, 1H), 3.75(s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(N(CC)CC)C.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>C1COCC1>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:1][C:2]2[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=2[C:4]([NH2:6])=[O:5])=[O:28])=[CH:25][CH:24]=1
Reactant: COc1cc(N)c(C(N)=O)cc1OC
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(NC(=O)c2ccc(Cl)cc2)c(C(N)=O)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-amino-4,5-dimethoxybenzamide (2.0 g, 10.47 mmol) in THF (15 mL) and triethyl amine (3 mL, 20.91 mol) was added solution of 4-chlorobenzoyl chloride (2.2 g, 12.57 mol) in THF (5.0 mL) at rt for 10 min. The reaction mixture was stirred at rt 16 h. The solution was poured into ice cold water and stirred for 10 min. The separated solid was filtered, washed with ice cold water and dried to the product as a pale yellow color solid (2.9 g, 85%), mp 120-122° C. 1H NMR (400 MHz, DMSO-d6): δ 13.38 (1H, s), 8.48 (1H, br s), 8.33 (1H, br s), 7.94 (2H, d, J=8.0 Hz), 7.66 (1H, s), 7.65 (2H, d, J=8.0 Hz), 7.46 (1H, s), 3.84 (3H, s), 3.81 (3H, s); LC-MS (negative ion mode): m/z 333, 335 (M−H)−.
Reaction SMILES: [O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([OH:9])[CH2:2]1.C1COCC1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C:3](=[O:9])[CH2:2]1
Reactant: O[C@H]1CO[C@H]2OCC[C@H]21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1CO[C@H]2OCC[C@@H]12
Temperature: 0 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
Enantiomerically pure (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (bis-THF) 27 (85 mg, 0.65 mmol) was diluted in dry CH2Cl2 (6 mL) under argon, the solution was cooled to 0° C. and anhydrous Na2HPO4 (52 mg, 0.36 mol) was added. Dess-Martin periodinane (360 mg, 0.85 mmol) was added at once at 0° C. and the resulting suspension warmed to 23° C. and stirred for 3 h. The reaction was then quenched by successive addition of sat. aq. NaHCO3 and sat. aq. Na2SO3 solutions (1.5+1.5 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 then EtOAc. The combined organic phases were dried (Na2SO4), filtered on a small pad of silica gel, and evaporated to dryness. The residue was purified by column chromatography on silica gel using hexanes/EtOAc (3:1) to furnish ketone 28 (73 mg, 87%) as a white crystalline solid. TLC: Rf=0.57 (hexanes/EtOAc=1:1); Spectral data corresponded to those previously reported in the literature.35
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])=[N:5][S:4][N:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23].O>CN(C)C=O>[C:22]([NH:1][C:2]1[C:6]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])=[N:5][S:4][N:3]=1)(=[O:24])[CH3:23]
Reactant: Nc1nsnc1-c1c(Cl)cccc1Cl
Reactant: CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)Nc1nsnc1-c1c(Cl)cccc1Cl
Temperature: 60 °C
Reaction time: 12 h
Yield: 43.6 %

Procedure:
To a solution containing 0.49 g of 3-amino-4-(2,6-dichlorophenyl)-1,2,5-thiadiazole and 0.22 g of triethylamine in N,N-dimethylformamide, 0.20 g of acetyl chloride was added and the mixture was stirred at 60° C. for 12 hours. After allowing to cool, the mixture was poured into water and was extracted with ether. The ether layer was washed twice with dilute hydrochloric acid, twice with water and twice with saturated aqueous sodium chloride solution. The resultant was dried over anhydrous sodium sulfate, concentrated and purified by silica gel chromatography to obtain 0.25 g of 3-acetylamino-4-(2,6-dichlorophenyl)-1,2,5-thiadiazole.
Reaction SMILES: [OH:1][C:2]1[C:7](C(CC)(C)C)=[CH:6][C:5]([C:13](CC)(C)C)=[CH:4][C:3]=1[N:18]=[N:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-])=O.OC1C=CC(C)=CC=1N=NC1C=CC=CC=1[N+]([O-])=O.[OH-].[Na+].[N+](C1C=CC=CC=1N=NC1C=CC=CC=1)([O-])=O>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:13])=[CH:4][C:3]=1[N:18]1[N:19]=[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]2=[N:26]1
Reactant: CCC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)CC)c1
Agent: Cc1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Agent: O=[N+]([O-])c1ccccc1N=Nc1ccccc1
Agent: [Na+]
Product: Cc1ccc(O)c(-n2nc3ccccc3n2)c1

Procedure:
When in Example 1, the 2'-hydroxy-3',5'-di-tert-amyl-2-nitroazobenzene was replaced by an equivalent amount of 2'-hydroxy-5'-methyl-2-nitroazobenzene and the mole ratio of sodium hydroxide to o-nitroazobenzene intermediate was increased from 0.42/1 to 1.26/1, the reaction went rapidly to yield the product 2-(2-hydroxy-5-methylphenyl)-2H-benzotriazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:29])[N:10]2[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[N:5][CH:4]=1>C(Cl)(Cl)Cl.FC(F)(F)C(O)=O>[NH2:21][CH:18]1[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[N:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:29])[CH2:20][CH2:19]1
Reactant: COc1cnc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
To a solution of 4.36 g of tert-butyl (1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate in 50 mL of chloroform, 10 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off under reduced pressure, the reaction mixture was alkalified with a saturated aqueous sodium hydrogen carbonate solution, the solvent was then distilled off under reduced pressure, and the resultant residue was purified by silica gel column chromatography using silica gel; Chromatorex-NH made by Fuji Silysia Chemical Ltd., and an eluent of chloroform:methanol=10:1 to obtain 2.16 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one as a yellow oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1([CH:23]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[C:24]([NH:26][C@H:27]2[C@H:34]3[C@H:30]([CH2:31][NH:32][CH2:33]3)[CH2:29][CH2:28]2)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.OC1C2N=NNC=2C=CC=1.CC[N+](CCCN(C)C)=C=N>ClCCl>[CH:35]1([CH:23]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:24]([NH:26][C@H:27]2[C@H:34]3[C@H:30]([CH2:31][N:32]([C:14](=[O:16])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:33]3)[CH2:29][CH2:28]2)=[O:25])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(N[C@@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Agent: CC[N+](=C=N)CCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@H]2CC[C@@H](NC(=O)C(C3CCCCC3)C3CCCCC3)[C@@H]2C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
N-(tert-Butoxycarbonyl)-D-leucine (72.7 mg, 0.314 mmol), 2,2-dicyclohexyl-N-[(3aS,4R,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide (95 mg, 0.286 mmol) from Example 74, and hydroxybenzotriazole (48.1 mg, 0.314 mmol) were combined in dichloromethane (10 mL). After 20 minutes, N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (0.056 mL, 0.314 mmol) was added, and the reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with water. The separated organic layer was reduced in volume, and the crude material was applied to a silica gel cartridge (Analogix®, Burlington, Wis., RS-12) and eluted first with 10% to 100% ethyl acetate/hexanes and then with 1-10% methanol (2 N ammonia)/dichloromethane to give tert-butyl(R)-1-((3aS,4R,6aR)-4-(2,2-dicyclohexylacetamido)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-methyl-1-oxopentan-2-ylcarbamate: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.26 (dd, J=7.2, 24.0, 1H), 7.91 (d, J=8.6, 1H), 4.48-4.36 (m, 1H), 4.12-3.96 (m, 1H), 3.87 (dd, J=7.4, 10.3, 1H), 3.70 (ddd, J=8.0, 14.4, 23.7, 1H), 3.40 (dd, J=5.7, 12.3, 1H), 2.77 (s, 1H), 2.58 (d, J=6.1, 1H), 2.08 (s, 1H), 2.01 (dd, J=5.6, 10.4, 2H), 1.96-1.55 (m, 17H), 1.54-1.50 (m, 9H), 1.49-1.37 (m, 2H), 1.19 (qdd, J=12.3, 22.3, 24.7, 11H), 1.00 (t, J=6.6, 3H), 0.88 (d, J=6.6, 1H).
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]1([C:10]2[CH:11]=[C:12]([CH2:16]O)[CH:13]=[CH:14][CH:15]=2)[CH:9]=[CH:8][N:7]=[CH:6]1>CN(C=O)C>[Cl:3][CH2:16][C:12]1[CH:11]=[C:10]([N:5]2[CH:9]=[CH:8][N:7]=[CH:6]2)[CH:15]=[CH:14][CH:13]=1
Reactant: OCc1cccc(-n2ccnc2)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: ClCc1cccc(-n2ccnc2)c1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
Thionyl chloride (4.0 ml, 54.0 mmol) was added to a solution of (3-imidazol-1-yl-phenyl)-methanol (3.17 g, 17.0 mmol) in DMF (50 ml) and the reaction stirred at room temperature for 40 h. The solvent was evaporated, the residue diluted with DCM and washed with water, neutralised with aqueous sodium bicarbonate (pH 9-10) and then extracted with DCM (3×). The organic phase was dried over sodium sulfate, filtered and concentrated to give 1-(3-chloromethyl-phenyl)-1H-imidazole as an orange oil (5.3 g, crude contaminated with DMF).
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[CH2:8]=[O:9]>>[OH:9][CH2:8][N:5]1[C:4](=[O:6])[CH:3]=[CH:2][C:1]1=[O:7]
Reactant: O=C1C=CC(=O)N1
Reactant: C=O
Product: O=C1C=CC(=O)N1CO
Reaction time: 8 h

Procedure:
Maleimide (2.0 g) and 10% formaline (6.8 g) were stirred at 100° C. for 60 minutes. The reaction was let to cool and then kept overnight at 4° C. The product was filtered, washed with water and ethanol. Yield: 1.3 g, melting point 96,5-97° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[C:16]([C:19]#N)[CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:10]3[CH:21]=[CH:22][CH:23]=[CH:24][C:9]2=3)[CH2:4][CH2:3]1.C(O)=[O:26]>[Al].[Ni]>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[C:16]([CH:19]=[O:26])[CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:10]3[CH:21]=[CH:22][CH:23]=[CH:24][C:9]2=3)[CH2:4][CH2:3]1
Reactant: O=CO
Reactant: CN1CCC(=C2c3ccccc3C=Cc3ccc(C#N)cc32)CC1
Agent: [Ni]
Agent: [Al]
Product: CN1CCC(=C2c3ccccc3C=Cc3ccc(C=O)cc32)CC1

Procedure:
A mixture of 1.70 g of 1-methyl-4-(3-cyano-5H-dibenzo[a,d]cycloheptene-5-ylidene)piperidine (prepared as described in U.S. Pat. No. 3,988,342 (1976)), 1.70 g of Raney nickel-aluminum alloy, and 25 ml of 75% aqueous formic acid was stirred under reflux for 1.5 hours. The cooled mixture was filtered and the filtrate was made basic by the additional of solid sodium bicarbonate. Extraction of the neutralized mixture with chloroform and evaporation of the solvent gave 1.30 g of 1-methyl-4-(3-formyl-5H-dibenzo[a,d]cycloheptene-5-ylidene)piperidine.
Reaction SMILES: [CH3:1][C@@H:2]([NH:11][CH3:12])[C@@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CC(C)=O>C(OCC)(=O)C>[CH3:1][C@H:2]([NH:11][CH3:12])[C@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN[C@H](C)[C@@H](O)c1ccccc1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CN[C@@H](C)[C@H](O)c1ccccc1
Temperature: 25 °C

Procedure:
The hydroxy acid obtained above, 18.43 g. (0.093 mole) was dissolved in 200 ml. of ethyl acetate with gentle warming and to the solution was addeda solution of 15.04 g. (0.91 mole) of d-ephedrine, [α]578 =(+)11.4 (acetone), in 80 ml. ethyl acetate. The mixture was stirred at room temperature over night during which time a crop of crystals formed, was removed by filtration and air dried to obtain 18.3 g., M.P. 97°-99° C. This material was recrystallized by dissolving itin a minimum amount of hot ethyl acetate and allowing to stand at ambient temperature over night. After three such recrystallizations, 8.9 g. of thed-ephedrine salt of l-4-hydroxy-4-(p-fluorophenyl)butyric acid, M.P. 105.5°-106.5° C. was obtained.
Reaction SMILES: Cl.[CH2:2]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][NH:10][C:11](=[O:25])[C:12]1[C:17]([O:18][CH2:19][CH3:20])=[CH:16][CH:15]=[C:14]([Br:21])[C:13]=1[O:22]CC)[CH3:3].B(Br)(Br)Br>C(Cl)Cl>[CH2:2]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][NH:10][C:11](=[O:25])[C:12]1[C:17]([O:18][CH2:19][CH3:20])=[CH:16][CH:15]=[C:14]([Br:21])[C:13]=1[OH:22])[CH3:3]
Reactant: CCOc1ccc(Br)c(OCC)c1C(=O)NCC1CCCN1CC
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: CCOc1ccc(Br)c(O)c1C(=O)NCC1CCCN1CC
Reaction time: 2 h

Procedure:
5.0 g (0.0115 mole) of N-ethyl-2-(3-bromo-2,6-diethoxybenzamidomethyl)pyrrolidine hydrochloride is dissolved in 125 ml of methylene chloride. 1.25 ml (0.013 mole) of boron tribromide is added. The mixture is left for two hours at room temperature. It is then washed with 2M NH3 and with water. The organic phase is dried over Na2SO4 and evaporated. The oily base obtained crystallizes after treatment with petroleum ether. The precipitate is filtered off and is recrystallized from ethanol. M.p. 83°-83.5° C. Yield 2.4 g (56%).
Reaction SMILES: N1CCCCC1.[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][C:9]=1[O:16][CH3:17].C([CH2:21][C:22]([NH:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28])=[O:23])(O)=O.Cl>C1(C)C=CC=CC=1>[OH:7][C:8]1[CH:15]=[CH:14][C:11](/[CH:12]=[CH:21]/[C:22]([NH:24][C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=[O:28])=[O:23])=[CH:10][C:9]=1[O:16][CH3:17]
Reactant: COc1cc(C=O)ccc1O
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1O
Yield: 78 %

Procedure:
Piperidine (0.50 mL, 5.1 mmol) was added to a suspension of 4-hydroxy-3-methoxybenzaldehyde (0.77 g, 5.1 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (1.0 g, 4.5 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. (E)-2-[[3-(4-Hydroxy-3-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (1.1 g, 78%) was obtained as a yellow crystalline solid; mp 207.5-208.5° C., lit. [25] 230-233° C.; δH (500 MHz, DMSO-d6) 3.83 (s, 3H, OCH3), 6.71 (d, J=15.5 Hz, 1H, CH═CHCO), 6.80 (d, J5′,6′=8.5 Hz, 1H, H5′), 7.13 (dd, J5′,6′=8.5, J2′,6′=1.5 Hz, 1H, H6′), 7.15 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.34 (d, J2′,6′=1.5 Hz, 1H, H2′), 7.52 (d, J=15.5 Hz, 1H, CH═CHCO), 7.60 (td, J4,5=J5,6=8.0, J3,5=2.0 Hz, 1H, H5), 8.00 (dd, J3,4=8.0, J3,5=2.0 Hz, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 9.57 (s, 1H, OH), 11.27 (s, 1H, NH), 13.61 (br s, 1H, CO2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([OH:30])=[CH:25][CH:24]=2)=[O:20])[CH3:17]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:16]([O:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([O:30][C:2]1[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=1)=[CH:25][CH:24]=2)=[O:20])[CH3:17]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(Oc3ccnc4cc(OC)c(OC)cc34)ccc2[nH]1
Temperature: 180 °C

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-quinoline (0.4 g, 1.8 mmol), 5-hydroxy-1H-indole-2-carboxylic acid ethyl ester (0.37 g, 1.8 mmol, Biosynth AG) and DMAP (0.22 g, 1.8 mmol, Aldrich) in toluene (in a microwave tube) was heated in a microwave (Personal Chemistry, Emrys Optimizer) at 180° C. for 2 h. The mixture was cooled to RT and diluted with 30 mL of EtOAc. The solution was washed with 10 mL of brine twice, dried over Na2SO4 and concentrated in vacuo. The residue was further purified with silica gel column chromatography (50% to 100% EtOAc in hexanes) to provide a white foam as the desired compound. MS (ESI pos. ion) m/z: 393 (M+H). Calc'd Exact Mass for C22H20N2O5: 392.40.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Rh]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C@@H:15]1[CH2:24][CH2:23][C@H:18]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [Rh]
Solvent: CCO
Product: COC(=O)[C@H]1CC[C@@H](OC[C@@H]2CCCN2C(=O)OC(C)(C)C)CC1

Procedure:
Methyl 4-(1-tert-butoxycarbonyl-(2S)-pyrrolidinyl)methoxybenzoate (1.0 g, 2.9 mmol) and 5% Rh on alumina (500 mg) in 10 ml EtOH/1 ml AcOH was hydrogenated at rt at 5 atm for 36 hr. The catalyst filtered off, the filtrate concentrated in vacuo and the residue purified by column chromatography on silica gel with n-hexane-EtOAc (6:1, v/v) as eluent to give methyl cis-4-[(1-tert-butoxycarbonyl-(2S)-pyrrolidinyl)methoxy]cyclohexanecarboxylate (900 mg, 89%) pale yellow oil. 1H-NMR (CDCl3) δ1.46(s,9H),1.46-2.00(m,12H),2.34(m,1H),3.20-3.55 (m,5H),3.67(s,3H), 3.84-3.92(m,1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:8]([NH2:10])=O)=[O:4].B>C1COCC1>[N+:14]([C:12]1[CH:13]=[C:5]([CH:6]=[C:7]([CH2:8][NH2:10])[CH:11]=1)[C:3]([O:2][CH3:1])=[O:4])([O-:16])=[O:15]
Reactant: COC(=O)c1cc(C(N)=O)cc([N+](=O)[O-])c1
Agent: B
Solvent: C1CCOC1
Product: COC(=O)c1cc(CN)cc([N+](=O)[O-])c1
Yield: 34.4 %

Procedure:
A mixture of 3-methoxycabonyl-5-nitrobenzamide (1120 mg, 5 mmol) and 1M BH3 in THF (11.5 mL) was refluxed for 90 minutes. For a detailed description of techniques for borane reduction, see Brown, H. C.; Heim, P. J. Org. Chem. 1973, 38, 912-916. The solvent was evaporated and MeOH (15 mL) was added. HCl gas was introduced into the solution and the reaction mixture was refluxed for 70 minutes. The mixture was added saturated NaHCO3 aq. (50 mL) and extracted with CH2Cl2 (5×40 mL). The organic layers were combined, washed with brine and dried over Na2SO4. The dried solution was applied directly to SiO2 column and developed with AcOEt then 1/10=MeOH/AcOEt. The elution was evaporated to give the desired product (361 mg, 34%): 1H NMR (300 MHz, CDCl3) δ 8.696 (s, 1H), 8.403 (s, 1H), 8.320 (s, 1H), 4.051 (s, 2H), 3.961 (s, 3H); 13C NMR (300 MHz, CDCl3) δ 165.0, 148.3, 145.9, 133.7, 131.7, 125.8, 122.8, 52.7, 45.2; HRMS m/e calc'd for C9H10 N2O4 : 209.0562, found 209.0565.
Reaction SMILES: [C:1]([C:9]1[C:10]([CH3:28])=[N:11][C:12]([CH2:26][CH3:27])=[CH:13][C:14]=1[NH:15]S(C1C=CC(C)=CC=1)(=O)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OCC)=O>C1(C)C(C)=CC=CC=1>[NH2:15][C:14]1[CH:13]=[C:12]([CH2:26][CH3:27])[N:11]=[C:10]([CH3:28])[C:9]=1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(NS(=O)(=O)c2ccc(C)cc2)c(C(=O)c2ccccc2)c(C)n1
Agent: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1C
Product: CCc1cc(N)c(C(=O)c2ccccc2)c(C)n1
Yield: 46.3 %

Procedure:
A mixture of compound C (1.1 g) and (carbethoxymethylene)-triphenylphosphorane (6 g) in xylene (200 ml) was stirred and heated at reflux for 4 hours. The solution was then concentrated by evaporation and a solution of sodium (2.6 g) in methanol (200 ml) was added. The mixture was stirred and heated at reflux for 4 hours. Volatile material was removed by evaporation and water was added to the residue. The mixture was then acidified by the addition of concentrated hydrochloric acid and extracted twice with ether. The ether extracts were discarded. The aqueous phase was basified with solid potassium carbonate and extracted twice with ethyl acetate. The combined extracts were washed with water, saturated sodium chloride solution and dried (MgSO4). Solvent was removed by evaporation to leave a residue which was recrystallised from acetone to give 5,7-diethyl-4-methyl-1,6-naphthyridin-2(1H)-one (D) (0.31 g) as a solid, m.p. 220°-223° C.; NMR (d6 -DMSO): 1.22(t, 3H), 1.24(t, 3H), 2.62(s, 3H), 2.69(q, 2H), 3.16(q, 2H), 6.33(s, 1H), 6.91(s, 1H), 11.68(s, 1H); mass spectrum (CI, ammonia): 217 (M+H)+ ; microanalysis, found: C, 71.5; H, 7.1; N, 12.9%; C13H16N2O requires: C, 72.2; H, 7.5; N, 13.0%.
Reaction SMILES: O=C1COCC(=O)N1.CS([O-])(=O)=O.[C:14]1(=[O:21])[O:20][C:18](=[O:19])[CH2:17][O:16][CH2:15]1.[NH2:22][CH2:23][CH2:24][CH2:25][OH:26]>>[OH:26][CH2:25][CH2:24][CH2:23][NH:22][C:18](=[O:19])[CH2:17][O:16][CH2:15][C:14]([OH:20])=[O:21]
Reactant: NCCCO
Reactant: O=C1COCC(=O)O1
Agent: CS(=O)(=O)[O-]
Agent: O=C1COCC(=O)N1
Product: O=C(O)COCC(=O)NCCCO

Procedure:
4-[2-(4-Bis(2-bromo-p-tolyl)methyl)piperidino)propyl]-3,5-dioxomorpholine.methanesulfonate by (a) reacting diglycolic anhydride and 3-aminopropanol to produce [2-(3-hydroxypropyl)amino-2-oxoethoxy]acetic acid, (b) heating to cyclize the latter to obtain 4-(3-hydroxypropyl)-3,5-dioxomorpholine, (c) esterifying the latter with methanesulfonyl chloride to produce 3-(3,5-dioxomorpholino)propyl methanesulfonate and (d) reacting the mesylate with 4-[bis(2-bromo-p-tolyl)methyl]piperidine.