Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:7]([C:10]2[N:14]3[CH:15]=[CH:16][C:17]([C:19](N(CC)CC)=[O:20])=[CH:18][C:13]3=[N:12][C:11]=2[CH:26]([CH3:28])[CH3:27])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].C([O:33]CC)C>C(O)C(C)C>[CH:1]1([S:7]([C:10]2[N:14]3[CH:15]=[CH:16][C:17]([C:19]([OH:20])=[O:33])=[CH:18][C:13]3=[N:12][C:11]=2[CH:26]([CH3:27])[CH3:28])(=[O:8])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCN(CC)C(=O)c1ccn2c(S(=O)(=O)C3CCCCC3)c(C(C)C)nc2c1
Reactant: CCOCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)CO
Product: CC(C)c1nc2cc(C(=O)O)ccn2c1S(=O)(=O)C1CCCCC1
Reaction time: 8 h
Yield: 42 %

Procedure:
Compound 13 (237 mg, 0.584 mmol) was dissolved in isobutyl alcohol (1.2 mL), and the solution was stirred overnight under heat and reflux after adding a 5 mol/L sodium hydroxide aqueous solution (1.2 mL). The reaction mixture was stirred after adding diethyl ether, and the aqueous layer was removed. Then, 3 mol/L hydrochloric acid (2.0 mL) was added to the aqueous layer, and the mixture was stirred. The precipitated crystals were collected by filteration to give 3-cyclohexylsulfonyl-2-isopropylimidazo[1,2-a]pyridine-7-carboxylic acid (86.2 mg, yield 42%).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([N:19]3[CH:23]([OH:24])[C:22]4[S:25][CH2:26][CH:27]([O:30][CH3:31])[CH2:28][S:29][C:21]=4[C:20]3=[O:32])=[N:16]2)=[CH:11][CH:10]=1.Cl.Cl[C:35]([N:37]1[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]1)=[O:36].N1C=CC=CC=1>C(Cl)Cl>[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([N:19]3[CH:20]([O:32][C:35]([N:37]4[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]4)=[O:36])[C:21]4[S:29][CH2:28][CH:27]([O:30][CH3:31])[CH2:26][S:25][C:22]=4[C:23]3=[O:24])=[N:16]2)=[CH:11][CH:10]=1
Reactant: COC1CSC2=C(SC1)C(O)N(c1ccc3ccc(Cl)cc3n1)C2=O
Reactant: CN1CCN(C(=O)Cl)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1CSC2=C(SC1)C(OC(=O)N1CCN(C)CC1)N(c1ccc3ccc(Cl)cc3n1)C2=O
Temperature: 45 °C
Yield: 41.7 %

Procedure:
Triethylamine (29.5 cc) is added, at about 15° C., to a suspension of 7-(7-chloroquinol-2-yl)-6-hydroxy-3-methoxy-8-oxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (6.0 g) and 1-chlorocarbonyl-4-methylpiperazine hydrochloride (30.2 g) in anhydrous methylene chloride (150 cc), and anhydrous pyridine (65 cc) is then added to the resulting mixture. The reaction mixture is heated for 10 hours at 45° C. After cooling, the mixture is diluted by adding methylene chloride (300 cc). The organic phase is washed twice with an N aqueous sodium hydroxide solution (total 600 cc) and five times with distilled water (total 1000 cc), dried over sodium sulphate and evaporated. The residue is treated with boiling ethanol (50 cc). After cooling the mixture for 1 hour at 2° C., the crystals are filtered off, washed twice with ice-cooled ethanol (total 20 cc) and dried under reduced pressure (20 mm Hg). The resulting product (4.6 g; m.p. 228° C.) is dissolved in a boiling mixture of acetonitrile (50 cc) and ethanol (150 cc). After cooling the solution for 16 hours at 2° C., the resulting crystals are filtered off, washed with ice-cooled ethanol (5 cc) and dried under reduced pressure (0.2 mm Hg) at 55° C. 7-(7-Chloroquinol-2-yl)-3-methoxy-6-(4-methylpiperazin-1-yl)carbonyloxy-8-oxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (3.3 g), melting at 228° C., is obtained.
Reaction SMILES: C([O:4][C:5]1[C:6]([CH2:40][CH3:41])=[C:7]([CH2:25][C:26]([N:28]([CH2:37][CH2:38][OH:39])[CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:27])[C:8]([C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[C:9]([O:11]CC=C)[CH:10]=1)C=C.C([O-])=O.[NH4+]>O1CCOCC1.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd][P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH2:40]([C:6]1[C:5]([OH:4])=[CH:10][C:9]([OH:11])=[C:8]([C:15](=[O:24])[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:7]=1[CH2:25][C:26]([N:28]([CH2:37][CH2:38][OH:39])[CH2:29][CH2:30][N:31]1[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1)=[O:27])[CH3:41]
Reactant: C=CCOc1cc(OCC=C)c(C(=O)c2ccc(OC)cc2)c(CC(=O)N(CCO)CCN2CCOCC2)c1CC
Agent: Cc1ccccc1[P]([Pd][P](c1ccccc1C)(c1ccccc1C)c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: CCc1c(O)cc(O)c(C(=O)c2ccc(OC)cc2)c1CC(=O)N(CCO)CCN1CCOCC1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 52.3 %

Procedure:
2-[3,5-Diallyloxy-2-ethyl-6-(4-methoxybenzoyl)-phenyl]-N-(2-hydroxyethyl)-N-(2-morpholinoethyl)acetamide (0.31 g, 0.55 mmol) obtained in Example 110, Step 2 was dissolved in 1,4-dioxane (1.5 mL), and ammonium formate (0.14 g, 2.2 mmol) and bis(triphenylphosphine)palladium (II) dichloride (0.012 g, 0.017 mmol) were added thereto, followed by stirring at 100° C. for 1.5 hours in an atmosphere of argon. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was purified by C18 silica gel column chromatography (water-water/acetonitrile=1/1) to obtain Compound III (0.14 g, 51%).
Reaction SMILES: CI.[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1([CH:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[CH2:18][CH2:17][NH:16]2)[CH2:14][CH2:13][CH2:12]1.[C:29](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1([CH:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[CH2:18][CH2:17][N:16]2[CH3:29])[CH2:12][CH2:13][CH2:14]1
Reactant: O=C([O-])[O-]
Reactant: COc1cc2c(cc1OC)C(C1(c3ccc(Cl)cc3Cl)CCC1)NCC2
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc2c(cc1OC)C(C1(c3ccc(Cl)cc3Cl)CCC1)N(C)CC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of methyl iodide (1.9 g) in acetone (20 ml) was added dropwise to a stirred suspension of 1-[1-(2,4-dichlorophenyl)cyclobutyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (4 g prepared as described in Example RC9) and anhydrous potassium carbonate (3.1 g) in acetone (70 ml). The mixture was stirred at ambient temperature for 90 minutes and the solvent removed by evaporation. Water was added and the mixture extracted with ether. The ether layer yielded 1-[1-(2,4-dichlorophenyl)cyclobutyl]-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline as an oil. A portion of this oil was characterised by conversion into its 1.5 oxalate salt, m.p. 125°-132° C.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[C:4]([NH:6][C:7](=[N:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([O:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([Cl:29])=[CH:21][CH:20]=2)=[C:13]([Cl:30])[C:12]=1[CH3:31])SC)=[O:5].O1CCCC1.C(O)C.[CH3:44][NH:45][CH3:46]>O>[Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[C:4]([N:6]=[C:7]([NH:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([O:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([Cl:29])=[CH:21][CH:20]=2)=[C:13]([Cl:30])[C:12]=1[CH3:31])[N:45]([CH3:46])[CH3:44])=[O:5]
Reactant: CSC(=Nc1cc(C)c(Oc2ccc(Cl)c3ccccc23)c(Cl)c1C)NC(=O)c1ccccc1Cl
Reactant: CNC
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(NC(=NC(=O)c2ccccc2Cl)N(C)C)c(C)c(Cl)c1Oc1ccc(Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture containing 5.0 grams of 1-(2-chlorobenzoyl)-3-[3-chloro-4-(4-chloro-1-naphthoxy)-2,5-dimethylphenyl]-S-methylisothiourea prepared in Part A, 25 milliliters of tetrahydrofuran, 10 milliliters of ethanol and 50 milliliters of a 40% aqueous dimethylamine solution was refluxed in a nitrogen atmosphere for 5 hours. An additional 25 milliliters of 40% aqueous dimethylamine solution was added and reflux was continued for an additional 16 hours. After cooling to room temperature, the mixture was poured into 200 milliliters of water. This aqueous mixture was extracted twice with methylene chloride and twice with ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate. Removal of the solvents afforded 3.97 grams of a crude material. Chromatography of the crude material on silica gel using 9:1 ethyl acetate:methanol for elution afforded 1.87 grams of 2-(2-chlorobenzoyl)-3-[3-chloro-4-(4-chloro-1-naphthoxy)-2,5-dimethylphenyl]-1, 1-dimethylguanidine as an amphomorous solid having a melting point of 85° C.-97° C. Elemental analysis of the amphomorous solid indicated the following:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[CH3:13][N:14]1[C:19]([NH:20][CH2:21][CH2:22][NH:23][C:24](=O)[C:25]2[CH:30]=CC([N+]([O-])=O)=CC=2)=[CH:18][C:17](=[O:35])[N:16]([CH3:36])[C:15]1=[O:37].[C:38]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:39]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:13][N:14]1[C:19]([N:20]2[CH2:21][CH2:22][N:23]([CH2:24][CH2:25][CH2:30][O:9][C:6]3[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][C:5]=3[N+:10]([O-:12])=[O:11])[CH2:39][CH2:38]2)=[CH:18][C:17](=[O:35])[N:16]([CH3:36])[C:15]1=[O:37]
Reactant: CSc1ccc(O)c([N+](=O)[O-])c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cn1c(NCCNC(=O)c2ccc([N+](=O)[O-])cc2)cc(=O)n(C)c1=O
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: CSc1ccc(OCCCN2CCN(c3cc(=O)n(C)c(=O)n3C)CC2)c([N+](=O)[O-])c1
Yield: 112 %

Procedure:
1.5 g of 4-methylthio-2-nitrophenol, 2.0 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound 139) and 2.2 g of triphenylphosphine were suspended in 30 ml of anhydrous tetrahydrofuran, followed by the addition of 1.35 ml of diethyl azodicarboxylate. The thus-prepared mixture was treated in a similar manner to Example 84-(2), thereby obtaining 2.9 g of 1,3-dimethyl-6-{4-[3-(4-methylthio-2-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione as crystals.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[NH2:17][CH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].Cl>C(#N)C>[CH3:24][C:23]([O:22][C:20](=[O:21])[CH2:19][CH2:18][NH:17][C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=1)([CH3:26])[CH3:25]
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCNc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine (1.0 g, 4.4 mmol, 1 equiv.) in acetonitrile (10 mL) at 0° C. was added triethylamine (0.672 mL, 4.8 mmol, 1.1 equiv.) and H-beta-Ala-OtBu HCl (0.8 g, 4.4 mmol, 1 equiv.). After removing the cooling bath the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and to the residue water (20 mL) was added. The precipitate was collected, washed with water and ether to afford N-(5-bromo-2-chloro-4-pyrimidinyl)-β-alanine 1,1-dimethylethyl ester (0.52 g).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][CH2:16][C:17](=[O:26])[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(C)C=CC(S([N:36]=[N+:37]=[N-])(=O)=O)=CC=1>C(#N)C>[CH2:8]([O:15][CH2:16][C:17](=[O:26])[C:18](=[N+:36]=[N-:37])[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(C)(C)OC(=O)CC(=O)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)C(=[N+]=[N-])C(=O)COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
5,54 ml (40 mmols--2 equivalents) of triethylamine was added dropwise to a solution, cooled to 0° C., of 5,29 g (20 mmols) of tert.-butyl 4-benzyloxyacetoacetate and 4,34 g. (22 mmols) of 4-toluenesulphonyl azide in 40 ml of anhydrons acetonitrile. The mixture was stirred for 30 minutes at 0° C., treated with 8 g of Celite and evaporated in vacuo. Chromatography of the residue on 100 g of silica gel (toluene:ethyl acetate 95:5) yielded 3,98 g of the title compound as colorless crystals, melting point: 68° C., RF : 0,31 (toluene:ethyl acetate 95:5).
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][CH:9]=[CH:10][N:11]=1.C=O.[C:15](=[O:18])([O-])[O-].[K+].[K+].[CH3:21][O:22]CCO>O>[C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:11][C:10]([CH2:15][OH:18])=[C:9]([CH2:21][OH:22])[N:8]=1
Reactant: Cc1ccccc1-c1ncc[nH]1
Reactant: O=C([O-])[O-]
Reactant: COCCO
Agent: C=O
Agent: [K+]
Solvent: O
Product: Cc1ccccc1-c1nc(CO)c(CO)[nH]1
Temperature: 90 °C
Yield: 5 %

Procedure:
A mixture of 15.8 g (0.1 mole) of 2-o-tolylimidazole 9 g (0.3 mole) of paraformaldehyde, 2 g (0.015 mole) of potassium carbonate and 50 ml of methyl cellosolve was heated at 90° C. for 30 minutes with stirring in the same way as in Example 1. Then, 200 ml of water was added, and the reaction mixture was boiled for a while and cooled. The crystals were collected by filtration, boiled together with 20 g of toluene, and collected by filtration. The crystals collected were dissolved in acetone, and a small amount of activated carbon was added. The mixture was filtered, and the filtrate was evaporated to dryness to afford 2-o-tolyl-4,5-dihydroxymethyl imidazole as a final product in an amount of 1 g (yield 5%). The thin-layer chromatography (alumina G, ethanol) of the crystals gave only one spot at Rf = 0.6-0.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([S:8]([N:11]2[C:15]3[CH:16]=[C:17]([C:22]([OH:24])=O)[CH:18]=[C:19]([O:20][CH3:21])[C:14]=3[O:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.[NH2:27][C:28]1[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=1>>[CH2:35]([O:34][C:32](=[O:33])[C:31]1[CH:37]=[CH:38][C:28]([NH:27][C:22]([C:17]2[CH:18]=[C:19]([O:20][CH3:21])[C:14]3[O:13][CH2:12][N:11]([S:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:25][CH3:26])(=[O:9])=[O:10])[C:15]=3[CH:16]=2)=[O:24])=[CH:29][CH:30]=1)[CH3:36]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1COc2c(OC)cc(C(=O)O)cc21
Reactant: CCOC(=O)c1ccc(N)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2cc(OC)c3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CO3)cc1

Procedure:
Reaction of 3-(5-chloro-2-methoxy-benzenesulfonyl)-7-methoxy-2,3-dihydro-benzooxazole-5-carboxylic acid with ethyl 4-aminobenzoate in analogy with example 30, step 4 gave 4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-7-methoxy-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoic acid ethyl ester. White solid, MS (ISP)=547.2 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:32])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([N:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=3)[CH:18]=[CH:19][CH:20]=1)[C:11]([CH3:31])([CH3:30])[CH2:10]2)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[Cl:32][C:7]1[CH:8]=[C:9]2[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1)[NH:13][CH:12]([C:15]1[CH:16]=[C:17]([C:21]3[CH:22]=[CH:23][C:24]([N:27]([CH3:29])[CH3:28])=[CH:25][CH:26]=3)[CH:18]=[CH:19][CH:20]=1)[C:11]([CH3:31])([CH3:30])[CH2:10]2
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(-c3ccc(N(C)C)cc3)c1)C(C)(C)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CN(C)c1ccc(-c2cccc(C3Nc4c(cc(Cl)cc4C(=O)O)CC3(C)C)c2)cc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.7 %

Procedure:
To a stirred mixture solution of 6-chloro-2-(4′-dimethylamino-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (400 mg, 0.9 mmol) in methanol (5.0 mL) and tetrahydrofuran (6.0 mL) was added 50% sodium hydroxide in water (2.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 6-chloro-2-(4′-dimethylamino-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (351 mg, 90%) as a white solid: LC/MS m/e calcd for C26H27ClN2O2 (M+H)+: 435.98, observed: 435.0.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:37])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[O:23][CH:22]3[CH:24]([CH2:35][OH:36])[O:25][CH:26]([N:27]4[CH:32]=[CH:31][C:30](=[O:33])[NH:29][C:28]4=[O:34])[CH:21]3[O:20]2)=[CH:15][CH:14]=1)C.Cl>O.CO>[O:34]=[C:28]1[NH:29][C:30](=[O:33])[CH:31]=[CH:32][N:27]1[CH:26]1[CH:21]2[CH:22]([O:23][CH:19]([C:16]3[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:37])=[O:5])=[CH:18][CH:17]=3)[O:20]2)[CH:24]([CH2:35][OH:36])[O:25]1
Reactant: CCOC(=O)CCCCCOc1ccc(C2OC3C(CO)OC(n4ccc(=O)[nH]c4=O)C3O2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCOc1ccc(C2OC3C(CO)OC(n4ccc(=O)[nH]c4=O)C3O2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of NaOH (12.6 g, 315 mmol) in H2O (100 mL) was added to a suspension of 6 (50 g, 102 mmol) in MeOH (750 mL) and stirred for 8 h at room temperature. Approximately half of the solvent was removed in vacuo and the remainder was treated dropwise with 1 M aqueous HCl (315 mmol, 315 mL). The white precipitate was filtered, washed with H2O (2×200 mL) and Et2O (3×200 mL) and dried in vacuo to afford a white powder (15, 46.7 g, 100 mmol, 99%) as a mixture of two diastereomers: M.p.: 158-160° C.; 1H-NMR (400 MHz, (CD3)2SO3) δ=11.95 (s, 1H, 1H′), 11.38 (s, 1H, 1H′), 7.85 (d, J=8.0, 1H), 7.77 (d, J=8.0, 1H′), 7.41 (d, J=8.5, 2H), 7.37 (d, J=8.5, 2H′), 6.96 (d, J=8.5, 2H), 6.93 (d, J=8.5, 2H′), 6.04 (s, 1H′), 5.93 (m, 1H, 1H′), 5.90 (s, 1H), 5.64 (d, J=8.0, 1H), 5.63 (d, J=8.0, 1H′), 5.2 (broad, 1H, 1H′), 4.99-4.83 (m, 2H, 2H′), 4.23 (m, 1H), 4.13 (m, 1H′), 3.97 (m, 2H, 2H′), 3.62 (m, 2H, 2H′), 2.20 (m, 2H, 2H′), 1.70 (m, 2H, 2H′, 1.54 (m, 2H, 2H′), 1.41 (m, 2H, 2H′); 13C -NMR (400 MHz, (CD3)2SO3) δ=176.0, 176.0, 164.1, 164.1, 160.6, 160.5, 151.2, 151.2, 143.0, 143.0, 129.3 (2C), 129.3 (2C), 128.9, 128.9, 115.1 (2C), 115.0 (2C), 107.4, 103.4, 102.8, 102.6, 92.2, 91.3, 87.3, 85.1, 84.8, 83.7, 82.6, 80.8, 68.3, 68.3, 62.2, 62.2, 35.1, 35.1, 29.3, 29.3, 26.1, 26.1, 25.4, 25.4; IR (film) ν=3467, 3132, 2938, 1696, 1677, 1245, 1108, 1077, 1046, 1019, 976, 828, 809; HRMS (MALDI-FTMS) m/z 485.1534 (485.1536 calculated for C22H26N2O9Na (M+Na)+).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[O:20][CH2:19][CH2:18][O:17]2)=[CH:12][N:11]=1>[Zn].[Ni](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[CH2:1]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[O:17][CH2:18][CH2:19][O:20]2)=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(C2OCCO2)cn1
Reactant: BrCc1ccccc1
Agent: Cl[Ni]Cl
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(Cc2ccc(C3OCCO3)cn2)cc1
Reaction time: 4 h
Yield: 61.7 %

Procedure:
To a suspension of zinc (5.0 g, 77 mmol, highly reactive Rieke metal, 100 mL tetrahydrofuran suspension) and tetrahydrofuran (300 mL) was added dropwise benzyl bromide (7.9 mL, 66 mmol) at 0° C., which was stirred for 4 hours at the same temperature. To this suspension were added bis(triphenylphosphine) nickel (II) chloride (5.8 g, 8.8 mmol) and 2-bromo-5-[1,3]dioxolan-2-yl-pyridine (11 g, 49 mmol) described in Manufacturing Example 210-1-2, which was stirred for another 2 hours at room temperature. The reaction solution was partitioned into ethyl acetate and an ammonium chloride aqueous solution. The organic layer was separated and concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1, 1:1) to obtain the title compound (7.3 g, 62%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(=O)(O)[O-].[Na+]>O1CCCC1>[N:16]1([C:13](=[O:15])[CH2:12][CH2:11][CH2:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: O=C(O)CCCc1ccc([N+](=O)[O-])cc1
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CCCc1ccc([N+](=O)[O-])cc1)N1CCOCC1
Temperature: 35 °C
Reaction time: 1 h

Procedure:
A room temperature solution of 1.1180 gms. 4-(4-nitro-phenyl)-butyric acid in tetrahydrofuran (3 mL) is treated with 0.9052 gms. 1′,1′-carbonyl-diimidizole using an ice bath to attenuate the intensity of the reaction. The reaction mixture is stirred for 1 h. The reaction mixture is then treated with 0.5 mL morpholine. The reaction is heated overnight at 35° C. The reaction is then allowed to cool to room temperature, and is made basic with the addition of saturated aqueous sodium bicarbonate. The resulting mixture is extracted with ethyl acetate. The organics are dried over anhydrous sodium sulfate, filtered and evaporated to dryness in vacuo. The crude product residue is then chromatographed by flash silica gel chromatography using 60% ethyl acetate in hexanes as the eluant. Following evaporation of solvent, 1-morpholin-4-yl-4-(4-nitro-phenyl)-butan-1-one is isolated as a white solid in the amount of 1.3925 gms.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:11](=[O:12])[NH:10][C:9]2[N:8]=[CH:7][C:6](/[CH:13]=[CH:14]/[C:15]([O:17]C(C)(C)C)=[O:16])=[CH:5][C:4]=2[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:22])[C:11](=[O:12])[NH:10][C:9]2[N:8]=[CH:7][C:6](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])=[CH:5][C:4]=2[CH2:3]1
Reactant: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)CC(C)(C)C(=O)N2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)Cc2cc(/C=C/C(=O)O)cnc2NC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (E)-tert-butyl 3-(6,6-dimethyl-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylate (165 mg, 0.55 mmol) in CH2Cl2 (10 mL) was treated with TFA (10 mL). After stirring at room temperature for 2 h, the solution was concentrated in vacuo. The resulting crude product was treated with anhydrous HCl in dioxane (4 mL, 4.0 M) and sonicated for 15 min. The off-white solid product was then isolated by filtration and dried under vacuum. Yield: 152 mg (quant); 1H NMR (300 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.38 (s, 1H), 8.04 (s, 1H), 7.56 (d, J=16.1 Hz, 1H), 6.54 (d, J=16.1 Hz, 1H), 2.81 (s, 2H), 1.09 (s, 6H); ESI MS m/z 247 [C13H14N3O4+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:13][NH2:14].[CH:15]1([N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:26]3[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16]1>>[CH:15]1([N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:26]3[CH:33]=[CH:32][C:29]([C:30]4[N:14]([CH3:13])[C:4](=[O:6])[C:3]5[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][CH:7]=5)[N:1]=4)=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16]1
Reactant: COc1ccc(C(=O)O)c(N)c1
Reactant: O=Cc1ccc(OC2CCN(C3CCC3)CC2)cc1
Reactant: CN
Product: COc1ccc2c(=O)n(C)c(-c3ccc(OC4CCN(C5CCC5)CC4)cc3)nc2c1

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 2-amino-4-methoxybenzoic acid, methylamine and 4-[(1-cyclobutyl-4-piperidinyl)oxy]benzaldehyde.