Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:21]1[C:38]2[C:29](=[CH:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=3[CH:37]=2)[CH:28]=[C:27]2[C:22]=1[C:23]1[CH:54]=[CH:53][C:52]3[C:39](=[CH:40][C:41]4[C:50]([CH:51]=3)=[CH:49][C:48]3[C:43](=[CH:44][C:45](Br)=[CH:46][CH:47]=3)[CH:42]=4)[C:24]=1[CH:25]=[CH:26]2>O.[Cu]>[C:8]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:21]2[C:38]3[C:29](=[CH:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=4[CH:37]=3)[CH:28]=[C:27]3[C:22]=2[C:23]2[CH:54]=[CH:53][C:52]4[C:39](=[CH:40][C:41]5[C:50]([CH:51]=4)=[CH:49][C:48]4[C:43](=[CH:44][C:45]([N:7]([C:8]6[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=6)[C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)=[CH:46][CH:47]=4)[CH:42]=5)[C:24]=2[CH:25]=[CH:26]3)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: Brc1ccc2cc3cc4ccc5c(ccc6cc7cc8ccccc8cc7c(Br)c65)c4cc3cc2c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: c1ccc(N(c2ccccc2)c2ccc3cc4cc5ccc6c(ccc7cc8cc9ccccc9cc8c(N(c8ccccc8)c8ccccc8)c76)c5cc4cc3c2)cc1

Procedure:
Naphthacenonaphthacene is dissolved in carbon tetrachloride. While the resultant mixture is cooled, 1 mol equivalent of bromine is added thereto. The mixture is reacted for 4 hours and brominated. Thereafter, the mixture is purified in accordance with a usual method, and 6,13-dibromonaphthacenonaphthacene is obtained. Diphenylamine, potassium carbonate, and copper powder are added to the 6,13-dibromonaphthacenonaphthacene obtained in this way, and the mixture is reacted for 30 hours at 200° C. After the reaction solution is diluted with water, the reactant is eluted with chloroform. Thereafter, the resultant substance is purified in accordance with a usual method, and the 6,13-bis(diphenylamino)naphthacenonaphthacene represented by the following formula is synthesized. (Note that, in the formula, “Ph” represents a phenyl group.)
Reaction SMILES: CO.B(F)(F)F.C([NH:10][C:11]1[C:12]([F:32])=[CH:13][C:14]([Cl:31])=[C:15]([CH:30]=1)[O:16][C:17]1[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=1[O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(=O)C>>[NH2:10][C:11]1[C:12]([F:32])=[CH:13][C:14]([Cl:31])=[C:15]([CH:30]=1)[O:16][C:17]1[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=1[O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)COc1ccccc1Oc1cc(NC(C)=O)c(F)cc1Cl
Agent: FB(F)F
Solvent: CO
Product: CCOC(=O)COc1ccccc1Oc1cc(N)c(F)cc1Cl

Procedure:
Into a boron trifluoride methanol complex methanol solution is added ethyl [2-(5-acetylamino-2-chloro-4-fluorophenoxy)phenoxy]acetate, and the mixture is heated while stirring. Thereafter, the reaction solution is concentrated, the residue is dissolved in ethyl acetate, and washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated to obtain ethyl [2-(5-amino-2-chloro-4-fluorophenoxy)phenoxy]acetate [Intermediate compound A3-23].
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@:3]1([OH:19])[C:15]([O:17][CH3:18])=[O:16].Cl.[CH3:21][C:22]1[CH:31]=[C:30]([CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:19][C@@:3]1([C:15]([O:17][CH3:18])=[O:16])[C@H:2]([NH:1][S:40]([C:37]2[CH:38]=[CH:39][C:34]([O:33][CH2:32][C:30]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[C:22]([CH3:21])[CH:31]=3)=[CH:35][CH:36]=2)(=[O:41])=[O:42])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4]1
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Reactant: COC(=O)[C@@]1(O)CN(C(=O)OC(C)(C)C)CC[C@H]1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@]1(O)CN(C(=O)OC(C)(C)C)CC[C@H]1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.3 %

Procedure:
A suspension of 1-tert-butyl 3-methyl (3R,4R)-4-amino-3-hydroxypiperidine-1,3-dicarboxylate (1.63 g, 5.96 mmol), 4-((2-methylquinolin-4-yl)methoxy)benzene-1-sulfonyl chloride hydrochloride (4.6 g, 11.92 mmol, 2.0 eq), CH2Cl2 (100 mL) and saturated NaHCO3 (50 mL) was stirred at room temperature overnight, and then diluted with CH2Cl2. The organic phase was washed with water, then brine, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel eluting with 50-70% ethyl acetate/hexane to yield 1.65 g (47%) of 1-tert-butyl 3-methyl (3R,4R)-3-hydroxy-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]piperidine-1,3-dicarboxylate as white solid. MS: (M+H)+=586.1.
Reaction SMILES: [Cl:1][C:2]1[C:18]([F:19])=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:20]=[C:21]=S.[Cl:23][C:24]1[C:25]([N:33]2[CH2:38][CH2:37][CH:36]([C:39]([F:42])([F:41])[F:40])[CH2:35][CH2:34]2)=[CH:26][C:27]([NH:31][CH3:32])=[C:28]([CH:30]=1)[NH2:29].CC(C)N=C=NC(C)C>CN(C=O)C>[Cl:1][C:2]1[C:18]([F:19])=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[NH:20][C:21]1[N:31]([CH3:32])[C:27]2[CH:26]=[C:25]([N:33]3[CH2:38][CH2:37][CH:36]([C:39]([F:41])([F:42])[F:40])[CH2:35][CH2:34]3)[C:24]([Cl:23])=[CH:30][C:28]=2[N:29]=1
Reactant: O=C(NCc1cc(F)c(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Reactant: CNc1cc(N2CCC(C(F)(F)F)CC2)c(Cl)cc1N
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)cc(F)c2Cl)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21

Procedure:
The title compound was prepared in analogy to the procedure in Example 76 using N-(4-chloro-5-fluoro-3-isothiocyanatobenzyl)-1-trifluoromethyl-cyclopropane carboxamide (211 mg; 0.60 mmol), 5-chloro-2-methylamino-4-(4-trifluoromethyl-piperidin-1-yl)aniline (184 mg; 0.60 mmol), DIC (78 mg; 0.60 mmol) and DMF (4 mL).
Reaction SMILES: Br[CH:2]([C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[CH:12][N:13]3[C:18]([C:19]=2[CH3:20])=[C:17]([CH:21]2[CH2:23][CH2:22]2)[CH:16]=[C:15]([C:24]([O:26]CC)=[O:25])[C:14]3=[O:29])[CH:7]=[CH:8][CH:9]=1)[CH3:3].[CH3:30][NH2:31]>O1CCCC1>[CH:21]1([C:17]2[CH:16]=[C:15]([C:24]([OH:26])=[O:25])[C:14](=[O:29])[N:13]3[C:18]=2[C:19]([CH3:20])=[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([CH:2]([NH:31][CH3:30])[CH3:3])[CH:5]=2)[CH:11]=[CH:12]3)[CH2:23][CH2:22]1
Reactant: CN
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3cccc(C(C)Br)c3)ccn2c1=O
Solvent: C1CCOC1
Product: CNC(C)c1cccc(-c2ccn3c(=O)c(C(=O)O)cc(C4CC4)c3c2C)c1
Reaction time: 10 h

Procedure:
46.1 mg of ethyl 8-[3-(1-bromoethyl)phenyl]-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was dissolved in 2 ml of tetrahydrofuran. 0.1 ml of a solution of 2.0 M of methylamine in tetrahydrofuran was added to the obtained solution and they were stirred for 10 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in 1 N hydrochloric acid. After washing the obtained solution with ethyl acetate, the aqueous layer was concentrated under reduced pressure. The obtained residue was dissolved in 2 ml of methanol. 1 ml of 1 N aqueous sodium hydroxide solution was added to the obtained solution, and they were stirred at 50° C. for 1 hour. The reaction mixture was made acidic with 1 N hydrochloric acid to obtain 8.1 mg of 1-cyclopropyl-9-methyl-8-[3-(1-methylaminoethyl)phenyl]-4-oxo-4H-quinolizine-3-carboxylic acid in the form of crystals.
Reaction SMILES: C([Li])CCC.CC(C)=O.C(=O)=O.Br[C:14]1[CH:32]=[CH:31][C:17]([N:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=1.C(O[B:37]1[O:41][C:40]([CH3:43])([CH3:42])[C:39]([CH3:45])([CH3:44])[O:38]1)(C)C>C1COCC1>[C:19]1([N:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]2[CH:31]=[CH:32][C:14]([B:37]3[O:41][C:40]([CH3:43])([CH3:42])[C:39]([CH3:45])([CH3:44])[O:38]3)=[CH:15][CH:16]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC1(C)OB(c2ccc(N(c3ccccc3)c3ccccc3)cc2)OC1(C)C
Temperature: -78 °C
Reaction time: 12 h
Yield: 72.4 %

Procedure:
n-Butyllithium was added dropwise via syringe to a −78° C. (acetone-dry ice cooling bath) solution of 4-bromo-N,N-diphenylaniline (24 g, 0.074 mole) in 175 ml dry THF. Stirring was continued at −78° C. for an hour and then at −50° C. for an hour. The mixture was cooled to −78° C. and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (17.22 g, 0.0925 mole) added via syringe in one portion. The temperature was maintained at −78° C. for three hours. The cooling bath was removed and the reaction left to warm to room temperature while standing for 12 hours. The reaction mixture was poured into saturated ammonium acetate and extracted with ether. The ether layer was dried over magnesium sulfate and concentrated to give a viscous oil. Purification by column chromatography (silica gel eluting with hexane:toluene mixtures of increasing gradient from 100% hexane to 40% hexane) gave N,N-diphenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as an oil (19.9 g, 72.8% yield), which slowly crystallized to a solid on standing.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:19])=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]3[N:16]=[C:15]([CH3:17])[O:14][N:13]=3)[C:6]=2[CH:18]=1.Cl[C:21](OC(Cl)(Cl)Cl)=[O:22]>O1CCOCC1>[F:19][C:3]1[C:2]([N:1]=[C:21]=[O:22])=[CH:18][C:6]2[N:7]([CH2:11][C:12]3[N:16]=[C:15]([CH3:17])[O:14][N:13]=3)[C:8](=[O:10])[S:9][C:5]=2[CH:4]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Cc1nc(Cn2c(=O)sc3cc(F)c(N)cc32)no1
Solvent: C1COCCO1
Product: Cc1nc(Cn2c(=O)sc3cc(F)c(N=C=O)cc32)no1
Yield: 100.5 %

Procedure:
A mixture of 5-amino-6-fluoro-3-(5-methyl-1,2,4-oxadiazol-3-ylmethyl)-2(3H)-benzothiazolone (1.33 g) and dioxane (23 g) was prepared. To this mixture was dropwise added trichloromethyl chloroformate (1 g). The reaction mixture was heated under refluxing for 3 hours. The components with lower boiling points were distilled off, and the residue was dissolved in toluene (50 ml). The resulting solution was concentrated under a reduced pressure to dryness, so that the aimed compound, i.e. 6-fluoro-5-isocyanato-3-(5-methyl-1,2,4-oxadiazol-3-ylmethyl)-2-(3H)-benzothiazolone (1.46 g) was obtained. m.p. 125°-127° C.
Reaction SMILES: Br[C:2]1[C:3]([CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=[O:8])[NH:6][CH:7]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].C(OCC)(=O)C>CN(C=O)C.C(N(CC)CC)C>[CH3:13][Si:14]([C:17]#[C:18][C:2]1[C:3]([CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=[O:8])[NH:6][CH:7]=1)([CH3:16])[CH3:15]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1c(Br)c[nH]c(=O)c1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(C#C[Si](C)(C)C)c[nH]c(=O)c1[N+](=O)[O-]
Temperature: 90 °C
Yield: 96.4 %

Procedure:
A mixture of 5-bromo-4-methyl-3-nitro-2-pyridone (1.0 g, 2.8 mmol), trimethylsilylacetylene (1.2 mL, 8.5 mmol), bis(triphenylphosphine)Pd(II) chloride (0.100 g) and cuprous iodide (0.025 g) in DMF (4 mL) and triethylamine (2 mL) was heated at 90 ° C. in a sealed tube for 7 hours. Ethyl acetate was added, and the mixture was washed with water, dried, filtered and evaporated. Chromatography of the residue over silica gel (40% ethyl acetate/hexane) gave 5-trimethylsilylethynyl-4-methyl-3-nitro-2-pyridone (1.0 g, 2.7 mmol, 96%)
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([O:9][C:10]2[CH:11]=[C:12]([CH3:26])[C:13]3[CH:17]([CH2:18][C:19]([O:21]CC)=[O:20])[O:16][B:15]([OH:24])[C:14]=3[CH:25]=2)=[N:6][CH:5]=1)(=[NH:3])[NH2:2].[OH-].[Na+].Cl>CO>[C:1]([C:4]1[S:8][C:7]([O:9][C:10]2[CH:11]=[C:12]([CH3:26])[C:13]3[CH:17]([CH2:18][C:19]([OH:21])=[O:20])[O:16][B:15]([OH:24])[C:14]=3[CH:25]=2)=[N:6][CH:5]=1)(=[NH:2])[NH2:3]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ncc(C(=N)N)s3)cc(C)c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(Oc2ncc(C(=N)N)s2)cc2c1C(CC(=O)O)OB2O

Procedure:
The crude ethyl 2-(6-(5-carbamimidoylthiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate in 6 ml methanol was treated with aqueous NaOH solution (500 mg, 6 ml water) for one hour. It was acidified with 1N HCl to pH 5 and then concentrated. HPLC purification gave desired product as white flakes. 1H NMR (400 MHz, DMSO-d6) δ 12.4 (b, 1H), 9.22 (b, 2H), 9.01 (b, 2H), 8.21 (s, 1H), 7.44 (d, J=2 Hz, 1H), 7.32 (d, J=1.6 Hz, 1H), 5.50 (dd, J=9.2, 2.4 Hz, 1H), 3.05 (dd, J=15.6, 2.4 Hz, 1H), 2.28 (s, 3H), 2.12 (dd, J=15.6, 9.6 Hz, 1H). MS (ESI) m/z=348 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[C:28]4[C:23](=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:26][CH:27]=4)[N:22]=[CH:21][C:20]=3[CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:14]=2)=[CH:7][CH:6]=1.[CH2:41]=O>>[CH2:33]([C:20]1[CH:21]=[N:22][C:23]2[C:28]([C:19]=1[C:15]1[CH:14]=[C:13]([N:12]([CH2:11][C:8]3[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:2])=[O:40])=[CH:10][CH:9]=3)[CH3:41])[CH:18]=[CH:17][CH:16]=1)=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([F:30])([F:32])[F:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)Cc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Reactant: C=O
Product: CN(Cc1ccc(CC(=O)O)cc1)c1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from (4-{[3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamino]-methyl}-phenyl)-acetic acid methyl ester and formaldehyde according to the procedure of Example 66. MS (ES) m/z 541.3.
Reaction SMILES: [S:1]1(=[O:9])(=[O:8])[CH2:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2]1.CC(C)=O.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>C(O)(C)C>[S:1]1(=[O:9])(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1
Reactant: O=S1(=O)CCCC(O)C1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: O=C1CCCS(=O)(=O)C1
Yield: 67.5 %

Procedure:
To a solution of tetrahydrothiopyran-3-ol-1,1-dioxide (7.5 g, 0.05 moles) and acetone (150 mL) was slowly added enough Jones reagent to maintain a brown color for at least 10 minutes without need for additional reagent. The excess reagent was reduced by addition of isopropanol (5 mL). The mixture was filtered through anhydrous magnesium sulfate and the chromium salts were washed 3× with acetone. The solvent was removed in vacuo to give a solid which was triturated with ethanol. The resulting crystals were isolated by filtration and rinsed 3× with diethyl ether. After drying, 5.0 g of product was obtained. H' NMR CDCl3 4.0 (singlet, 2H) 3.3 (triplet, 2H) 2.6 (triplet, 2H) 2.3 (multiplet, 2H).
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1[O-])([O-])=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]2[O:21][CH2:22][CH2:23][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[C:30]1([C:36]#[C:37][C:38]([O:40][CH3:41])=[O:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C=O.O>[C:30]1([C:36]2[C:37]([C:38]([O:40][CH3:41])=[O:39])=[C:16]3[C:17]4[CH2:23][CH2:22][O:21][C:18]=4[CH:19]=[CH:20][N:15]3[N:14]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: N[n+]1ccc2c(c1)CCO2
Reactant: COC(=O)C#Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(-c2ccccc2)nn2ccc3c(c12)CCO3
Temperature: 25 °C
Reaction time: 14 h
Yield: 18.1 %

Procedure:
To a mixture of 5-amino-2,3-dihydrofuro[3,2-c]pyridin-5-ium 2,4-dinitrobenzenolate (1.00 g, 3.12 mmol) and potassium carbonate (640 mg, 4.37 mmol) in dimethylformamide (20 mL) was added methyl 3-phenylpropiolate (506 μL, 3.43 mmol) under ice-cooling, and the mixture was stirred at room temperature for 14 hr. The reaction solution was diluted with water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→40/60) to give the title compound (166 mg, yield 18%).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][C:31]=1[CH3:37]>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][C:31]=1[CH3:37])=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(O)ccc1N
Reactant: CCCC(=O)c1cnc2c(COC(=O)c3ccc(OC)cc3)cccc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(COC(=O)c3ccc(OC)cc3)cccc2c1Nc1ccc(O)cc1C
Yield: 76.1 %

Procedure:
A solution of 3-butyryl-4-chloro-8-(4-methoxybenzoyloxymethyl)quinoline (2.56 g, 6.4 mmol) and 4-amino-3-methylphenol (1.18 g, 9.6 mmol) in 1,4-dioxan (30 ml) was heated at reflux for 2 hours, then evaporated. Chromatography (silica gel, 1% methanol in dichloromethane) and recrystallisation from ethanol gave 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-(4-methoxybenzoyloxymethyl)-quinoline, (2.36 g, 76%), m.p. 171°-175°.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[C:7]([CH:20]=[CH:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH:25]([CH3:27])[CH3:26])[N:5]=1)([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:36])C=1>C(Cl)Cl>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([S:18]([CH3:19])=[O:36])=[CH:16][CH:17]=2)[C:7]([CH:20]=[CH:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH:25]([CH3:26])[CH3:27])[N:5]=1)([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(SC)cc1
Solvent: ClCCl
Product: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(S(C)=O)cc1
Temperature: 0 °C
Yield: 50 %

Procedure:
2,6Diisopropyl-3-hydroxymethyl-4-[4-(methylthio)phenyl]-5-(pent-1-enyl)pyridine (100 mg, 0.261 mmol) (Example 174) was dissolved in methylene chloride (1.5 mL) and stirred at 0° C. under an argon atmosphere. To this mixture was added a solution containing 3-chloroperoxybenzoic add (“mCPBA”) (85%, 53 mg, 0.261 mmol) in methylene chloride (1 mL). The mixture was stirred for 1.5 h at 0° C. and quenched with the addition of a saturated aqueous solution of NaHSO3 (3 mL). The reaction mixture was further diluted through the addition of water (5 mL) and then extracted with methylene chloride (3×10 mL). The combined organic layer was washed sequentially with a saturated aqueous solution of sodium bicarbonate (10 mL) and brine (10 mL), dried (Na2SO4), and concentrated under reduced pressure. The resultant residue was purified by flash chromatography to yield the title compound (52 mg, 50%) as a white solid, mp 133-135° C. 1H NMR (300 MHz, CDCl3): δ 0.77 and 0.69 (t, J=7.5 Hz, 3 H), 1.08-1.36 (m, 14 H), 1.70-1.92 (m, 3 H), 2.75 and 2.76 (s, 3 H), 3.19-3.51 (m, 2 H), 4.32-4.40 (m, 2 H), 5.20-5.45 (m, 1 H), 5.93-6.00 (m, 1 H), 7.31-7.38 (m, 2 H), 7.59-7.70 (m, 2 H). Anal. calc. for C24H33NO2S: C, 71.86; H, 8.29; N, 3.39; S, 7.73. Found: C, 72.14; H, 8.32; N, 3.51; S, 8.02.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH:9]1([NH:14][OH:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:16][C:17]1[O:18][CH:19]=[CH:20][C:21]=1[C:22](Cl)=[O:23]>C1C=CC=CC=1>[CH:9]1([N:14]([C:22]([C:21]2[CH:20]=[CH:19][O:18][C:17]=2[CH3:16])=[O:23])[OH:15])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: ONC1CCCC1
Reactant: Cc1occc1C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1occc1C(=O)N(O)C1CCCC1
Reaction time: 1 h

Procedure:
30 Parts of triethylamine is added to a suspension of 20 parts of N-cyclopentylhydroxylamine hydrochloride in 300 parts of benzene and the whole is stirred for 1 hour. At room temperature, 10 parts of 2-methylfuran-3-carboxylic chloride is dripped in. After the mixture has been stirred for a further 3 hours it is suction filtered, the residue is washed with benzene, and the organic phase is washed with water, dried with sodium sulfate and evaporated. There is obtained 25 parts of N-cyclopentyl-2-methylfuran-3-hydroxamic acid in the form of an oil. This oil is dissolved in 300 parts of dichloromethane; while stirring and at room temperature, 16 parts of sodium hydroxide in 70 parts of water, and 26 parts of dimethyl sulfate are added to the solution. After the mixture has been stirred for 2 hours the organic phase is separated, washed with water until neutral and dried with anhydrous sodium sulfate. Distillation gives 21 parts of O-methyl-N-cyclopentyl-2-methylfuran- 3-hydroxamic acid having a boiling point at 0.01 mm Hg of 104° to 108° C and the refractive index nD25 : 1.5073. ##SPC14##
Reaction SMILES: C[O:2][C:3](=[O:20])[C@H:4]([CH:17]([CH3:19])[CH3:18])[NH:5][C:6]([N:8]([CH3:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:7].[OH-].[Li+]>O1CCOCC1>[CH3:16][N:8]([C:6]([NH:5][C@H:4]([C:3]([OH:20])=[O:2])[CH:17]([CH3:19])[CH3:18])=[O:7])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: COC(=O)[C@@H](NC(=O)N(C)Cc1ccccn1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)N(C)Cc1ccccn1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of 4.47 g (16 mmol) of N-((N-methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valine methyl ester in 65 ml of dioxane was treated with 65 ml of 0.5M aqueous lithium hydroxide. After being stirred at ambient temperature for 1 h, the resulting solution was concentrated in vacuo to a small volume (ca. 5 ml), neutralized to pH 5 with 1M aqueous HCl, and extracted with three 100 ml portions of ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to provide 3.61 g (85%) of the desired compound as an oil.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH:22]([C:27]([O:29][CH3:30])=[O:28])[C:23]([O:25][CH3:26])=[O:24])[CH2:17][CH2:16]1>C(O)(=O)C>[CH2:7]([N:15]1[CH2:16][CH2:17][CH:18]([CH2:21][CH:22]([C:27]([O:29][CH3:30])=[O:28])[C:23]([O:25][CH3:26])=[O:24])[CH2:19][CH2:20]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)C(CC1CCNCC1)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)C(CC1CCN(Cc2ccccc2)CC1)C(=O)OC
Temperature: 62.5 °C
Reaction time: 12 h

Procedure:
Sodium carbonate (1,550 g) and benzyl chloride (582.3 g) were added to the solution of the acetic acid salt of dimethyl (4-piperidylmethyl)malonate [XXIXa] from the previous step. The obtained slurry was stirred for 12 hours at 60-65° C. and evaporated under reduced pressure. Water was added to the residue and the mixture was extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate, passed through short silica gel column and evaporated under reduced pressure. The residue was washed with hexane and dried under reduced pressure to give dimethyl (N-benzyl-4-piperidylmethyl)malonate [XXIIa]. 1H NMR (CDCl3) δ1.10-1.37 (m, 3H), 1.50-1.75 (m, 2H), 1.75-2.00 (m, 4H), 2.83 (br. d, 2H, J=12 Hz), 3.44 (s, 2H), 3.70 (s, 6H), 7.26 (m, 5H).
Reaction SMILES: C([NH:4][C:5]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([Cl:19])=[CH:12][C:6]=1[CH2:7][O:8]C(=O)C)(=O)C.[OH-].[Na+].Cl>CO.O>[NH2:4][C:5]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([Cl:19])=[CH:12][C:6]=1[CH2:7][OH:8]
Reactant: CC(=O)Nc1c(COC(C)=O)cc(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1c(CO)cc(Cl)cc1[N+](=O)[O-]
Yield: 260 %

Procedure:
Acetic acid 2-acetylamino-5-chloro-3-nitro-benzyl ester (0.454 g, 0.45 mmol) and sodium hydroxide (0.436 g, 11 mmol) were dissolved in methanol-water (1:3, 40 ml) and the resulting solution heated at reflux for 5 h. After cooling the mixture was taken to pH 6 by the addition of conc. HCl. The precipitate formed was collected by filtration to give (2-amino-5-chloro-3-nitro-phenyl)-methanol as a dark orange solid (0.237 g, 73%). (LC/MS: Rt 2.63, [M−H]− 200.96).