Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=C(OC)C=C(F)C=1C1SC=C(C(O)=O)N=1.[F:19][C:20]1[CH:21]=[C:22]([CH:36]([OH:38])[CH3:37])[CH:23]=[C:24]([F:35])[C:25]=1B1OC(C)(C)C(C)(C)O1.Br[C:40]1[N:45]=[C:44]([C:46]([O:48]C)=[O:47])[CH:43]=[CH:42][C:41]=1[F:50]>>[F:35][C:24]1[CH:23]=[C:22]([CH:36]([OH:38])[CH3:37])[CH:21]=[C:20]([F:19])[C:25]=1[C:40]1[N:45]=[C:44]([C:46]([OH:48])=[O:47])[CH:43]=[CH:42][C:41]=1[F:50]
Reactant: CC(O)c1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: COC(=O)c1ccc(F)c(Br)n1
Agent: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Product: CC(O)c1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with 1-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanol (Intermediate 106) and replacing methyl 2-bromothiazole-4-carboxylate with methyl 6-bromo-5-fluoropicolinate (see US2012/225062) gave the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[C:18]1([S:24]([CH2:27][C:28]2[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=2)[NH2:31])(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1.CC(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:31][C:30]2[CH:32]=[CH:33][CH:34]=[C:28]([CH2:27][S:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)(=[O:26])=[O:25])[CH:29]=2)[N:7]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: Nc1cccc(CS(=O)(=O)c2ccccc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CC(C)O
Product: O=S(=O)(Cc1cccc(Nc2ncnc(Cl)n2)c1)c1ccccc1
Yield: 191.5 %

Procedure:
To a stirred solution of 2,4-dichloro-1,3,5-triazine (150 mg, ABCR GmbH & CO. KG) in THF/i-PrOH (1:1; 1.90 mL) DIPEA (0.35 mL) was added at −40° C. Then a suspension of 3-[(phenylsulfonyl)methyl]aniline (248 mg) in THF/i-PrOH (1:1, 0.94 mL) was added at this temperature. Under stirring the temperature of the reaction mixture was slowly raised over 2 hours to 0° C. The reaction mixture was then concentrated in vacuo to give the crude title compound (691 mg) which was used without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=1.N1C=CC=CC=1>C(Cl)Cl.O>[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: Nc1ccccn1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccccn2)cc1Cl
Temperature: 0 °C
Yield: 81.4 %

Procedure:
A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirred at 0° C. until it was completely dissolved and became light purple in color. The reaction mixture was then treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 97, 200 mg, 0.61 mmol). The reaction mixture was stirred at 0° C. for 20 min and then warmed to 25° C. where it was stirred for 30 min. After such time, the reaction mixture was treated with 2-aminopyridine (85 mg, 0.91 mmol) and pyridine (0.088 mL, 1.09 mmol), and the reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (10 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 60/40 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide (202 mg, 81.5%) as a white foam: [α]23589=−41.8° (c=0.098, chloroform); EI-HRMS m/e calcd for C20H23ClN2O3S (M+) 406.1118, found 406.1119.
Reaction SMILES: C(OC[O:5][CH:6]1[CH2:23][CH:22]2[CH:8]([C:9](=[O:36])[N:10]([CH3:35])[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][CH:17]3[C:19]([C:25]([NH:27][S:28]([C:31]4([CH3:34])[CH2:33][CH2:32]4)(=[O:30])=[O:29])=[O:26])([NH:20][C:21]2=[O:24])[CH2:18]3)[CH2:7]1)C.Cl.C(=O)([O-])O.[Na+]>C1COCC1.CO.O>[OH:5][CH:6]1[CH2:23][CH:22]2[CH:8]([C:9](=[O:36])[N:10]([CH3:35])[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][CH:17]3[C:19]([C:25]([NH:27][S:28]([C:31]4([CH3:34])[CH2:33][CH2:32]4)(=[O:30])=[O:29])=[O:26])([NH:20][C:21]2=[O:24])[CH2:18]3)[CH2:7]1
Reactant: CCOCOC1CC2C(=O)NC3(C(=O)NS(=O)(=O)C4(C)CC4)CC3C=CCCCCN(C)C(=O)C2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN1CCCCC=CC2CC2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)C2CC(O)CC2C1=O
Reaction time: 6.5 h
Yield: 93.6 %

Procedure:
To a stirred solution of the cyclopropylmethyl derivative (119) (0.38 g, 0.72 mmol) in 1:1:1 THF-methanol-H2O (6 ml) was added conc. hydrochloric acid (0.89 ml), then stirred at r for 6.5 h. The reaction mixture was then neutralized using sodium hydrogen carbonate (approx. 0.9 g solid) and concentrated into approx. half the volume. The residue was partitioned between aq. 10% citric acid (40 ml) and dichloromethane (10 ml). The water layer was washed with dichloromethane (3×10 ml), and the combined organic layers were dried (sodium sulfate), filtered and concentrated. Flash chromatography of the residue using stepwise gradient elution (methanol in ethyl acetate 5-10%) gave after concentration of the appropriate fractions the title compound as a colorless foam (0.315 g, 93%). LR-MS: Calcd for C22H34N3O6S: 468. Found: 468 [M+H].
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[C:37](=[O:38])[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[CH:29]3)[C:23]=2[CH3:39])=[C:8]2[C:12]=1[NH:11][C:10]1[CH:13]=[N:14][C:15]([C:17]([O:19]CC)=[O:18])=[CH:16][C:9]2=1)(=[O:3])[NH2:2].O.[OH-].[Li+]>C1COCC1.C(O)C.O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[C:37](=[O:38])[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[CH:29]3)[C:23]=2[CH3:39])=[C:8]2[C:12]=1[NH:11][C:10]1[CH:13]=[N:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:9]2=1)(=[O:3])[NH2:2]
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1c(C(N)=O)ccc(-c3cccc(-n4cnc5ccccc5c4=O)c3C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cnc(C(=O)O)cc4c23)cccc1-n1cnc2ccccc2c1=O
Temperature: 50 °C
Reaction time: 18 h
Yield: 83.4 %

Procedure:
A solution of ethyl 8-carbamoyl-5-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-3-carboxylate (0.26 g, 0.502 mmol) and lithium hydroxide monohydrate (0.070 g, 1.757 mmol) in THF-ethanol-water (3:1:1, 20.10 mL) was stirred at room temperature overnight. After 18 h, residual starting material was observed by LCMS. The mixture was heated at 50° C. for 2 h, then cooled to room temperature and concentrated. The residue was suspended in water and treated with 1 M aqueous HCl (to pH 1-2). The precipitate was collected by filtration, washed with water and dried to provide the desired product as a pale yellow solid (0.205 g, 76%). LCMS (M+H)+ m/z 490.1.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][N:15]=[CH:16]OCC)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>CO>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([NH:33][CH:16]=[N:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:9]=2)(=[O:31])=[O:32])=[CH:28][CH:29]=1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: CCOC=NCCCOc1cccc(CN2CCCCC2)c1
Solvent: CO
Product: O=S(=O)(NC=NCCCOc1cccc(CN2CCCCC2)c1)c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To the crude product composed by ethyl N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]formimidate, 7.7 g of p-bromobenzenesulfonamide in 50 ml of methanol are dropwise added under stirring and at room temperature. The mixture is kept under stirring for 1 hour at room temperature, the solvent is removed by distillation under reduced pressure, and the obtained residue is purified by 60-silica gel column chromatography. 14.0 g of N-p-bromobenzene-sulphonyl-N'-[3-[3-(1-pipidinylmethyl)phenoxy]propyl]formamidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[CH2:26][CH2:25][C:16]2([O:20][C@H:19]([CH2:21][OH:22])[C@@H:18]([CH2:23][OH:24])[O:17]2)[CH:15]=[C:14]1[C:27]([O:29][CH2:30][CH3:31])=[O:28])(=[O:12])=[O:11].CI.[C:34](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:30]([O:29][C:27]([C:14]1[CH:13]([S:10](=[O:12])(=[O:11])[N:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])[CH3:34])[CH2:26][CH2:25][C:16]2([O:17][C@H:18]([CH2:23][OH:24])[C@@H:19]([CH2:21][OH:22])[O:20]2)[CH:15]=1)=[O:28])[CH3:31]
Reactant: CCOC(=O)C1=CC2(CCC1S(=O)(=O)Nc1ccc(F)cc1Cl)O[C@H](CO)[C@@H](CO)O2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)C1=CC2(CCC1S(=O)(=O)N(C)c1ccc(F)cc1Cl)O[C@H](CO)[C@@H](CO)O2
Temperature: 50 °C
Reaction time: 3 h
Yield: 72.3 %

Procedure:
235 mg (0.49 mmol) of ethyl (2R,3R)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 17 was dissolved in 1.5 ml of acetone, and 84 mg (0.59 mmol) of methyl iodide and 138 mg (1.00 mmol) of potassium carbonate were added sequentially, followed by stirring for 3 hours at 50° C. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane ethyl acetate=1:3) to give 175 mg of the title compound as a white amorphous substance (yield: 73%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:15]1([NH2:18])[CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+].[Cl:38]CCCl>C(O)(=O)C>[CH:15]1([NH:18][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:17][CH2:16]1.[ClH:38]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NC1CC1
Reactant: ClCCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: C1CC(NC2CC2)CCN1
Product: Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 1-tert-butoxycarbonylpiperidin-4-one (1 g, 5 mmol) and cyclopropylamine (352 μl) in 15 ml of 1,2-dichloroethane is stirred at RT for 20 min after which sodium trisacetoxyborohydride (1.6 g, 7 mmol) and 0.3 ml of acetic acid are added. After having been stirred at RT for 15 h, the reaction mixture is hydrolysed with a saturated solution of sodium hydrogen carbonate and extracted with 2×50 ml of dichloromethane. The combined organic phases are washed with a saturated solution of sodium chloride, dried, filtered and evaporated. The residue is taken up in 4 ml of diethyl ether after which 8 ml of hydrochloric acid (4 N in dioxane) are added. After stirring at RT for 15 h, the precipitate is filtered off and washed with diethyl ether. The desired product is obtained as hydrochloride. Yield: 0.96 g
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I.CS[C:22]1[NH:23][CH2:24][C:25](=[O:27])[N:26]=1.C(N(CC)CC)C>C(O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:22]2[NH:23][CH2:24][C:25](=[O:27])[N:26]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CSC1=NC(=O)CN1
Agent: I
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1CNC(NCCCOc2cccc(CN3CCCCC3)c2)=N1

Procedure:
3-(3-Piperidinomethylphenoxy)propylamine (3.01 g), 2-methylthio-imidazolin-4-one hydroiodide (2.60 g) and triethylamine (2.18 g) were refluxed in ethanol (20 ml) for 3 hours.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@H:28]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C1COCC1.CCO.[OH-].[Na+]>>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@H:28]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: COC(=O)C[C@@H](CC(C)C)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2cc(COc3ccc([C@@H](CC(=O)O)CC(C)C)cc3)ccc2C(C)(C)C)c1
Reaction time: 19 h
Yield: 81.2 %

Procedure:
To a stirred solution of 46.2 (0.047 g, 0.09 mmol) in THF (2.00 mL, 0.10 mmol) and EtOH (2.00 mL, 0.10 mmol) at 23° C. was added a 1 M solution of sodium hydroxide (1 mL, 1 mmol). The resulting reaction mixture was stirred for 19 hours. The resulting reaction was concentrated in vacuo. 1 N HCl was added to bring the pH to 1, and the resulting mixture was extracted EtOAc, dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford compound 46 (36 mg, 80% yield) as a colorless oil. MS ESI (neg.) m/e: 983.5 (M−H)+, 491.2 (M−H)+.
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].[H-].[Na+].CS(C)=O.C[O:13][C:14](=O)[C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([N:22]([CH3:24])[CH3:23])=[C:17]([CH3:25])[CH:16]=1>C(O)(=O)C.O>[CH3:24][N:22]([CH3:23])[C:18]1[C:17]([CH3:25])=[CH:16][C:15]([C:14](=[O:13])[CH2:1][S:2]([CH3:5])(=[O:4])=[O:3])=[CH:20][C:19]=1[CH3:21]
Reactant: COC(=O)c1cc(C)c(N(C)C)c(C)c1
Reactant: CS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: Cc1cc(C(=O)CS(C)(=O)=O)cc(C)c1N(C)C
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A suspension of 24.5 g. of dimethylsulfone and 9.1 g. of sodium hydride (50% dispersion in oil) in 50 ml. of absolute dimethylsulfoxide was stirred at 50° C. under an atmosphere of nitrogen and the exclusion of moisture for 3 hours. Then, it was treated with 16 g. of 4-(dimethylamino)-3,5-dimethyl-benzoic acid methyl ester. The mixture was stirred at 80° C. for 45 minutes, cooled and dissolved in 300 ml. of water. The solution was neutralized with glacial acetic acid. The precipitate was removed by filtration with suction, washed with water and recrystallized from alcohol, whereby there was obtained 4'-(dimethylamino) 3',5'-dimethyl-2-(methylsulfonyl)-acetophenone having a melting point of 132°-133° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]([N:12]2[C:16]([C:17]([OH:19])=[O:18])=[CH:15][N:14]=[CH:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:20])[O:3]1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH:33](O)([CH3:35])[CH3:34]>ClCCl>[CH:33]([O:18][C:17]([C:16]1[N:12]([CH:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:20])[O:3][C:2]2([CH3:21])[CH3:1])[CH:13]=[N:14][CH:15]=1)=[O:19])([CH3:35])[CH3:34]
Reactant: CC(C)O
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1cncn1C1c2ccccc2C(=O)OC1(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(3,3-Dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carboxylic acid (0.075 g, 0.262 mmol) (Example 23) is dissolved in dichloromethane (2 mL). Catalytic amount of dimethylformamide (0.002 mL, 0.0262 mmol) is added to the reaction mixture and cooled to 0° C. Oxalyl chloride (0.016 mL, 0.655 mmol) is added and the cooling bath is removed. The mixture is stirred at room temperature for 2 h and concentrated in vacuo. The residue obtained is redissolved in dichloromethane, and isopropanol (10 mL) is added. The reaction mixture is stirred at room temperature for 1 h, whereupon the volatiles are removed in vacuo. Saturated aqueous sodium bicarbonate is added and extracted with dichloromethane. The combined organic phase is dried over Na2SO4 and concentrated in vacuo. The residue is purified by silica gel chromatography (hexane-ethyl acetate, 1:1) to give 3-(3,3-dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carboxylic acid isopropyl ester; MS (ESI) m/z 329.0 (M+H); 1H NMR (400 MHz, MeOD) of the HCl salt δ ppm 1.34 (s, 3 H), 1.48 (d, J=5.9 Hz, 3 H), 1.49 (d, J=5.9 Hz, 3 H), 1.62 (s, 3 H), 5.42 (sept, J=5.9 Hz, 1 H), 7.02 (s, 1 H), 7.67 (d, J=7.6 Hz, 1 H), 7.75-7.81 (m, 1 H), 7.82-7.90 (m, 1 H), 8.33 (dd, J=7.8, 1.5 Hz, 1 H), 8.38 (d, J=1.3 Hz, 1 H), 8.76 (d, J=1.0 Hz, 1 H)
Reaction SMILES: [OH-].[NH4+:2].[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10](=O)[CH2:11][C:12](=[O:22])[CH2:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=O)[CH:5]=1.Cl>C(O)(C)C>[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[NH:2][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:13][C:12](=[O:22])[CH:11]=2)[CH:5]=1
Reactant: [NH4+]
Reactant: O=C(CC(=O)c1ccccn1)CC(=O)c1cc(Cl)ccn1
Agent: Cl
Agent: [OH-]
Solvent: CC(C)O
Product: O=c1cc(-c2ccccn2)[nH]c(-c2cc(Cl)ccn2)c1

Procedure:
110 ml of 25 per cent strength ammonium hydroxide solution are added to 1-(4-chloropyridin-2-yl)-5-pyridin-2-ylpentane-1,3,5-trione obtained as described above in 100 ml of isopropanol and the mixture is boiled under reflux for 4.5 hours. At room temperature, the pH is brought to 5 with 6N hydrochloric acid and the mixture is filtered. The residue is filtered through silica gel (eluent: chloroform/methanol/ammonium hydroxide solution 4:1:0.1) and evaporated. After recrystallization from acetone, 4-chloro-1′H-[2,2′;6′,2″]terpyridin-4′-one is obtained as a grey solid which is processed further without any particular purification steps. 1H-NMR (360 MHz, DMSO-de): 8.728.63 (m, 2H); 8.62-8.53 (m, 2H); 7.98 (ddd, 1H, J=7.7,7.7,1.8 Hz); 7.87 (d, 1H, J=2.2 Hz); 7.83 (d, 1H, J=2.2 Hz); 7.59 (dd, 1H, J=5.4,2.2 Hz); 7.43-7.51 (m, 1H); 2.07 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH:11]=[CH:10]1.[CH2:16](N(CC)CC)C>CO>[O:13]=[C:12]1[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH:11]1[CH2:10][C:9]([O:14][CH3:16])=[O:15]
Reactant: CCN(CC)CC
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccccc1O
Solvent: CO
Product: COC(=O)CC1Oc2ccccc2NC1=O
Temperature: 25 °C

Procedure:
A mixture of 76.4 g of 2-aminophenol and 68.6 g of maleic anhydride in 1 liter of methanol was stirred at room temperature. After addition of 100 ml of triethylamine, the yellow mass dissolved and the solution was heated for 7 hours at reflux temperature. The methanol was then removed by evaporation under reduced pressure, and the remaining oil was added to ice-water. The mixture was extracted with dichloromethane, and the organic extract was dried over sodium sulfate and evaporated. The remaining residue was crystallized from ethanol. In this way, 47.5 g of methyl (3-oxo-2,3-dihydro-4H-1,4-benzoxazin-2-yl)acetate were obtained as white crystals having a melting point of 140° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH:14]=[CH2:15].CCN(C(C)C)C(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:12]=[C:7]1[NH:8][C:9]2[N:10]=[CH:11][C:2](/[CH:15]=[CH:14]/[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:3][C:4]=2[CH2:5][CH2:6]1
Reactant: O=C1CCc2cc(Br)cnc2N1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.3 %

Procedure:
A solution of 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (12.99 g, 57 mmole), tert-butyl acrylate (34 mL, 232 mmole), DIEA (21.2 mL, 122 mmole), Pd(OAc)2 (1.3 g, 5.8 mmole) and P(o-tol)3 (3.5 g, 11.5 mmole) in propionitrile (200 mL) and DMF (50 mL) was purged with Ar, then was heated at reflux. After 18 h the reaction was allowed to cool to room temperature and was concentrated to dryness. The residue was purified by flash chromatography on silica gel (2-4% MeOH/CHCl3). The resulting residue was triturated with 1:1 Et2O/petroleum ether, collected, and dried, and the resulting material was triturated with 1:1 MeOH/H2O, collected, and dried, to give the title compound (7.09 g, 45%) as an off-white solid: 1H NMR (400 MHz, d6-DMSO) δ 10.70 (s, 1H), 8.35 (d, J=2.0 Hz, 1H), 8.04 (s, 1H), 7.50 (d, J=16.0 Hz, 1H), 6.51 (d, J=16.0 Hz, 1H), 2.89 (t, 2H), 2.53 (t, 2H), 1.48 (s, 9H); MS (ES) m/e 275.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[CH:6][CH:7]=1.[CH3:11][O:12][C:13]([C:15]1[C:19]([NH2:20])=[CH:18][NH:17][N:16]=1)=[O:14].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:11][O:12][C:13]([C:15]1[C:19]([NH:20][C:8](=[O:10])[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:18][NH:17][N:16]=1)=[O:14]
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: COC(=O)c1n[nH]cc1N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)c1n[nH]cc1NC(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 93.8 %

Procedure:
A mixture of p-toluic acid (272 mg), 4-amino-1H-pyrazole-3-carboxylic acid methyl ester (310 mg), EDC (460 mg) and HOBt (324 mg) in DMF (8 ml) was stirred at ambient temperature for 48 h. The mixture was reduced in vacuo, partitioned between EtOAc and saturated aqueous NaHCO3 and then the organic portion washed with brine, dried (MgSO4) and reduced in vacuo to give 4-(4-methyl-benzoylamino)-1H-pyrazole-3-carboxylic acid methyl ester (486 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([OH:16])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[CH2:17][CH2:18][CH2:19][CH3:20])=[O:5])[CH3:2].CI.[C:23](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH3:23])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[CH2:17][CH2:18][CH2:19][CH3:20])=[O:5])[CH3:2]
Reactant: CCCCc1c(C(=O)OCC)cc(O)c2ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCCCc1c(C(=O)OCC)cc(OC)c2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.9 %

Procedure:
1-Butyl-4-hydroxy-2-naphthalenecarboxylic acid ethyl ester (27 g) was reacted with methyl iodide (17 mL) in acetone (200 mL) containing potassium carbonate (13.8 g) with stirring at room temperature for 24 hours. The crude product obtained after the usual work up was distilled on a Kugelrohr apparatus (135°-138° C.; 0.1 mm) to provide 25.8 g of 1-butyl-4-methoxy-2-naphthalenecarboxylic acid ethyl ester as oil. Anal. Calcd for C18H22O3 : C, 75.50; H, 7.74 Found: C, 75.36; H, 7.84