Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[NH:18][C:19]([CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])=[N:20][N:21]=4)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[NH:18][C:19]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[N:20][N:21]=4)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1nnc(-c2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1nnc(-c2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)[nH]1
Reaction time: 8 h
Yield: 31.3 %

Procedure:
To a flask containing ethyl 3-{5-{3-(4-fluorophenyl)-1H-indazole-5-yl]-4H-1,2,4-triazol-3-yl}propanoate (37 mg, 0.1 mmol) was added lithium hydroxide monohydrate (8.2 mg, 0.2 mmol). This was taken up in tetrahydrofuran and allowed to stir under a nitrogen atmosphere overnight. The reaction was acidified slightly. The product was found to be soluble in both the aqueous and organic layers. The layers were concentrated and the product was purified by semipreparative HPLC (20–80% acetonitrile with 0.1% formic acid over 30 minutes). The fractions containing the compound were concentrated to yield the title compound (11 mg, 32% yield). 1H NMR (DMSO-d6) δ 13.5 (s, 1H), 8.6 (s, 1H), 8.0 (m, 3H), 7.6 (d, 1H), 7.4 (t, 2H), 2.95 (m, 2H), 2.7 (m, 2H); ES-MS m/z 352 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]2[C:23]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)=[C:22]([O:31][CH2:32][CH2:33][OH:34])[N:21]=[CH:20][N:19]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)([CH3:7])[CH3:6].[Br:35][C:36]1[CH:37]=[N:38][C:39](Cl)=[N:40][CH:41]=1.Cl>CC(N(C)C)=O.O1CCCC1>[Br:35][C:36]1[CH:37]=[N:38][C:39]([O:3][CH2:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]3[C:23]([C:24]4[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=4)=[C:22]([O:31][CH2:32][CH2:33][O:34][C:39]4[N:40]=[CH:41][C:36]([Br:35])=[CH:37][N:38]=4)[N:21]=[CH:20][N:19]=3)(=[O:15])=[O:16])=[CH:10][CH:9]=2)([CH3:7])[CH3:6])=[N:40][CH:41]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)CO)cc3)ncnc2OCCO)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)COc4ncc(Br)cn4)cc3)ncnc2OCCOc2ncc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 33.8 %

Procedure:
To a suspension of sodium hydride (65 mg) in dimethylacetamide (0.5 ml) and tetrahydrofuran (0.5 ml) is added dropwise a solution of 4-(2-hydroxy-1,1-dimethylethyl)-N-{6-[2-hydroxyethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide (135 mg) in dimethylacetamide (2 ml) and THF (2 ml) solution over period of 5 minutes at room temperature, and thereto is added 5-bromo-2-chloropyrimidine (399 mg). The mixture is stirred at room temperature for 6 days. The reaction mixture is acidified with cold diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated to remove the solvent. The oily residue is purified by silica gel column chromatography (solvent; chloroform/ethyl acetate=100:1), and evaporated to remove the solvent. The resulting crude crystals are recrystallized from methylene chloride/isopropyl ether to give 4-[2-(5-bromopyrimidin-2-yloxy)-1,1-dimethylethyl]-N-{6-[2-(5-bromopyrimidin-2-yloxy)ethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide (77 mg) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.O.CS(O)(=O)=[O:15].CC(C)=O>CO>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:15])[CH2:1]1
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Reactant: CS(=O)(=O)O
Solvent: CO
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)CC(=O)CC(C)(C)N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 130 %

Procedure:
5.0 g. of Acetonine, 0.5 g. of water and 3.1 g. of methanesulfonic acid were added to a mixed solvent comprising 35 g. of acetone and 35 g. of methanol. The mixture was stirred at room temperature for 24 hours to effect the reaction. After completion of the reaction, the reaction mixture was purified in the same manner as in Example 5 to obtain triacetonamine in a yield of 130%.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[F:14][C:15]1[CH:21]=[C:20]([S:22][C:23]([F:28])([F:27])[CH:24]([F:26])[Cl:25])[CH:19]=[CH:18][C:16]=1[NH2:17]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([NH:6][C:7]([NH:17][C:16]1[CH:18]=[CH:19][C:20]([S:22][C:23]([F:28])([F:27])[CH:24]([F:26])[Cl:25])=[CH:21][C:15]=1[F:14])=[O:8])=[O:5]
Reactant: Nc1ccc(SC(F)(F)C(F)Cl)cc1F
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc(SC(F)(F)C(F)Cl)cc1F
Reaction time: 1 h

Procedure:
A 1.8 g quantity of 2,6-difluorobenzoyl isocyanate was added dropwise to a solution of 2.6 g of 2-fluoro-4-(1,1,2-trifluoro-2-chloroethylthio)aniline in 15 ml of toluene at room temperature (20°to 25° C.). After the reaction was allowed to proceed at the same temperature for 1 hour, the crystals which separated out were recovered by filtration and washed with toluene to give 3.6 g of N-(2,6-difluorobenzoyl)-N'-[2-fluoro-4-(1,1,2-trifluoro-2-chloroethylthio)phenyl]urea, m.p. of 172°-173° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.[Cl:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.O1CCCC1>[Cl:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:18][CH:19]=1
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: OCCCCCCCCCl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc(-c2ccc(OCCCCCCCCCl)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.1 %

Procedure:
A solution of diethyl azodicarboxylate (3.5 g; 20 mmol) and tetrahydrofuran (10 ml) was added dropwise at 0° C. to a solution of 4,4′-dihydroxybiphenyl (7.4 g; 40 mmol), 8-chloro-1-octanol (3.3 g; 20 mmol), triphenylphosphine (5.2 g; 20 mmol) and tetrahydrofuran (120 ml) and stirred at room temperature 72 h. The reaction mixture was added to water (400 ml) and extracted with ethyl acetate (3×150 ml). The combined organic layers were washed with water (2×150 ml), dried over magnesium sulphate and filtered. The solvent was removed in vacuo. The residue (19.2 g) was purified by flash chromatography on a silica gel column using a toluene/ethyl acetate mixture (95:5) as eluent, to give 2.6 g (40%) of 4′-[(8-chlorooctyl)oxy]-4-biphenylol.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].Cl.N1C=CC=CC=1>C(OCCO)C>[Br:16][C:17]1[CH:18]=[C:19]([NH:20][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])[CH:21]=[CH:22][CH:23]=1
Reactant: COc1cccc2c(Cl)c(C#N)cnc12
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cccc2c(Nc3cccc(Br)c3)c(C#N)cnc12
Yield: 89.6 %

Procedure:
A solution of 328.0 mg (1.5 mmol) of 4-chloro-8-methoxy -3-quinolinecarbonitrile, 309.7 mg (1.8 mmol) of 3-bromoaniline and 173.3 mg (1.5 mmol) of pyridine hydrochloride in 15 ml of 2-ethoxyethanol was refluxed under nitrogen for 0.5 hours. The solvent was removed and the residue was diluted with water followed by neutralization to pH 7-8 with diluted sodium carbonate solution. The precipitate was collected and washed with ether and dried in vacuo to give 476.1 mg (89.6%) of the product as a yellow solid, m.p. 210-212° C.; mass spectrum (electrospray, m/e): M+H 353.8, 355.8.
Reaction SMILES: [C:1](=[S:3])=[S:2].Cl[C:5]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:6]=1[NH2:7].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:12][C:10]1[CH:11]=[CH:5][C:6]2[N:7]=[C:1]([SH:3])[S:2][C:8]=2[CH:9]=1
Reactant: S=C=S
Reactant: Nc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Sc1nc2ccc(Cl)cc2s1
Temperature: 150 °C
Yield: 93 %

Procedure:
91 g of carbon disulfide are added dropwise to a stirred suspension of 162 g of 2,4-dichloroaniline and 414 g of potassium carbonate in 1,000 ml of dimethylformamide at about 25°-30° C. in the course of 40 minutes, under a nitrogen atmosphere. The mixture is then warmed to an internal temperature of 150° C. in the course of 2 hours, and this temperature is maintained for 16 hours. The batch is cooled and filtered and the filtrate is largely freed from dimethylformamide. 600 ml of water are added to the residue which remains, the mixture is acidified and the product which precipitates is filtered off and dried. 187.6 g (93.2% of theory) of 6-chloro-2-mercaptobenzothiazole of melting point 258° C. are obtained.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:29]3=[N:30][CH:31]=[N:32][C:33](Cl)=[C:28]3[CH:27]=[N:26]2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][CH:22]([N:25]2[C:29]3=[N:30][CH:31]=[N:32][C:33]([O:11][C:6]4[CH:7]=[CH:8][CH:9]=[C:10]5[C:5]=4[CH:4]=[CH:3][CH:2]=[N:1]5)=[C:28]3[CH:27]=[N:26]2)[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Oc1cccc2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4cccc5ncccc45)ncnc32)CC1
Temperature: 160 °C
Yield: 46.6 %

Procedure:
A mixture of quinolin-5-ol (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 26 mg, 0.178 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tertbutyl ester (Intermediate 19; 60 mg, 0.178 mmol), and potassium carbonate (54 mg, 0.391 mmol) in dimethylformamide (1 mL) was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture, and the mixture was then filtered through a pad of silica gel to remove the precipitate. The silica gel pad was washed with methanol and the solvents were evaporated from the filtrate. The residue was purified by HPLC to afford 4-[4-(quinolin-5-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (37 mg, 47%) as a white solid. Mass spectrum MH+=447.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([NH:18][CH2:19][C:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])=[O:21])=[N:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=O)C.[BH4-].[Na+].[Cl-].[Li+].Cl>C(O)C.O1CCCC1>[OH:3][CH2:4][C:6]1[C:7]([NH:18][CH2:19][C:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])=[O:21])=[N:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][CH:11]=1
Reactant: CCCN(CCC)C(=O)CNc1nc(-c2ccccc2)ncc1C(=O)OCC
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCN(CCC)C(=O)CNc1nc(-c2ccccc2)ncc1CO
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.9 %

Procedure:
To a mixture of 2-(5-ethoxycarbonyl-2-phenyl-4-pyrimidinylamino)-N,N-dipropylacetamide (3.0 g) obtained in Example 126, sodium borohydride (0.6 g), lithium chloride (0.7 g) and tetrahydrofuran (20 ml) is added dropwise anhydrous ethanol (30 ml) at 0 to 5° C. The reaction mixture is stirred at room temperature for five hours, and the pH value thereof is adjusted to pH 5 with 1N hydrochloric acid, and concentrated under reduced pressure. To the residue are added a brine and chloroform, and the chloroform layer is collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from isopropanol to give the desired compound (2.0 g), m.p. 167-168° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].[C:24]([O:28][C:29]([NH:31][C@@H:32]([CH2:36][C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:17]=2)[CH2:10][CH2:9][N:8]([C:33](=[O:34])[C@@H:32]([NH:31][C:29]([O:28][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:30])[CH2:36][C:37]2[S:38][CH:39]=[CH:40][CH:41]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)O
Reactant: COC(=O)C1(Cc2ccc(-c3ccccc3)cc2)CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1(Cc2ccc(-c3ccccc3)cc2)CCN(C(=O)[C@H](Cc2cccs2)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-biphenyl-4-ylmethyl-piperidine-4-carboxylic acid methyl ester (8.73 mmol; 2.7 g) in DMF (20 mL) was added (S)-2-tert-butoxycarbonylamino-3-thiophen-2-yl-propionic acid (9.58 mmol; 2.60 g), N,N-diisopropyl-N-ethylamine (17.46 mmol; 3.1 mL) and HBTU (10.48 mmol; 3.97 g), and the resulting mixture was stirred at room temperature overnight. Ethyl acetate (200 mL) was added and the resulting solution was washed with a 1N hydrochloric acid solution (2×50 mL) and brine (50 mL), and dried over magnesium sulfate. After filtration and evaporation, the residue was purified via flash column chromatography (eluent gradient: 0 to 60% EtOAc in heptane) to yield 4-biphenyl-4-ylmethyl-1-[2-(S)-tert-butoxycarbonylamino-3-thiophen-2-yl-propionyl]-piperidine-4-carboxylic acid methyl ester after evaporation. MS (ESI) m/z 565.36 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:9]([C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[CH:22]1([CH2:25][NH2:26])[CH2:24][CH2:23]1.O>CN1CCCC1=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:26][CH2:25][CH:22]3[CH2:24][CH2:23]3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: NCC1CC1
Reactant: Nc1ccc(OS(=O)(=O)c2ccc(F)cc2)cc1[N+](=O)[O-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1ccc(OS(=O)(=O)c2ccc(NCC3CC3)cc2)cc1[N+](=O)[O-]

Procedure:
A solution of 4-fluoro-benzenesulfonic acid 4-amino-3-nitro-phenyl ester (800 mg) and cyclopropylmethylamine (890 μl) in N-methylpyrrolidinone (8 ml) was heated at 110° C. in a sealed tube for 14 hours. The reaction mixture was then poured into water (150 ml) and extracted three times with ethyl acetate (40 ml). The combined extracts were dried over magnesium sulfate and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and heptane (50:50, v/v) to give 4-(cyclopropylmethyl-amino)-benzenesulfonic acid 4-amino-3-nitro-phenyl ester (786 mg) as a yellow solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([CH3:29])[CH2:7][CH:8]([NH:25][C:26](=[O:28])[CH3:27])[C:9]1[S:10][C:11]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([O:4][CH2:5][C@H:6]([CH3:29])[CH2:7][CH:8]([NH:25][C:26](=[O:28])[CH3:27])[C:9]1[S:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC(C[C@@H](C)COC(C)=O)c1ccc(C#CCCCc2ccccc2)s1
Agent: [Pd]
Solvent: CO
Product: CC(=O)NC(C[C@@H](C)COC(C)=O)c1ccc(CCCCCc2ccccc2)s1
Reaction time: 16 h
Yield: 93.3 %

Procedure:
(2R)-Acetylamino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butyl acetate (337 mg, 0.82 mmol) obtained in Example 49(a) was dissolved in methanol (17 ml), and 10% palladium-charcoal (170 mg) was added thereto followed by stirring for 16 hours under a hydrogen atmosphere. After the catalyst was filtered out through Celite, the filtrate was evaporated to dryness under reduced pressure to give (2R)-acetylamino-2-methyl-4-[5-(5-phenylpentyl)thiophen-2-yl]butyl acetate (318 mg, 93% yield). The obtained (2R)-acetylamino-2-methyl-4-[5-(5-phenylpentyl)thiophen-2-yl]butyl acetate (298 mg, 0.72 mmol) was dissolved in 6 ml of a mixture solvent (tetrahydrofuran:methanol:water=1:1:1), and lithium hydroxide monohydrate (301 mg, 7.17 mmol) was added thereto followed by stirring for 6 hours at 50° C. The reaction solution was poured into water, extracted with ethyl acetate, and after the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was evaporated in vacuo. The residue (243 mg) was dissolved in methanol, and oxalic acid (65 mg, 0.72 mmol) was added thereto to precipitate crystals. The crystals were filtered off to afford the title compound (251 mg, 83% yield) as white crystals.
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5](=[O:12])[NH:4][C:3]=1[CH3:13].[CH3:14]I>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+].[Ag+]>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([O:12][CH3:14])=[N:4][C:3]=1[CH3:13]
Reactant: Cc1[nH]c(=O)c2c(c1Br)CCCC2
Reactant: CI
Agent: [Ag+]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: COc1nc(C)c(Br)c2c1CCCC2
Temperature: 50 °C
Reaction time: 3 h
Yield: 82.8 %

Procedure:
8.9 g (36.8 mmol) of 4-bromo-3-methyl-5,6,7,8-tetrahydro-2H-isoquinolin-1-one are dissolved in 200 ml of chloroform and, after addition of 13.7 g (49.6 mmol) of silver(I) carbonate and 16.2 ml (36.5 g, 257 mmol) of methyl iodide, stirred at 50° C. for 3 h. After a further 24 h at RT, the suspension is filtered through Celite, concentrated and chromatographed on silica gel using n-heptane with addition of 2% ethyl acetate. A colorless oil (7.8 g, 83% yield) is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CC(C)([O-])C.[Na+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>O>[N:12]1([C:2]2[CH:3]=[N:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: Brc1cncc2cccnc12
Reactant: C1CNCCN1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Product: c1cnc2c(N3CCNCC3)cncc2c1
Temperature: 120 °C
Yield: 35.4 %

Procedure:
To an oven-dried 100 mL flask under a nitrogen atmosphere was added 8-bromo-[1,6]-naphthyridine (1.3 g, 6.2 mmol), piperazine (3.21 g, 37.3 mmol), and sodium t-butoxide (900 mg, 9.33 mmol). The solids were suspended in anhydrous o-xylenes (40 mL), and Pd(dba) (285 mg, 5 mol %) and P(t-Bu)3 (0.31 mL, 1.24 mmol) were added. The reaction mixture was heated at 120° C. for 3 hours. The cooled reaction mixture was poured into H2O (100 mL) and extracted into EtOAc (1×100 mL) and CH2Cl2 (2×100 mL). The organic fractions were combined, dried over Na2SO4, concentrated, and the resulting oil was chromatographed (10% MeOH/CH2Cl2+NH4OH) affording 470 mg (35%) of the title compound as a dark gold oil. An analytical sample was prepared as the HCl salt from EtOAc giving a brown solid: mp decomposes above 200° C. MS (+) APCI m/z 215 [M+H]+.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]=[CH:20][S:21][C:14]=12.O>CS(C)=O>[F:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]=[CH:20][S:21][C:14]=12)[NH2:3]
Reactant: Nc1ccc(O)c(F)c1
Reactant: Clc1ccnc2ccsc12
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 67.6 %

Procedure:
To a stirred suspension of NaH (0.432 g, 18.0 mmol) in DMSO (30 mL) was carefully added 4-amino-2-fluorophenol (1.91 g, 15.0 mmol) in portions. The reaction was stirred under N2 for 15 minutes. 7-Chlorothieno[3,2-b]pyridine (2.54 g, 15.0 mmol) was added as a solid. The reaction was heated to 100° C. for 2 hours. The reaction was allowed to cool to room temperature, and water (40 mL) was carefully added. The suspension was filtered. The brown solid was washed with water (2×10 mL), and dried by toluene azeotrope (5×20 mL) by rotary evaporation at 50° C. The solid was recrystallized from hot toluene (10 mL) to obtain a brown, crystalline solid (2.64 g, 68%). 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J=6 Hz, 1H), 7.73 (d, J=6 Hz, 1H), 7.56 (d, J=6 Hz, 1H), 7.04 (t, J=9 Hz, 1H), 6.51 (m, 3H), 3.83 (br s, 2H). LRMS (APCI pos) m/e 261 (M+1).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:6]=[CH:5][CH:4]=1.[C:15]([N:18]1[CH2:22][C:21](=O)[N:20]=[CH:19]1)(=[O:17])[CH3:16]>>[C:15]([N:18]1[CH2:22][CH2:21][N:20]=[C:19]1[NH:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:6]=[CH:5][CH:4]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)N1C=NC(=O)C1
Reactant: Nc1ccnn1-c1ccccc1Cl
Agent: Cl
Product: CC(=O)N1CCN=C1Nc1ccnn1-c1ccccc1Cl

Procedure:
5-Amino-1(2-chlorophenyl) pyrazole hydrochloride (Farmaco, 22, 68, 1967) (20.5 g.) and 1-acetyl-2-imidazolinone (12.6 g.) were reacted as described in Example I to give 17.11 g. product mp 179°-181° (crystallized from CH3CN)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1I)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:19]1[CH:20]=[CH:21][C:16]([Br:15])=[CH:17][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccsc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)Nc1ccsc1-c1ccc(Br)cc1
Yield: 5.9 %

Procedure:
Heat (tert-Butoxy)-N-(2-iodo(3-thiophenyl))carboxamide (16.88 g, 0.52 mol), 4-bromophenylboronic acid (15.65 g, 0.78 mol), Na2CO3 (1.01 g, 1.04 mol) and Pd(PPh3)4 (5.79 g, 0.052 mol) in 375 ml of an anhydrous and deoxygenated 2:1 DME/EtOH mixture to 80° C. under nitrogen atmosphere for 24 h. Evaporate the organic solvents prior to the addition of water (200 mL). Extract the mixture with methylene chloride (3×150 mL) and combine the organic phases, dry (anh MgSO4), filter, and concentrate to furnish a crude mixture as a yellowish solid. Purification by flash chromatography (Silica gel-Hexane/EtOAc 49:1) yields 10.8 g (60%) of (tert-butoxy)-N-[2-(4-bromophenyl)(3-thiophenyl)]carboxamide as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([CH:16]([F:18])[F:17])=[CH:14][NH:13][C:12](=[O:19])[CH:11]=2)[CH:3]=1.Br[CH:21]([CH3:25])[C:22]([OH:24])=[O:23]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([CH:16]([F:17])[F:18])=[CH:14][N:13]([CH:21]([CH3:25])[C:22]([OH:24])=[O:23])[C:12](=[O:19])[CH:11]=2)[CH:3]=1
Reactant: CC(Br)C(=O)O
Reactant: N#Cc1ccc(Cl)cc1-c1cc(=O)[nH]cc1C(F)F
Product: CC(C(=O)O)n1cc(C(F)F)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
215 mg (purity 64%, 0.5 mmol) of 4-chloro-2-[5-(difluoromethyl)-2-oxo-1,2-dihydropyridin-4-yl]benzonitrile and 1.5 eq. of 2-bromopropanoic acid (racemate) were reacted according to General Method 4A at 50° C. Yield: 256 mg of crude product (purity 64%, 95% of theory)