Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[C:14]([N+:22]([O-])=O)[CH:13]=2)[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]>C(O)C.[Pd]>[NH2:22][C:14]1[CH:13]=[C:12]([C:4]2[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH:19]([CH3:21])[CH3:20]
Reactant: CCOC(=O)c1sc(-c2ccc(OC(C)C)c([N+](=O)[O-])c2)nc1C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(OC(C)C)c(N)c2)nc1C
Temperature: 50 °C
Reaction time: 14 h
Yield: 99.8 %

Procedure:
A reaction mixture solution prepared by suspending 1.38 g of ethyl 4-methyl-2-[3-nitro-4-(propan-2-yloxy)phenyl]-1,3-thiazole-5-carboxylate in 15 mL of ethanol and adding 100 mg of palladium/carbon (10 wt %) to the suspension was heated under stirring at 50° C. for 14 hours under a hydrogen atmosphere. The reaction mixture solution was celite-filtered and the filtrate was concentrated under reduced pressure to obtain 1.26 g of ethyl 2-[3-amino-4-(propan-2-yloxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylate.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][NH:8][C:9]2[C:10]([CH3:16])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])C(=O)C2=CC=CC=C12.NC1C(C)=NN(C)C=1C.BrCCN1C(=O)C2=CC=CC=C2C1=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:10]([CH3:16])=[N:11][N:12]([CH3:15])[C:13]=1[CH3:14]
Reactant: Cc1nn(C)c(C)c1NCCN1C(=O)c2ccccc2C1=O
Agent: Cc1nn(C)c(C)c1N
Agent: O=C([O-])[O-]
Agent: O=C1c2ccccc2C(=O)N1CCBr
Solvent: CC#N
Product: Cc1nn(C)c(C)c1NCCN

Procedure:
The 4-(2-phthalimidoethylamino)-1,3,5-trimethylpyrazole used as starting material is obtained in good yield by reacting 4-amino-1,3,5-trimethylpyrazole with N-(2-bromoethyl)-phthalimide in acetonitrile in the presence of potassium carbonate for 16 hours under reflux. It is obtained in the form of yellowish crystals which melt at 122°-123° C., after recrystallization from ethanol.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CO[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[O:24][CH2:25][C:26]([CH3:29])([CH3:28])[N:27]=1>O1CCCC1>[CH2:1]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[O:24][CH2:25][C:26]([CH3:29])([CH3:28])[N:27]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC[Mg]Br
Reactant: COc1ccccc1C1=NC(C)(C)CO1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1ccccc1C1=NC(C)(C)CO1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To freshly prepared dodecylmagnesium bromide (from 30.13 mmoles of dodecyl bromide and 26.20 mmoles of magnesium) in distilled tetrahydrofuran (50 ml) was added 2-(2-methoxyphenyl)-4,4-dimethyloxazoline [A. I. Meyers et al., J. Org Chem., 43, 1372 (1978)] (17.88 mmoles) in tetrahydrofuran (30 ml). The resultant yellow solution was stirred under argon at ambient temperature for 20 hours. The solution was cooled in an ice water bath and quenched with aqueous ammonium chloride (100 ml). The reaction product was extracted into diethyl ether (100 ml) and the organic phase was washed with saturated sodium chloride solution (50 ml) and then dried over anhydrous magnesium sulfate. Evaporation of the organic phase afforded a colorless oil which was purified by flash chromatography over silica gel with 5 percent ethyl acetate in hexane as eluant to afford the desired product as a pale yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:7]([CH2:8][OH:9])[O:6][N:5]=[C:4]1[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[O:16]COC>C(Cl)Cl.FC(F)(F)C(O)=O>[OH:1][CH2:2][CH:3]1[CH:7]([CH2:8][OH:9])[O:6][N:5]=[C:4]1[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[OH:16]
Reactant: COCOc1cnccc1C1=NOC(CO)C1CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OCC1ON=C(c2ccncc2O)C1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 150.4 %

Procedure:
To a solution of intermediate compound 12 (3.8 g, 0.0142 mol) in 100 ml of DCM, 25 ml of triflouroacetic acid were added portionwise at room temperature. The reaction was stirred overnight at room temperature. The solvent was evaporated and the residue was co-evaporated with ethanol. Yielding 4.79 g (100, crude product) of 4-(4,5-bis-hydroxymethyl-4,5-dihydro-isoxazol-3-yl)-pyridin-3-ol (intermediate compound 13).
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+:9](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:66]([OH:68])=O)[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]3[C:53]4[C:48](=[CH:49][N:50]=[C:51]([C:54]5[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=5)[CH:52]=4)[N:47]([CH:60]4[CH2:65][CH2:64][CH2:63][CH2:62][O:61]4)[N:46]=3)[N:40]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[Cl-].[NH4+].C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:66]([C:33]1([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:26])([CH3:27])[CH3:28])[CH2:34][CH2:35][N:36]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]3[C:53]4[C:48](=[CH:49][N:50]=[C:51]([C:54]5[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=5)[CH:52]=4)[N:47]([CH:60]4[CH2:65][CH2:64][CH2:63][CH2:62][O:61]4)[N:46]=3)[N:40]=2)[CH2:37][CH2:38]1)(=[O:68])[NH2:9]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(-c5cccnc5)cc34)n2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(N)=O)CCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(-c5cccnc5)cc34)n2)CC1
Reaction time: 18 h

Procedure:
N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate 45.6 mg, 0.120 mmol) was added to a mixture of 4-(tert-butoxycarbonylamino)-1-(6-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidine-4-carboxylic acid (60.0 mg, 0.100 mmol), ammonium chloride 21 mg (0.40 mmol) and N,N-Diisopropylethylamine (0.087 ml, 0.50 mmol) in 2 ml of N,N-dimethylformamide. The mixture was stirred for 18 hours and concentrated. The residue was partitioned between ethyl acetate and 1% of aqueous citric acid. The organic extracts were washed with water, 5% aqueous solution of NaHCO3, brine, dried over MgSO4 and concentrated to give tert-Butyl 4-carbamoyl-1-(6-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-4-ylcarbamate. Yield 47 mg (78%). ESI MS m/z 599.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=[CH:5][CH:4]=1.C(Cl)(=O)C(C)(C)C.Cl.[N:40]1([CH:45]2[CH2:48][NH:47][CH2:46]2)[CH:44]=[N:43][CH:42]=[N:41]1.N1C=NC=N1.C(N(C(C)C)CC)(C)C>O1CCCC1.C(#N)C.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([N:47]3[CH2:48][CH:45]([N:40]4[CH:44]=[N:43][CH:42]=[N:41]4)[CH2:46]3)=[O:29])[CH2:10]2)=[CH:30][CH:31]=1
Reactant: c1ncn(C2CNC2)n1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Agent: c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC(n4cncn4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 62.2 %

Procedure:
1.13 g of (2S, 4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid were dissolved in 11 ml of dry tetrahydrofuran, and the resulting solution was cooled to 0° C. 280 mg of triethylamine were added to the solution, followed by 320 mg of pivaloyl chloride, and the mixture was stirred at the same temperature for 5 minutes. At the end of this time, a mixture of 1.36 g of 3-(1-1,2,4-triazolyl)azetidine hydrochloride [prepared by a procedure similar to that described in Preparation 122(a) and (b), but using 1,2,4-triazole], 956 mg of diisopropylethylamine and 6 ml of dry acetonitrile was added to the mixture, after which the mixture was stirred at 0° C. for 30 minutes and at room temperature for 30 minutes. The reaction mixture was then filtered, and the solvent was removed by evaporation under reduced pressure. The resulting residue was diluted with ethyl acetate, and the diluted solution as washed with an aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography, using a 10:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 870 mg of the title compound, as a powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[CH:11]([CH2:17][CH2:18][CH2:19][CH2:20]C)[CH2:12][C:13]([O:15][CH3:16])=[O:14].C(OC1C=CC(C(CCCC)CC(O)=O)=C(OC)C=1)C1C=CC=CC=1>>[OH:9][C:7]1[CH:6]=[CH:5][C:4]([CH:11]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CCCCCC(CC(=O)OC)c1ccc(OC)cc1OC
Agent: CCCCC(CC(=O)O)c1ccc(OCc2ccccc2)cc1OC
Product: CCCCC(CC(=O)OC)c1ccc(O)cc1OC

Procedure:
Following a similar procedure to that described in Preparation 32(i), but using 3-(4-benzyloxy-2-methoxyphenyl)heptanoic acid prepared as described in Preparation 30G), the corresponding methyl ester derivative was obtained. Hydrogenolysis of this derivative and subsequent treatment of the reaction mixture were conducted in a similar manner to that described in Example 124 to give the title compound as an oily substance.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]([CH3:16])([C:10]1[NH:14][C:13](=[O:15])[O:12][N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].CO.[C:20]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]([CH3:9])([C:10]1[N:14]([CH3:20])[C:13](=[O:15])[O:12][N:11]=1)[CH3:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1noc(=O)[nH]1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(C(C)(C)NC(=O)OC(C)(C)C)noc1=O
Temperature: 2.5 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
To a colorless solution of [1-methyl-1-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-ethyl]-carbamic acid tert-butyl ester (1.5 g, 6.17 mmol) in THF (30.0 mL) was added methanol (296 mg, 374 μl, 9.25 mmol) and triphenylphosphine (1.94 g, 7.4 mmol). The mixture was cooled to 0-5° C. and diisopropyl azodicarboxylate (1.5 g, 1.46 ml, 7.4 mmol) was added slowly over a period of 20 minutes at max: 5° C. The mixture was stirred for another 30 minutes at 0-5° C. and for 16 hours at room temperature. Solvents were removed in vacuo and the residue was purified by flash chromatography (silica gel, 70 g, 0% to 100% ethyl acetate in heptane) to give the title compound (1.4 g, 89%) as white solid; GC-MS (EI) 98%, 257.0 (M)+.
Reaction SMILES: C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[Al].[C:21]([O:33][CH2:34][CH2:35][CH2:36][CH:37]=[CH2:38])(=[O:32])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]C=C.ClC(Cl)C(OC)=O>C1(C)C=CC=CC=1>[C:21]1(=[O:32])[O:33][CH2:34][CH2:35][CH2:36][CH:37]=[CH:38][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C=CCCCCCCCCC(=O)OCCCC=C
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: COC(=O)C(Cl)Cl
Agent: [Al]
Solvent: Cc1ccccc1
Product: O=C1CCCCCCCCC=CCCCO1
Temperature: 80 °C
Reaction time: 16 h
Yield: 40.1 %

Procedure:
0.05 g of tricyclohexylphosphine, 0.06 g (0.1 mmol) of di-μ-chlorobis((p-cymene)chlororuthenium), 10 ml of toluene, 0.05 g (1.85 mmol) of an aluminum powder, 0.252 g (1 mmol) of 4-pentenyl 10-undecenoate and 0.021 ml (0.2 mmol) of methyl dichloroacetate were blended and the mixture was stirred at 80° C. for 16 hours in a nitrogen stream. A solvent was distilled and the residue was refined by silica gel column chromatography (toluene/ethyl acetate=10/1) to obtain 0.09 g of an object material (yield: 40%). The result of 1H-NMR of the above reaction solution is as follows:
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:10]([C:11](=[O:20])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][N:8]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:7]1)=[O:5])C>O1CCOCC1.O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:11]([C@H:10]2[CH2:9][N:8]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:7][C@@H:6]2[C:4]([OH:5])=[O:3])=[O:20])=[CH:14][CH:15]=1
Reactant: CCOC(=O)[C@H]1CN(S(C)(=O)=O)C[C@@H]1C(=O)Nc1ccc(Cl)cc1
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)N1C[C@H](C(=O)O)[C@@H](C(=O)Nc2ccc(Cl)cc2)C1
Temperature: 25 °C

Procedure:
Compound 39d (0.9 g; 2.4 mmol) is dissolved in a mixture of 1,4-dioxane/water (1:1; 15 ml). LiOH monohydrate (0.302 g; 7.2 mmol) is added as a solid and the mixture is stirred for 18 at 25° C. The mixture is evaporated to dryness and dissolved in ethyl acetate and the product is extracted with saturated aqueous Na2CO3 solution. The aqueous phase is cooled to 10° C. and acidified with 25% aqueous HCl solution until pH=1. The product is extracted several times with ethylacetate (3×100 ml). The combined organic phases are washed with brine and dried over Na2SO4. After filtration the organic phase is evaporated to dryness. Yield: 0.7 g (84.1%), ESI-MS: m/z=345 [M−H]−, Cl-pattern
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[CH2:4][CH2:3]1.[Cl-].[NH4+].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=2)[C:25]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:24][N:23]=1.[OH-].[Na+]>C(O)CCC.O>[CH3:33][O:32][C:29]1[CH:30]=[C:31]2[C:26]([C:25]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[N:24][N:23]=[C:22]2[NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][C:9]3[CH:18]=[CH:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH:10]=3)[CH2:6][CH2:7]2)=[CH:27][CH:28]=1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Reactant: COc1ccc2c(-c3ccccc3)nnc(Cl)c2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Product: COc1ccc2c(-c3ccccc3)nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c2c1
Temperature: 135 °C
Yield: 44.6 %

Procedure:
373 mg (1.5 mmol) of 4-amino-1-(naphthalen-2-ylmethyl)piperidine and 69 mg (1.3 mmol) of ammonium chloride are added to a suspension of 350 mg (1.3 mmol) of 4-chloro-6-methoxy-1-phenylphthalazine in 6 mL of n-butanol. The mixture is heated at 135° C. for 20 hours. The reaction medium is cooled to room temperature, hydrolysed with 50 mL of water and then basified to pH 10 with 1 N sodium hydroxide solution. The mixture is then extracted with ethyl acetate. The organic phase is washed with brine, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel (solvent: 95/5 (v/v) dichloromethane/methanol). The yellow oil thus obtained forms a solid by trituration in isopropyl ether. After filtering and drying, 275 mg of product are obtained in the form of a beige-coloured powder.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)O1.Br[C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[N:24][CH:25]=1>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>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)=[CH:25][N:24]=1
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])cc2)OC1(C)C
Reactant: COc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(-c2ccc([N+](=O)[O-])cc2)cn1

Procedure:
The title compound was prepared from 4,4,5,5-tetramethyl-2-(4-nitro-phenyl)-[1,3,2]dioxaborolane (899 mg, 3.60 mmol), 5-bromo-2-methoxy-pyridine (616 mg, 3.28 mmol) and Pd(PPh3)4 (380 mg, 0.360 mmol) according to the procedure in Example 44, step (b) (615 mg, 94%). Mass spectrum (ESI, m/z): Calcd. for C12H10N2O3, 231.0 (M+H), found 231.2.
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:17]([CH3:19])[N:18]=2)[CH:12]=[C:13]([CH3:15])[CH:14]=1)C1C=CC=CC=1>ClCCl.C(O)C.[Pd]>[OH:8][C:9]1[C:10]2[N:11]([C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:17]([CH3:19])[N:18]=2)[CH:12]=[C:13]([CH3:15])[CH:14]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3ccccc3)cc(C)cn12
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1c(C)nc2c(O)cc(C)cn12
Reaction time: 8 h

Procedure:
74 g (228 mmol) of ethyl 8-(benzyloxy)-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate Example 16A were initially charged in 1254 ml of dichloromethane and 251 ml of ethanol, and 20.1 g 10% palladium on activated carbon (moistened with water 50%) were added under argon. The reaction mixture was hydrogenated overnight at RT and atmospheric pressure. The reaction mixture was filtered off through kieselguhr and concentrated. The crude product was purified by silica gel chromatography (dichloromethane:methanol=95:5). This gave 50.4 g (94% of theory) of the target compound.
Reaction SMILES: [Na+].[C:2]([S:5][CH2:6][CH:7]([CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]([NH:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([O-:16])=[O:15])=[O:9])(=[O:4])[CH3:3].Cl>O>[C:2]([S:5][CH2:6][CH:7]([CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:8]([NH:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=[O:15])=[O:9])(=[O:4])[CH3:3]
Reactant: CC(=O)SCC(CCCc1ccccc1)C(=O)Nc1cccc(C(=O)[O-])c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(=O)SCC(CCCc1ccccc1)C(=O)Nc1cccc(C(=O)O)c1
Yield: 77.5 %

Procedure:
3-[(2-Acetylthiomethyl-5-phenylpentanoyl)amino]benzoic acid sodium salt (compound of Example 38) (1.5 g) is dissolved in water (30 ml), and the mixture is adjusted to pH 2.5 with 10% hydrochloric acid under ice cooling, and the mixture is extracted with ethyl acetate (50 ml). The extract is washed with water and dried over anhydrous magnesium sulfate, and then ethyl acetate is distilled off to give the title compound (1.1 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[CH3:15])=[O:7].[H-].[Na+].C(OC(=O)C)C>CN(C=O)C.C1COCC1>[CH3:15][C:14]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:8]1[CH2:2][CH2:3][CH2:4][NH:5][C:6]1=[O:7]
Reactant: Cc1ccncc1NC(=O)NCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccncc1N1CCCNC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
1-(3-Chloro-propyl)-3-(4-methyl-pyridin-3-yl)-urea (I-130a: 2 g, 9.25 mmol) in dry DMF (15 mL) was added to a stirred mixture of sodium hydride (330 mg, 13.87 mmol) in THF (30 mL) at 0° C. The reaction was stirred at room temperature for 1 hour. The reaction was monitored by TLC (100% ethylacetate). The reaction mixture was quenched with MeOH at 0° C., concentrated under reduced pressure and partitioned between ice water and chloroform. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated under reduced pressure to afford 1.7 g (96.5% yield) of 1-(4-methyl-pyridin-3-yl)-tetrahydro-pyrimidin-2-one.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:17])([F:16])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]([NH2:15])[CH3:14])=[N:11][CH:12]=1.[Br:18][C:19]1[CH:29]=[CH:28][C:22]([O:23][CH2:24][C:25](O)=[O:26])=[CH:21][CH:20]=1.C(N(CC)CC)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.N>ClCCl>[Br:18][C:19]1[CH:29]=[CH:28][C:22]([O:23][CH2:24][C:25]([NH:15][C@@H:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]([F:3])([F:16])[F:17])=[CH:12][N:11]=2)[CH3:14])=[O:26])=[CH:21][CH:20]=1
Reactant: C[C@@H](N)c1ccc(OCC(F)(F)F)cn1
Reactant: O=C(O)COc1ccc(Br)cc1
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)COc1ccc(Br)cc1)c1ccc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
To a suspension of (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine 2HCl salt (173 mg, 0.79 mmol) and 2-(4-bromophenoxy)acetic acid (200 mg, 0.87 mmol) in dichloromethane (5 mL) were added triethylamine (400 mg, 3.9 mmol), EDC (180 mg, 0.94 mmol) and HOBT (60 mg, 0.39 mmol) respectively. The reaction mixture was stirred at room temperature for 18 hours. Sat. ammonia hydrochloride aqueous solution was added to the mixture. The organic layer was extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After the filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give the residue, which was applied to a silica gel chromatography column and eluted with a hexane/ethylacetate=2/1 (v/v) to furnish 276 mg (81% yield) of the title as a colorless oil;
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1.[S:12]1(=[O:18])(=[O:17])[CH2:16][CH2:15][CH2:14][NH:13]1.[H-].[Na+].O>CN(C)C=O>[O:17]=[S:12]1(=[O:18])[CH2:16][CH2:15][CH2:14][N:13]1[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1
Reactant: COC(=O)c1cnc(Cl)nc1
Reactant: O=S1(=O)CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(N2CCCS2(=O)=O)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.7 %

Procedure:
Methyl 2-chloropyrimidine-5-carboxylate (173 mg) and isothiazolidine 1,1-dioxide (145 mg) were dissolved in N,N-dimethylformamide (1 mL), and sodium hydride (48 mg, 60% in oil) was added under ice-cooling. After stirring at room temperature for 6 hr, water was added, and the mixture was extracted with ethyl acetate. The solvent was evaporated, diisopropyl ether and ethyl acetate were added, and the precipitated solid was collected by filtration to give the title compound (185 mg).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].Cl[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][N:15]=2)[N:10]=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18].O>ClCCl>[CH3:3][CH:2]([CH3:4])[CH2:1][NH:5][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][N:15]=2)[N:10]=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Reactant: CC(C)CN
Solvent: ClCCl
Solvent: O
Product: CC(C)CNc1c([N+](=O)[O-])cnc2cccnc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
Isobutylamine (15.6 mL, 157 mmol) was added dropwise to a 5° C. solution of 4-chloro-3-nitro[1,5]naphthyridine (15.0 g, 71.6 mmol) in dichloromethane (300 mL). The reaction was allowed to stir at room temperature for 4 hours, then was concentrated under reduced pressure to afford a residue that was treated with water (300 mL). The mixture was stirred for 30 minutes, then a solid was isolated by filtration, rinsed with water (100 mL), and dried in a vacuum oven at 50° C. overnight to afford 17.25 g of N-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine as a yellow solid.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([CH:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([C:24](=[O:35])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=4)[CH:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]O)[CH2:15]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:42]([SH:48])[CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>>[CH3:34][O:33][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[O:31][CH3:32])[C:24]([N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]([N:12]2[C:13]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:15][CH:16]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][S:48][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:35]
Reactant: CCCCCCS
Reactant: COc1ccc(C(=O)N2c3ccccc3C(n3c4ccccc4c4ccccc43)CC2CCCCCO)cc1OC
Product: CCCCCCSCCCCCC1CC(n2c3ccccc3c3ccccc32)c2ccccc2N1C(=O)c1ccc(OC)c(OC)c1
Yield: 7 %

Procedure:
Starting with 5-[4-(9H-9-carbazolyl)-1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-2-quinolinyl]-1-pentanol (0.08 g, 0.15 mmol) prepared in Example 135 and n-hexylmercaptan (0.3 ml), the same procedure as shown in Example 136 was repeated to give the titled compound (0.01 g, yield: 7%) as a white crystal (cis:trans=6:1).