Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([Cl:27])=[C:4]([N:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[Cl-].[Li+].C([Mg+])(C)C.[Cl-].[O:35]=[C:36]1[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37]1>C1COCC1>[C:13]([O:12][C:11]([N:10]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:4]1[C:3]([Cl:27])=[C:2]([C:36]2([OH:35])[CH2:37][N:38]([C:40]([O:42][C:43]([CH3:45])([CH3:44])[CH3:46])=[O:41])[CH2:39]2)[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=1)=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2cc(C#N)cc(Br)c2Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(C)[Mg+]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2cc(C#N)cc(C3(O)CN(C(=O)OC(C)(C)C)C3)c2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (3-bromo-2-chloro-5-cyanophenyl)(4-methoxybenzyl)carbamate (Intermediate (500 mg, 1.107 mmol) in THF (2.5 ml) at 0° C. was added drop wise isopropylmagnesium lithium chloride (1.3 M in THF) (0.937 mL, 1.218 mmol) under nitrogen. After stirring at 0° C. for 30 min, removal of the cooling bath and stirred at room temperature for 30 min. The reaction mixture was cooled to −14° C. (NaCl-ice bath), to this was added drop wise a solution of tert-butyl 3-oxoazetidine-1-carboxylate (208 mg, 1.218 mmol) in THF (2 mL), and left stirring in the cooling bath for 2 h, during this time the temperature rose to −4° C. The reaction was quenched with sat, aqueous NH4Cl solution (5 ml), and diluted with EtOAc, washed with water, brine, and dried over Na2SO4. Solvent was removed. The crude residue was purified by ISCO (12 g) column chromatography, eluting with hexane containing 0 to 40% EtOAc to afford tert-butyl 3-(3-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-2-chloro-5-cyanophenyl)-3-hydroxyazetidine-1-carboxylate (408 mg).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C@H:2]([CH3:4])[OH:3].[CH:7](=O)[C:8]([CH3:11])([CH3:10])[CH3:9].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>OS(O)(=O)=O.CCCCC>[C:8]([C@@H:11]1[O:5][C:1](=[O:6])[C@H:2]([CH3:4])[O:3]1)([CH3:10])([CH3:9])[CH3:7]
Reactant: CC(C)(C)C=O
Reactant: C[C@H](O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCCCC
Product: C[C@@H]1O[C@H](C(C)(C)C)OC1=O
Temperature: -80 °C

Procedure:
A mixture of L-Lactic acid (106 g of 85% in H2O), pivalaldehyde (220 mL), p-toluene sulfonic acid mono hydrate (2.0 g) and H2SO4 conc. (8 drops) in pentane (800 mL) was refluxed with azeotropic removal of the water formed using a Dean-Stark trap. The supernatant was decanted, washed with water, dried over MgSO4 and concentrated. The resulting residue was dissolved in hexane (800 mL) and cooled to -80° C. for 20 h. Crystals were collected by filtration in a cold room (5° C.) and washed with cold hexane (-78° C.). The crystals were dissolved in Et2O, dried over MgSO4 and concentred to give the title compound as a colorless oil. 1H NMR(CD3COCD3): δ0.95 (9H, s), 1.38 (3H,d), 4.47 (1H, m), 5.24 (1H, s).
Reaction SMILES: [CH2:1]([C:3]1[C:11]([C:12]([O:14]CC)=[O:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].[OH-].[Na+].Cl>CO.O>[CH2:1]([C:3]1[C:11]([C:12]([OH:14])=[O:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: CCOC(=O)c1c(CC)nn2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1nn2ccccc2c1C(=O)O
Temperature: 60 °C
Yield: 93.7 %

Procedure:
Ethyl 2-ethylpyrazolo[1,5-a]pyridine-3-carboxylate (5.0 g, 23 mmol) was stirred in methanol (200 mL) and a solution of sodium hydroxide in water (100 mL, 3 N) was added. The mixture was heated at 60° C. for 16 h. Evaporation gave a thick suspension which was treated with aqueous hydrogen chloride (100 mL, 3 N). The solids briefly dissolved and a new precipitate formed. The solid was filtered and washed with water to give the desired compound (4.1 g, 96%). LCMS for C10H11N2O2 (M+H)+: m/z=191.1. 1H NMR (300 MHz, DMSO-d6): δ 8.52 (m, 1H), 8.15 (m, 1H), 7.23 (m, 1H), 6.81 (m, 1H), 3.05 (m, 2H), 1.22 (m, 3H).
Reaction SMILES: [NH2:1][C@H:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C@@H:3]([NH:5]C(OC(C)(C)C)=O)[CH3:4].[ClH:28]>O1CCOCC1>[ClH:28].[ClH:28].[NH2:5][C@H:3]([C@H:2]([NH2:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:4]
Reactant: CCCCCCCCCCCCCCC[C@@H](N)[C@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCC[C@@H](N)[C@H](C)N
Temperature: 25 °C
Reaction time: 5 h
Yield: 56 %

Procedure:
To a solution of N-Boc derivative 96 (22 mg, 0.057 mmol) in dioxane (0.4 mL), anhydrous HCl solution in dioxane (5.3M, 0.43 mL, 2.29 mmol) was added. After stirring at room temperature for 5 h, the solvent was removed in vacuo. The resulting solid was washed with dioxane to obtain dihydrochloride 97 as a white solid (11.5 mg, 56% yield).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([C:22]([OH:24])=O)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][NH2:33])[CH2:27][CH2:26]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([C:22]([NH:33][CH2:32][CH2:31][N:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: NCCN1CCOCC1
Reactant: CC(C)(C)n1ncc(-c2nc(C(=O)O)cs2)c1-c1ccc(F)cc1
Product: CC(C)(C)n1ncc(-c2nc(C(=O)NCCN3CCOCC3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazole-4-carboxylic acid and 2-morpholinoethanamine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [C:1]([OH:14])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.[CH2:15](O)[CH3:16].Cl>CCCCCC.C(OCC)(=O)C>[C:1]([O:14][CH2:15][CH3:16])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Reactant: CCO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)/C=C/c1ccc(O)c(OC)c1
Yield: 85.3 %

Procedure:
Ferulic acid (4.85 g) and then ethyl alcohol (50 ml) containing hydrogen chloride (4%) were placed in an egg-plant type flask (200 ml), and heated under reflux for 2.5 hours. The disappearance of the starting material was confirmed by TLC (n-hexane/ethyl acetate=2/1), then the solvent was evaporated under reduced pressure by a rotary evaporator. Benzene was added to the residue, and then, the solvent was again evaporated by a rotary evaporator to obtain the wine-colored crude product (5.79 g). The resulting crude product was separated and purified by silica gel column chromatography (diameter=5.5×7.0 cm; 60 g; n-hexane/ethyl acetate=3/1) to obtain the above-identified compound (5.06 g; 91.2%). The product was crystallized from n-hexane to obtain a white crystal (4.743 g, 85.3%). Melting point: 41°-43° C.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][CH2:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=[O:6].Cl.[OH:24][NH2:25].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:20][C:19](=[N:25][OH:24])[C:17]1[CH:16]=[CH:15][N:14]=[C:13]([N:10]2[CH2:9][CH2:8][N:7]([C:5](=[O:6])[CH2:4][CH2:3][C:2]([CH3:22])([CH3:21])[CH3:1])[CH2:12][CH2:11]2)[N:18]=1
Reactant: CC(C)(C)CCC(=O)N1CCN(c2nccc(C#N)n2)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)CCC(=O)N1CCN(c2nccc(C(N)=NO)n2)CC1
Yield: 79.4 %

Procedure:
1-(4,4-Dimethylpentanoyl)-4-(4-cyanopyrimidin-2-yl)piperazine (540 mg) obtained in Example 54 was dissolved in ethanol (5 mL), and hydroxyamine hydrochloride (386 mg) and potassium carbonate (995 mg) were added thereto and heated under reflux for 2 hours. Then, the solvent was evaporated away, and the resulting residue was diluted with ethyl acetate, washed with water and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away to obtain 476 mg of the entitled compound.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[NH2:16][CH:17]([CH3:20])[CH2:18][OH:19].O>CO>[OH:19][CH2:18][CH:17]([NH:16][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:9])[CH3:20]
Reactant: CC(N)CO
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Solvent: CO
Solvent: O
Product: CC(CO)NC(c1ccccc1)C(O)c1ccccc1
Yield: 79 %

Procedure:
A mixture of trans-stilbene oxide (3.93 g, 0.020 mole) and 2-amino-1-propanol (4.51 g, 0.060 mole) was heated on a steam bath for 18 hours. The reaction mixture was dissolved in methanol (20 ml) and the solution poured into water (200 ml). The viscous oil which separated from the solution crystallized on standing. The solid was collected to obtain 4.29 g (79%) of material which was recrystallized from toluene to give 3.36 g of a white solid. The solid was dried in vacuo for 2 hours, m.p. 104°-105° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]1[CH:24]=[CH:23][N:22]2[N:25]=[CH:26][C:27]([C:28]([NH:30][CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[O:29])=[C:21]2[CH:20]=1.CCN(CC)CC>C(Cl)Cl>[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]1[CH:24]=[CH:23][N:22]2[N:25]=[CH:26][C:27]([C:28]([NH:30][CH:31]3[CH2:36][CH2:35][N:34]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:33][CH2:32]3)=[O:29])=[C:21]2[CH:20]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NC1CCNCC1)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(NC(=O)c2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)cc23)CC1
Reaction time: 4 h
Yield: 133.1 %

Procedure:
Methane sulfonyl chloride (10 mg, 0.09 mmol) was added to cold (0-5° C.) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(piperidin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (35 mg, 0.08 mmol) and Et3N (10 mg, 0.1 mmol) in DCM (1 mL); stirring was continued at 25-35° C. for 4 h. Reaction mixture was diluted with DCM, washed with water, aqueous NaHCO3 solution followed by brine to afford the crude compound, which was purified by preparative TLC (using Silicagel GF254, 1000 u coated 20×20 cm dimension glass plate and 10% MeOH in CHCl3 as eluent) to afford 53.63 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=S)[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[OH:36][CH2:37][C:38]([NH:40][NH2:41])=O>CC1C=CC(C)=CC=1>[OH:36][CH2:37][C:38]1[N:26]2[C:21]3[CH:20]=[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:18]([C:15]4[CH:16]=[CH:17][C:12]([C:8]5([NH:7][C:6](=[O:35])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:11][CH2:10][CH2:9]5)=[CH:13][CH:14]=4)=[N:28][C:22]=3[O:23][CH2:24][C:25]2=[N:41][N:40]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=S)CO4)cc2)CCC1
Reactant: NNC(=O)CO
Solvent: Cc1ccc(C)cc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(CO)nnc3CO4)cc2)CCC1
Temperature: 150 °C
Yield: 14.8 %

Procedure:
A suspension of tert-butyl(1-(4-(7-phenyl-2-thioxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (250 mg, 0.513 mmol) and 2-hydroxyacetohydrazide (230 mg, 2.56 mmol) in p-xylene (1.5 ml) was heated to 150° C. for 30 minutes under microwave irradiation. The resulting reaction mixture was concentrated to dryness under reduced pressure and purified by Biotage silica gel chromatography (gradient 0% to 20% ethyl acetate in n-hexanes) to give the title compound (40 mg, 15%). LCMS (Method D): RT=1.297 min, M+1=526. 1H NMR (500 MHz, CDCl3) δ 8.33 (1H, s), 7.37-7.32 (2H, m), 7.31-7.27 (5H, m), 7.25-7.20 (2H, m), 5.59 (2H, s), 5.06 (2H, bs), 5.02 (1H, bs), 2.53-2.43 (4H, m), 2.14-2.02 (1H, m), 1.88-1.76 (1H, m), 1.45-1.27 (9H, bs).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:30])[CH2:7][CH:8]1[C:17]2[C:12](=[C:13]([CH3:22])[C:14]([C:18]([NH:20][OH:21])=[NH:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[Cl:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][C:47]=1[O:48][CH:49]([CH3:51])[CH3:50])[C:42](Cl)=O>O1CCOCC1>[CH2:1]([O:5][C:6](=[O:30])[CH2:7][CH:8]1[C:17]2[C:12](=[C:13]([CH3:22])[C:14]([C:18]3[N:19]=[C:42]([C:41]4[CH:45]=[CH:46][C:47]([O:48][CH:49]([CH3:50])[CH3:51])=[C:39]([Cl:38])[CH:40]=4)[O:21][N:20]=3)=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)CC1c2ccc(C(=N)NO)c(C)c2CCN1C(=O)OC(C)(C)C
Reactant: CC(C)Oc1ccc(C(=O)Cl)cc1Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCCOC(=O)CC1c2ccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c(C)c2CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 21.3 %

Procedure:
To a solution of 1,1-dimethylethyl 1-[2-(butyloxy)-2-oxoethyl]-6-[(hydroxyamino)(imino)methyl]-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 19; 264 mg, 0.629 mmol) in dioxane (4 ml) was added triethylamine (0.263 ml, 1.89 mmol) followed by dropwise addition of 3-chloro-4-[(1-methylethyl)oxy]benzoyl chloride (Preparation 33; 176 mg, 0.755 mmol) in dioxane (2 ml). The resulting mixture was stirred at room temperature for 90 min, followed by heating at 100° C. for 24 h. The mixture was cooled to room temperature, most of the solvent was removed in vacuo, and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The layers were separated and the aqueous layer further extracted with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography, eluting with 5-25% ethyl acetate in cyclohexane, gave the title compound as a pale yellow oil (80 mg).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([N:8]([CH2:22][CH3:23])[CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][N:14]=1)[CH3:7].[OH-:24].[K+].Cl>O>[CH2:22]([N:8]([CH2:6][CH3:7])[CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[CH:20]=2)[NH:15][N:14]=1)[CH3:23]
Reactant: [OH-]
Reactant: CCN(CC)CCCNc1n[nH]c2ccccc12
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: CCN(CC)CCCNc1n[nH]c2ccc(O)cc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
To 4.3 g of 95% sulfuric acid was added 9.25 g of the 3-(3-diethylaminopropylamino)indazole, and the mixture was stirred for 3 hours at 80° C. To the mixture was added 13 ml of water, and the pH of the mixture was adjusted to 14 with potassium hydroxide. The mixture was washed twice with 20 ml of chloroform, and water was removed under reduced pressure. To the residue thus obtained were added 12.5 g of potassium hydroxide and 0.6 ml of water, and the mixture was stirred for 8 hours at 250° C. After cooling, to the mixture was added hydrochloric acid to separate crystals. Then the crystals were obtained by filtration and dried to give 4.39 g of 3-(3-diethylaminopropylamino)-5-hydroxyindazole having the following analytical values in a yield of 40%.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH2:8])=[O:7].CCN(C(C)C)C(C)C.Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])=O>CN1C(=O)CCC1.Cl>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[C:20]1[N:8]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[O:7][CH:19]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Reactant: NC(=O)c1ccco1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Clc1ccc(-c2coc(-c3ccco3)n2)c(Cl)c1
Temperature: 130 °C
Yield: 55 %

Procedure:
To the solution of furan-2-carboxamide (56 mg, 0.5 mmol. 1 eq) and DIEA (0.13 mL, 0.75 mmo, 1.5 eq) in NMP (1 mL) was added 2-bromo-1-(2,4-dichlorophenyl)ethanone (0.6 mmol, 1.2 eq). Reaction mixture was heated at 130° C. for 15 h. The mixture was cooled down, diluted with 1 M HCl (30 mL) and extracted with EtOAc (40 mL). The organic layer was washed with 1 M HCl (30 mL), 5% solution of NaHCO3 (30 mL), brine (2×40 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The resulting residue was purified by HPLC purification to provide desired 4-(2,4-Dichloro-phenyl)-2-furan-2-yl-oxazole in a yield of 55% and HPLC 99.9% purity. LC-MS [M+H]-280.4 (C13H7Cl2NO2+H, requires 281.11). 1H NMR (DMSO-d6) δ 8.84 (s, 1H), 8.13 (d, 1H, J=8.5), 8.01 (s, 1H), 7.78 (s, 1H), 7.58 (d, 1H, J=8.5), 7.29 (d, 1H, J=3.5), 6.77 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[C:7]([CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[C:20]([F:23])([F:22])[F:21].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:8]2[C:7]([CH3:11])=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([F:1])[CH:9]=2)=[CH:15][C:14]=1[C:20]([F:21])([F:22])[F:23]
Reactant: Cc1cc(C=O)c(F)cc1F
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc(C=O)c(F)cc1Oc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 48.8 %

Procedure:
To a solution of 2,4-difluoro-5-methylbenzaldehyde (100 mg, 0.64 mmol) and 4-chloro-3-trifluoromethylphenol (126 mg, 0.64 mmol) in DMSO was added potassium carbonate. The reaction was stirred at room temperature for 36 hours. The reaction was diluted with ethyl acetate (30 mL) and washed with water (2×50 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was purified using reverse phase column chromatography eluting with acetonitrile:water (plus 0.1% aqueous formic acid) 5:95 to 100:0 to furnish the title compound as a white solid 104 mg, 49%.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:10]([N:14]=[C:15]=[O:16])[CH2:11][CH2:12][CH3:13].Cl.[F:18][B-:19]([F:22])([F:21])[F:20].[Na+]>C(OCC)(=O)C.CO>[F:18][B-:19]([F:22])([F:21])[F:20].[CH2:10]([NH:14][C:15]([NH:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:16])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCN
Reactant: CCCCN=C=O
Agent: Cl
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCCCCNC(=O)NCCCC
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
A four necked flask equipped with a thermometer, stirrer and drip funnel was charged with 2.58 g of octylamine and 200 g of ethyl acetate. To this was added dropwise a solution of 1.98 g of n-butylisocyanate in 30 g of ethyl acetate with stirring over 30 minutes while maintaining the inner temperature at 10° C. and allowed to react until the absorption of isocyanato group (2240 cm-1) disappeared IR spectrometrically. After dissolving the solidified reaction product in 50 g of methanol, a mixture of 2.086 g of 35% hydrochloric acid and 50 g of methanol was added dropwise to the solution over 30 minutes and allowed to react at room temperature for 20 hours. Then a solution of 2.2 g of sodium tetrafluoroborate in 50 g of methanol was added dropwise over 30 minutes and allowed to react at room temperature for 20 hours. The reaction mixture was then filtered to remove NaCl by-product and evaporated to remove the solvent. 6.1 g of the title compound was obtained as a pale yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]([OH:15])=O)=[C:8]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:28][CH2:27]2)=[O:24])=[CH:19][CH:18]=1.[CH2:39]([N:47]1[CH2:52][CH2:51][CH:50]([NH2:53])[CH2:49][CH2:48]1)[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N1CCC(=O)CC1)CC1C=CC=CC=1>>[C:41]1([CH2:40][CH2:39][N:47]2[CH2:52][CH2:51][CH:50]([NH:53][C:13]([C:9]3[CH:10]=[N:11][C:12]4[C:7]([C:8]=3[NH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([NH:25][CH:26]5[CH2:31][CH2:30][N:29]([CH2:32][C:33]6[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=6)[CH2:28][CH2:27]5)=[O:24])=[CH:19][CH:18]=3)=[CH:6][CH:5]=[CH:4][C:3]=4[O:2][CH3:1])=[O:15])[CH2:49][CH2:48]2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: NC1CCN(CCc2ccccc2)CC1
Reactant: COc1cccc2c(Nc3ccc(C(=O)NC4CCN(Cc5ccccc5)CC4)cc3)c(C(=O)O)cnc12
Agent: O=C1CCN(CCc2ccccc2)CC1
Product: COc1cccc2c(Nc3ccc(C(=O)NC4CCN(Cc5ccccc5)CC4)cc3)c(C(=O)NC3CCN(CCc4ccccc4)CC3)cnc12

Procedure:
N-[1-(2-Phenylethyl)-4-piperidinyl]-8-methoxy-4-[[4-[[[1-(phenylmethyl)- 4piperidinyl]amino]carbonyl]phenyl]amino]-3-quinolinecarboxamide was prepared by coupling 8-methoxy-4-[[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]carbonyl]phenyl]amino]-3-quinolinecarboxylic acid and 1-phenethyl-4-aminopiperidine as described for Example 17, Step 5. 1-phenethyl-4-aminopiperidine can be prepared from 1-phenethyl-4-piperidone as described in U.S. Pat. No. 3,875,165: mp 216°-220 ° C.; 1H NMR (Me2SO-d6, 400 MHz) δ 9.51 (s, 1 H), 8.79 (s, 1 H), 8.40 (d, 5=7.7 Hz, 1 H), 8.00 (d, J=7.7 Hz, 1 H), 7.71 (d, J=8.7 Hz, 2 H), 7.57 (d, J=8.5 Hz, 1 H), 7.41 (m, 1 H), 7.10- 7.35 (m, 11 H), 6.88 (d, J=8.7 Hz, 2 H), 3.93 (s, 3 H), 3.7-3.8 (m, 1 H), 3.4-3.6 (m, 3 H), 2.6-2.9 (m, 6 H), 2.4-2.5 (m, 2 H), 1.85-2.10 (m, 4 H, 1.7-1.8 (m, 2 H), 1.5-1.7 (m, 4 H), 1.3-1.5 (m, 2 H).
Reaction SMILES: [N:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=O)=[CH:13][CH:14]=3)[N:9]([C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[CH3:25][C:26]1[N:30]=[C:29]([C@H:31]([NH2:33])[CH3:32])[O:28][N:27]=1.CN1CCOCC1.ON1C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:25][C:26]1[N:30]=[C:29]([C@H:31]([NH:33][C:16]([C:12]2[CH:11]=[C:10]3[C:15]([C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[N:8][N:9]3[C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)=[CH:14][CH:13]=2)=[O:18])[CH3:32])[O:28][N:27]=1
Reactant: Cc1noc([C@@H](C)N)n1
Reactant: O=C(O)c1ccc2c(N3CCOCC3)nn(-c3ccsc3)c2c1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1noc([C@@H](C)NC(=O)c2ccc3c(N4CCOCC4)nn(-c4ccsc4)c3c2)n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(morpholin-4-yl)-1-(thiophen-3-yl)-1H-indazole-6-carboxylic acid (20.0 mg, 45.0 μmol), (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine hydrochloride (18.1 mg, 90 μmol, and N-methylmorpholine (24.8 μL, 226 μmol) in N,N-dimethylformamide (226 μL) were added N-[2-(dimethylamino)ethyl]-N-ethylcarbodiimide hydrochloride (15.1 mg, 79.0 μmol), 1-hydroxy-7-azabenzotriazole (3.1 mg, 23 pawl). The mixture was stirred at 50° C. for 1 h. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.05% ammonium hydroxide) gave the title compound (19 mg). HRMS [M+1] found=439.1545. 1H NMR (400 MHz, DMSO-d6) δ: 9.37 (1H, d, J=7.33 Hz), 8.20 (1H, s), 8.05 (1H, d, 8.57 Hz), 7.77-7.74 (2H, m), 7.64 (1H, dd, J=8.56, 1.33 Hz), 7.56 (1H, 4.58, 2.12 Hz), 5.43-5.37 (1H, m), 3.83 (4H, t, J=4.39 Hz), 3.43 (4H, t, J=4.39 Hz), 2.33 (3H, s), 1.64 (3H, d, J=7.15 Hz).