Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:33]=[CH:32][C:23]([CH2:24][CH:25]([C:29]([NH2:31])=[O:30])[C:26]([NH2:28])=[O:27])=[CH:22][CH:21]=1.C(=O)(O)[O-].[Na+]>Cl.CN1C(=O)CCC1.O>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:24][CH:25]([C:26]([NH2:28])=[O:27])[C:29]([NH2:31])=[O:30])=[CH:32][CH:33]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: NC(=O)C(Cc1ccc(N)cc1)C(N)=O
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: NC(=O)C(Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1)C(N)=O
Temperature: 140 °C
Yield: 45 %

Procedure:
A 10-mL microwave vial was charged with 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.100 g, 0.33 mmol), 2-(4-aminobenzyl)malonamide (0.110 g, 0.53 mmol) and conc. HCl (1 drop) in NMP (3 mL). The resulting mixture was heated at 140° C. under microwave irradiation for 3 h. After this time, the reaction mixture was cooled, diluted with water (15 mL) and then treated with saturated sodium bicarbonate until pH˜8. The resulting solid was isolated by filtration and purified by preparative HPLC (water/acetonitrile with 0.05% TFA) to afford the free base of the title compound (0.070 g, 56%) as an off-white solid. MW=434.92. 1H NMR (DMSO-d6, 500 MHz) δ 8.07 (s, 1H), 7.90 (s, 1H), 7.75-7.70 (m, 1H), 7.46-7.38 (m, 2H), 7.24 (s, 2H), 7.21-7.13 (m, 5H), 7.02 (s, 2H), 4.08-4.00 (m, 1H), 2.96 (d, J=7.0 Hz, 2H), 2.93-2.87 (m, 2H), 2.85-2.78 (m, 2H), 2.22-2.13 (m, 2H). MS: ESI+, m/z 435 [M+H]+. Treatment with 1.25M HCl in methanol (0.19 mL, 0.24 mmol, 1.5 eq.) afforded the title compound (0.048 g, 64%) as an off-white solid. MW=471.38. m.p. 219-222° C. 1H NMR (DMSO-d6, 500 MHz) δ 13.95 (br s, 1H), 9.71 (s, 1H), 7.90-7.87 (m, 1H), 7.70-7.74 (m, 2H), 7.60 (t, J=8.0 Hz, 1H), 7.31 (s, 5H), 7.03 (s, 2H), 6.97 (s, 1H), 3.36-3.33 (m, 1H), 3.13 (t, J=7.5 Hz, 2H), 3.01 (d, J=7.5 Hz, 2H), 3.13 (t, J=7.0 Hz, 2H), 2.28-2.19 (m, 2H); ESI MS m/z 435 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[CH3:17])=[C:6]([NH:18][C:19](=O)[CH2:20][C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=1.Cl.O>O1CCOCC1>[CH3:17][C@@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[N:10]1[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:27])=[CH:5][C:6]=2[N:18]=[C:19]1[CH2:20][C:21]1[S:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(N[C@@H]2CCCC[C@H]2C)c(NC(=O)Cc2cccs2)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1CCCC[C@H]1n1c(Cc2cccs2)nc2cc(C(=O)O)ccc21
Temperature: 130 °C
Yield: 74 %

Procedure:
To 8.32 g 4-((1R,2R)-2-Methyl-cyclohexylamino)-3-(2-thiophen-2-yl-acetylamino)-benzoic acid methyl ester were added 40 ml of 4M hydrochloric acid in dioxane and the mixture was heated in four portions in a microwave reactor to 130° C. for 20 min. 2 ml of water were added to each vial and the reactions were heated to 130° C. for 40 min. The reactions were then combined and concentrated and the pH was adjusted to 6 by addition of saturated aqueous sodium bicarbonate. The resulting mixture was extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulphate and concentrated. The product precipitated upon treatment with diisopropylether and 5.65 g (76%) of 1-((1R,2R)-2-Methyl-cyclohexyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid were obtained.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[O:30]=[C:31]1[N:37]([CH:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C@H:47]([CH2:64][C:65]3[CH:70]=[C:69]([C:71]([F:74])([F:73])[F:72])[C:68]([NH2:75])=[C:67]([Cl:76])[CH:66]=3)[C:48]([N:50]3[CH2:55][CH2:54][CH:53]([N:56]4[CH2:60][CH2:59][CH2:58][C@@H:57]4[C:61]([OH:63])=[O:62])[CH2:52][CH2:51]3)=[O:49])=[O:45])[CH2:40][CH2:39]2)[CH2:36][CH2:35][C:34]2[CH:77]=[CH:78][CH:79]=[CH:80][C:33]=2[NH:32]1.O[CH2:82][C:83]([N:85]([CH3:87])[CH3:86])=[O:84]>CN(C=O)C>[O:30]=[C:31]1[N:37]([CH:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C@H:47]([CH2:64][C:65]3[CH:70]=[C:69]([C:71]([F:72])([F:74])[F:73])[C:68]([NH2:75])=[C:67]([Cl:76])[CH:66]=3)[C:48]([N:50]3[CH2:51][CH2:52][CH:53]([N:56]4[CH2:60][CH2:59][CH2:58][C@@H:57]4[C:61]([O:63][CH2:82][C:83](=[O:84])[N:85]([CH3:87])[CH3:86])=[O:62])[CH2:54][CH2:55]3)=[O:49])=[O:45])[CH2:40][CH2:39]2)[CH2:36][CH2:35][C:34]2[CH:77]=[CH:78][CH:79]=[CH:80][C:33]=2[NH:32]1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC[C@@H]3C(=O)O)CC2)cc1C(F)(F)F
Reactant: CN(C)C(=O)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)COC(=O)[C@H]1CCCN1C1CCN(C(=O)[C@@H](Cc2cc(Cl)c(N)c(C(F)(F)F)c2)OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
25 mg (0.08 mmol) TBTU and 11 μL (0.08 mmol) triethylamine were added to a solution of 50 mg (0.07 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-((R)-2-carboxy-pyrrolidin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 1 mL DMF and stirred for 10 min at RT. 8.1 mg (0.08 mmol) 2-hydroxy-N,N-dimethyl-acetamide were added to the reaction mixture and this was shaken overnight at RT. After filtration through a syringe filter the reaction solution was purified by HPLC without further working up. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([I:21])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=C(C)C=C(C)C=1S(O[NH2:42])(=O)=O>CN(C=O)C>[NH2:42][N:12]1[C:13]2[C:18](=[CH:17][C:16]([I:21])=[CH:15][CH:14]=2)[C:19](=[O:20])[C:10]([C:8]([NH:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:23][CH:22]=2)=[O:9])=[CH:11]1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(I)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)ccc21
Reaction time: 24 h
Yield: 65.3 %

Procedure:
A suspension of N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide (2.0 g) of Preparation No. 4 and of potassium carbonate (2.0 g) in DMF (40 mL) is stirred at room temperature for 5 hrs and then treated with of O-(mesitylsulfonyl)hydroxylamine (1.5 g). After 24 hrs, the solvent is evaporated under reduced pressure and the residue is diluted with water(150 mL). The resulting solid is filtered and washed with water (3×) and ether (2×). Recrystallization from hot acetic acid/water affords 1.35 g of the title compound as a tan solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:10]1[CH:11]=[CH:12][C:13]([O:19][CH2:20][CH2:21][CH3:22])=[C:14]([CH:18]=1)[C:15]([OH:17])=O)(=[O:9])[CH3:8].[NH2:23][C:24]1[C:25]([C:39]([NH2:41])=[O:40])=[N:26][N:27]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:28]=1[CH2:29][CH2:30][CH3:31]>CN(C)C=O.ClCCl>[C:7]([C:10]1[CH:11]=[CH:12][C:13]([O:19][CH2:20][CH2:21][CH3:22])=[C:14]([CH:18]=1)[C:15]([NH:23][C:24]1[C:25]([C:39]([NH2:41])=[O:40])=[N:26][N:27]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:28]=1[CH2:29][CH2:30][CH3:31])=[O:17])(=[O:9])[CH3:8]
Reactant: CCCOc1ccc(C(C)=O)cc1C(=O)O
Reactant: CCCc1c(N)c(C(N)=O)nn1Cc1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCOc1ccc(C(C)=O)cc1C(=O)Nc1c(C(N)=O)nn(Cc2ccccn2)c1CCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Oxalyl chloride (1.6 ml, 18 mmol) was added to an ice-cooled solution of 5-acetyl-2-n-propoxybenzoic acid (WO 9312095) (2 g, 9 mmol) in N,N-dimethylformamide (0.2 ml) and dichloromethane (200 ml) under nitrogen. Once addition was complete the solution was allowed to warm to room temperature for 3 hours and the solvent was removed under reduced pressure. The intermediate acid chloride was dissolved in pyridine (50 ml) and 4-amino-5-propyl-1-(pyridin-2-ylmethyl)-1H-pyrazole -3-carboxamide (WO 9954333) (1.5 g, 5.8 mmol) and the reaction was stirred at reflux for 3 hours, then at room temperature for 18 hours. The mixture was partitioned between dilute sodium carbonate solution and dichloromethane, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane:methanol (100:0 changing to 98:2 then 92:8) to afford the title compound as a beige solid, 1.5 g.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Br:19])[CH:13]=3)[C:10](=[O:20])[O:9][N:8]=2)=[N:4][O:5][N:6]=1.CO[CH:23](OC)[CH2:24][NH:25][S:26]([NH:29][C:30](=[O:37])[O:31][CH2:32][C:33]([Cl:36])([Cl:35])[Cl:34])(=[O:28])=[O:27].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Br:19][C:14]1[CH:13]=[C:12]([N:11]2[C:10](=[O:20])[O:9][N:8]=[C:7]2[C:3]2[C:2]([NH:1][CH2:23][CH2:24][NH:25][S:26]([NH:29][C:30](=[O:37])[O:31][CH2:32][C:33]([Cl:36])([Cl:34])[Cl:35])(=[O:28])=[O:27])=[N:6][O:5][N:4]=2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: COC(CNS(=O)(=O)NC(=O)OCC(Cl)(Cl)Cl)OC
Reactant: Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90.3 %

Procedure:
A suspension of 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (5, 0.680 g, 1.99 mmol) and 2,2,2-trichloroethyl {[(2,2-dimethoxyethyl)amino]sulfonyl}carbamate (17d, 2.22 g, 6.17 mmol, 3.1 equiv.) in dichloromethane (DCM, 6.0 mL) was stirred at room temperature. To this mixture was added triethylsilane (1.27 mL, 7.95 mmol, 4.0 equiv.) and a solution of trifluoroacetic acid (TFA, 3.0 mL, 39.0 mmol) in dichloromethane (DCM, 2.0 mL) while maintaining the reaction temperature below 30° C. The reaction mixture became homogenous after 5 min with agitation at room temperature and was stirred at room temperature for 1 h. HPLC indicated reaction completion. The reaction was filtered and the precipitate was suspended in a mixture of dichloromethane and heptane (ratio of dichloromethane to heptane was 1 to 9 by volume). The suspension was stirred at room temperature overnight. The precipitate was collected by filtration and washed with 10% dichloromethane in heptane and dried in vacuum to give the desired product (1.15 g, 90.4%) as an off-white solid, which was used in the subsequent reaction without further purification. 1H NMR (300 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.07 (m, 2H), 7.70 (m, 1H), 7.57 (t, 1H, J=8.7 Hz), 6.56 (m, 1H), 4.88 (m, 2H), 3.37 (m, 2H), 3.16 (m, 2H); C15H12BrCl3FN7O7S (MW 639.62), LCMS (EI) m/e 638/640/642 (M++H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:26]([O-:29])([O-])=[O:27].[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.COCCOC>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([C:8](=[C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[C:5]2[CH:6]=[CH:7][C:2]([C:2]3[CH:7]=[CH:6][C:5]([C:26]([OH:29])=[O:27])=[CH:4][CH:3]=3)=[CH:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(Br)cc2)CC(C)(C)C1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: COCCOC
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(-c3ccc(C(=O)O)cc3)cc2)CC(C)(C)C1
Reaction time: 144 h

Procedure:
To a round-bottomed flask were added 4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14) (0.105 g, 0.26 mmol), 4-dihydroxyborane-benzoic acid (0.093 g, 0.56 mmol, 2.2 eq), tetrakis(triphenylphosphine)palladium(0) (0.023 g, 0.02 mmol, 0.08 eq), aqueous Na2CO3 (2 M, 3 mL), and ethylene glycol dimethyl ether (5 mL). The reaction mixture was heated overnight at reflux with stirring under a nitrogen atmosphere. The reaction mixture was allowed to stand at RT under nitrogen for six days. To the reaction mixture were added 4-dihydroxyborane-benzoic acid (0.099 g, 0.60 mmol, 2.3 eq), tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol, 0.10 eq), aqueous sodium carbonate (2 M, 2 mL), and ethylene glycol dimethyl ether (2 mL). The stirred reaction mixture was heated overnight at reflux under nitrogen. The reaction mixture was allowed to stand at RT under nitrogen for one week. The reaction mixture was partitioned between 1 N HCl (aqueous) and CH2Cl2. The organic phase was separated, washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated to give the crude product as an oil. The crude product was partially purified by flash chromatography on silica gel with a CH2Cl2:MeOH (100:0 to 96:4) gradient to give 0.052 g of the impure product as a an oil. The impure product was purified by reverse phase preparative HPLC using a C18 column and an CH3CN:H2O (75:25 to 100:0) gradient with 0.05% TFA as a modifier to give 9.3 mg (8%) of compound 103 as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 0.89 (br s, 12H), 1.26 (br s, 2H), 1.93 (br s, 4H), 6.67 (d, J=8.5 Hz, 2H), 6.96 (d, J=8.4 Hz, 2H), 7.23 (d, J=8.1 Hz, 2H), 7.65 (d, J=8.1 Hz, 2H), 7.77 (d, J=8.2 Hz, 2H), 7.98 (d, J=8.4 Hz, 2H), 9.29 (s, 1H), 12.94 (br s, 1H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][C:7]([CH3:12])([CH3:11])[CH2:6]1)(=[O:4])=[O:3].[N:13]([O-])=[O:14].[Na+].O.Cl>CO>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([N:13]=[O:14])[C:7]([CH3:12])([CH3:11])[CH2:6]1)(=[O:3])=[O:4]
Reactant: CC1(C)CN(S(C)(=O)=O)CCN1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(C)CN(S(C)(=O)=O)CCN1N=O

Procedure:
A mixture, cooled to 0°-5° C., of 45 g of 4-methanesulphonyl-2,2-dimethylpiperazine, 19.3 g of sodium nitrite, 250 ml of water and 100 ml of methanol is adjusted to pH 1.0 using conc. HCl and stirred at a gradually increasing temperature for 12 hours. The precipitate is filtered off with suction, washed with water and dried in vacuo.
Reaction SMILES: CO[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=2)[CH:6]=[CH:5][N:4]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1nccc2ccc(C(F)(F)F)cc12
Product: FC(F)(F)c1ccc2ccnc(Cl)c2c1

Procedure:
A solution of 1-Methoxy-7-(trifluoromethyl)isoquinoline (50 mg, 0.22 mmol) from above step B in phosphorus oxychloride (1 mL) was heated at 150° C. for 18 h. Phosphorus oxychloride was removed under vacuum and the residue was purified by silica column chromatography to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[C:23](=[O:24])[CH2:22][S:21][C:20]3=[O:25])=[CH:12][CH:11]=[CH:10][N:9]2[CH:26]=1)=[O:5])[CH3:2].[CH:27](=O)[CH2:28][CH2:29][CH3:30].N1CCCCC1>C(O)C>[CH:27](=[C:22]1[S:21][C:20](=[O:25])[N:19]([CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:13]2[C:8]3[N:9]([CH:26]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=3)[CH:10]=[CH:11][CH:12]=2)[C:23]1=[O:24])[CH2:28][CH2:29][CH3:30]
Reactant: CCOC(=O)c1cn2cccc(OCCCCN3C(=O)CSC3=O)c2n1
Reactant: CCCC=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCCCOc2cccn3cc(C(=O)OCC)nc23)C1=O

Procedure:
To a solution of 1.88 g (5.0 mmol) of 3-[4-(2-ethoxycarbonylimidazo[1,2-a]pyridin-8-yloxy)butyl]-thiazolidine-2,4-dione and 0.45 ml (5.0 mmol) of n-butyraldehyde in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/2) to yield 2.14 g (99.2%, yellow oily substance) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH:15][C@H:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH:15][C@H:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1)(=[O:39])=[O:38]
Reactant: COC(=O)[C@H](NC(=O)c1cc(-c2ccc(N)cc2)no1)C(C)C
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H](NC(=O)c1cc(-c2ccc(NS(=O)(=O)c3ccccc3F)cc2)no1)C(C)C
Reaction time: 0.17 h
Yield: 54.9 %

Procedure:
To a solution of 500 mg (1.57 mmol) of (R)-methyl 2-(3-(4-aminophenyl)isoxazole-5-carboxamido)-3-methylbutanoate (example 151, step 3) in DCM, 1.2 eq of pyridine was added and stirred for 10 minutes, then 368 mg (1.89 mmol) 2-fluorobenzene-1-sulfonyl chloride was added and the reaction mixture was stirred for 3 hours. DCM was removed under vacuum, the reaction mixture was washed with 1NHCl and extracted with EtOAc. The organic layer was concentrated and purified by precipitation using DCM and petroleum ether to yield 410 mg (86%) of title compound. MS (ESI): m/z 476(M+H)+; 1HNMR (DMSO-d6, 300 MHz): δ 11.039 (s, 1H), 9.215 (d, 1H), 7.942 (m, 1H), 7.805 (d, 2H), 7.718 (m, 1H), 7.625 (s, 1H), 7.465 (m, 2H), 7.271(d, 2H), 4.314 (t, 1H), 3.690 (s, 3H), 2.228 (m, 1H), 0.971 (d, 6H).
Reaction SMILES: [CH:1]([NH:5][C:6]1[C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([O:18]C)=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2].[H-].[Na+].[CH3:28]I.Cl>O1CCCC1>[CH:1]([N:5]([CH3:28])[C:6]1[C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)Nc1nc2cc(C(=O)OC)ccc2nc1-c1ccccc1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(sec-butylamino)-2-phenylquinoxaline-6-carboxylate (133.6 mg, 0.40 mmol, 1.00 equiv) in tetrahydrofuran (12 mL), and sodium hydride (96 mg, 4.00 mmol, 10.03 equiv). The resulting solution was stirred 1 h at room temperature. Then a solution of methyl iodide (284 mg, 2.00 mmol, 5.01 equiv) in tetrahydrofuran (1 mL) was added dropwise with stirring. The resulting solution was stirred overnight at room temperature. The pH value of the solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting solution was concentrated under vacuum. The residue was purified by silica gel chromatography with dichloromethane/petroleum ether (10:1). The crude product (130 mg) was purified by Prep-HPLC under the following conditions (1#-Waters 2767-1): Column, SunFire Prep C18, 5 um, 19*100 mm; mobile phase, water with 0.05% TFA and CH3CN (60% CH3CN up to 80% in 6 min, up to 100% in 1 min, down to 60% in 1 min); Detector, UV 220 254 nm. This resulted in 52 mg (39%) of 3-(sec-butyl(methyl)amino)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])[CH3:3]>O1CCOCC1.ClCCl>[NH:15]1[CH2:16][CH2:17][CH:12]([C:8]2[CH:7]=[C:6]([NH:5][C:2](=[O:4])[CH3:3])[CH:11]=[CH:10][CH:9]=2)[CH2:13][CH2:14]1
Reactant: CC(=O)Nc1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(C2CCNCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 121.6 %

Procedure:
A solution of HCl in dioxane (4N, 5 mL) was added to tert-butyl 4-[3-(acetylamino)phenyl]-1-piperidinecarboxylate (660 mg) in dry dichloromethane (15 mL). The reaction mixture was stirred at room temperature overnight and concentrated in vacuo, giving the desired product (550 mg): mp 102-104° C.; 1H NMR (CDCl3) δ 2.02 (d, J=13.2 Hz, 2H), 2.11-2.45 (m, 5H), 2.67-2.77 (m, 1H), 3.00-3.10 (m, 2H), 3.51 (d, J=10.5 Hz, 2H), 6.94 (d, J=7.5 Hz, 1H), 7.20-7.46 (m, 3H), 7.60 (s, 1H); Anal. Calcd. For C13H19N2OCl+0.86 CH2Cl2: C, 50.78; H, 6.37; N, 8.55. Found: C, 50.80; H, 7.55; N, 7.01.
Reaction SMILES: [C:1]1([C:7]2[S:11][CH:10]=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:21])=[C:17]([CH:20]=1)[CH:18]=O>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:21])=[C:17]([CH2:18][C:10]2[S:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][N:9]=2)[CH:20]=1
Reactant: c1ccc(-c2cncs2)cc1
Reactant: O=Cc1cc(Br)ccc1Cl
Product: Clc1ccc(Br)cc1Cc1ncc(-c2ccccc2)s1

Procedure:
The above 5-phenylthiazole and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 100 to give 5-bromo-2-chloro-1-(5-phenyl-2-thiazolylmethyl)benzene as a yellow solid. APCI-Mass m/Z 364/366 (M+H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][N:13]2[CH:18]=[N:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)=[N:15][C:14]2=[O:32])(=O)=O)=CC=1.N12CCCN=C1CCCCC2.[NH:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=[N:45]1>ClCCl>[N:44]1[N:45]([CH2:12][N:13]2[CH:18]=[N:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)=[N:15][C:14]2=[O:32])[CH:46]=[C:47]2[C:52]=1[CH:51]=[CH:50][CH:49]=[CH:48]2
Reactant: c1ccc2[nH]ncc2c1
Reactant: Cc1ccc(S(=O)(=O)OCn2cnc(N3CCN(c4ccc(F)cc4)CC3)nc2=O)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)ncn1Cn1cc2ccccc2n1
Yield: 5.8 %

Procedure:
To a dichloromethane solution of {4-[4-(4-fluorophenyl)piperazin-1-yl]-2-oxo-1,3,5-triazin-1(2H)-yl}methyl 4-methylbenzenesulfonate (165 mg, 0.36 mmol) synthesized in Reference Synthesis Example 4, 1,8-diazabicyclo[5.4.0]undeca-7-ene (65 μL, 0.44 mmol) and 1H-indazole (43 mg, 0.40 mmol) were added at room temperature and the resultant mixture was stirred at room temperature for 30 minutes. After the completion of the reaction, the reaction solution was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (8.5 mg, yield: 5.2%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[C:22](O)([CH3:25])([CH3:24])[CH3:23].C(OCC)(=O)C>CCCCCC>[C:22]([O:20][C:19](=[O:21])[CH2:18][O:17][C:14]1[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:16][N:15]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)O
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Yield: 8 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using tert-butyl alcohol (9.6 mg, 0.13 mmol) as the source alcohol. Chromatography (1:1 ethyl acetate:hexane) through SiO2 yielded 5 mg (8%) of the titled compound. ESI-MS m/z 348 (MH+), 346 (M−H−).