Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:13][S:12][C:11]([NH2:19])=[N:10]2.[Br:20]N1C(=O)CCC1=O.CCOCC.C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O>[Br:20][C:5]1[C:6]([F:8])=[CH:7][C:2]([F:1])=[C:3]([C@:9]23[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[CH2:13][S:12][C:11]([NH2:19])=[N:10]3)[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: NC1=N[C@@]2(c3ccc(F)cc3F)CCCC[C@H]2CS1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Product: NC1=N[C@@]2(c3cc(Br)c(F)cc3F)CCCC[C@H]2CS1
Reaction time: 2 h
Yield: 95.6 %

Procedure:
(±)-(4aR*,8aS*)-8a-(2,4-Difluoro-phenyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-ylamine (270 mg) was dissolved in concentrated sulfuric acid (3 mL). N-Bromosuccinimide (170 mg) was added in an ice bath, and the mixture was stirred at the same temperature for two hours. Ice was added to terminate the reaction, followed by dilution with ether. The reaction solution was neutralized with a sodium bicarbonate solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (330 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH2:19]([N:26]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:27][CH2:28]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5](=[C:6]([O:10][CH2:28][CH2:27][N:26]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:7]=[CH:8][CH:9]=1)[OH:11]
Reactant: ClCCN(Cc1ccccc1)Cc1ccccc1
Reactant: COC(=O)c1cccc(O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cccc(OCCN(Cc2ccccc2)Cc2ccccc2)c1O

Procedure:
2,3-dihydroxybenzoic acid methyl ester is reacted in the presence of potassium carbonate in acetonitrile with 1.1 equivalents of 1-dibenzylamino-2-chloroethane for 18 hours at 82°. The crude 3-(2-dibenzylaminoethoxy)salicylic acid methyl ester obtained after working up is put to further use without further purification.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[C:22]1([CH3:34])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:31]2[CH2:32][CH2:33][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH3:34])[CH2:29][CH2:30]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: Cc1ccccc1N1CCNCC1
Product: CCc1cc(NC(=O)N2CCN(c3ccccc3C)CC2)c(OC)nc1C
Yield: 89 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-tolyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[N+:13]([O-])([O-:15])=[O:14].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:13]([C:12]1[C:2]([OH:1])=[C:3]([CH:9]=[CH:10][CH:11]=1)[CH:4]=[CH:5][C:6]([OH:8])=[O:7])([O-:15])=[O:14]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(O)C=Cc1ccccc1O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)C=Cc1cccc([N+](=O)[O-])c1O
Reaction time: 24 h
Yield: 52.3 %

Procedure:
2-Hydroxycinnamic acid (3.00 g, 18.3 mmol) was dissolved in methylene chloride (40 mL) followed by the addition of sodium nitrate (2.21 g, 26.1 mmol). The addition of sulfuric acid (30 mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product (2.0 g, 52%). 1H NMR (CD3COCD3): δ8.21 (d, 1H), 8.16 (d, 1H), 8.05 (d, 1H), 7.19 (t, 1H), 6.72 (d, 1H).
Reaction SMILES: C([N:14]1[CH2:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH2:29][C:28]([C:34]4[CH:39]=[C:38]([Cl:40])[C:37]([Cl:41])=[C:36]([Cl:42])[CH:35]=4)([C:30]([F:33])([F:32])[F:31])[O:27][N:26]=3)=[CH:21][C:20]=2[Br:43])([F:18])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>CC#N.C(Cl)Cl>[Br:43][C:20]1[CH:21]=[C:22]([C:25]2[CH2:29][C:28]([C:34]3[CH:39]=[C:38]([Cl:40])[C:37]([Cl:41])=[C:36]([Cl:42])[CH:35]=3)([C:30]([F:33])([F:31])[F:32])[O:27][N:26]=2)[CH:23]=[CH:24][C:19]=1[C:16]1([F:18])[CH2:17][NH:14][CH2:15]1
Reactant: FC1(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Br)CN(C(c2ccccc2)c2ccccc2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC#N
Solvent: ClCCl
Product: FC1(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Br)CNC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.9 %

Procedure:
To a solution of 3-(4-(1-benzhydryl-3-fluoroazetidin-3-yl)-3-bromophenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (Preparation 29, 515 mg, 0.76 mmol) in MeCN/DCM (5:1, 60 mL) at 0° C. was added 1-chloroethyl chloroformate (275 uL, 2.5 mmol). The reaction was heated to reflux for 3 hours then allowed to cool to room temperature while stirring for 18 hours. Next, the reaction mixture was concentrated under vacuum, re-dissolved in anhydrous MeOH (50 mL), and refluxed for 1 hour. The reaction was cooled, concentrated under reduced pressure, and diethyl ether was added to residue. The resulting precipitate was filtered, rinsed with diethyl ether, and air dried to afford the intermediate (365 mg, 87%) as a solid. M/z (Cl) 713 ([M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]([CH3:13])([NH2:12])[CH3:11])[CH2:4][CH2:3]1.[C:15](ON1C(=O)CCC1=O)([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C1COCC1>[CH3:1][C:2]1([CH3:14])[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][C:10]([NH:12][C:15](=[O:16])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH3:13])[CH3:11])[CH2:6][CH2:7]1
Reactant: CC(C)(N)CCN1CCC(C)(C)CC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: C1CCOC1
Product: CC1(C)CCN(CCC(C)(C)NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 48.9 %

Procedure:
Crude 4-(4,4-dimethylpiperidin-1-yl)-2-methylbutan-2-amine (5.80 g, 29.2 mmol) was dissolved into THF (100 mL). To this solution was added CbzOSu (7.29 g, 1 equiv, 29.2 mmol) in one portion. The reaction was left to stir at room temperature for 3 d. The solvent was removed and the residue was taken up in a mixture of diethyl ether (150 mL) and water (50 mL). The layers were separated and the organic layer washed with 1 M sodium carbonate (2×50 mL), 1M HCl (50 mL), and brine (100 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a pale yellow oil. The crude oil was purified on an ISCO purification system with gradient elution from 10-80% ethyl acetate in hexanes. The desired fractions were collected and concentrated to give a white solid (4.75 g, yield: 49.0%). 1H NMR (CDCl3, 400 MHz): δ 0.92 (s, 6H), 1.35-1.40 (bm, 10H), 1.58-1.63 (t, J=10.8, 2 H), 2.40 (bs, 4H), 2.44-2.52 (t, J=10.8, 2H), 5.03 (s, 2H), 7.27-38 (m, 5H). LRMS (ESI+) for C20H32N2O2 (332.2); Found: 333 (MH+).
Reaction SMILES: [Cl:1][N:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([NH:9][C:10]2[CH:11]=[C:12](S(O)(=O)=O)[C:13]([CH:16]=[CH:17][C:18]3[C:19](S(O)(=O)=O)=[CH:20][C:21]([NH:24][C:25]4[NH:30][N:29]([Cl:31])[N:28]=[C:27](Cl)[CH:26]=4)=[CH:22][CH:23]=3)=[CH:14][CH:15]=2)[NH:3]1.[NH2:41][C:42]1[C:51]([S:52]([OH:55])(=[O:54])=[O:53])=[CH:50][C:49]2[C:44](=[C:45]([S:60]([OH:63])(=[O:62])=[O:61])[CH:46]=[C:47]([S:56]([OH:59])(=[O:58])=[O:57])[CH:48]=2)[CH:43]=1>>[Cl:1][N:2]1[N:7]=[C:6]([NH:41][C:42]2[C:51]([S:52]([OH:55])(=[O:54])=[O:53])=[CH:50][C:49]3[C:44](=[C:45]([S:60]([OH:63])(=[O:62])=[O:61])[CH:46]=[C:47]([S:56]([OH:59])(=[O:57])=[O:58])[CH:48]=3)[CH:43]=2)[CH:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]([CH:16]=[CH:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]4[NH:30][N:29]([Cl:31])[N:28]=[C:27]([NH:41][C:42]5[C:51]([S:52]([OH:55])(=[O:54])=[O:53])=[CH:50][C:49]6[C:44](=[C:45]([S:60]([OH:63])(=[O:62])=[O:61])[CH:46]=[C:47]([S:56]([OH:59])(=[O:57])=[O:58])[CH:48]=6)[CH:43]=5)[CH:26]=4)=[CH:20][CH:19]=3)[C:12]([S:56]([OH:59])(=[O:58])=[O:57])([S:52]([OH:55])(=[O:54])=[O:53])[CH:11]=2)[NH:3]1
Reactant: O=S(=O)(O)c1cc(NC2=CC(Cl)=NN(Cl)N2)ccc1C=Cc1ccc(NC2=CC(Cl)=NN(Cl)N2)cc1S(=O)(=O)O
Reactant: Nc1cc2c(S(=O)(=O)O)cc(S(=O)(=O)O)cc2cc1S(=O)(=O)O
Product: O=S(=O)(O)c1cc(S(=O)(=O)O)c2cc(NC3=NN(Cl)NC(NC4=CC(S(=O)(=O)O)(S(=O)(=O)O)C(C=Cc5ccc(NC6=CC(Nc7cc8c(S(=O)(=O)O)cc(S(=O)(=O)O)cc8cc7S(=O)(=O)O)=NN(Cl)N6)cc5)C=C4)=C3)c(S(=O)(=O)O)cc2c1

Procedure:
4,4′-Bis-(2,4-dichlorotriazin-6-ylamino)-stilbene-2,2′-disulfonic acid was reacted with 2-aminonaphthalene-3,6,8-trisulfonic acid in a similar manner to Example 5.
Reaction SMILES: [CH3:1][O-].[Na+].CO.CC1C=CC(S([O:16][CH2:17][C@@H:18]2[CH2:22][CH2:21][C:20](=[O:23])[O:19]2)(=O)=O)=CC=1.CO>C(O)(=O)C>[O:16]1[CH2:17][C@@H:18]1[CH2:22][CH2:21][C:20]([O:19][CH3:1])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCC(=O)O2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)CC[C@H]1CO1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.7 %

Procedure:
28% Sodium methoxide/MeOH solution (74.0 g, 383.35 mmol) was added to a mixture of (S)-(5-oxotetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate (51.81 g, 191.67 mmol) and dehydrated MeOH (280 mL) at room temperature, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was cooled under ice-cooling, and the mixture was neutralized with acetic acid (about 15 mL). The reaction mixture was concentrated to about half-volume under reduced pressure, and ice water (350 mL) was added thereto. Then, the mixture was extracted with a mixed solvent of ethyl acetate/diethyl ether (3:1) (×3). The organic layer was washed successively with aqueous sodium hydrogencarbonate solution, water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give crude methyl (S)-3-(oxiran-2-yl)propanoate (13.12 g, 101 mmol, 53%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].OC1C2C(=CC=C([C:28]([F:31])([F:30])[F:29])C=2)N=CC=1C(OCC)=O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:28]([F:31])([F:30])[F:29])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cnc2ccc(C(F)(F)F)cc2c1O
Reactant: CCOC(=O)c1cnc2ccccc2c1Cl
Product: CCOC(=O)c1cnc2ccc(C(F)(F)F)cc2c1Cl

Procedure:
The title compound was prepared following the procedure described in Step 2 for the synthesis of 3a using 2h instead of 2a. 1H NMR (CDCl3) δ (ppm): 1.46 (3H, t, J=7.14 Hz), 4.51 (2H, q, J=7.14 Hz), 8.00 (1H, dd, J=8.79, 1.92 Hz), 8.26 (1H, d, J=8.79 Hz), 8.78 (1H, dd, J=1.92, 0.83 Hz), 9.34 (1H, s). m/z 304.6 (MH+).
Reaction SMILES: [CH:1]1[C:12]2=[C:13]3[CH:8]([CH2:9][CH2:10][CH2:11]2)[CH2:7][CH2:6][CH2:5][C:4]3=[CH:3][C:2]=1[NH2:14].[Cl-].[C:16]([O:27][CH3:28])(=[O:26])[C:17]1[CH:25]=[CH:24][C:20]([C:21]([O-])=[O:22])=[CH:19][CH:18]=1.Cl>C1C=CC=CC=1.N1C=CC=CC=1>[CH:1]1[C:12]2=[C:13]3[CH:8]([CH2:9][CH2:10][CH2:11]2)[CH2:7][CH2:6][CH2:5][C:4]3=[CH:3][C:2]=1[NH:14][C:21]([C:20]1[CH:24]=[CH:25][C:17]([C:16]([O:27][CH3:28])=[O:26])=[CH:18][CH:19]=1)=[O:22]
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Reactant: Nc1cc2c3c(c1)CCCC3CCC2
Agent: Cl
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)Nc2cc3c4c(c2)CCCC4CCC3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
A solution of 5,6,6a,7,8,9-hexahydro-4H-2-phenalenylamine (0.260 g) in anhydrous benzene (10 ml) and pyridine (3 ml) was added with monomethyl terephthalate chloride (0.304 g), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added with 2 N aqueous hydrochloric acid and thereby made acidic, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, 10% aqueous sodium carbonate, water and saturated brine, and then dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from chloroform-n-hexane to obtain the title compound (0.460 g, yield: 95%) as colorless needles (melting point: 217-218° C.).
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5]C=C(C)C=1.[CH2:9]([O:13]CC1OC1)[CH:10]1[O:12][CH2:11]1.C1(CN)C=CC=C(CN)C=1.OC1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1>C(O)CO.C(C1OC1)Cl>[CH2:9]([O:13][CH2:5][CH2:6][CH2:1][CH3:8])[CH:10]1[O:12][CH2:11]1
Reactant: C(OCC1CO1)C1CO1
Reactant: Cc1cccc(C)c1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: NCc1cccc(CN)c1
Solvent: ClCC1CO1
Solvent: OCCO
Product: CCCCOCC1CO1
Temperature: 80 °C
Reaction time: 1 h
Yield: 210 %

Procedure:
In the same reaction vessel as in Example 1 was fed 270 g of the modified polyamine synthesized in Production Example 1 (corresponding to the modified polyamine based on 1 mol of metaxylene, 0.125 mol of methoxypolyethylene glycol and 0.14 mol of epichlorohydrin), and then 186 g (1 mol) of 2-ethylehexyl glycidyl ether (epoxy equivalent of 186, produced by NOF Corporation, the trademark "Epiol EH") was added dropwise thereto over one hour at 80° C. in an atmosphere of nitrogen under stirring. After the completion of the dropwise addition, the reaction was carried out for one hour at a reaction temperature raised 100° C. Then, the vessel interior was cooled to 80° C., and then 231 g (1.70 mol) of metaxylylenediamine was added thereto. Then, a mixture of 307 g (0.807 mol) of epoxy resin in a liquid form of bisphenol A type (epoxy equivalent 190, produced by Yuka Shell Epoxy Co., Ltd., the trademark "Epicoat 828) with 278 g (2.1 mol) of butyl glycidyl ether (epoxy equivalent of 132, produced by NOF Corporation, the tradmark "Epiol B") was added dropwise thereto over one hour at 80° C.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[N:33]1([C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:31])[F:32])=[CH:4][CH:5]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:30])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc2cc(C(=O)N3CCCCC3)cnc2c1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (50 mg, 0.11 mmol) was combined with piperidine (10 mg, 0.11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 0.14 mmol), 1-hydroxybenzotriazole (17 mg, 0.13 mmol), and triethylamine (0.064 ml, 0.46 mmol) in 1 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was concentrated, the residue was suspended in water, and the solid was collected by vacuum filtration to afford 45 mg of the title compound as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9](=[O:10])[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccncc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 56.3 %

Procedure:
A suspension of (2-amino-5-chlorophenyl) (pyridin-4-yl)methanone (156 g) in pyridine (2350 mL) was heated at 60° C. N,N-Dimethyl-4-aminopyridine (8.21 g) and 4-tert-butylbenzenesulfonyl chloride (180 g) were added, and the mixture was heated at 75° C. for 18 hr. 4-tert-Butylbenzenesulfonyl chloride (15.6 g) was further added, and the mixture was stirred for 1 hr, and this operation was repeated 6 times. The solvent was evaporated under reduced pressure, ethyl acetate was added, and the mixture was washed twice with water (500 mL), and twice with saturated aqueous sodium hydrogen carbonate solution (500 mL). The organic layer was washed twice with 2N hydrochloric acid (200 mL), once with saturated aqueous sodium hydrogen carbonate solution (500 mL), and once with saturated brine (500 mL). The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, 2-propanol was added to the residue and the mixture was stirred at 50° C. for 1 hr. After cooling, the solid was washed with cold 2-propanol (600 mL) and hexane, and dried. 2-Propanol/ethyl acetate (800 mL/80 mL) was added, and the mixture was stirred at 50° C. for 1 hr. After cooling, the solid was washed with cold 2-propanol and hexane, and dried to give the object 4-tert-butyl-N-(4-chloro-2-isonicotinoylphenyl)benzenesulfonamide (162 g, pale-yellow solid). The filtrate was purified by silica gel column chromatography (ethyl acetate/chloroform) to give the object 4-tert-butyl-N-(4-chloro-2-isonicotinoylphenyl)benzenesulfonamide (29 g, pale-yellow solid). A total of 191 g of the object product 4-tert-butyl-N-(4-chloro-2-isonicotinoylphenyl)benzenesulfonamide was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(O)C.Cl[CH:13]([CH:19]=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][N:5]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19][N:8]=[C:4]2[CH:3]=1
Reactant: CCOC(=O)C(Cl)C=O
Reactant: Nc1cc(F)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cnc2cc(F)ccn12
Temperature: 60 °C

Procedure:
4-Fluoropyridin-2-amine (10.0 g, 48.0 mmol) was mixed with ethanol (40 mL) in a reaction flask, under an atmosphere of dry nitrogen. A solution of ethyl 2-chloro-3-oxopropanoate (5% in benzene, 178 mL, Commercial solution from Toronto Research Chemicals Inc.) was added. The mixture was heated to 60° C. under nitrogen for 4 hours. After allowing the mixture to cool the solvent was removed under vacuum to give a brown solid. The solid was mixed with ethyl acetate (300 mL) and sodium bicarbonate solution (75 mL) and stirred to dissolve. The phases were separated and the bicarbonate solution was extracted further with ethyl acetate (75 mL). The combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated under vacuum to give a solid. The crude material was dissolved in ethyl acetate and passed through a short column of silica, eluting with ethyl acetate. Fractions containing the product were concentrated to give ethyl 7-fluoroimidazo[1,2-a]pyridine-3-carboxylate as a white solid (13 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:29]3[CH2:33][CH2:32][CH2:31][NH:30]3)=[N:9][C:10]=2[C:11]2[CH:28]=[CH:27][C:14]([C:15]([NH:17][C:18]3[S:19][C:20]4[CH2:26][CH2:25][CH2:24][CH2:23][C:21]=4[N:22]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:34](O)(=[O:38])[C:35]#[C:36][CH3:37]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:29]3[CH2:33][CH2:32][CH2:31][N:30]3[C:34](=[O:38])[C:35]#[C:36][CH3:37])=[N:9][C:10]=2[C:11]2[CH:28]=[CH:27][C:14]([C:15]([NH:17][C:18]3[S:19][C:20]4[CH2:26][CH2:25][CH2:24][CH2:23][C:21]=4[N:22]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4nc5c(s4)CCCC5)cc3)c12
Reactant: CC#CC(=O)O
Product: CC#CC(=O)N1CCC[C@H]1c1nc(-c2ccc(C(=O)Nc3nc4c(s3)CCCC4)cc2)c2c(N)nccn12
Yield: 19.2 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from (S)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzamide (intermediate 15) and 2-butynoic acid, to afford the title compound (7 mg, 19.2%). Data: UPLC (C) Rt: 2.41 min; m/z 526.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([CH2:21][C:22]4[CH:27]=[C:26](O)[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].[Cl-].CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:45]>CC#N>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([CH2:21][C:22]4[CH:27]=[C:26]([Cl:45])[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30]
Reactant: O=C(Nc1ccc(F)c(C(F)(F)F)c1)c1cccc2cc(Cc3cc(O)ncn3)ccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: O=C(Nc1ccc(F)c(C(F)(F)F)c1)c1cccc2cc(Cc3cc(Cl)ncn3)ccc12
Temperature: 75 °C
Reaction time: 1 h

Procedure:
To a solution of 200 mg (0.453 mMol) 6-(6-hydroxy-pyrimidin-4-ylmethyl)-naphthalene-1-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide in 15 ml CH3CN, 165.7 mg (1.0 mMol) tetrmethylammonium chloride, 127 μl (1.0 mMol) N,N-dimethylaniline and 0.55 ml (6.0 mMol) POCl3 are added. The mixture is heated up to 75° C. for 1 h, cooled to rt and poured into 30 g ice. After 1 h of vigorous stirring, the title compound can be filtered off and washed with 6 ml CH3CN/H2O 1:2: MS: [M+1]+=460/462; HPLC: tRet=16.5.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>[Pd]>[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1
Reactant: Cc1ccccc1B(O)O
Reactant: Brc1cncnc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccccc1-c1cncnc1
Yield: 98.9 %

Procedure:
A suspension of 5-bromopyrimidine(1.52 g),2-methylphenylboronic acid (1.43 g), sodium carbonate (3.04 g) and 10% palladium on charcoal (50% wet, 0.85 g) was refluxed for 24 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. To the residue ethyl acetate was added and the mixture was washed with water and brine. The separated organic layer was dried over magnesium sulfate and evaporated under pressure to give 5-(2-methylphenyl)pyrimidine (1.61 g, 98.7%).