Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([S:17]([CH3:20])(=[O:19])=[O:18])=[N:15][N:14]=[N:13]2)=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:22]([O:24][CH2:25][CH2:26][N:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH:36][CH:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][C:45]2([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH2:49][CH2:48][NH:47][CH2:46]2)[CH2:39][CH2:38]1)[CH3:23]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([S:17]([CH3:20])(=[O:19])=[O:18])=[N:15][N:14]=[N:13]2)=[CH:8][C:4]=1[C:5]([N:47]1[CH2:48][CH2:49][C:45]([CH2:44][CH2:43][N:40]2[CH2:41][CH2:42][CH:37]([NH:36][C:28]3[N:27]([CH2:26][CH2:25][O:24][CH2:22][CH3:23])[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[N:29]=3)[CH2:38][CH2:39]2)([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:46]1)=[O:7]
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(-n2nnnc2S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-n5nnnc5S(C)(=O)=O)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 2-methoxy-5-(5-methylsulfonyltetrazol-1-yl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]=[C:9]=[O:10].[Cl:11][C:12]1[C:13]([O:22][C:23]2[CH:27]=[C:26]([CH2:28][CH3:29])[NH:25][N:24]=2)=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1.Cl>C(OCC)(=O)C>[CH3:7][NH:8][C:9]([N:25]1[C:26]([CH2:28][CH3:29])=[CH:27][C:23]([O:22][C:13]2[C:12]([Cl:11])=[CH:17][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:15][N:14]=2)=[N:24]1)=[O:10]
Reactant: CN=C=O
Reactant: CCc1cc(Oc2ncc(C(F)(F)F)cc2Cl)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCc1cc(Oc2ncc(C(F)(F)F)cc2Cl)nn1C(=O)NC
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
Potassium carbonate (1.16 g, 8.4 mmol) and methyl isocyanate (0.40 g, 7.0 mmol) were added to a solution of 3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-ethylpyrazole (2.45 g, 8.4 mmol) in ethyl acetate (30 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with diethyl ether (30 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/5), to give a white solid of N-methyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-ethylpyrazole-1-carboxamide (1.97 g, yield: 80.7%). mp: 85-87° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.31 (t, J=7.5 Hz, 3H), 2.95 (d, J=5.0 Hz, 3H), 3.13 (dq, J=6.0 and 7.5 Hz, 2H), 6.08 (s, 1H), 6.85-7.15 (m, 1H), 8.02 (d, J=2.1 Hz, 1H), 8.36 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:5]([NH2:7])=O.C(N(CC)CC)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.O>ClCCl>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:5]#[N:7]
Reactant: COc1ccc(Cc2ccc(C(N)=O)cc2O)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cc2ccc(C#N)cc2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of 3-hydroxy-4-(4-methoxybenzyl)benzamide (0.047 g) and triethylamine (0.30 mL) in dichloromethane (1.8 mL) was added trifluoromethanesulfonic anhydride (0.34 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (eluent: dichloromethane/methanol=9/1) to give 3-hydroxy-4-(4-methoxybenzyl)benzonitrile (0.014 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[C:33]1([NH:43]N)[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:43][C:33]2[C:34]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:35][CH:36]=[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=21
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3F)CC2)c1
Reactant: NNc1cccc2ccccc12
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4F)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-naphthylhydrazine hydrochloride: ESMS m/e: 547.7 (M+H)+.
Reaction SMILES: [Br:1][C:2]([Br:30])=[CH:3][C:4]([C:22]1[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=1)([CH3:21])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.[I-].[Na+].C[Si](Cl)(C)C>C(#N)C>[Br:30][C:2]([Br:1])=[CH:3][C:4]([C:22]1[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=1)([CH3:21])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1
Reactant: COc1ccc(C(C)(C=C(Br)Br)CCCc2cccc(Oc3ccccc3)n2)cc1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C=C(Br)Br)(CCCc1cccc(Oc2ccccc2)n1)c1ccc(O)cc1
Temperature: 0 °C
Yield: 93 %

Procedure:
Under a nitrogen atmosphere, 2.0 g of 1,1-dibromo-3-(4-methoxyphenyl)-3-methyl-6-(6-phenoxypyridin-2-yl)-1-hexene were dissolved in 50 ml of dry acetonitrile, and 1.69 g of sodium iodide and 1.23 g of trimethylsilyl chloride were added thereto. The mixture was then heated under reflux for 6 hours. The reaction solution was poured into ice water and extracted twice with ethyl acetate. The ethyl acetate layer was successively washed with an aqueous dilute sodium sulfite solution and a saturated aqueous sodium chloride solution. The solvent was then removed by evaporation under reduced pressure to obtain 1.81 g of the desired 1,1-dibromo-3-(4-hydroxyphenyl)-3-methyl-6-(6-phenoxypyridin-2-yl)-1-hexene.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[Br:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][N:11]=[CH:12]2.[OH-].[NH4+]>OS(O)(=O)=O>[Br:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[C:10]([N+:1]([O-:4])=[O:2])[N:11]=[CH:12]2
Reactant: O=[N+]([O-])[O-]
Reactant: Brc1cccc2cnccc12
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [NH4+]
Product: O=[N+]([O-])c1cc2c(Br)cccc2cn1
Reaction time: 3 h
Yield: 96 %

Procedure:
A solution of potassium nitrate (1.78 g, 8.56 mmol) was added slowly to a solution of 5-bromoisoquinoline in 12 mL H2SO4. After stirring for 3 hours the reaction mixture was poured onto ice and neutralised with conc. ammonium hydroxide. The yellow precipitate was extracted with ethyl acetate (3x), and the combined organic layers were washed with saturated NaCl, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel (40% ethyl acetate in hexane as eluent) to give 5-bromo-3-nitroisoquinoline in 96% yield.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][N:10]3[CH:17]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)#[N:25]>C1(C)C=CC=CC=1.CO.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[O:6][C:5]([C:7]3[N:8]=[C:9]4[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][N:10]4[CH:17]=3)=[CH:4][CH:3]=2)=[CH:28][CH:27]=1)#[N:25]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ccc2nc(-c3ccc(Br)o3)cn2c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-c2ccc(-c3cn4cc(C#N)ccc4n3)o2)cc1
Temperature: 80 °C
Yield: 82 %

Procedure:
To a stirred solution of 3a (10 mmol), and tetrakis(triphenylphosphine) palladium (350 mg) in toluene (20 mL) under a nitrogen atmosphere was added 10 mL of a 2 M aqueous solution of Na2CO3 followed by 4-Cyanophenyl boronic acid (12 mmol) in 10 mL of methanol. The vigorously stirred mixture was warmed to 80° C. for 24 h, then cooled, and the precipitate was filtered. The precipitate was partitioned between methylene chloride (500 mL) and 2 M aqueous Na2CO3 (50 mL) containing 6 mL of concentrated ammonia. The organic layer was dried (Na2SO4), and then concentrated to dryness under reduced pressure to afford 4a. Yield 82%, mp 298-300° C. (DMF). 1H NMR (DMSO-d6); δ 7.11 (d, J=3.6 Hz, 1H), 7.37 (d, J=3.6 Hz, 1H), 7.53 (d, J=9.6 Hz, 1H), 7.72 (d, J=9.6 Hz, 1H), 7.90 (d, J=8.4 Hz, 2H), 7.98 (d, J=8.4 Hz, 2H), 8.45 (s, 1H), 9.32 (s, 1H). 13C NMR; δ 152.0, 150.4, 145.1, 138.6, 135.0, 134.4, 133.6, 126.1, 124.6, 119.5, 118.0, 117.6, 112.2, 111.3, 110.2, 98.1. MS (m/z, rel.int.); 310 (M+, 100), 281 (10), 208 (5), 180 (10). High resolution mass calcd. for C19H10N4O: 310.08546. Observed: 310.07852. Anal. Calcd. for 4a (C19H10N4O): C % 73.54, H % 3.25, N % 18.06. Found: C % 73.28, H % 3.26, N % 17.75.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5](=[O:30])[CH:6]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Br:31][CH2:32][CH2:33]Br>C(O)C>[CH3:3][O:4][C:5](=[O:30])[CH:6]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:33][CH2:32][Br:31])=[CH:10][CH:9]=1
Reactant: BrCCBr
Reactant: COC(=O)C(Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1cccnc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C(Cc1ccc(OCCBr)cc1)Nc1ccccc1C(=O)c1cccnc1
Yield: 28.1 %

Procedure:
To a solution of potassium hydroxide (0.17 g, 2.95 mmol) in ethanol (20 ml) is added 2-((2-nicotinoylphenyl)amino)-3-(4-hydroxyphenyl)-propionic acid methyl ester (1.10 g, 2.95 mmol) and 1,2-dibromoethane (5.54 g, 29.50 mmol). Then the mixture is heated to reflux for 8 hours. After cooled, the reaction mixture is filtered to remove the solid formed, and then the filtrate is evaporated under a vacuum. The crude product is purified by silica gel chromatography using hexane/EtOAc (4:1) as eluent to give the title compound (0.40 g, 28.2%).
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:15][CH2:16][CH3:17])=[C:7]([O:12][CH2:13][CH3:14])[CH:8]=2)[N:3]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>>[F:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[CH:11]=[N:10][C:9]3[C:4](=[CH:5][C:6]([O:15][CH2:16][CH3:17])=[C:7]([O:12][CH2:13][CH3:14])[CH:8]=3)[N:3]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: Nc1cccc(F)c1
Reactant: CCOc1cc2ncc(Cl)nc2cc1OCC
Product: CCOc1cc2ncc(Nc3cccc(F)c3)nc2cc1OCC
Yield: 54.1 %

Procedure:
To 0.25 g (0.989 mmol) of 2-chloro-6,7-diethoxyquinoxaline is added 2 mL of m-fluoroaniline. This mixture is heated under nitrogen overnight to 120° C. The resulting mixture is chromatographed (30:1 CH2Cl2: EtOH) to yield partially purified product. This solid is triturated with ethyl acetate to give 0.175 g of the product as a brownish yellow solid in 54.1% yield (m.p. 193° C.). Anal. Calcd for C18H18N3O2F.0.25H2O: C, 65.15; H, 5.62; N, 12.66. Found: C, 65.30; H, 5.30; N, 12.41.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:27][O:28][C:29](=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:20][S:21][CH2:22][CH2:23][C:24]([OH:26])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl.[C:47]([O:51][C:52](=[O:59])[CH2:53][NH:54][C:55](=[O:58])[CH2:56][NH2:57])([CH3:50])([CH3:49])[CH3:48].P(C#N)(OCC)(OCC)=O.O>CN(C)C=O.C(N(CC)CC)C>[C:47]([O:51][C:52](=[O:59])[CH2:53][NH:54][C:55](=[O:58])[CH2:56][NH:57][C:24](=[O:26])[CH2:23][CH2:22][S:21][CH2:20][CH:19]([O:18][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:27][O:28][C:29](=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])([CH3:50])([CH3:48])[CH3:49]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Reactant: CC(C)(C)OC(=O)CNC(=O)CN
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)NCC(=O)NCC(=O)OC(C)(C)C)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 17 h
Yield: 78 %

Procedure:
To a solution of 6,7-bis(palmitoyloxy)-4-thiaheptanoic acid as obtained in Reference Example 4 (200 mg) and glycylglycine t-butyl ester hydrochloride (80 mg) in dimethyl formamide (3 ml), triethylamine (0.099 ml) and diethyl cyanophosphate (73 mg) were added, followed by stirring at room temperature for 17 hours. After addition of water, the reaction mixture was extracted with chloroform. The extract was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:3) to yield the title compound (191 mg, yield 78%) as a wax-like substance.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([CH:44]=[O:45])=[C:25]2[C:29]=1[N:28]=[C:27]1[N:30]([C:34]3[C:35]([CH3:43])=[N:36][C:37]([O:41][CH3:42])=[N:38][C:39]=3[CH3:40])[CH2:31][CH2:32][CH2:33][N:26]21.C[Si](C)(C)[C:48]([F:51])([F:50])[F:49].Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[F:49][C:48]([F:51])([F:50])[CH:44]([C:24]1[C:25]2[N:26]3[CH2:33][CH2:32][CH2:31][N:30]([C:34]4[C:35]([CH3:43])=[N:36][C:37]([O:41][CH3:42])=[N:38][C:39]=4[CH3:40])[C:27]3=[N:28][C:29]=2[C:21]([O:20][CH3:19])=[CH:22][CH:23]=1)[OH:45]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1nc(C)c(N2CCCn3c2nc2c(OC)ccc(C=O)c23)c(C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: COc1nc(C)c(N2CCCn3c2nc2c(OC)ccc(C(O)C(F)(F)F)c23)c(C)n1
Temperature: 0 °C
Reaction time: 1.17 h
Yield: 40.3 %

Procedure:
Tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 0.13 mL, 0.13 mmol) was added to a stirred solution of the 9-methoxy-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (467 mg) and trimethyl(trifluoromethyl)silane (361 mg, 2.54 mmol) in tetrahydrofuran (5.0 mL) at 0° C., and the mixture was stirred at 0° C. for 30 min, at room temperature for 70 min. 1N Hydrochloric acid (5.0 mL) was added to the mixture at room temperature, and the mixture was stirred for 15 min. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-7% methanol/ethyl acetate gradient mixture. The eluate was concentrated in vacuo to give the title compound as a colorless solid (224 mg, 0.512 mmol).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[CH3:19][O:20][C:21]1[C:26]2[N:27]=[C:28]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[S:29][C:25]=2[CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:33]1[CH2:34][CH2:35][N:30]([C:28]2[S:29][C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([O:20][CH3:19])[C:26]=3[N:27]=2)[CH2:31][CH2:32]1)=[O:9])([CH3:2])[CH3:3]
Reactant: COc1cccc2sc(N3CCNCC3)nc12
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Solvent: C1CCOC1
Product: COc1cccc2sc(N3CCN(C(=O)c4cc(S(C)(=O)=O)ccc4OC(C)C)CC3)nc12

Procedure:
Prepared in analogy to example 1.1 b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.2) and 4-Methoxy-2-piperazin-1-yl-benzothiazole hydrochloride in tetrahydrofuran. The crude material was purified by chromatography (SiO2, heptane/ethyl acetate), and the residue was then triturated in ether to yield the title compound as a white solid.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:30][C:29]([CH:31]=O)=[N:28][N:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.Cl.[OH:34][CH:35]1[CH2:38][NH:37][CH2:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.C(N(CC)CC)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:30][C:29]([CH2:31][N:37]5[CH2:38][CH:35]([OH:34])[CH2:36]5)=[N:28][N:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: O=Cc1nnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Reactant: OC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3nnc(CN4CC(O)C4)s3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.8 %

Procedure:
To a solution of 5-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3,4-thiadiazole-2-carbaldehyde (300 mg) in tetrahydrofuran (20 mL) were added 3-hydroxyazetidine hydrochloride (105 mg), sodium triacetoxyborohydride (270 mg) and triethylamine (177 μL) and the mixture was stirred at room temperature for 18 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography to give pale-yellow amorphous solid from a fraction eluted with ethyl acetate-methanol (9:1, volume ratio). The pale-yellow amorphous solid was purified by preparative HPLC to give the title compound (97 mg, yield 29%) as a pale-yellow amorphous solid. MS: 529 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=1.O1CCCOB1[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C(OCC)(=O)C.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.O.C(O)C>[Cl:8][C:6]1[CH:7]=[C:2]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[N:3]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:5]=1
Reactant: C[C@H](Nc1nc(Cl)cc(Cl)n1)c1ccc(F)cc1
Reactant: c1cncc(B2OCCCO2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: C[C@H](Nc1nc(Cl)cc(-c2cccnc2)n1)c1ccc(F)cc1
Temperature: 110 °C
Reaction time: 3 h
Yield: 37.9 %

Procedure:
500 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine (Reference Example 1), 314 mg of 3-(1,3,2-dioxaborinan-2-yl)pyridine, 927 mg of sodium carbonate and 202 mg of tetrakis(triphenylphosphine)palladium were added in turn to a degassed mixed solvent of 15 ml of toluene, 7 ml of ethanol and 10 ml of water, and the mixture was stirred at 110° C. for 3 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 218 mg of the objective compound as white powder.
Reaction SMILES: O.[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[O:5][S:6]([N:9]=C=O)(=[O:8])=[O:7].C(=O)=O>ClC(Cl)(Cl)Cl>[S:6](=[O:8])(=[O:7])([O:5][C:4]1[C:3]([Cl:2])=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:16])[NH2:9]
Reactant: O=C=NS(=O)(=O)Oc1c(Cl)cccc1Cl
Agent: O=C=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: NS(=O)(=O)Oc1c(Cl)cccc1Cl
Temperature: 0 °C

Procedure:
2.6 ml of water are added dropwise at 30° C. to 40° C. to a solution of 24.4 g of 2,6-dichlorophenoxysulfonyl isocyanate in 200 ml of tetrachloromethane. The mixture is then stirred at room temperature until the evolution of carbon dioxide is complete and cooled to 0° C., the product is filtered off with suction and the residue is then washed with ice-cold tetrachloromethane. After drying in vacuo, 21.4 g of 2,6-dichlorophenyl sulfamate of melting point 108°-110° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([O:36]C)=[O:35])[CH:28]=[CH:27]4)=[CH:20][CH:19]=2)=[C:12]([CH:38]([CH3:40])[CH3:39])[O:11][N:10]=1.O1CCCC1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([OH:36])=[O:35])[CH:28]=[CH:27]4)=[CH:22][CH:23]=2)=[C:12]([CH:38]([CH3:40])[CH3:39])[O:11][N:10]=1
Reactant: COC(=O)c1ccc2cc(-c3ccc(OCCCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCCOc1ccc(-c2ccc3nc(C(=O)O)ccc3c2)cc1
Temperature: 90 °C
Yield: 87.5 %

Procedure:
To a solution of methyl 6-[4-({3-[3-(2,6-dichlorophenyl) -5-(1-methylethyl)-4-isoxazolyl]propyl}oxy)phenyl]-2-quinolinecarboxylate (14 mg, 0.024 mmol) in 1:1 tetrahydrofuran:methanol (1 mL) was added 1 N sodium hydroxide (0.089 mL, 0.089 mmol). The solution was heated in a microwave reactor at 90° C. for 10 minutes. Then 1 N hydrochloric acid (0.089 mL, 0.089 mmol) was added and the mixture was concentrated. Water and ethyl acetate were added to the residue and the layers were separated. The ethyl acetate layer was dried over magnesium sulfate and concentrated to afford 12 mg of 6-[4-({3-[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]propyl}oxy)phenyl]-2-quinolinecarboxylic acid as a yellow solid (0.021 mmol, 89%). 1H-NMR (400 MHz, DMSO-d6) δ 8.42 (d, J=9 Hz, 1H), 8.28 (d, J=9 Hz, 1H), 8.19 (d, J=9 Hz, 1H), 8.06-8.04 (m, 2H), 7.64 (d, J=9 Hz, 2H), 7.41-7.29 (m, 3H), 6.93 (d, J=9 Hz, 2H), 3.90 (t, J=6 Hz, 2H), 3.20 (septet, J=7 Hz, 1H), 2.52 (t, J=6 Hz, 2H), 1.83-1.77 (m, 2H), 1.34 (d, J=7 Hz, 6H). HRMS (ESI) C31H26Cl2N2O4 calculated: 561.1342 (M+H)+, found: 561.1344 (M+H)+.