Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=3)=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)cc2)C1
Reactant: Clc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Nc3ccc(Cl)cn3)cc2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
(RS)-2-(4-Amino-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (60 mg, CAS 1002726-96-6), 2,5-dichloropyridine (31.9 mg, CAS 16110-09-1) and cesium carbonate (105 mg) were combined with dioxane (2 ml) to give a yellow suspension. The mixture was degassed by bubbling argon into the mixture for several minutes. Xantphos (7.48 mg) and tris(dibenzylideneacetone)dipalladium chloroform complex (6.69 mg) were then added. The reaction mixture was then capped and stirred at 100° C. overnight. The crude reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel; gradient: 0% to 70% EtOAc in hexanes) to afford (RS)-2-[4-(5-chloro-pyridin-2-ylamino)-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (52 mg, 62%) as a yellow amorphous solid. MS (ISP): 392.0 ([{37Cl}M+H]+), 390.1 ([{35Cl}M+H]+), 336.4 ([{37Cl}M+H—C4H8]+), 334.3 ([{35Cl}M+H—C4H8]+).
Reaction SMILES: [NH3:1].[O:2]=[C:3]1[C:8]2[CH:9]=[CH:10]O[C:7]=2[CH2:6][CH2:5][CH2:4]1>C(O)C>[O:2]=[C:3]1[CH2:4][CH2:5][CH2:6][C:7]2[NH:1][CH:10]=[CH:9][C:8]1=2
Reactant: N
Reactant: O=C1CCCc2occc21
Solvent: CCO
Product: O=C1CCCc2[nH]ccc21
Yield: 96 %

Procedure:
To a mixture of 3 ml of ethanol and 7 ml of 29% aqueous ammonia was added 1.0 g of 4-oxo-4,5,6,7-tetrahydrobenzofuran, and then the mixture was subjected to reaction in a sealed tube at 150° C. for 12 hours. After completing the reaction, the reaction mixture was concentrated. The resulting residue was applied to a column of silica gel and eluted with a mixed solvent of acetone and ethyl acetate to give 950 mg (yield: 96%) of 4-oxo-4,5,6,7-tetrahydroindole being a light yellowish crystal.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:11]=1[NH2:12].CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C1(C)C=CC=CC=1>[Cl:9][C:10]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:11]=1[NH:12][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1Cl
Reactant: Fc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: Fc1ccc(Nc2ccc(F)cc2Cl)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 68.5 %

Procedure:
A round bottom flask was charged with 1-bromo-4-fluorobenzene (6.011 g, 34.4 mmol), 2-chloro-4-fluoroaniline (5.000 g, 34.3 mmol), Xantphos (0.795 g, 1.4 mmol), anhydrous toluene (200 mL), and sodium tert-butoxide (4.952 g, 51.5 mmol). The mixture was degassed and filled with nitrogen, and then tris(dibenzylideneacetone)dipalladium(0) (0.944 g, 1.0 mmol) was added and the reaction was stirred under nitrogen at 100° C. for 16 hrs. After cooling to room temperature, the mixture was filtered through Celite and the filter cake washed with methylene chloride. The filtrate was concentrated and the residue purified by silica gel chromatography (0-20% ethyl acetate/hexanes) to afford a yellowish oil (5.63 g, 68%). 1H NMR (300 MHz, CDCl3) δ 7.14 (dd, 1H, J=8.4, 3.0 Hz), 7.12-6.98 (m, 5H), 6.88 (td, 1H, J=8.7, 3.0 Hz), 5.80 (br s, 1H).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:23][CH:24]2[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]2)=[C:10]([C:12]2[C:13]3[CH:22]=[CH:21][NH:20][C:14]=3[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)[CH:11]=1)(=[O:5])=[O:4])[CH3:2].[BH4-].[Na+]>O1CCCC1>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:23][C@H:24]2[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26][CH2:25]2)=[C:10]([C:12]2[C:13]3[CH:22]=[CH:21][NH:20][C:14]=3[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)[CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(OC2CCC(=O)CC2)c(-c2cn(C)c(=O)c3[nH]ccc23)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(O[C@H]2CC[C@@H](O)CC2)c(-c2cn(C)c(=O)c3[nH]ccc23)c1

Procedure:
A mixture of Example 199 (0.052 g, 0.121 mmol) and sodium tetrahydroborate (6.89 mg, 0.182 mmol) in tetrahydrofuran (5 mL) was heated at 60° C. for 2 hours. The solvent was removed, and the solid was treated with MeOH and a couple of drops of TFA. The resulting solution was purified by Preparative HPLC (C18, 10-80% CH3CN/water (0.1% TFA)) to give the title compound (second eluting peak, 0.036 g, 0.084 mmol, 68.9% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.06 (s, 1H), 7.78-7.82 (m, 2H), 7.36-7.38 (m, 2H), 7.30 (t, J=2.75 Hz, 1H), 6.14-6.16 (m, 1H), 4.62-4.63 (m, 1H), 3.51-3.58 (m, 5H), 3.25-3.31 (m, 2H), 1.75-1.81 (m, 2H), 1.50-1.64 (m, 4H), 1.32-1.40 (m, 2H), 1.14 (t, J=7.32 Hz, 3H). MS (ESI+) m/z 431.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34](O)=[O:35])[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:9][CH:8]=1.Cl.Cl.C[O:45][C:46](=[O:64])[C@@H:47]([NH2:63])[CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][N:58]=[C:57]([CH3:61])[C:56]=2[CH3:62])=[CH:51][CH:50]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34]([NH:63][C@@H:47]([CH2:48][C:49]5[CH:54]=[CH:53][C:52]([C:55]6[CH:60]=[CH:59][N:58]=[C:57]([CH3:61])[C:56]=6[CH3:62])=[CH:51][CH:50]=5)[C:46]([OH:45])=[O:64])=[O:35])[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:11][CH:12]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccnc(C)c2C)cc1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCc2cccc(Cl)c2)cc1)O3
Agent: Cl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccnc(C)c2C)cc1)C(=O)O)OC[C@H](c1ccc(OCc2cccc(Cl)c2)cc1)O3

Procedure:
(3S,8S)-3-(4-Hydroxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester (20 mg) was reacted with 3-chloro-benzyl bromide according to General Procedure J and the resulting ester was hydrolyzed according to General Procedure AB to provide (3S,8S)-3-[4-(3-chloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (20 mg). The title compound (18 mg) was prepared from (3S,8S)-3-[4-(3-chloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (20 mg) and (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride according to General Procedures L and B. LCMS (m/z): 823.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:34])[NH:10][C@@H:11]([CH2:27][C:28]2[N:32]([CH3:33])[CH:31]=[N:30][CH:29]=2)[C:12]([NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:19]=2)=[O:13])[O:7]1)=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:19]=[C:15]([NH:14][C:12](=[O:13])[C@@H:11]([NH:10][C:9]([C@H:8]3[O:7][C@@H:6]3[C:4]([OH:5])=[O:3])=[O:34])[CH2:27][C:28]3[N:32]([CH3:33])[CH:31]=[N:30][CH:29]=3)[S:16][CH:17]=2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cncn1C)C(=O)Nc1nc(-c2ccc(F)cc2)cs1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cn1cncc1C[C@H](NC(=O)[C@H]1O[C@@H]1C(=O)O)C(=O)Nc1nc(-c2ccc(F)cc2)cs1
Yield: 46.9 %

Procedure:
Synthesized following general saponification procedure using the following quantities: the corresponding peptidomimetic epoxide ethyl ester 20 (129 mg, 0.26 mmol): LiOH (6.3 mg, 0.26 mmol); THF/MeOH/H2O (2.5 mL: 1.5 mL: 1.5 mL); yielded 35 as a white solid (56 mg, 46.1%). 1H NMR (DMSO-d6, 400 MHz): 8.92-8.90 (d, 1H); 7.96-7.91 (m, 2H): 7.68 (s, 1H); 7.35-7.24 (m, 3H); 4.94-4.87 (m, 1H); 4.64-4.56 (m, 2H); 3.82-3.50 (m, 5H). 13C NMR (400 MHz, DMSO-d6): 171.52, 167.50, 165.57, 162.45, 161.02, 148.42, 138.62, 131.27, 128.18, 128.01, 127.83, 127.05, 116.17, 115.99, 106.70, 53.24, 52, 58, 51.90, 31.29, 29.52. ESI-HRMS (m/z): [M+H+] calcd. for C20H18FN5O5S: 460.1085; observed, 460.1092; Rt=17.8 min, purity=93.6%.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[N:27]=[C:28]=[O:29]>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:28]([NH:27][C:18]2[CH:19]=[CH:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=2)=[O:29])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1ccc2ccccc2c1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc3ccccc3c2)cc1-c1c(Br)cnn1C
Yield: 75 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.035 g, 0.12 mmol) was treated with 2-naphthyl isocyanate (0.023 g, 0.13 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 14 (0.040 g, 0.09 mmol, 70%) as a white solid. LCMS m/z (%)=451 (M+H79Br, 95), 453 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.30 (s, 1H), 8.20 (s, 1H), 8.19 (d, J=1.8 Hz, 1H), 7.56-7.84 (m, 3H), 7.72 (dd, J=2.7, 9.0 Hz, 1H), 7.56 (dd, J=2.1, 8.8 Hz, 1H), 7.50 (s, 1H), 7.48 (d, J=2.7 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 3.83 (s, 3H), 3.70 (s, 3H).
Reaction SMILES: [OH-].[Li+].[O:3]=[C:4]([NH:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][CH:8]=1>CO>[O:3]=[C:4]([NH:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1ccc(OCC(=O)NCc2cccnc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(COc1ccc(C(=O)O)cc1)NCc1cccnc1
Reaction time: 2 h
Yield: 79.7 %

Procedure:
0.17 g of lithium hydroxide was added to a methanol (30 ml) solution including 1 g (3.2 mmole) of ethyl 4-{2-oxo-2-[(pyridin-3-ylmethyl)amino]ethoxy}benzoate, and reaction was then carried out at 60° C. for 2 hours. After the solvent had been removed, the residue was dissolved in water and then neutralized with hydrochloric acid, and the deposited solid was collected by filtration, washed with water, and then dried to obtain 0.73 g (yield: 79%) of 4-{2-oxo-2-[(pyridin-3-ylmethyl)amino]ethoxy}benzoic acid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@:10]1([CH2:16][OH:17])[O:14][C:13](=[O:15])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.CN(C1C=CC=CN=1)C.[C:33](Cl)(=[O:47])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@:10]1([CH2:16][O:17][C:33](=[O:47])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[O:14][C:13](=[O:15])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCCC(=O)Cl
Reactant: O=C1CC[C@](CO)(COCc2ccccc2)O1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCC(=O)OC[C@]1(COCc2ccccc2)CCC(=O)O1
Yield: 91.8 %

Procedure:
A solution of 2.14 (0.024 g, 0.1 mmol) in CH2Cl2 (5 mL) was stirred with pyridine (0.032 mL, 0.4 mmol), a catalytic amount of dimethylaminopyridine, and tetradecanoyl chloride (0.054 mL, 0.2 mmol) for 2 h at room temperature. The solution was concentrated and the residue was purified by flash column chromatography over silica gel with hexane:EtOAc (2:1) as eluant to give 2.15 (0.041 g, 92%) as an oil; [α]22D +1.43° (c 4.2, CHCl3); IR (neat) 1783 and 1743 cm-1 (C=O); 1H NMR (CDCl3) δ 0.85 (distorted triplet, 3 H, CH3), 1.10-1.40 (m, 20 H, CH3 (CH2)10CH2CH2CO), 1.60 (br m, 2 H, CH3 (CH2)10CH2CH2CO), 2.00-2.30 (m, 2 H, H-4), 2.30 (t, J=7.5 Hz, 2 H, CH3 (CH2)10CH2CH2CO), 2.50-2.75 (m, 2 H, H-3), 3.60 (br s, 2 H, CH2OCH2Ph), 4.20 (AB q, J=11.9 Hz, 2 H, CH2OCO), 4.55 (br s, 2 H, CH2OCH2Ph), 7.20-7.40 (m, 5 H, Ph); 13C NMR (CDCl3) δ 14.09, 22.65, 24.81, 26.40, 28.78, 29.07, 29.20, 29.32, 29.42, 29.57, 29.61, 29.64, 31.89, 34.03, 65.99, 72.21, 73.76, 84.94, 127.63, 127.93, 128.49, 137.33, 173.14, 176.30. Anal. Calcd for C27H42O5 : C, 72.61; H, 9.48. Found: C, 72.70; H, 9.50.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH2:8][CH2:9][O:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]2[N:17]=[CH:18][S:19][C:15]=2[CH:14]=1.C(=O)=O.[CH3:25][O:26][CH2:27][CH2:28][O:29][CH2:30][O:31][C:32]1[CH:42]=[CH:41][C:35]([C:36](OCC)=[O:37])=[CH:34][CH:33]=1.[NH4+].[Cl-]>CCCCCC.O1CCCC1.CC(C)=O>[CH3:6][O:7][CH2:8][CH2:9][O:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]2[N:17]=[C:18]([C:36](=[O:37])[C:35]3[CH:34]=[CH:33][C:32]([O:31][CH2:30][O:29][CH2:28][CH2:27][O:26][CH3:25])=[CH:42][CH:41]=3)[S:19][C:15]=2[CH:14]=1
Reactant: CCOC(=O)c1ccc(OCOCCOC)cc1
Reactant: COCCOCOc1ccc2ncsc2c1
Agent: O=C=O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CCCCCC
Product: COCCOCOc1ccc(C(=O)c2nc3ccc(OCOCCOC)cc3s2)cc1
Yield: 77.8 %

Procedure:
A solution of 1.3 N of n-butyllithium in hexane (0.7 ml) was added to a solution of 220 mg of 6-[(2-methoxyethoxy)methoxy]benzothiazole (obtained as in paragraph 1 above) in 30 ml of tetrahydrofuran at -78° C. cooled by dry ice--acetone. The mixture was added dropwise into a solution of 234 mg of ethyl 4-[(2-methoxyethoxy)methoxy]benzoate (obtained as in paragraph 2 above) in tetrahydrofuran (3 ml) cooled by dry ice--acetone. NH4Cl was added to the reaction mixture and the mixture was extracted with ether. The extracts were washed with water and dried over sodium sulfate. After being concentrated, the residue was recrystallized from ethyl acetate to yield 320 mg of 6-(2-methoxyethoxy)methoxy-2-{4-[(2-methoxyethoxy)methoxy]benzoyl}benzothiazole (Compound 1). mp: 46° C. 1H-NMR(CDCl3): 3.38(s,3H), 3.38(s,3H), 3.58(m,4H), 3.86(m,4H), 5.38(s,4H), 7.18(d,J=8.8 Hz,2H), 7.28(dd,J=9.1,2.2 Hz,1H), 7.67(d,J=2.2 Hz,1H), 8.10(d,J=9.1 Hz,1H), 8.59(d,J=8.8 Hz,2H) IR(KBr) cm-1 : 2877, 1598, 1488, 1214, 1117, 987 MS m/z: 447(M+), 89, 59 Elementary analysis (C22H25NO7S): Calculated (C=59.05,H=5.63,N=3.13); Found (C=59.15,H=5.58,N=2.93)
Reaction SMILES: [F:1][C:2]([F:28])([C:13]1N2N=C(C3C=NN(C)C=3)C=CC2=[N:15][N:14]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.C([OH:31])C.O>>[F:1][C:2]([F:28])([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2)[C:13]([NH:14][NH2:15])=[O:31]
Reactant: CCO
Reactant: Cn1cc(-c2ccc3nnc(C(F)(F)c4ccc5ncccc5c4)n3n2)cn1
Solvent: O
Product: NNC(=O)C(F)(F)c1ccc2ncccc2c1

Procedure:
Form I of the compound of formula (I) (0.5 g, as prepared in Example 1) is heated at 60° C. in acetone/water mixture (50/50, vol/vol; 12 mL) for 1 hour. The solids are filtered and dried at 50° C. to provide 0.48 g of Form III.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[C:5]([Cl:12])[C:4]=1[F:13].[CH2:14]([CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)[CH2:15][CH2:16][CH2:17][CH3:18].Cl>C1COCC1.C1(C)C=CC=CC=1>[Cl:12][C:5]1[C:4]([F:13])=[C:3]([C:22]2([OH:25])[CH2:21][CH2:20][CH:19]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:24][CH2:23]2)[CH:8]=[CH:7][C:6]=1[O:9][CH2:10][CH3:11]
Reactant: CCOc1ccc(Br)c(F)c1Cl
Reactant: CCCCCC1CCC(=O)CC1
Agent: Cl
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCCC1CCC(O)(c2ccc(OCC)c(Cl)c2F)CC1
Temperature: 43 °C
Reaction time: 1.5 h
Yield: 102 %

Procedure:
2.9 g of well dried magnesium and 20 mL of THF were placed in a reactor under nitrogen atmosphere, and heated to 43° C. 30.0 g of 1-bromo-3-chloro-4-ethoxy-2-fluoro benzene (1) dissolved in 80 mL of THF was slowly added dropwise thereto at a temperature range of from 38 to 46° C., followed by stirring for 90 minutes. Thereafter, 19.0 g of 4-pentylcyclo hexanone dissolved in 20 mL of THF was slowly added dropwise thereto at a temperature range of from 38 to 44° C., followed by stirring for 60 minutes. After cooling the resulting reaction mixture to 30° C., the reaction mixture was mixed with 100 mL of 3N hydrochloric acid and 100 mL of toluene in a vessel and separated into an organic layer and an aqueous layer by standing still, so as to attain extraction. The resulting organic layer was fractionated and washed with water, a 2N sodium hydroxide aqueous solution, a saturated sodium bicarbonate aqueous solution and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain 39.5 g of 1-(3-chloro-4-ethoxy-2-fluorophenyl)-4-pentylcyclohexanol (3). The resulting compound (3) was a yellow oily matter.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]([N:13]2[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14]2)[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[NH2:26][NH2:27].O.C(OCC)(=O)C>C(O)C(C)C>[F:10][C:9]([F:12])([F:11])[CH:8]([N:13]1[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14]1)[C:5]1[CH:6]=[N:7][C:2]([NH:26][NH2:27])=[CH:3][CH:4]=1
Reactant: NN
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(c2ccc(Cl)nc2)C(F)(F)F)C1
Solvent: CCOC(C)=O
Solvent: CC(C)CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(c2ccc(NN)nc2)C(F)(F)F)C1
Temperature: 25 °C
Yield: 94.1 %

Procedure:
A solution of tert-butyl (3S)-1-(1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (5.74 g, 15.11 mmol) and anhydrous hydrazine (4.74 mL, 151.1 mmol) in i-BuOH (20 mL) in a sealed tube was stirred at 130° C. for 18 hours. After cooling to ambient temperature, water (10 mL) and ethyl acetate (30 mL) were added. The organic layer was separated, washed with saturated sodium bicarbonate and brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to give tert-butyl (3S)-1-(2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (5.34 g, 94.1%) as a white foam solid.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1(O)C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[CH3:46][O:47][C:48]1[C:53]([CH2:54][NH2:55])=[C:52]([C:56]([F:59])([F:58])[F:57])[CH:51]=[C:50]([CH3:60])[N:49]=1>ClCCl.O>[CH3:46][O:47][C:48]1[C:53]([CH2:54][NH:55][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:16][CH:15]=2)=[C:52]([C:56]([F:59])([F:57])[F:58])[CH:51]=[C:50]([CH3:60])[N:49]=1
Reactant: COc1nc(C)cc(C(F)(F)F)c1CN
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1nc(C)cc(C(F)(F)F)c1CNC(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
To a solution of 4-phenoxybenzoic acid (640 mg, 3 mmol) in anhydrous dichloromethane (30 mL) were added 1H-benzo[d][1,2,3]triazol-1-ol (600 mg, 4.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (864 mg, 4.5 mmol) and triethylamine (1.1 g, 10 mmol). After stirring at room temperature for 0.5 hour, (2-methoxy-6-methyl-4-(trifluoromethyl)pyridin-3-yl)methanamine (0.47 g, 2.1 mmol) was added. After stirring at room temperature for 4 hours, to the mixture was added water (20 mL). The resultant mixture was extracted with dichloromethane (20 mL×2). Organic layers were combined and concentrated to give a residue. The residue was purified by chromatography (petroleum ether/ethyl acetate=1:1) to give N-((2-methoxy-6-methyl-4-(trifluoromethyl)pyridin-3-yl)methyl)-4-phenoxybenzamide (600 mg, 67.5%). LRMS (M+H) m/z: calcd 416.13. found 416. 1H NMR (300 MHz, CD3OD): δ 7.78 (d, J=8.7 Hz, 2H), 7.40 (t, J=7.8 Hz, 2H), 7.18 (t, J=7.2 Hz, 1H), 7.12 (s, 1H), 7.05 (d, J=8.1 Hz, 2H), 6.97 (d, J=8.7 Hz, 2H), 4.63 (s, 2H), 4.01 (s, 3H), 2.53 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:23][CH:22]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:32])([F:33])[F:19])=[CH:26][CH:25]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3)n2)o1

Procedure:
Following general procedure A followed by either B or C, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and (E)-3-(4-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: [OH:1][CH2:2]/[C:3](/[CH3:13])=[CH:4]/[CH2:5][CH2:6]/[C:7](/[CH3:12])=[CH:8]\[C:9]([OH:11])=O.[CH2:14]([N:16](CC)[CH2:17][CH3:18])[CH3:15].C(Cl)(=O)OCC.C(NCC)C>ClCCl>[CH2:14]([N:16]([CH2:17][CH3:18])[C:9](=[O:11])/[CH:8]=[C:7](/[CH3:12])\[CH2:6][CH2:5]/[CH:4]=[C:3](\[CH3:13])/[CH2:2][OH:1])[CH3:15]
Reactant: CCN(CC)CC
Reactant: C/C(=C/C(=O)O)CC/C=C(\C)CO
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCNCC
Product: CCN(CC)C(=O)/C=C(/C)CC/C=C(\C)CO

Procedure:
Following the same manner as in Example 5, the reaction and after-treatment were conducted by using 1.0 g of (E,E) and (Z,E)-8-hydroxy-3,7-dimethyl-2,6-octadienoic acid, 0.9 ml of triethylamine, 0.62 ml of ethyl chlorocarbonate and 0.67 ml of diethylamine in 20 ml of dichloromethane to afford 850 mg of the end product.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11]([NH:12][C@@H:13]3[CH2:17][CH2:16][C@:15]([CH3:22])([C:18]([O:20]C)=[O:19])[C:14]3([CH3:24])[CH3:23])=[C:10]([C:25](=[O:27])[NH2:26])[CH:9]=[N:8][N:7]2[CH:28]=1>C(O)C.C(OCC)(=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:11]([NH:12][C@@H:13]3[CH2:17][CH2:16][C@:15]([CH3:22])([C:18]([OH:20])=[O:19])[C:14]3([CH3:24])[CH3:23])=[C:10]([C:25](=[O:27])[NH2:26])[CH:9]=[N:8][N:7]2[CH:28]=1
Reactant: COC(=O)[C@@]1(C)CC[C@@H](Nc2c(C(N)=O)cnn3cc(Br)cc23)C1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1(C)[C@H](Nc2c(C(N)=O)cnn3cc(Br)cc23)CC[C@]1(C)C(=O)O
Temperature: 75 °C
Yield: 89.4 %

Procedure:
A 4.5 M aqueous solution of potassium hydroxide (210 μl, 0.945 mmol) was added dropwise to a solution of (1S,3R)-methyl 3-(6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-ylamino)-1,2,2-trimethylcyclopentanecarboxylate (200 mg, 0.472 mmol) in ethanol (3.2 ml). The reaction was heated at 75° C. for 24 hrs. The reaction was cooled to room temperature and concentrated under reduced pressure to yield an oil. The oil was diluted with ethyl acetate and washed with water. The aqueous layer was acidified with 1.0 N HCl and was extracted with ethyl acetate (3×). The organic extracts were combined, dried with sodium sulfate, filtered and concentrated under reduced pressure, yielding the title compound (182 mg, 0.422 mmol, 89% yield) as a pale yellow solid. LC/MS found [M+H]+=410.7.