Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[CH3:15][C:16]1[N:17]=[CH:18][NH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C(N)CN>CN(C)C=O.COCCCC.[Na+].[Cl-].C(OC(C)C)(=O)C.[Cu]I>[CH3:15][C:16]1[N:17]=[CH:18][N:19]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=2)[CH:20]=1
Reactant: O=[N+]([O-])c1cc(Br)cc(C(F)(F)F)c1
Reactant: Cc1c[nH]cn1
Agent: [Cu]I
Agent: CCCCOC
Agent: O=C([O-])[O-]
Solvent: CC(=O)OC(C)C
Solvent: NCCN
Solvent: CN(C)C=O
Product: Cc1cn(-c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)cn1
Temperature: 110 °C
Yield: 21.1 %

Procedure:
To a stirred suspension of 1-bromo-3-nitro-5-trifluoromethyl-benzene (4.05 g, 15 mmol), 4-methyl-1H-imidazole (2.01 g, 24 mmol, 98%) and potassium carbonate (3.73 g, 27 mmol) in N,N-dimethylformamide (10 mL) are added ethylenediamine (0.141 mL, 2.1 mmol) and copper(I) iodide (0.204 g, 1.05 mmol). The vigorously stirred mixture is heated to 110° C. for 23 hours. After that, most of the 1-bromo-3-nitro-5-trifluoromethyl-benzene is converted, and the suspension is allowed to cool down to room temperature. The mixture is diluted with tent-butyl methyl ether (30 mL) and 5% aqueous NaCl solution (30 mL) and isopropyl acetate (15 mL) are added. The aqueous layer is separated and extracted with a mixture of tert-butyl methyl ether (10 mL) and isopropyl acetate (5 mL). The organic layers are combined and filtered. The filtrate is washed with water (10 mL), treated for 5 minutes with ethylenediamine (0.303 mL), washed with water (10 mL), 5% aqueous sodium metabisulfite solution (10 mL) and water (10 mL) before it is treated with activated carbon (1.2 g) at room temperature for 1 hour. The suspension is filtered using filter aid, and the filtrate is evaporated to dryness under reduced pressure to give a clear, red-brown oil which solidifies upon standing at room temperature. The obtained solid is purified by column chromatography on silica gel eluting with a 4:5 mixture of ethyl acetate and hexane (in the presence of 0.5 volume % of triethylamine) to afford mainly 4-methyl-1-(3-nitro-5-trifluoromethyl-phenyl)-1H-imidazole as a pale yellow solid. Yield: 21.1% (HPLC purity: 96.7 area %) Melting point: 118-119° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:11][O:12][CH2:13][O:14][CH3:15])[C:6]=1[S:7]([NH2:10])(=[O:9])=[O:8].[CH2:16]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[O:33])[C:25](=[C:34](SC)SC)[C:24]1=[O:39])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[CH2:16]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([OH:33])=[C:25]([C:34]2[NH:1][C:2]3[S:3][CH:4]=[C:5]([CH2:11][O:12][CH2:13][O:14][CH3:15])[C:6]=3[S:7](=[O:8])(=[O:9])[N:10]=2)[C:24]1=[O:39])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COCOCc1csc(N)c1S(N)(=O)=O
Reactant: CSC(SC)=C1C(=O)c2ccccc2N(Cc2ccccc2)C1=O
Solvent: Cc1ccccc1
Product: COCOCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(Cc3ccccc3)c1=O)N2
Yield: 72.6 %

Procedure:
The product of Example 309G (35 mg, 0.14 mmol) and the product of Example 309B (50 mg, 0.14 mmol) were reacted in toluene (3 mL) at 100° C. for 3 hours. The resulting precipitate was collected by filtration and washed with toluene and diethyl ether to give the title compound (52 mg, 73.3%). The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.26 (s, 3 H), 4.65 (s, 2 H), 4.72 (s, 2 H), 5.62 (s, 2 H), 7.28 (m, 7 H), 7.43 (s, 2 H), 7.51 (d, J=8.09 Hz, 1 H), 7.75 (m, 1 H), 8.22 (d, J=8.09 Hz, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([CH2:12][O:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[C:17]([C:23](O)=[O:24])[NH:18]4)=[CH:10][O:11][C:7]=2[CH:6]=[C:5]([O:26][CH3:27])[CH:4]=1.[ClH:28].Cl.Cl.[C@H:31]1([CH2:41][N:42]2[CH2:47][CH2:46][CH:45]([NH2:48])[CH2:44][CH2:43]2)[C@@H:40]2[N:35]([CH2:36][CH2:37][CH2:38][CH2:39]2)[CH2:34][CH2:33][CH2:32]1>>[ClH:28].[ClH:28].[C@H:31]1([CH2:41][N:42]2[CH2:47][CH2:46][CH:45]([NH:48][C:23]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[C:14]([O:13][CH2:12][C:9]3[C:8]5[C:3]([O:2][CH3:1])=[CH:4][C:5]([O:26][CH3:27])=[CH:6][C:7]=5[O:11][CH:10]=3)[CH:22]=[CH:21][CH:20]=4)=[O:24])[CH2:44][CH2:43]2)[C@@H:40]2[N:35]([CH2:36][CH2:37][CH2:38][CH2:39]2)[CH2:34][CH2:33][CH2:32]1
Reactant: COc1cc(OC)c2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2c1
Reactant: NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1
Agent: Cl
Product: COc1cc(OC)c2c(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)coc2c1

Procedure:
This compound is synthesized from 4-(4,6-dimethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid 126 (preparation see below) and amine 61 analogously to the method described in example 1.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)O)=[C:5]([CH3:25])[O:4][N:3]=1.[N:26]1C=CC=CC=1.O=S(Cl)Cl>C1COCC1>[NH2:26][C:10]1([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:25])[CH:8]=2)[NH:12][C:11]1=[O:16]
Reactant: c1ccncc1
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(O)(c1ccc(F)cc1)C(=O)N2
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1ccc2c(c1)C(N)(c1ccc(F)cc1)C(=O)N2
Reaction time: 0.33 h
Yield: 26.9 %

Procedure:
Under N2, to a solution of 5-(3,5-dimethylisoxazol-4-yl)-3-(4-fluorophenyl)-3-hydroxyindolin-2-one (52 g, 154 mmol, 1.0 eq) in THF (500 mL) was added pyridine (40 mL, 496 mmol, 3.2 eq) and SOCl2 (16 mL, 219 mmol, 1.4 eq) slowly at −15° C.˜−20° C., the mixture was stirred for 20 min at −15° C.˜−20° C., quenched with brine, washed with brine (300 mL×2), to the THF layer was added NH3/H2O (100 mL), the mixture was stirred for 2 hours at room temperature, washed with brine, dried, concentrated, purified by silicon gel to give a crude product which was recrystallized from i-PrOH/toluene to give 14 g (yield 27%) product as white solid. 1H NMR (DMSO-d6) δH 10.57 (s, 1H), 7.40-7.44 (m, 2H), 7.22-7.24 (dd, 1H, J=8.0 Hz, 1.6 Hz), 7.11-7.16 (m, 3H), 6.98-7.00 (d, 1H, J=8.0 Hz), 2.75 (s, 2H), 2.33 (s, 3H), 2.16 (s, 3H)
Reaction SMILES: Cl[C:2]1[C:3]2[C:4](=[N:14][N:15]([CH3:17])[CH:16]=2)[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[Na].[CH2:19]([OH:21])[CH3:20]>>[CH2:19]([O:21][C:2]1[C:3]2[C:4](=[N:14][N:15]([CH3:17])[CH:16]=2)[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)[CH3:20]
Reactant: CCO
Reactant: Cn1cc2c(Cl)cc(-c3ccccc3)nc2n1
Agent: [Na]
Product: CCOc1cc(-c2ccccc2)nc2nn(C)cc12

Procedure:
8.5 g. of 4-chloro-2-methyl-6-phenyl-2H-pyrazolo[3,4-b]pyridine (0.035 mol.) are added to a solution of 0.9 g. of sodium (0.038 mol.) in 100 ml. of absolute ethanol. The mixture is heated at 150° in an autoclave for 5 hours. After cooling, the crystallized 4-ethoxy-2-methyl-6-phenyl2H-pyrazolo[3,4-b]pyridine is filtered off, washed with alcohol and then with water, yield: 6.2 g.; m.p. 170°-171°. An additional crop of 2.4 g. is obtained by evaporation of the mother liquor, total yield: 8.6 g. (97%). Recrystallization from ethanol gives a product of the melting point 171°-172°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=O)[C:11]1=[O:20].Cl.[NH2:22][OH:23]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[N:22][OH:23])[C:11]1=[O:20]
Reactant: Cc1ccc(Cl)c(N2C(=O)C(=O)c3ccccc32)c1Cl
Reactant: NO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(Cl)c(N2C(=O)C(=NO)c3ccccc32)c1Cl
Yield: 81.3 %

Procedure:
A solution of 1-(2,6-dichloro-3-methylphenyl)-1H-indole-2,3-dione (0.3 g) and hydroxylamine hydrochloride (0.07 g) in pyridine (2 ml) is stirred at room temperature for 20 minutes. The reaction mixture is diluted with ethyl acetate (20 ml) and washed with 1 N HCl (2×100 ml). The organic layer is dried (MgSO4) and evaporated. Flash chromatography (silica, CH2Cl2) followed by recrystallization from isopropyl ether affords 1-(2,6-dichloro-3-methylphenyl)-1H-indole-2,3-dione 3-oxime (256 mg, 80%), mp 190°-191° C.
Reaction SMILES: [N:1]1([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.OS(O)(=O)=O.[N+:21]([O-])([OH:23])=[O:22].[OH-].[Na+]>O>[CH3:14][N:13]([CH3:15])[CH2:12][CH2:11][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:21]([O-:23])=[O:22])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])O
Reactant: CN(C)CCN1CCCc2ccccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)CCN1CCCc2ccc([N+](=O)[O-])cc21
Reaction time: 0.33 h
Yield: 79.6 %

Procedure:
A solution of compound 3 (0.87 g, 4.285 mmol) in con. H2SO4 (10 mL) was treated with fuming HNO3 (0.2 mL, 4.285 mmol, 90%) drop wise over a period of 10 min. at 0° C. and was stirred at same temperature for additional 20 min. The reaction was diluted with water (50 mL), basified to pH ˜10 using 2 N NaOH solution and product was extracted into CH2Cl2 (3×20 mL). The combined organic layer was washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 2.5:97.5 to obtain compound 4 (0.85 g, 80%) including some dinitro derivative, which was separated at later stage.
Reaction SMILES: [CH:1]([NH:3][CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:2].[N+:15]([C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Cl)([O-:17])=[O:16]>[O-]CC.[Na+]>[CH:1]([NH:3][C:4]([CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=1[N+:15]([O-:17])=[O:16])([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1CCl
Reactant: CCOC(=O)C(NC=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(Cc1ccccc1[N+](=O)[O-])(NC=O)C(=O)OCC
Yield: 75.4 %

Procedure:
Diethyl (formylamino)malonate (20.3 g, 0.1 mol) was added to a stirred solution of sodium ethoxide (250 mL of 0.4 M). 2-Nitrobenzyl chloride (17.2 g, 0.1 mol) was added, the mixture was refluxed for 2 hours and the solvent was then removed under reduced pressure. The material was partitioned between ethyl acetate and water, the ethyl acetate was separated and evaporated to give 40.3 g of crude product. The compound was crystallized from ethyl acetate:hexane to give 25.5 g of diethyl (formylamino)((2-nitrophenyl)methyl)propanedioate; mp 129°-132° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=O.[CH3:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[NH2:19]>>[CH3:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([CH3:1])[C:3]=1[C:4]([NH:19][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[CH3:12])=[O:6]
Reactant: Cc1cccc(C)c1C(=O)O
Reactant: CC1CCCCC1N
Product: Cc1cccc(C)c1C(=O)NC1CCCCC1C
Yield: 59 %

Procedure:
Prepared in a similar manner to Example 162 using 2,6-dimethylbenzoic acid and 2-methylcyclohexylamine. Yield: 59%. 1H NMR (500 MHz, CDCl3): δ 0.88-0.94 (3H, dd), 1.14-1.89 (9H, m), 2.21-2.22 (6H, d), 3.39-3.45 (1H, m), 7.02-7.03 (2H, d), 7.12-7.15 (1H, t), 8.11-8.13 (1H, d). MS (M+H, 246.2).
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.Cl.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:33]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[C:1]1([C:7]2[N:8]([S:38]([C:34]3[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=3)(=[O:40])=[O:39])[CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: O=Cc1c[nH]c(-c2ccccc2)n1
Agent: C1COCCOCCOCCOCCO1
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: O=Cc1cn(S(=O)(=O)c2cccnc2)c(-c2ccccc2)n1
Reaction time: 0.5 h
Yield: 41.4 %

Procedure:
To a solution of 2-phenyl-1H-imidazole-4-carbaldehyde (1.00 g) in tetrahydrofuran (50 mL) was added sodium hydride (60% in oil, 697 mg) at room temperature, and the mixture was stirred for 30 min. 15-Crown-5 (3.84 g) was added dropwise, and the mixture was further stirred for 10 min. 3-Pyridylsulfonyl chloride hydrochloride (1.62 g) was added to the reaction mixture, and the mixture was stirred for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=3:2→42:3), and the obtained oil was crystallized from diisopropyl ether to give the title compound as colorless crystals (yield 754 mg, 41%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[CH:13]=[CH:14]/[CH2:15][OH:16])=[CH:5][CH:4]=1>[O-2].[O-2].[Mn+4]>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[CH:13]=[CH:14]/[CH:15]=[O:16])=[CH:7][CH:8]=1
Reactant: OC/C=C/C=C/C=C/c1ccc(C(F)(F)F)cc1
Agent: [Mn+4]
Agent: [O-2]
Product: O=C/C=C/C=C/C=C/c1ccc(C(F)(F)F)cc1
Yield: 88 %

Procedure:
(2E,4E,6E)-7-[4-(Trifluoromethyl)phenyl]-2,4,6-heptatrien-1-ol was treated with active manganese dioxide in the same manner as in Reference example 22 to obtain the title compound in a yield of 88%.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:11]N1C(=O)CCC1=O>ClCCl>[Cl:1][C:2]1[C:3]2[C:10]([Cl:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Clc1c[nH]c2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.9 %

Procedure:
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (154 mg, 1.0 mmol) was suspended in 6.0 mL of dry dichloromethane in a flame-dried flask and to this mixture was added N-chlorosuccinimide (147 mg, 1.1 mmol) in one portion. The resulting mixture stirred at room temperature for 18 h, at which time the solvent was removed under reduced pressure. The residue was triturated with water and isolated by filtration to afford 137 mg (72%) of the title compound as a gray solid, mp 224-227° C. (dec). LRMS: 188 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13](O)=[O:14])[CH:5]=[CH:6][CH:7]=1.[NH2:29][C:30]1[S:31][CH:32]=[CH:33][N:34]=1>>[S:31]1[CH:32]=[CH:33][N:34]=[C:30]1[NH:29][C:13]([C:12]1[S:11][C:10]([N:16]2[C:20]3[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=3[N:18]=[CH:17]2)=[N:9][C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:14]
Reactant: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(=O)O)s3)c2cc1OC
Reactant: Nc1nccs1
Product: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(=O)Nc4nccs4)s3)c2cc1OC
Yield: 79.5 %

Procedure:
In a similar manner as described for Example 53, 4-(3-Chloro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (41 mg, 0.1 mmol) and 2-aminothiazole (10.0 mg, 0.1 mmol, Aldrich) gave 4-(3-Chloro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid thiazol-2-ylamide (39.6 mg, 79.5%) as a white solid. MS m/z 498 (M+1).
Reaction SMILES: [CH2:1]([CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([OH:27])=[O:26]>C(O)(=O)C>[C:25]([C:24]1[CH:23]=[C:22]([N:21]2[C:11]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[CH2:18][CH2:19][C:10]=3[CH:1]=[C:2]2[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:30]=[CH:29][CH:28]=1)([OH:27])=[O:26]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: O=C(CC1CCc2ccccc2C1=O)c1ccccc1
Solvent: CC(=O)O
Product: O=C(O)c1cccc(-n2c(-c3ccccc3)cc3c2-c2ccccc2CC3)c1

Procedure:
A solution of 10.5 g. (0.04 mole) of 2-phenacyl-1-tetralone (m.p. 73°-76°), 5.5 g. (0.04 mole) of m-aminobenzoic acid, and 35 ml. of glacial acetic acid was heated under reflux for 31/2 hours, cooled and filtered. The filter cake was washed with water and dried to provide 8.6 g. of solid, m.p. 225°-228°. Recrystallization from ethanol and from ethanol-water gave off-white crystals, m.p. 253.5°-255°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH:12]([CH3:22])[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:8][C:7]([CH3:24])([CH3:23])[CH:6]1[CH2:25][CH2:26][CH2:27][CH:28]([CH2:29][OH:30])[CH:5]21.[ClH:31].[O:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][C:41](O)=[O:42])[CH2:34][CH2:33]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:31].[O:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][C:41]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[CH:12]([CH3:22])[CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:8][C:7]([CH3:23])([CH3:24])[CH:6]2[CH2:25][CH2:26][CH2:27][CH:28]([CH2:29][OH:30])[CH:5]32)=[O:42])[CH2:34][CH2:33]1
Reactant: O=C(O)CCCN1CCOCC1
Reactant: CC(CCCc1ccccc1)c1cc2c(cc1O)C1C(CO)CCCC1C(C)(C)N2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CC(CCCc1ccccc1)c1cc2c(cc1OC(=O)CCCN1CCOCC1)C1C(CO)CCCC1C(C)(C)N2
Temperature: 25 °C

Procedure:
To a 25° C. solution of 5,6,6a,7,8,9,10,10a-octahydro-2-hydroxy-10-hydroxymethyl-6,6-dimethyl-3-(1-methyl-4-phenylbutyl)benzo[c]quinoline (626 mg., 1.5 mmole) in dry methylene chloride (25 ml.) is added 4-morpholinobutyric acid hydrochloride (0.315 g., 1.5 mmole) and the mixture stirred at room temperature under a nitrogen atmosphere. A 0.1 M solution of dicyclohexylcarbodiimide in methylene chloride (12.5 ml., 1.5 mmole) is added dropwise and the mixture stirred for 6 hours. It is then cooled in ice, filtered and evaporated to give the title product which is purified as the free base by column chromatography on silica gel.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:39])=[C:8]([S:10]([N:13]([CH2:32][C:33]2[N:34]=[C:35]([CH3:38])[S:36][CH:37]=2)[CH2:14][CH2:15][C:16]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][C:17]=2[O:18][CH2:19][C:20]([O:22]CC)=[O:21])(=[O:12])=[O:11])[CH:9]=1)(=[NH:3])[NH2:2].[OH-].[Na+]>C(O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:39])=[C:8]([S:10]([N:13]([CH2:32][C:33]2[N:34]=[C:35]([CH3:38])[S:36][CH:37]=2)[CH2:14][CH2:15][C:16]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:30])[CH3:31])=[CH:25][C:17]=2[O:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:11])=[O:12])[CH:9]=1)(=[NH:2])[NH2:3]
Reactant: CCOC(=O)COc1cc(C(C)C)ccc1CCN(Cc1csc(C)n1)S(=O)(=O)c1cc(C(=N)N)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(CN(CCc2ccc(C(C)C)cc2OCC(=O)O)S(=O)(=O)c2cc(C(=N)N)ccc2O)cs1
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
To a stirred solution of 100 mg of ethyl [2-[2-[(5-carbamimidoyl-2-hydroxybenzenesulfonyl)-(2-methyl-1,3-thiazol-4-ylmethyl)amino]ethyl]-5-isopropylphenoxy]acetate in 0.8 mL of ethanol was added 0.183 mL of 2 mol/L sodium hydroxide solution under ice-cooling. After being stirred at the same temperature for 30 minutes, the reaction mixture was concentrated under reduced pressure. To the stirred solution of the residue in a mixture of 0.8 mL of acetonitrile and 0.8 mL of water was added 0.174 mL of 1 mol/L hydrochloric acid under ice-cooling, and the mixture was stirred at the same temperature for 5 minutes. To the mixture was added additional 0.174 mL of 1 mol/L hydrochloric acid under ice-cooling, and the mixture was stirred at the same temperature for 5 minutes. The precipitate was collected by filtration, and washed with water to give 74 mg of [2-[2-[(5-carbamimidoyl-2-hydroxybenzenesulfonyl)-(2-methyl-1,3-thiazole-4-ylmethyl)amino]ethyl]-5-isopropylphenoxy]acetic acid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([CH3:15])[C:5]=1[CH:6]=O.[C:16]([O:19][CH2:20][CH3:21])(=[O:18])[CH3:17]>O1CCCC1.[Cl-].[Na+].O>[CH3:14][O:13][C:10]1[CH:9]=[C:8]([CH3:15])[C:5]([CH:6]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[O:18])=[C:4]([CH3:3])[C:11]=1[CH3:12]
Reactant: COc1cc(C)c(C=O)c(C)c1C
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1c(C)cc(OC)c(C)c1C
Temperature: 0 °C

Procedure:
A suspension of NaH (9.3 g, 50% dispersion in oil, 0.19 mol) in 150 mL of tetrahydrofuran (THF) was stirred in an ice bath under an atmosphere of nitrogen and triethyl phosphonoacetate (43.5 g, 0.19 mol) was added dropwise within 15 min. The mixture was stirred for 1 hr in the ice bath and a solution of 2,3,6-trimethyl-p-anisaldehyde (24.3 g, 0.14 mol) in 100 mL of THF was added. The resulting mixture was stirred at room temperature for 18 hrs and brine (250 mL) and ethyl acetate (250 mL) was added. The layers were separated; the organic layer was washed with brine and dried (Na2SO4). Removal of solvent in vacuo afforded 32.3 g of yellow oil. A small portion of this product was recrystallized from ethyl ether to give white powders: mp 42°-44° C.; MS(CI): 249(m+ +1), 203. The rest of the product was used in the reaction described in Example 3 without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[F:15][C:16]([F:30])([F:29])[CH2:17][CH2:18][O:19][C:20]1[N:25]=[CH:24][C:23]([CH:26]([NH2:28])[CH3:27])=[CH:22][CH:21]=1>>[Cl:13][C:12]1[C:3]2[CH2:2][N:28]([CH:26]([C:23]3[CH:24]=[N:25][C:20]([O:19][CH2:18][CH2:17][C:16]([F:30])([F:15])[F:29])=[CH:21][CH:22]=3)[CH3:27])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: CC(N)c1ccc(OCCC(F)(F)F)nc1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: CC(c1ccc(OCCC(F)(F)F)nc1)N1Cc2c(ccnc2Cl)C1=O
Yield: 47 %

Procedure:
The title compound is prepared in 47% yield (102 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (154 mg, 0.57 mmol, Amine-15, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH2:13])=[N:9]2)[CH2:4][O:3]1.[I:15][C:16]1[CH:17]=[N:18][N:19]([CH:23]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:24](O)=[O:25])[C:20](=[O:22])[CH:21]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:14])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:24](=[O:25])[CH:23]([N:19]3[C:20](=[O:22])[CH:21]=[C:16]([I:15])[CH:17]=[N:18]3)[CH2:27][CH:28]([CH3:30])[CH3:29])=[N:9]2)[CH2:4][O:3]1
Reactant: CC(C)CC(C(=O)O)n1ncc(I)cc1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(I)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
A solution of 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4, 708.7 mg, 3.59 mmol) in N,N-dimethylformamide was added to 2-(4-iodo-6-oxo-6H-pyridazin-1-yl)-4-methyl-pentanoic acid (Intermediate 86, 1.42 g, 4.23 mmol). At this point, the reaction was treated with 4-dimethylaminopyridine (21.9 mg, 0.18 mmol) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (823.7 mg, 4.31 mmol). The resulting reaction was stirred at 25° C. overnight. The reaction was then diluted with ethyl acetate (200 mL), was washed with water (200 mL) and a saturated aqueous sodium chloride solution (200 mL), filtered, and concentrated in vacuo onto silica gel. Chromatography (ISCO Combiflash, 10-60% ethyl acetate/hexanes) afforded 2-(4-iodo-6-oxo-6H-pyridazin-1-yl)-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide as a white/yellow solid (950 mg, 51%); ES+-HRMS m/e calcd for C19H26N5O4I [M+Na+] 538.0921, found 538.0921. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.83 (d, J=5.7 Hz, 3H), 0.85 (d, J=5.7 Hz, 3H), 1.23 (s, 3H), 1.29 (s, 3H), 1.35 (br. s., 1H), 1.76 (ddd, J=13.3, 9.4, 4.2 Hz, 1H), 2.03-2.21 (m, 1H), 3.71 (dd, J=8.4, 6.0 Hz, 1H), 3.98 (dd, J=8.4, 6.5 Hz, 1H), 4.03-4.18 (m, 2H), 4.33 (quin, J=6.0 Hz, 1H), 5.47 (dd, J=11.0, 4.1 Hz, 1H), 6.36 (d, J=2.1 Hz, 1H), 7.58 (d, J=1.8 Hz, 1H), 7.59 (d, J=2.1 Hz, 1H), 8.23 (d, J=1.8 Hz, 1H), 10.82 (s, 1H).