Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]([C:29](=O)[CH2:30][CH3:31])[C:6]1[C:18]2[C:17]3[CH2:16][CH2:15][CH:14]=[CH:13][C:12]=3[N:11]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[C:10]=2[N:9]=[C:8]([CH3:28])[CH:7]=1)(=O)[CH2:2][CH3:3]>C1COCC1>[CH2:29]([N:5]([CH2:1][CH2:2][CH3:3])[C:6]1[C:18]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:11]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[C:10]=2[N:9]=[C:8]([CH3:28])[CH:7]=1)[CH2:30][CH3:31]
Reactant: CCC(=O)N(C(=O)CC)c1cc(C)nc2c1c1c(n2-c2c(C)cc(C)cc2C)C=CCC1
Solvent: C1CCOC1
Product: CCCN(CCC)c1cc(C)nc2c1c1c(n2-c2c(C)cc(C)cc2C)CCCC1

Procedure:
N,N-Dipropionyl-2-methyl-9-(2,4,6-trimethylphenyl)-5H-pyrido[2,3-b] indol-4-amine 1c (312 mg) is refluxed in 8 mL THF with borane-methylsulfide complex (10 M, 1.2 mL) for 10 hours. After cooling the solution, it is carefully quenched with 5 mL of methanol. The resulting solution is refluxed for another 2 hours and then concentrated. The dialkylamine product is purified on silica gel using 20% ethyl acetate in hexanes as eluant to afford N,N-Dipropyl-2-methyl-6,7,8,9-tetrahydro-9-(2,4,6-trimethylphenyl)-5H-pyrido[2,3-b]indol-4-amine (Compound 1) as a white solid, m.p.: 117-118° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([N:15]1[C:20](=[O:21])[C:19]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:25][CH:24]=2)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]2[N:40]=[CH:41][N:42]=[C:16]12)[CH3:14]>C(OCC)(=O)C>[CH2:13]([N:15]1[C:20](=[O:21])[C:19]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:3][C:4](=[O:7])[O:5][N:36]=3)=[CH:27][CH:28]=2)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]2[N:40]=[CH:41][N:42]=[C:16]12)[CH3:14]
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC)c2ncnn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
A mixture of hydroxylammonium chloride (1.4 g), sodium hydrogen carbonate (2.3 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-[(4-ethyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.54 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.26 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.21 g, 34%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Cl[CH2:12][CH2:13][CH2:14][OH:15]>CN(C)C=O.O>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][CH2:13][CH2:14][OH:15]
Reactant: OCCCCl
Reactant: Oc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCCOc1cccc(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To a pre-dried round bottom flask, equipped with a magnetic stirrer, add sodium hydride (60% dispersion in mineral oil, 4.80 g, 0.120 mol) under a nitrogen atmosphere. Wash the sodium hydride with hexanes (3×100 mL) to remove the mineral oil then dimethylformamide (165 mL) is added. The resulting suspension is cooled to 0° C. and a solution of 3-fluorophenol (11.20 g, 0.100 mol) in dimethylformamide (35 mL) is added dropwise resulting in gas evolution and a color change from green to blue-green. After stirring the reaction mixture at rt for approximately 30 min the reaction is recooled to 0° C. and a solution of 3-chloro-1-propanol (9.46 g, 0.100 mol) in dimethylformamide (35 mL) is added dropwise. The resulting reaction mixture is heated to 60° C. for 2.5 h. The solution is cooled, the dimethylformamide is removed under reduced pressure and the resulting reaction mixture is diluted with water (250 mL) and extracted with diethyl ether (3×150 mL). The combined organic extracts are washed with water (200 mL), 2 M aqueous sodium hydroxide (200 mL), water (200 mL) and brine (200 mL). The organic layer is dried over magnesium sulfate, filtered and concentrated to afford the slightly impure title compound (13.32 g, 78%) as an amber oil which is used directly in the next reaction without purification: Rf 0.40 (19:1 CH2Cl2/MeOH); 1H NMR (300 MHz; CDCl3), δ 1.68 (t, J=5.1 Hz, 1H), 2.04 (quintuplet, J=6.0 Hz, 2H), 3.83-3.89 (m, 2H), 4.10 (t, J=6.0 Hz, 2H), 6.59-6.70 (m, 3H), 7.17-7.25 (m, 1H); 19FNMR (282 MHz, CDCl3), δ-112.13; APCI MS m/z 153 [C9H11FO2+H—H2O]+.
Reaction SMILES: CS([C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([CH3:13])[N:7]2[N:6]=1)(=O)=O.[Cl:16][C:17]1[CH:26]=[CH:25][C:20]([O:21][CH2:22][CH2:23][NH2:24])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:26]=[CH:25][C:20]([O:21][CH2:22][CH2:23][NH:24][C:5]2[N:15]=[C:8]3[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([CH3:13])[N:7]3[N:6]=2)=[CH:19][CH:18]=1
Reactant: Cc1cc(C)n2nc(S(C)(=O)=O)nc2n1
Reactant: NCCOc1ccc(Cl)cc1
Product: Cc1cc(C)n2nc(NCCOc3ccc(Cl)cc3)nc2n1
Yield: 26 %

Procedure:
The title compound was prepared according to the experimentals described for Example 18 above from 2-methanesulfonyl-5,7-dimethyl-[1,2,4]-triazolo[1,5-a]pyrimidine and 2-(4-chlorophenoxy)ethylamine in 26% yield; EM (calc.): 317.1; MS (ESI) m/e: 318.2 (M+H)+. 1H NMR (DMSO-d6, 400 MHz) δ ppm: 7.31 (dt, 2H), 7.03 (d, 1H), 6.98 (dt, 2H), 6.85 (s, 1H), 4.13 (t, 2H), 3.60 (q, 2H), 2.57 (s, 3H), 2.45 (s, 3H).
Reaction SMILES: [Cl:1]C1C2C(=CC=CC=2)C=NC=1.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[S:23](Cl)(=[O:25])=[O:24])[CH:16]=[N:15][CH:14]=1.C(OC([N:34]1[CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)=O)(C)(C)C>>[ClH:1].[ClH:12].[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[S:23]([N:34]2[CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)(=[O:25])=[O:24])[CH:16]=[N:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1cccc2cncc(Cl)c12
Reactant: Clc1cncc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Product: Cl
Product: O=S(=O)(c1cccc2cncc(Cl)c12)N1CCCNCC1

Procedure:
Using 2.08 g of 4-chloroisoquinoline (synthesized in accordance with J. Org. Chem., 1961, 26, 468), 4-chloro-5-chlorosulfonylisoquinoline was synthesized as in Reference Example 1. Then, 1.30 g of this compound was reacted with 1.20 g of 1-(tert-butoxycarbonyl)-hexahydro-1H-1,4-diazepine and the reaction mixture was after-treated in the same manner as in Example 1 to provide 0.80 g of the objective compound (white crystals).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[C:10]([O:17][CH3:18])[C:9]=1[O:19][CH3:20].[F:21][C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=1I.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:28][C:25]1[CH:24]=[CH:23][C:22]([F:21])=[C:27]([C:11]2[CH:12]=[CH:13][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[C:9]([O:19][CH3:20])[C:10]=2[O:17][CH3:18])[CH:26]=1
Reactant: Fc1ccc(Br)cc1I
Reactant: COc1c(B(O)O)ccc(-c2ccccc2F)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1c(-c2ccccc2F)ccc(-c2cc(Br)ccc2F)c1OC
Temperature: 25 °C
Yield: 80.1 %

Procedure:
In the atmosphere of argon, 15.2 g of 2′-fluoro-2,3-dimethoxybiphenyl-4-boronic acid, 16.5 g of 2-fluoro-5-bromoiodobenzene, 1.27 g of tetrakistriphenylphosphine palladium (0), 180 mL of toluene and 90 mL of an aqueous 2M sodium carbonate solution were placed in a flask. The resulting solution was stirred with heating under reflux for 8 hours. After cooling to room temperature, the reaction solution was extracted with toluene. An aqueous phase was removed, and an organic phase was washed with saturated saline. The organic phase was dried with magnesium sulfate, and concentrated. Residues were purified by means of silica gel column chromatography, whereby 17.8 g (yield: 80%) of 5-bromo-2-fluoro-2′,3′-dimethoxy-2″-fluoro-p-terphenyl was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[C:7]2[C:8](O[C:11](=O)[NH:12][C:6]2=[CH:5][CH:4]=1)=[O:9].CSC(=N)[NH:20][S:21]([CH2:24]Cl)(=[O:23])=[O:22].[H-].[Na+].Cl.C[N:31]1CCCC1=O>>[CH3:16][O:15][C:14]1[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[C:6]2[C:7]=1[C:8](=[O:9])[N:31]1[CH2:24][S:21](=[O:22])(=[O:23])[NH:20][C:11]1=[N:12]2
Reactant: CSC(=N)NS(=O)(=O)CCl
Reactant: COc1ccc2[nH]c(=O)oc(=O)c2c1OC
Reactant: CN1CCCC1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2nc3n(c(=O)c2c1OC)CS(=O)(=O)N3
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 5,6-dimethoxyisatoic anhydride (8.93 g, 40 mmol) and S-methyl-N-(chloromethanesulfonyl)isothiourea (90% pure, 9.73 g, 44 mmol) in N-methyl-2-pyrrolidinone (50 ml) under nitrogen is added sodium hydride (1.65 g of 60% dispersion in oil, 41 mmol). After 15 min at room temperature, the mixture is stirred at 80° C. for 18 hr, then cooled and poured into 0.5N aqueous hydrochloric acid (150 ml). The precipitate is collected by filtration, and washed with water, then with ether. Recrystallization from DMF containing 5% water provides the title compound as a tan solid, mp >300° C. (2.55 g, 21%).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:32][C@@H:33]1[CH2:38][NH:37][CH2:36][CH2:35][N:34]1C(O)=O>>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:18]=[C:17]4[CH2:29][N:37]3[CH2:36][CH2:35][NH:34][C@H:33]([CH3:32])[CH2:38]3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: C[C@@H]1CNCCN1C(=O)O
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCN[C@H](C)C3)c2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 81 using the product of Example 75 step i) and (R)-2-methyl-piperazine-1-carboxylic acid tert, butyl ester and the product purified by SiO2 chromatography (eluting with 93:5:2 dichloromethane:methanol:ammonia).
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.[CH:29]1([C:32]2[N:37]=[CH:36][C:35]([CH2:38]O)=[CH:34][CH:33]=2)[CH2:31][CH2:30]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:29]1([C:32]2[N:37]=[CH:36][C:35]([CH2:38][N:15]=[N+:16]=[N-:17])=[CH:34][CH:33]=2)[CH2:31][CH2:30]1
Reactant: OCc1ccc(C2CC2)nc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCc1ccc(C2CC2)nc1
Reaction time: 3 h
Yield: 99.7 %

Procedure:
Diphenylphosphoryl azide (0.49 ml, 2.3 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.34 ml, 2.3 mmol) were added dropwise in that order at room temperature to a solution of (6-cyclopropyl-3-pyridyl)methanol (283 mg, 1.90 mmol) in toluene (4 ml) and the mixture was stirred for 3 hours. After confirming completion of the reaction by thin layer chromatography, it was diluted with ethyl acetate and washed with water and brine. Drying was performed with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (330 mg, quant.) as a colorless oil.
Reaction SMILES: IC.[C:3](=O)([O-])[O-].[Cs+].[Cs+].[OH:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=2)[N:12]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:11]=1>CC(C)=O>[CH3:3][O:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=2)[N:12]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:11]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)n1nc(O)c2cc([N+](=O)[O-])ccc21
Agent: [Cs+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)n1nc(OC)c2cc([N+](=O)[O-])ccc21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
Iodomethane (10 ml) and cesium carbonate (4.89 g) were added to an acetone (20 ml) solution containing ethyl 3-hydroxy-5-nitro-1H-indazol-1-carboxylate (2.51 g) obtained in the 2nd step under ice cooling in a nitrogen atmosphere, followed by stirring at 80° C. for 0.5 hours. An insoluble precipitate was removed by filtration and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 4:1). A white solid of ethyl 3-methoxy-5-nitro-1H-indazol-1-carboxylate (1.24 g) was thus obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:13][C:12]3[C:14]([O:19][CH3:20])=[CH:15][C:16]([CH3:18])=[CH:17][C:11]=3[CH2:10][O:9][C:8](=[O:21])[C:7]=2[C:22]=1[O:23][CH3:24].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:26].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C)C=O>[C:2]([C:3]1[CH:4]=[CH:5][C:6]2[S:13][C:12]3[C:14]([O:19][CH3:20])=[CH:15][C:16]([CH3:18])=[CH:17][C:11]=3[CH2:10][O:9][C:8](=[O:21])[C:7]=2[C:22]=1[O:23][CH3:24])([OH:26])=[O:1]
Reactant: COc1cc(C)cc2c1Sc1ccc(CO)c(OC)c1C(=O)OC2
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C)cc2c1Sc1ccc(C(=O)O)c(OC)c1C(=O)OC2

Procedure:
560 mg (1.62 mmol) of the compound from Example VI are stirred overnight at 25° C. with 9.13 g (24.3 mmol) of pyridinium dichromate in 20 ml of dimethylformamide. The mixture is poured into water and washed with ether, the ether phase is washed with water and dried over sodium sulphate and, after concentrating in vacuo, the residue is chromatographed on silica gel using methylene chloride/ethanol 10:1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.N1C=CN=C1.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19].CCOCC>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24])[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Yield: 99.2 %

Procedure:
10 g of 6-bromo-2-naphthol, 13.4 g of imidazole and 15 g of t-butyldimethylchlorosilane were stirred at room temperature in 75 ml of dimethylformamide for 18 hrs. Thereafter, 500 ml of ether were added thereto and the organic phase was washed 5 times with 100 ml of water each time. The organic phases were concentrated and the residue was dried in a high vacuum. 15.0 g of 6-bromo-2-t-butyl-dimethylsilyloxy-naphthaline were isolated as a yellowish solid. Yield: 99%. Mass spectrum (ISP): peaks inter alia at m/e: 338 and 336 (M+, in each case 34%), 281 (100%), 279 (98%), 200 (98%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]SC1SCC(=O)N=1.[OH:24][C:25]1[C:34]2[C:29](=[N:30][C:31]([CH3:35])=[CH:32][CH:33]=2)[N:28]=[CH:27][C:26]=1[C:36]([OH:38])=[O:37].[OH-].[Na+:40]>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:28]1[C:29]2[C:34](=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=2)[C:25](=[O:24])[C:26]([C:36]([O-:38])=[O:37])=[CH:27]1.[Na+:40]
Reactant: COc1ccc(OCCCCCCSC2=NC(=O)CS2)c(Cl)c1
Reactant: Cc1ccc2c(O)c(C(=O)O)cnc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1ccc(OCCCCCCn2cc(C(=O)[O-])c(=O)c3ccc(C)nc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Stir overnight at room temperature 1 gm. of the iodide prepared in Examples 2 and 3, 10 ml. DMF, 834 mg. 4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxylic acid and 326 mg. sodium hydroxide in a reaction flask. Wash with water in methylene chloride. Elute on a coarse silica column with methylene chloride then 3% methanol/methylene chloride to isolate the title compound as the carboxylic acid.
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Li+].C(O)C.Cl>O>[S:31]1[CH:32]=[CH:33][CH:34]=[C:30]1[C:27]1[CH:26]=[CH:25][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:35])=[O:3])=[CH:14][CH:13]=3)[N:19]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4cccs4)cc3)oc2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3cccs3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1

Procedure:
To a 20 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-thiophen-2-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (0.268 mmoles), lithium hydroxide (0.535 mmoles, 0.268 mL of a 2N solution), and ethanol (5 mL). This solution was heated to reflux for 2 h. Distilled water was added to the mixture and the pH was adjusted to 3 using a 1N HCl solution. The organic layer was extracted with ethyl acetate, washed with brine, and concentrated in-vacuo. This crude oil was re-solvated in pure ethyl acetate and filtered over a pad of Celite. The filtrate was concentrated in-vacuo, and the crude oil was crystallized using acetonitrile. The crystals were collected and dried in-vacuo affording 2-(4-{2-[2-(4-thiophen-2-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid. 1H NMR (400 MHz, CDCl) 8.74 (2H, m), 8.39 (2H, d), 8.26 (1H, m), 8.16 (2H, m), 7.64 (2H, d), 7.55 (2H, d), 4.18 (2H, t), 3.00 (2H, t) 2.39 (3H, s), 1.53 (6H, s)
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:8](Cl)=[O:9].[S-:22][C:23]#[N:24].[K+].[CH2:26]([SH:28])[CH3:27]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:8]([NH:24][C:23](=[S:22])[S:28][CH2:26][CH3:27])=[O:9]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c(Oc2ccc(F)cc2F)c1
Reactant: CCS
Reactant: N#C[S-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCSC(=S)NC(=O)c1ccc([N+](=O)[O-])c(Oc2ccc(F)cc2F)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of 3-(2,4-difluorophenoxy)-4-nitrobenzoyl chloride (2.1 g) and potassium thiocyanate (2.8 g) in toluene (20 ml) was refluxed overnight. Ethyl mercaptan (2.6 ml) was added to the resulting mixture. The mixture was stirred for 4 hours at 60° C. and concentrated. The residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate and concentrated to give crystals of ethyl N-[3-(2,4-difluorophenoxy)-4-nitrobenzoyl]dithiocarbamate (2.2 g).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.[C:16]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)(=[O:18])[CH3:17].C([BH3-])#N.[Na+].C(OCC)(=O)C>CO.O>[ClH:1].[ClH:1].[C:16]([N:19]1[CH2:24][CH2:23][CH:22]([NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:5]=2)[CH2:21][CH2:20]1)(=[O:18])[CH3:17]
Reactant: Nc1cccc(N2CCCCC2)c1
Reactant: CC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC(=O)N1CCC(Nc2cccc(N3CCCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 132.1 %

Procedure:
To a solution of N-(3-aminophenyl)piperidine dihydrochloride (3.73 g) and 1-acetyl-4-piperidone (2.1 g) in methanol (30 ml) was added sodium cyano borohydride (1.9 g), followed by stirring at room temperature for 5 hours. To the mixture were added ethyl acetate ester (20 ml) and water (30 ml), the organic layer was dried over anhydrous sodium sulfate and then the solvent was distilled off. The residual oily compound was separated and purified by silica gel column chromatography (developing solvent: ethyl acetate ester). The oily compound was dissolved in dioxane (10 ml) and to the mixture was added 6N solution of hydrogen chloride in dioxane (2 ml). Then, the solvent was removed to obtain a colorless amorphous solid (3.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:13][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>ClCCl.CO>[CH3:13][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([I:12])[C:9]([Cl:11])=[CH:10][C:2]=1[Cl:1]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cc(I)c(Cl)cc1Cl
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(I)c(Cl)cc1Cl

Procedure:
Sodium iodate (4.4 g) and iodine (11.1 g) were added to 90% sulfuric acid (330 mL), and stirred at room temperature for 8 hours. 2,4-Dichlorobenzoic acid (21 g) commercially available was added and stirred at the same temperature for 24 hours. The reaction solution was poured into ice water (3 L), and the precipitated solid material was collected by filtration. Further, the solid material was washed with water, and dried under reduced pressure. 2,4-Dichloro-5-iodobenzoic acid (16.8 g) was obtained by recrystallization (acetic acid-water). The resulting 2,4-dichloro-5-iodobenzoic acid (2 g) was dissolved in a mixture of dichloromethane (20 mL) and methanol (20 mL). Trimethylsilyldiazomethane (hexane solution, 2 M) was added dropwise until the solution became yellow. A small amount of acetic acid was added, and then the resulting mixture was concentrated under reduced pressure. The resulting residue was recrystallized using hexane to give the title compound 2,4-dichloro-5-iodobenzoic acid methyl ester as white solid (2 g).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:5][CH:4]=1.C([Li])CCC.[I:21]CCI>CCCCCC.C(OCC)C>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][C:11]([I:21])=[CH:12][N:13]=2)=[CH:7][CH:8]=1
Reactant: ICCI
Reactant: FC(F)(F)c1ccc(-c2nccs2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: FC(F)(F)c1ccc(-c2ncc(I)s2)cc1
Yield: 46.5 %

Procedure:
In a manner similar to Step C of Example 1, the reaction of 5.45 grams (0.0238 mole) of 2-(4-trifluoromethylphenyl)thiazole, 9.5 ml of a 2.5 M solution of n-butyllithium in hexane, and 6.71 grams (0.0238 mole) of 1,2-diiodoethane in 40 ml of diethyl ether produced 3.93 grams of 2-(4-trifluoromethylphenyl)-5-iodothiazole as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[N:21][CH:22]=3)[CH:11]=[C:10]([C:25](O)=[O:26])[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[NH:51]1[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[N:51]1([C:25]([C:10]2[CH:11]=[C:12]([C:14]([NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[N:21][CH:22]=3)=[O:24])[CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[CH:9]=2)=[O:26])[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1
Reactant: C1CCCNCC1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3cnc(C)nc3)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)nc3)cc(C(=O)N3CCCCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-((2-methylpyrimidin-5-yl)methylcarbamoyl)biphenyl-3-carboxylic acid (11 mg, 0.030 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (12 mg, 0.061 mmol), 1-hydroxybenzotriazole hydrate (4.7 mg, 0.030 mmol), and CH2Cl2 (2 mL) were added hexahydro-1H-azepine (4.5 mg, 0.046 mmol) and N,N-diisopropylethylamine (11 μL, 0.061 mmol). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 30-70% MeCN/water[10 mM Et2NH]) to yield a white foam.