Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[CH:6][C:5]([C:15]#[N:16])=[CH:4][C:3]=1[NH:17][C:18]1[N:23]=[C:22]([N:24]([CH:34]2[CH2:36][CH2:35]2)[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:21]2=[N:37][CH:38]=[C:39]([C:40]#[N:41])[N:20]2[N:19]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:6][C:5]([C:15]#[N:16])=[CH:4][C:3]=1[NH:17][C:18]1[N:23]=[C:22]([N:24]([CH:34]2[CH2:35][CH2:36]2)[CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[C:21]2=[N:37][CH:38]=[C:39]([C:40]#[N:41])[N:20]2[N:19]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCC(O)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCC(=O)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.6 %

Procedure:
To a round bottom flask charged with 2-((2-chloro-5-cyano-3-(4-hydroxypiperidin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (0.27 g, 0.474 mmol) in wet dichloromethane (3.16 ml) was added Dess-Martin periodinate (0.402 g, 0.947 mmol). The reaction mixture was stirred at room temperature 2.5 h. The reaction mixture was diluted with dichloromethane and quenched by the addition of sodium thiosulfate doped saturated aqueous sodium bicarbonate (25 g/100 mL). The mixture was stirred until 2 clear layers were visible. The mixture was transferred to a separatory funnel and the aqueous layer was extracted with dichloromethane (3×). The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. 2-((2-Chloro-5-cyano-3-(4-oxopiperidin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (0.2465 g) was isolated as a yellow solid.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1>>[CH3:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]=1[N+:6]([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Product: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
Conc. sulfuric acid (25 ml; 0.5 equiv.) was added over a period of 10 minutes to nitric acid at 0° C. (69-72%; 25 ml; 0.5 equiv.). The resulting mixture was stirred for 30 minutes at 0° C. Conc. sulfuric acid (75 ml; 1.5 equiv.) was added at room temperature, over a period of 20 minutes, to 4-methylbenzoic acid (50 g; 1 equiv.). The resulting suspension was cooled to 0° C., and the nitrating acid was added thereto over a period of 45 minutes. The resulting reaction mixture was stirred for 1 hour at 10-20° C. When the conversion was complete, the reaction mixture was poured onto ice-water and the resulting white solid was filtered out and dried. 4-Methyl-3-nitrobenzoic acid (66.5 g; 82.7%) was obtained in the form of a white solid.
Reaction SMILES: [CH2:1]([NH:7][C:8]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[N:13][C:14]([Cl:21])=[CH:15][C:16]=2[CH3:20])[NH:11]1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].I[CH2:23][CH2:24][CH2:25][CH3:26].C(N(CC)CC)C>CN(C=O)C>[CH2:1]([NH:7][C:8]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[N:13][C:14]([Cl:21])=[CH:15][C:16]=2[CH3:20])[N:11]1[CH2:23][CH2:24][CH2:25][CH3:26])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCI
Reactant: CCCCCCNC(=O)n1[nH]c2nc(Cl)cc(C)c2c1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCNC(=O)n1c(=O)c2c(C)cc(Cl)nc2n1CCCC

Procedure:
In analogy to example 2, 100 mg (0.32 mmol) of 6-chloro-4-methyl-3-oxo-1,3-dihydropyrazolo[3,4-b]pyridine-2-carboxylic acid hexylamide were reacted with 59.2 mg (0.32 mmol) of 1-iodobutane in DMF with triethylamine at RT. Yield: 23 mg (19%), M+H+: 367.27.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[N:7]=1.FC(F)(F)C(O)=O.[C:21]([O:25][C:26](=[O:44])[C@@H:27]([NH:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:37])=[O:36])[CH2:28][NH:29][C:30](=[O:33])[CH2:31][NH2:32])([CH3:24])([CH3:23])[CH3:22].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[C:21]([O:25][C:26](=[O:44])[C@@H:27]([NH:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:37])=[O:36])[CH2:28][NH:29][C:30](=[O:33])[CH2:31][NH:32][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][C:6]1[N:7]=[C:3]([NH2:2])[S:4][CH:5]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)CN)NS(=O)(=O)c1ccccc1
Reactant: Nc1nc(CCCC(=O)O)cs1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)CNC(=O)CCCc1csc(N)n1)NS(=O)(=O)c1ccccc1
Temperature: -15 °C
Reaction time: 8 h

Procedure:
Acid 1-4 (300 mg, 1.35 mmol), amine 1-7 (600 mg, 1.37 mmol), HOBT (219 mg, 1.14 mmol) and NMM (445 μL, 4.04 mmol) were combined in 13 mL DMF, cooled to -15° C., and EDC (310 mg, 1.61 mmol) was added. The reaction was warmed to RT, stirred overnight, then diluted with EtOAc, washed with water, sat. NaHCO3, and brine, dried (MgSO4), filtered and concentrated. Flash chromatography (silica, 20% MeOH/EtOAc) provided 1-8 as yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13](O)=[O:14])=[C:11](/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:10][N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+].[OH-].[Na+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[C:11](/[CH:16]=[CH:17]/[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1c(-c2ccc(F)cc2)noc1/C=C/c1ccccc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OCc1c(-c2ccc(F)cc2)noc1/C=C/c1ccccc1
Yield: 62.9 %

Procedure:
To a solution of 3-(4-fluoro-phenyl)-5-((E)-styryl)-isoxazole-4-carboxylic acid (19.0 g, 61.4 mmol) and triethylamine (8.6 mL, 61.4 mmol) in THF (475 mL) was added at room temperature a solution of ethyl chloroformate (5.97 mL, 61.4 mmol) in THF (55 mL). After 1 h the triethylamine hydrochloride salt was filtered off and washed with a small amount of THF. The mixture was added to a solution of sodium borohydride (6.05 g, 154 mmol) and water (55 mL). After stirring overnight at room temperature aqueous sodium hydroxide solution (1 N, 180 mL) was added. Extraction with tert-butylmethylether, removal of the solvent by distillation and chromatography (silica, dichloromethane:methanol=1:0 to 95:5) afforded the title compound (11.4 g, 63%) as light yellow solid. MS: m/e=296.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:7][C:6]2[CH:10]=[CH:2][CH:3]=[CH:4][CH:5]=2)=[C:6]([CH:10]=1)[C:7]([O:9][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:8]
Reactant: O=C(O)c1cc(F)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1)c1cc(F)ccc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A suspension of 5-fluoro-2-hydroxybenzoic acid (468 mg, 3 mmol), potassium carbonate (1037 mg, 7.50 mmol) and (bromomethyl)benzene (1283 mg, 7.50 mmol) in acetone (60 ml) was stirred at 50° C. overnight. The mixture was cooled and filtered. The filtrate was concentrated and the crude product was purified by silica gel chromatography, eluting with hexane:ethyl acetate (10:1) to yield the title compound as a colourless oil. 860 mg.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([F:22])[C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[N:9][N:10]=2)[CH:7]=1.ClC1C=C(F)C(NN)=NC=1.N1[C:42]2[C:37](=[CH:38][C:39](CC(OC)=O)=[CH:40][CH:41]=2)C=CC=1.Cl.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(B(O)O)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)CC(C(C)C)=CC=2C(C)C)CCCCC1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].O>[F:22][C:4]1[C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[N:9][N:10]=2)[CH:7]=[C:2]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:3]=1
Reactant: COC(=O)Cc1ccc2ncccc2c1
Reactant: Fc1cc(Cl)cn2c(Cc3ccc4ncccc4c3)nnc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2P(C2CCCCC2)C2CCCCC2)C(C(C)C)C1
Solvent: C1COCCO1
Solvent: O
Product: Fc1cc(-c2ccccc2)cn2c(Cc3ccc4ncccc4c3)nnc12
Temperature: 100 °C

Procedure:
6-((6-chloro-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinoline. A mixture of 1-(5-chloro-3-fluoropyridin-2-yl)hydrazine (500 mg, 3095 μmol) and methyl 2-(quinolin-6-yl)acetate (600 mg, 2982 μmol) in HCl (conc., 600 μL, 7200 μmol) was heat at 100° C. for 20 min. The mixture was then heated in a microwave at 180° C. for 40 min. The mixture was quenched with NaOH (5 N, 1.5 mL) and the suspension was filtered and washed with H2O. The resulting brown solid is mostly the desired product. The solid was then triturated with NaOH (5 N, 1 mL), filtered, and washed with H2O. LCMS (ESI pos. ion): calc'd for C16H10ClFN4: 312.0. found: 313.1 (M+1). 2) 6-((8-fluoro-6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinoline. A mixture of Pd(OAc)2 (6.46 mg, 28.8 μmol), potassium phosphate (367 mg, 1727 μmol), phenylboronic acid (211 mg, 1727 μmol), dicyclohexyl(2-(2,4,6-triisopropylcyclohexa-1,3-dienyl)phenyl)phosphine (27.6 mg, 57.6 μmol), and 6-((6-chloro-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinoline (180 mg, 576 μmol) in dioxane (6 mL)-H2O (2 mL) was heated to 100° C. under nitrogen for 20 h. The mixture was cooled to rt and partitioned between H2O and CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The residual was purified on silica using MeOH in DCM (0-5%) to give a pink solid. This solid was triturated with hexane-EtOAc-DCM (hot) to give a brown solid (105 mg). LCMS (ESI pos. ion): calc'd for C22H15FN4: 354.1. found: 355.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:20])[C:5]([NH:12][S:13]([NH:16][CH:17]([CH3:19])[CH3:18])(=[O:15])=[O:14])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].CO.C[O-].[Na+].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[NH:12][S:13](=[O:15])(=[O:14])[N:16]([CH:17]([CH3:19])[CH3:18])[C:7](=[O:8])[C:6]=2[CH:11]=1
Reactant: COC(=O)c1cc(Cl)cc(C)c1NS(=O)(=O)NC(C)C
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Solvent: O
Product: Cc1cc(Cl)cc2c1NS(=O)(=O)N(C(C)C)C2=O
Reaction time: 5 h

Procedure:
Methyl 5-chloro-3-methyl-2-((((1-methylethyl)amino)sulfonyl)amino)benzoate (26.31 grams; 0.08 mole) was mixed with 200 milliliters (ml) of methanol and sodium methoxide (8.84 grams; 0.164 mole) added thereto. The resulting reaction mixture was heated at the reflux temperature thereof for a period of 5 hours. The solvent was then removed in vacuo leaving a solid brown residue which was dissolved in 200 ml. of water. Sodium bicarbonate (20 grams) was added to the aqueous mixture and the resulting oily layer separated from the aqueous layer. The aqueous layer was acidified with dilute hydrochloric acid and the mixture extracted with ether. The ether extract was reduced in volume by evaporation in vacuo to give a light yellow oil which was dissolved in benzene, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give a light yellow powder. Recrystallization of the powder from methylene chloride and hexane gave the desired 6-chloro-8-methyl-3-(1-methylethyl)-1H-2,1,3-benzothiadiazin-4(3H)-one-2,2-dioxide product as a white crystalline solid having a melting point of 142°-144° C.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([NH:16][C@@H:17]([C@H:21]([OH:30])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19])=[O:15])([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:9]([O:13][C:14]([NH:16][C@@H:17]([C@H:21]([OH:30])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:18]([O:20][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:19])=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: BrCc1ccccc1
Reactant: COc1ccc([C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc([C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
Benzyl bromide (4.40 g, 25.7 mmol) was added dropwise to a mixture of (2S,3R)-2-(tert-butoxycarbonylamino)-3-hydroxy-3-(4-methoxyphenyl)propanoic acid (4.00 g, 12.9 mmol) and Cs2CO3 (4.20 g, 12.9 mmol) in DMF (80 mL) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. Water (80 mL) was added and the resulting mixture was extracted with EtOAc (100 mL×2). The combined extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=10:1 to 4:1) to afford (2S,3R)-benzyl 2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-(4-methoxyphenyl)propanoate (3.7 g, 66% yield) as a colorless solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([C:19]#[N:20])[CH:12]=2)[C@H:6]([C:8]([OH:10])=O)[CH3:7])[CH2:3][CH2:2]1.[CH2:21]([NH2:23])[CH3:22]>>[CH:1]1([CH2:4][N:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([C:19]#[N:20])[CH:12]=2)[C@H:6]([C:8]([NH:23][CH2:21][CH3:22])=[O:10])[CH3:7])[CH2:2][CH2:3]1
Reactant: C[C@@H](C(=O)O)N(CC1CC1)c1ccc(C#N)c(C#N)c1
Reactant: CCN
Product: CCNC(=O)[C@H](C)N(CC1CC1)c1ccc(C#N)c(C#N)c1

Procedure:
Synthesized in a manner similar to example 3 using N-(cyclopropylmethyl)-N-(3,4-dicyanophenyl)alanine and ethylamine: MS (ES) m/z 297 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5]>C1COCC1>[NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Cc1ccc(C(=O)O)c(N)c1
Solvent: C1CCOC1
Product: Cc1ccc(CO)c(N)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-amino-4-methylbenzoic acid (1.0 g, 6.62 mmol) in THF (10 mL) is added drop wise BH3 THF (1.0 M, 16.6 mL, 16.6 mmol) and the mixture is stirred at RT for 3 days. Excess BH3 is quenched with 1N HCl at 0° C. The solvent is evaporated to obtain a white solid. The solid is washed with water, and then hexane to remove the water. The solid is then dried in an oven to obtain the title compound).
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.[C:13]12(O)[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2.ClCCl.S(=O)(=O)(O)O>CCCCCCC>[C:13]12([C:6]3[C:7]([OH:12])=[CH:8][C:9]4[C:4]([CH:5]=3)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=4)[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)(O)O
Solvent: CCCCCCC
Solvent: ClCCl
Product: Oc1cc2ccc(Br)cc2cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
56 g (0.25 mol) of 6-bromo-2-naphthol, 38.2 g (0.25 mol) of 1-adamantanol and 500 ml of a mixture of dichloromethane and heptane (40/60) were introduced into a round-bottomed flask. 15 ml of concentrated sulfuric acid were added and the reaction mixture was stirred at room temperature for 48 hours. The solid was filtered off, washed with heptane (3×100 ml) and dissolved in ethyl ether and the organic phase was washed with water, separated by settling, dried over magnesium sulfate and evaporated. 60.1 g (67%) of the expected compound were collected, which compound had a melting point of 215°-6° C.
Reaction SMILES: CC1(C)CC=C(C2C=C(C)C=C(C)C=2)C2C=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=CC1=2.CC1(C)CC=C(C2C=CC(C)=CC=2)C2C=C(NC3C=CC=CC=3C([O-])=O)C=CC1=2.[CH3:63][C:64]1([CH3:95])[CH2:73][CH:72]=[C:71]([C:74]2[CH:79]=[CH:78][C:77]([CH3:80])=[CH:76][CH:75]=2)[C:70]2[CH:69]=[C:68]([C:81]([NH:83][C:84]3[CH:94]=[CH:93][C:87]([C:88]([O:90]CC)=[O:89])=[CH:86][CH:85]=3)=[S:82])[CH:67]=[CH:66][C:65]1=2.[OH-].[Na+]>CCO.C1COCC1>[CH3:63][C:64]1([CH3:95])[CH2:73][CH:72]=[C:71]([C:74]2[CH:79]=[CH:78][C:77]([CH3:80])=[CH:76][CH:75]=2)[C:70]2[CH:69]=[C:68]([C:81]([NH:83][C:84]3[CH:85]=[CH:86][C:87]([C:88]([OH:90])=[O:89])=[CH:93][CH:94]=3)=[S:82])[CH:67]=[CH:66][C:65]1=2
Reactant: CCOC(=O)c1ccc(NC(=S)c2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Agent: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cc(C)cc(C)c2)=CCC3(C)C)cc1
Agent: Cc1ccc(C2=CCC(C)(C)c3ccc(Nc4ccccc4C(=O)[O-])cc32)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C(=S)Nc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 84.0 mg (0.184 mmol) ethyl 4[[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl]amino]-benzoate (Compound 42) in 2.0 ml EtOH and 2.0 ml of THF was added 60.0 mg NaOH (1.50 mmol, 1.5 ml of a 1M aqueous solution). After stirring at room temperature overnight, the reaction was quenched by the addition of 10% HCl. Extraction with EtOAc, and drying of the organic layers over MgSO4, provided a solid after removal of the solvent under reduced pressure. Crystallization from CH3CN afforded the title compound as a yellow solid. 1H NMR (d6-acetone): δ 10.96 (1H, s), 8.05 (4H, m), 7.72 (1H, dd, J=2.0, 8.0 Hz), 7.54 (1H, s), 7.46 (1H, d, J=8.1 Hz), 7.20 (4H, m), 6.04 (1H, t, J=4.7 Hz), 2.38 (2H, d, J=4.7 Hz), 2.33 (3H, s), 1.35 (6H, s).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][N:9]2[C:13]([CH2:14][CH2:15][C:16]([OH:18])=O)=[CH:12][N:11]=[CH:10]2)=[CH:6][CH:5]=1)#[N:3].[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.CCOCC>CN(C=O)C.C(Cl)Cl.CCOC(C)=O.C(N(CC)CC)C>[ClH:21].[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:16](=[O:18])[CH2:15][CH2:14][C:13]2[N:9]([CH2:8][C:7]3[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:20][CH:19]=3)[CH:10]=[N:11][CH:12]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cccc(Cl)c1
Reactant: N#Cc1ccc(Cn2cncc2CCC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: N#Cc1ccc(Cn2cncc2CCC(=O)Nc2cccc(Cl)c2)cc1
Reaction time: 6 h

Procedure:
To a 0° C. solution of acid 6 (141 mg) in 2 mL of dry DMF was added triethylamine (0.089 mL), and 3-chloroaniline (0.046 mL). 1-Hydroxybenzotriazole hydrate (80 mg) was added, followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (106 mg). After six hours, the reaction was poured into EtOAc, washed with sat. aq. NaHCO3 solution and brine, then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. Purification by silica gel chromatography (2-6% MeOH/CH2Cl2) gave a white foam which was taken up in CH2Cl2, treated with 1 M HCl/ether solution, and concentrated in vacuo. The product hydrochloride 1 was isolated as a white powder.
Reaction SMILES: C(N1CCN([CH2:10][C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:22][C:21]=3[C:32]3[CH:37]=[C:36]([C:38](=[O:51])[NH:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=4)[CH:35]=[CH:34][N:33]=3)=[O:18])[CH:14]=[CH:13][CH:12]=2)CC1)(=O)C.[N:52]1([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:58][CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.N1(C(=O)C)CCNCC1>>[N:26]1([C:23]2[CH:24]=[CH:25][C:20]([NH:19][C:17]([C:15]3[N:16]=[C:11]([CH2:10][N:55]4[CH2:56][CH2:57][CH2:58][N:52]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:53][CH2:54]4)[CH:12]=[CH:13][CH:14]=3)=[O:18])=[C:21]([C:32]3[CH:37]=[C:36]([C:38](=[O:51])[NH:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:48])([F:49])[F:50])[CH:42]=4)[CH:35]=[CH:34][N:33]=3)[CH:22]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: CC(=O)N1CCN(Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)n2)CC1
Agent: CC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCCN(Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)n2)CC1

Procedure:
This compound was prepared using the procedure described for the preparation of 6-((4-acetylpiperazin-1-yl)methyl)-N-(4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)picolinamide 58, substituting tert-butyl 1,4-diazepane-1-carboxylate for -(piperazin-1-yl)ethanone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]([CH2:19][CH2:20]Cl)[C:9]2=[O:22])=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=1.C(N(CC)CC)C>CC#N>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]([CH2:19][CH2:20][S:30][C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)[C:9]2=[O:22])=[CH:4][CH:3]=1
Reactant: O=C1C(CCCl)C(c2ccc(O)cc2)N1c1ccc(F)cc1
Reactant: Fc1ccc(S)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1C(CCSc2ccc(F)cc2)C(c2ccc(O)cc2)N1c1ccc(F)cc1
Reaction time: 20 h

Procedure:
To a stirring solution of 1-(4-fluorophenyl)-3-(2-chloroethyl)-4-(4-hydroxyphenyl)azetidin-2-one (Method 12; 0.750 g, 2.35 mmol) in MeCN (10 ml) was added 4-fluorothiophenol (0.500 ml, 4.60 mmol) and triethylamine (0.500 ml, 3.59 mmol) at room temperature. After 20 hours there were still start materiel left (approximately 20%, LC/MS) and more 4-fluorothiophenol (0.250 ml, 2.30 mmol) and triethylamine (0.170 ml, 1.22 mmol) were added. After 24 hours, the solvent was removed under reduced pressure and the residue was partitioned between water (20 ml) and EtOAc (20 ml). The organic layer was washed with brine (5 ml), dried over magnesium sulphate and concentrated. The residue was refluxed in heptane for 30 minutes before the title compound was filtered off as a grey solid (0.946 g; 98%). NMR (CD3OD, 400 MHz) 2.00-2.20 (m, 2H), 3.05 (t, 2H), 3.25 (dt, 1H), 4.75 (d, 1H), 6.75-6.80 (m, 2H), 6.90-7.05 (m, 4H), 7.15-7.40 (m, 6H); m/z: 412.0.
Reaction SMILES: N1C=CN=C1.C(NCC(O)=O)(=O)C.P(Cl)(Cl)(Cl)=O.[CH3:19][N:20]([CH3:30])/[C:21](=[C:23]1/[N:24]=[C:25]([CH3:29])[O:26][C:27]/1=[O:28])/[CH3:22].[O-:31][CH2:32][CH3:33]>CC(N(C)C)=O>[C:32]([NH:24]/[C:23](=[C:21](/[N:20]([CH3:30])[CH3:19])\[CH3:22])/[C:27]([O:26][CH2:25][CH3:29])=[O:28])(=[O:31])[CH3:33]
Reactant: CC[O-]
Reactant: CC1=N/C(=C(\C)N(C)C)C(=O)O1
Agent: CC(=O)NCC(=O)O
Agent: c1c[nH]cn1
Solvent: CC(=O)N(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)/C(NC(C)=O)=C(/C)N(C)C
Temperature: 45 °C
Yield: 50 %

Procedure:
Another approach toward imidazole intermediate is described in Reaction Scheme 3. The original reaction sequence was published by F. Hoffmann-La Roche A G [F. Hoffmann-La Roche A G, WO 2005/003117, 2005]. N-acetylglycine (14) and phosphorous oxychloride are mixed and dimethylacetamide is added thereto dropwise slowly at low temperature (exothermic). The reaction mixture is then stirred and warmed at 45° C. In this way, (E)-4-(1-(dimethylamino)ethylidene)-2-methyloxazol-5(4H)-one (15) is generated in 50% yield. The oxazolone (15) is cleaved with in situ generated ethoxide to produce (E)-ethyl 2-acetamido-3-(dimethylamino)but-2-enoate (16). Next, an amine (17) is subjected to a reaction with the compound (16) in acetic acid at rt overnight to give a Michael adduct (18). The crude intermediate (18) is then refluxed together with fine powdered ammonium sulfate in hexamethyldisilazane at 145° C. to provide the corresponding imidazole ester (19) in 55˜73% yield for the three steps from the oxazolone (15). The imidazole ester (19) is hydrolyzed with sodium hydroxide to produce the corresponding sodium carboxylate (20) uneventfully.