Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=O)=[CH:7][CH:6]=[CH:5]2.CCN(C(C)C)C(C)C.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1>O=S(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:12]([C:8]2[C:9]3[C:4](=[CH:3][C:2]([OH:1])=[CH:11][CH:10]=3)[CH:5]=[CH:6][CH:7]=2)=[O:14])=[CH:27][CH:26]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(O)c1cccc2cc(O)ccc12
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cc1)c1cccc2cc(O)ccc12
Reaction time: 4 h

Procedure:
A slurry of 6-hydroxy-naphthalene-1-carboxylic acid (0.2 g, 1.06 mmol) in 10.6 mL of SOCl2 and 1 drop of DMF was heated to 40° C. After 4 h, the solution was concentrated to dryness and placed under high vacuum overnight. The crude residue was dissolved in 3.5 mL of CH2Cl2. To the resulting solution was added DIEA (0.554 mL, 3.18 mmol), 4-chlorophenylamine (0.162 g, 1.27 mmol) and a catalytic amount of DMAP. The reaction was stirred under an argon atmosphere for 2 days. The reaction was diluted with CH2Cl2, washed with saturated aqueous NH4Cl, saturated aqueous NaHCO3, and brine. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was passed through a medium-pressure silica gel column (solvent gradient: 94:6 CH2Cl2:MeOH; 95:5 CH2Cl2:MeOH; 90:10 CH2Cl2:MeOH) to afford the desired crude compound. The fractions were concentrated to dryness to afford a solid residue. The residue was triturated with CHCl3 to afford the desired compound as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])=[N:8][NH2:9].C(OC(O)C)C.[OH-].[K+]>O.ClCCl.Cl[Cu]>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:7]1[C:3]2[S:4][CH:5]=[CH:6][C:2]=2[NH:9][N:8]=1
Reactant: COc1ccccc1C(=NN)c1sccc1Br
Agent: Cl[Cu]
Agent: CCOC(C)O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1-c1n[nH]c2ccsc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.5 %

Procedure:
A mixture of 5.23 g of (3-bromthien-2-yl) (2-methoxyphenyl)methanone hydrazone and 47 ml of ethoxyethanol was heated at 75° C. and to it a solution of potassium hydroxide in water (1.88 g in 9.15 ml) was added. The reaction mixture was blanketed with nitrogen. After stirring for 10 minutes, 50 mg of CuCl was then added and stirring was continued until completion of the reaction (45 minutes). The reaction mixture was then allowed to cool to room temperature, quenched with water and the organics were extracted into ether/ethyl acetate (1:1). Washing, drying (over anhydrous magnesium sulfate) and then evaporation of the ether/ethyl acetate solution gave an oil containing some crystals. The oil was passed through a silica gel column packed in dichloromethane to give 2.07 g of crystals. This material was combined with another material prepared in the same manner. The combined product (3.1 g) was recrystallized from ether/hexane.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[NH2:14][C:15]1([CH2:20][OH:21])[CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([NH:14][C:15]2([CH2:20][OH:21])[CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: NC1(CO)CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Nc1cccc(S(=O)(=O)NC2(CO)CCCC2)c1
Yield: 59.2 %

Procedure:
A mixture of 3-nitro-benzenesulfonyl chloride (0.89 g, 4 mmol) and (1-amino-cyclopentyl)-methanol (0.46 g, 4 mmol) in dichloromethane (4 mL)/sat. sodium bicarbonate solution (4 mL) was stirred at 20° C. for 20 h. The mixture was diluted with dichloromethane (20 mL). The layers were separated and the organic layer was washed with water, dried (Na2SO4) and evaporated in vacuo. The solid residue was dissolved in ethanol (20 mL) and hydrogenated in the presence of 5% palladium-charcoal (0.2 g) to give the title compound (0.64 g, 59%). Off-white solid. MS (ISP) 271.4 [(M+H)+]; mp 130-132° C.
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[CH2:16][C:17]1[S:21][C:20]([NH:22][C:23]([N:25]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:24])=[N:19][CH:18]=1)=[O:10])C1C=CC=CC=1>[Pd].CO>[CH:32]1([N:25]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:23](=[O:24])[NH:22][C:20]2[S:21][C:17]([CH2:16][N:12]3[CH2:13][CH2:14][CH2:15][C@@H:11]3[C:9]([OH:10])=[O:8])=[CH:18][N:19]=2)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: [Pd]
Solvent: CO
Product: O=C(O)[C@H]1CCCN1Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Yield: 84.8 %

Procedure:
1-[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylmethyl]-pyrrolidine-2 (R)-carboxylic acid benzyl ester (50 mg, 0.095 mmol) was combined with palladium on carbon (25 mg) in MeOH. Vacuum was applied to degas the mixture. The reaction was subjected to hydrogen and vigorous stirring until no ester could be detected (36 h). After filtering and concentration, 35 mg (84%) pure acid was obtained by trituration.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[S:17](=[O:26])(=[O:25])[N:16]=2)=[C:11]([OH:27])[C:10]2[S:28][C:29](S(C)(=O)=O)=[N:30][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:35]>>[NH2:35][C:29]1[S:28][C:10]2[C:11]([OH:27])=[C:12]([C:15]3[NH:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[S:17](=[O:25])(=[O:26])[N:16]=3)[C:13](=[O:14])[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9]=2[N:30]=1
Reactant: N
Reactant: CS(=O)(=O)c1nc2c(s1)c(O)c(C1=NS(=O)(=O)c3ccccc3N1)c(=O)n2Cc1ccccc1
Product: Nc1nc2c(s1)c(O)c(C1=NS(=O)(=O)c3ccccc3N1)c(=O)n2Cc1ccccc1
Yield: 99.2 %

Procedure:
The product of Example 146 (0.011 g, 0.02 mmol) was reacted with ammonia (0.5 M in dioxane, 1.3 mL, 0.64 mmol) in a pressure tube at 70° C. for 17 hours. The reaction was cooled and the resulting precipitate was collected by filtration and dried to give the title compound as a white solid (0.009 g, 100%). MS (ESI) m/z 452 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 5.43 (s, 2 H), 6.91 (s, 1 H), 7.07 (s, 1 H), 7.30 (m, 4 H), 7.52 (dd, J=24.27, 8.82 Hz, 2 H), 7.69 (t, J=7.54 Hz, 1 H), 7.85 (d, J=8.82 Hz, 1 H), 9.03 (br s, 1 H), 14.57 (brs, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[NH:11][C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=1.[OH-].[Na+]>CN(C=O)C.C(OCC)(=O)C.C(O)C.C1COCC1>[C:30]([C:29]1[CH:34]=[CH:35][C:26]([CH2:25][N:11]2[C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6](=[O:7])[C:5]3[CH:20]=[CH:21][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:9][C:10]2=[O:19])=[CH:27][CH:28]=1)([OH:32])=[O:31]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=C1CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
300 mg (1.0 mmol) of 4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 10 ml of DMF. 48 mg (1.2 mmol) of sodium hydride was added to the obtained solution, and they were stirred at room temperature for 30 minutes. 300 mg (1.3 mmol) of methyl 4-bromomethylbenzoate was added to the obtained mixture, and they were stirred at 60° C. overnight. After the treatment with ethyl acetate as the extracting solvent, the obtained crude product was stirred together with 2 ml of THF, 2 ml of ethanol and 2 ml of 1 N aqueous sodium hydroxide solution at room temperature overnight. The obtained product was treated with ethyl acetate as the extracting solvent by an ordinary method to obtain the crude product.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:9]1([NH2:12])[CH2:11][CH2:10]1>C1(C)C=CC=CC=1>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][CH2:2][NH:12][CH:9]1[CH2:11][CH2:10]1)[CH3:8]
Reactant: NC1CC1
Reactant: CCOC(=O)CCBr
Solvent: Cc1ccccc1
Product: CCOC(=O)CCNC1CC1

Procedure:
14.0 ml of ethyl 3-bromopropionate are added to a solution of 15.4 ml of cyclopropylamine in 100 ml of toluene and the reaction mixture is heated to 90° for 3 hours. Subsequently, the precipitated salt is filtered and the filtrate is distilled. There are obtained 9.5 g of N-cyclopropyl-β-alanine ethyl ester, Fab-MS: 157 (M+H)+.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11].[BH4-].[Na+].Cl>CO.O>[F:3][C:4]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH2:10][OH:11]
Reactant: O=Cc1cccc(Oc2ccc(F)cc2F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1cccc(Oc2ccc(F)cc2F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydroxide solution (2 molar, 0.5 cm3) was added to a solution of 3-(2,4-difluorophenoxy)benzaldehyde (2 g) in methanol (20 cm3) and the mixture was cooled to 0° C. Sodium borohydride (0.5 g) was added, and the mixture stirred for 30 minutes. After this time, water was added, and the mixture acidified to pH 4 by addition of dilute hydrochloric acid. This mixture was extracted with diethyl ether (5×50 cm3). The combined organic layers were dried over anhydrous sodium sulphate, and the solvents evaporated under reduced pressure. The residue was purified by column chromatography on a silica gel support, using n-hexane containing 20% by volume ethyl acetate as eluent, to give 3-(2,4-difluorophenoxy)benzyl alcohol as a colourless oil.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[S:7][CH:8]=2)[CH2:3][CH2:2]1.C(#N)C.CC(O)=O.[Br:24]N1C(=O)CCC1=O>C([O-])(O)=O.[Na+]>[Br:24][C:8]1[S:7][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[N:5][C:4]=1[CH:1]1[CH2:2][CH2:3]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)Nc1nc(C2CC2)cs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1nc(C2CC2)c(Br)s1
Temperature: 0 °C
Yield: 86.1 %

Procedure:
To a 250 mL round-bottomed flask was added tert-butyl 4-cyclopropylthiazol-2-ylcarbamate (9.5 g, 40 mmol), ACN 100% (100 mL, 1914 mmol), and glacial AcOH (6.8 mL, 119 mmol). The solution was stirred at 0° C. and treated in portions with N-bromosuccinimide (3.4 mL, 40 mmol). The suspension was stirred for 1 hour, diluted with NaHCO3, and extracted with EtOAc. The organics were washed with saturated sodium chloride (1×50 mL) and water (1×50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give tert-butyl 5-bromo-4-cyclopropylthiazol-2-ylcarbamate (11 g, 86% yield), m/z (%): 320.3 (100%, M++H).
Reaction SMILES: C[O:2][C:3](=[O:13])[CH2:4][N:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].[OH-].[Na+]>O.CO>[CH3:6][N:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][C:3]([OH:13])=[O:2]
Reactant: COC(=O)CN(C)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(CC(=O)O)c1ccccc1

Procedure:
To 500 ml of water/methanol (1/4 weight ratio), 30 g of N-phenyl-N-methylglycine methyl ester and 12.3 g (1.1 equivalent weight) of NaOH were added and refluxed for 2 hours. The methanol was evaporated from the reaction mixture under reduced pressure. Then, water was added thereto and unreacted starting materials were extracted with methylene chloride. Subsequently, 10% hydrochloric acid was added to the aqueous layer to adjust the pH at about 5, followed by extraction with ether. The ether layer wad dried, and solvent distilled to yield N-methyl-N-phenylglycine in 27.1 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]=[C:10]2[NH:13]CC2C=CC=CC=2)=[CH:5][CH:4]=1>C1(OC2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[NH2:13])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(NCc1ccccc1)=CCC2
Agent: [Pd]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc2cccc(N)c2c1
Temperature: 25 °C
Yield: 76.1 %

Procedure:
To a solution of crude title compound of Step A (42.1 g) in diphenyl ether (320 mL) was added 10% palladium on carbon (17.8 g). The heterogeneous black mixture was heated at reflux for 5 h under N2 while stirring. The reaction mixture was allowed to cool to room temperature and filtered. The filtrate was acidified with concentrated HCl and the resulting white precipitate was collected by filtration, washed with CH2Cl2, dissolved in water and treated with 50% aqueous NaOH until basic. The aqueous mixture was then extracted four times with CH2Cl2. The combined organic extracts were dried (MgSO4), filtered and the filtrate was concentrated under reduced pressure to give 20.9 g of the title compound of Step B as a pink solid melting at 79-80° C. 1H NMR (CDCl3): δ 7.70 (d,1H), 7.29-7.13 (m,3H), 7.07 (d,1H), 6.80 (dd,1H), 4.0 (br s,2H), 3.94 (s,3H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[O:17][CH:18]=[CH:19][N:20]=3)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1>ClCCl>[O:17]1[CH:18]=[CH:19][N:20]=[C:16]1[C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(Cc2ccc(-c3ncco3)cc2)cc1
Solvent: ClCCl
Product: Oc1ccc(Cc2ccc(-c3ncco3)cc2)cc1
Temperature: 25 °C
Yield: 58.4 %

Procedure:
A solution of 2-[4-[(4-methoxyphenyl)methyl]phenyl]oxazole (0.4 g, 1.5 mmol) in dichloromethane (15 mL) was stirred and cooled to −78° C. as a solution of borontribromide in dichloromethane (1 N, 15 mL, 15 mmol) was added over 5 minutes. The cooling bath was removed and the reaction was allowed to warm to ambient temperature over 3 days. The reaction was diluted with methanol and concentrated, repeat twice. Purification on silica gel using a gradient of ethyl acetate in dichloromethane and hexane gave 0.22 g of 4-[[4-(2-oxazolyl)phenyl]methyl]phenol, 1H NMR (400 MHz, DMSO-d6) δ 9.19 (S, 1H), 8.17 (s, 1H), 7.88 (s, 2H), 7.35 (d, 2H), 7.02 (s, 2H), 6.66 (d, 2H), 3.84 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Cl[CH2:22][C:23]1[C:24]([CH3:29])=[N:25][O:26][C:27]=1[CH3:28]>>[CH3:29][C:24]1[C:23]([CH2:22][N:15]2[CH2:16][C:17](=[O:18])[N:13]([C:11]3[CH:10]=[N:9][N:8]([CH2:7][C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:20])[CH:12]=3)[C:14]2=[O:19])=[C:27]([CH3:28])[O:26][N:25]=1
Reactant: Cc1noc(C)c1CCl
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1noc(C)c1CN1CC(=O)N(c2cnn(Cc3c(C)noc3C)c2)C1=O
Yield: 50 %

Procedure:
Prepared as in Example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione and 4-(chloromethyl)-3,5-dimethylisoxazole. Yield: 50%. 1NMR (CDCl3, 400 MHz): 2.19 (s, 3H), 2.27 (s, 3H), 2.43-2.42 (d, J=5.2 Hz, 6H), 3.82 (s, 2H), 4.40 (s, 2H), 5.05 (s, 2H), 7.92 (s, 1H), 8.05 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.04 μM.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:27]2[N:36]=[CH:35][C:34]3[C:29](=[C:30]([F:41])[CH:31]=[C:32]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:33]=3)[C:28]2=[O:42])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=1)(=O)C.O.[OH-].[Li+]>C1COCC1.C(O)(C)C.O>[C:37]([C:32]1[CH:33]=[C:34]2[C:29](=[C:30]([F:41])[CH:31]=1)[C:28](=[O:42])[N:27]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:24]=[N:23][CH:22]=[CH:21][N:20]=4)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:36]=[CH:35]2)([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cnccn3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2cnccn2)c1=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
A mixture of 160b (120 mg, 0.21 mmol) and lithium hydroxide monohydrate (88 mg, 2.1 mmol) in THF/i-propanol (4:2, 6 mL) and water (2 mL) was stirred at 30° C. for 1 h. The mixture was evaporated under reduced pressure and the residue was diluted with water (10 mL). It was then extracted with ethyl acetate (2×20 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 160 (50 mg, 45%) as a white solid. MS-ESI: [M+H]+ 527.8. 1H NMR (500 MHz, CHCl3) δ 8.78 (d, J=2.5 Hz, 1H), 8.71 (d, J=5.0 Hz, 1H), 8.36 (d, J=2.0 Hz, 1H), 8.31 (s, 1H), 8.19 (s, 1H), 8.14 (s, 1H), 8.05 (d, J=2.0 Hz, 1H), 7.81 (d, J=2.5 Hz, 1H), 7.59 (s, 1H), 7.56-7.55 (m, 2H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][C:13](=[O:26])[C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]([O:22]C)[C:15]=1[O:24]C.B(Br)(Br)Br.C(OCC)(=O)C>ClCCl.[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][C:13](=[O:26])[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([OH:22])[C:15]=1[OH:24]
Reactant: COc1ccc(C(=O)Nc2cccc3cc(Br)cnc23)c(OC)c1OC
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc2cc(Br)cnc12)c1ccc(O)c(O)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.5 %

Procedure:
To a solution of 3-bromo-8-(2,3,4-trimethoxybenzoylamino)quinoline (700 mg) in dichloromethane (10 ml) was added 1M solution of boron tribromide in dichloromethane (5.5 ml) under ice-cooling, and the mixture was stirred for 2 hours at ambient temperature. To the mixture was added ice-water, and the mixture was stirred for 1.5 hours. The mixture was adjusted to pH 4 with IN sodium hydroxide solution, and ethyl acetate was added thereto. The mixture was stirred at ambient temperature overnight, and the insoluble material was filtered off. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (methanol-dichloromethane) to give 3-bromo-8-(2,3,4-trihydroxybenzoylamino)quinoline (110 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:24][C:25]1[CH:26]=[C:27]([C:31]2[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=2)[CH:28]=[N:29][CH:30]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)[CH2:24][C:25]2[CH:26]=[C:27]([C:31]3[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=3)[CH:28]=[N:29][CH:30]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(-c2cncc(CCl)c2)cc(OC)c1OC
Reactant: CSc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: COc1cc(-c2cncc(CN(c3ccc(SC)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[[4-(methylthio)phenyl]amino]piperidine (645 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14]([N:18]=[C:19]=[O:20])[CH:15]=[CH:16][CH:17]=1>>[I:1][C:2]1[CH:3]=[C:4]([NH:5][C:19]([NH:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([F:10])([F:21])[F:22])[CH:13]=2)=[O:20])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1I
Product: Cc1ccc(NC(=O)Nc2cccc(C(F)(F)F)c2)cc1I
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 3-iodo-4-methylaniline (1.17 g, 5 mmol) and 3-(trifluoromethyl)-phenylisocyanate (1.03 g, 5.5 mmol) was stirred at rt for 4 h. Filtration (ethyl acetate wash) yielded the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:26])[C:6]=1[C:7]1[CH:8]=[C:9]([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[F:24])[CH:10]=[CH:11][C:12]=1[OH:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC1C=NN(C)C=1C1C=C(NC(=O)C2C=CC(OC)=CC=2F)C=CC=1O.C1COCC1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F:91][C:92]([F:106])([F:105])[CH2:93][CH:94]([NH:97]C(=O)OC(C)(C)C)[CH2:95]O.[C:107]([OH:113])([C:109]([F:112])([F:111])[F:110])=[O:108]>C1COCC1>[F:110][C:109]([F:112])([F:111])[C:107]([OH:113])=[O:108].[NH2:97][CH:94]([CH2:93][C:92]([F:106])([F:105])[F:91])[CH2:95][O:13][C:12]1[CH:11]=[CH:10][C:9]([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[F:24])=[CH:8][C:7]=1[C:6]1[N:5]([CH3:26])[N:4]=[CH:3][C:2]=1[Cl:1]
Reactant: COc1ccc(C(=O)Nc2ccc(O)c(-c3c(Cl)cnn3C)c2)c(F)c1
Reactant: CC(C)(C)OC(=O)NC(CO)CC(F)(F)F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)Nc2ccc(OCC(N)CC(F)(F)F)c(-c3c(Cl)cnn3C)c2)c(F)c1
Reaction time: 0.08 h
Yield: 24.4 %

Procedure:
N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-2-fluoro-4-methoxybenzamide (20.0 mg, 53.2 μmol) was dissolved in anhydrous THF (0.3 mL). Triphenylphosphine (15.4 mg, 58.5 μmol), pre-dissolved in anhydrous THF (0.1 mL) was added to the N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-2-fluoro-4-methoxybenzamide/THF solution. The reaction was stirred for 5 minutes and then DIAD (16.6 μl, 85.2 μmol), pre-dissolved in anhydrous THF (0.1 mL) was added to the reaction. The mixture was stirred at r.t. for 5 more minutes and then tert-butyl 4,4,4-trifluoro-1-hydroxybutan-2-ylcarbamate (16.2 mg, 66.5 μmol), pre-dissolved in anhydrous THF (0.1 mL) was added. The reaction was then stirred for 4 hours and checked by LC/MS. While the reaction had not gone to completion, pushing the reaction by heating or extending the reaction time did not seem to improve the yield. Thus, the solvent was evaporated, the resulting oil re-suspended in CH2Cl2 (0.5 mL) and TFA (20.5 μl, 266 μmol) was added (to remove the Boc-protecting group from the amine). The reaction was stirred overnight at room temperature. The next day, the solvent was removed and the resulting oil was re-dissolved in DMSO (1 mL). The product was purified by Prep LC/MS (0-50% B, 30 min) to yield N-[4-(2-amino-4,4,4-trifluoro-butoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4-methoxy-benzamide trifluoroacetate (8.1 mg, 13.0 μmol, 24.5%) as a colorless oil. LCMS m/z 501.3 (M+H); 1H NMR (400 MHz, MeOH-d4) δ ppm 2.48-2.86 (m, 2 H), 3.75 (d, J=2.78 Hz, 3 H), 3.87-3.97 (m, 1 H), 3.89 (s, 3 H), 4.10-4.43 (m, 2 H), 6.85 (dd, J=12.88, 2.27 Hz, t H), 6.91 (dd, J=8.72, 2.40 Hz, 1 H), 7.30 (dd, J=9.09, 2.27 Hz, 1 H), 7.61 (d, J=2.53 Hz, 1 H), 7.65-7.69 (m, 1 H), 7.76 (t, J=8.59 Hz, 1 H), 7.90 (dd, J=8.97, 2.65 Hz, 1 H).