Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][C:14]([Br:19])=[CH:13][C:12]=3[N:11]=[C:10]([NH2:20])[C:9]=2[N:8]=[C:7]1[CH2:21][O:22][CH2:23][CH3:24].[CH:25]([N:28]=[C:29]=[O:30])([CH3:27])[CH3:26]>C(Cl)(Cl)Cl>[NH2:20][C:10]1[C:9]2[N:8]=[C:7]([CH2:21][O:22][CH2:23][CH3:24])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:29]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:30])[C:18]=2[C:17]2[CH:16]=[CH:15][C:14]([Br:19])=[CH:13][C:12]=2[N:11]=1
Reactant: CC(C)N=C=O
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCN
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCNC(=O)NC(C)C
Reaction time: 0.75 h
Yield: 76.4 %

Procedure:
A solution of 1-(4-aminobutyl)-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 5.1 mmol) in chloroform (36 mL) was cooled to 0° C., and a cold solution of isopropyl isocyanate (0.50 mL, 5.4 mmol) in chloroform (4 mL) was added slowly. A precipitate formed, and the reaction was stirred for 45 minutes. The reaction mixture was triturated with ethyl acetate (200 mL), and the precipitate was isolated by filtration and dried for three days in a drying oven to provide 1.86 g of N-{4-[4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-N′-(1-methylethyl)urea as a white solid, mp 211° C.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=1.[OH-].[Na+]>C1COCC1.C(O)C>[CH3:14][S:11]([O:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:15])=[O:2])(=[O:13])=[O:12]
Reactant: COC(=O)c1cccc(OS(C)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)Oc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
The above prepared 3-methanesulfonyloxy-benzoic acid methyl ester (3.81 g, 16 mmol) was dissolved in 100 ml of THF/ethanol=1/1 and treated with 50 ml of aq. NaOH (1M, 3 eq.). The mixture was stirred for 2 h at ambient temperature and was then poured onto crashed ice/AcOEt/HCl dil.; the organic layer was washed with water, dried over sodium sulfate, and evaporated to dryness to leave 3.38 g of the title compound as white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH2:24][C:25]3[N:26]=[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[N:28]4[CH:39]=3)[CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH2:24][C:25]3[N:26]=[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[N:28]4[CH:39]=3)[CH:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccnc(OCc3cn4c(-c5ccccc5)cccc4n3)c2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2ccnc(OCc3cn4c(-c5ccccc5)cccc4n3)c2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[2-(5-phenylimidazo[1,2-a]pyridin-2-ylmethoxy)-4-pyridylmethyl]-1H-pyrazol-4-yl]propionate (1030 mg), 1N aqueous sodium hydroxide solution (4 ml), tetrahydrofuran (8 ml) and ethanol (8 ml) was stirred at room temperature for 3 hours, 1 N hydrochloric acid (4 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[2-(5-phenylimidazo[1,2-a]pyridin-2-ylmethoxy)-4-pyridylmethyl]-1H-pyrazol-4-yl]propionic acid (922 mg, yield: 95%). This was recrystallized from ethanol-hexane. Melting point: 177–178° C.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[C:21]1([OH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[O:27]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3Oc3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.15 g of phenol, 0.55 g of potassium carbonate and 2 ml of DMF was stirred at room temperature for one hour, and then stirred while heating at 50° C. for four hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.24 g of 2-(3-phenoxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 38”).
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C@@H:8]([CH3:30])[CH2:9][O:10]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:4]1>C(O)=O.C(OCC)C>[F:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C@@H:8]([CH3:30])[CH2:9][OH:10])[CH2:4]1
Reactant: C[C@@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)N1CC[C@@H](CF)C1
Solvent: O=CO
Solvent: CCOCC
Product: C[C@@H](CO)N1CC[C@@H](CF)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
A mixture of (R)-3-(fluoromethyl)-1-((S)-1-(trityloxy)propan-2-yl)pyrrolidine (19.0 g, 47.1 mmol) and formic acid/diethyl ether (4:1, 189 mL) was stirred at room temperature for 8 h. This reaction mixture was concentrated on a rotary evaporator. The residue was dissolved in DCM, washed with sat'd aqueous K2CO3, and washed with brine. Organic layer was dried over Na2SO4, filtered, and concentrated to give the crude product that was purified by silica gel chromatography (10:7 ethyl acetate/hexanes to 10:7:2:1 ethyl acetate/hexane/methanol/triethylamine) to afford (S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propan-1-ol (3.9 g) as a dark orange oil. 1H NMR (400 MHz, DMSO-d6) δ 4.38-4.32 (m, 2H), 4.22-4.20 (m, 1H), 3.49-3.44 (m, 1H), 3.21-3.16 (m, 1H), 2.65-2.61 (m, 1H), 2.58-2.53 (m, 1H), 2.52-2.47 (m, 1H), 2.45-2.35 (m, 1H), 2.34-2.30 (m, 1H), 2.29-2.24 (m, 1H), 1.83-1.75 (m, 1H), 1.38-1.30 (m, 1H), 0.98 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[CH:7]=1.[CH3:22][C:23]([O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](O)=[O:32])([CH3:26])[C:24]#[CH:25].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.O>N1C=CC=CC=1>[C:14]([NH:13][C:11]1[S:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:31](=[O:32])[C:30]4[CH:34]=[CH:35][CH:36]=[C:28]([O:27][C:23]([CH3:22])([CH3:26])[C:24]#[CH:25])[CH:29]=4)[CH:21]=[CH:20][CH:19]=3)[CH:18]=[CH:17][C:9]=2[N:10]=1)(=[O:16])[CH3:15]
Reactant: C#CC(C)(C)Oc1cccc(C(=O)O)c1
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)cc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: C#CC(C)(C)Oc1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(C)=O)sc4c3)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)-1,3-benzothiazol-2-yl]acetamide (160 mg, 0.534 mmol) produced in Example A40(x), 3-[(1,1-dimethylprop-2-yn-1-yl)oxy]benzoic acid (215 mg, 1.07 mmol) in pyridine (5 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (407 mg, 1.07 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water (100 mL), and the mixture was extracted with ethyl acetate (100 mL). The organic layer was dried over anhydrous sodium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→0/100), and crystallized from ethyl acetate to give the title compound (181 mg, 70%) as colorless crystals.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[CH2:24](O)[CH3:25]>>[NH2:1][C@@H:2]([CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])[C:3]([O:5][CH2:24][CH3:25])=[O:4]
Reactant: N[C@@H](CCN1C(=O)c2ccccc2C1=O)C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@@H](N)CCN1C(=O)c2ccccc2C1=O

Procedure:
A solution of 2-(S)-Amino-4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)butanoic acid (2 g) and concentrated sulphuric acid (0.5 mL) in absolute ethanol (30 mL) was heated under reflux for 15 h. The solvent was evaporated and the residue was treated with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were dried (MgSO4) and evaporated. The residue was purified by chromatography using 20% ethyl acetate-dichloromethane then 75% ethyl acetate-dichloromethane as eluent to afford the title compound as a white solid (473 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:49][C:50]1C=[CH:53][S:52][C:51]=1CCCO.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:17]=3)[N:12]([CH2:49][CH2:50][CH2:51][S:52][CH3:53])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccsc1CCCO
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(CN3CCOCC3)cc2c1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSCCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A dry flask containing N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (0.20 gm) from Preparation No. 40 in dry THF (5 mL) under an argon atmosphere is added triphenylphosphine (396 mg), 3-methylthiolpropanol (0.16 mL) and diethyl azodicarboxylate (0.18 mL). The mixture is stirred at room temperature 48 hours and then concentrated under reduced pressure. The crude product is purified by flash column chromatography eluting with 2% to 6% methanol in dichloromethane and then by recrystallization from toluene-cyclohexane to afford 0.14 gm of the title compound as a white solid.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[O:9])=[CH:3][CH:2]=1.[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:17]([S:20]([CH:23]([F:25])[F:24])(=[O:22])=[O:21])=[CH:16][C:14]=1[NH2:15]>CCOC(C)=O>[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:17]([S:20]([CH:23]([F:24])[F:25])(=[O:21])=[O:22])=[CH:16][C:14]=1[NH:15][C:8]([NH:7][C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)=[O:9]
Reactant: Cc1ccc(N=C=O)cc1
Reactant: COc1ccc(S(=O)(=O)C(F)F)cc1N
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)C(F)F)cc1NC(=O)Nc1ccc(C)cc1
Reaction time: 72 h
Yield: 59.1 %

Procedure:
p-Tolyl isocyanate (0.058 mL, 0.46 mmol) was added to a solution of 2-methoxy-5-(difluoromethanesulfonyl)aniline (0.100 g, 0.42 mmol) in EtOAc (0.5 mL) and the reaction mixture was stirred at room temp. for 3 d. The resulting precipitate was filtered and washed with Et2O to provide the title compound as a white solid (0.092 g): 1H-NMR (CDCl3) δ 2.22 (s, 3H), 4.01 (s, 3H), 7.01-7.36 (m, 6H), 7.54 (dd, J=2.4, 8.6 Hz, 1H), 8.57 (s, 1H), 8.79 (d, J=2.6 Hz, 1H), 9.33 (s, 1H); EI-MS m/z 370 (M+). B1d. General Method for the Reaction of an Aryl Amine with an Aryl Isocyanate
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[N:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][N:27]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([O:25][C:26]2[N:27]=[CH:28][C:29]([CH2:32][CH3:33])=[CH:30][N:31]=2)=[CH:34][CH:35]=1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Reactant: CCc1cnc(Oc2ccc(I)cc2)nc1
Product: CCc1cnc(Oc2ccc(/C=C/CC(NC(=O)c3c(Cl)cccc3Cl)C(=O)OC)cc2)nc1
Yield: 75.1 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (50.0 mg) was reacted with 2-(4-iodophenoxy)-5-ethylpyrimidine (54.1 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(5-ethylpyrimidin-2-yloxy)phenyl]pent-4-enoic acid methyl ester (62.2 mg). Column chromatography (chloroform) and thin layer chromatography (cyclohexane/ethyl acetate=1/2) were used for purification.
Reaction SMILES: [N+:1](=[CH:3][CH3:4])=[N-:2].[C:5]([C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[CH:20]=[CH:21][C:22]#[N:23])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCOCC>[C:5]([C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1[C:21]([C:22]#[N:23])=[N:2][NH:1][C:3]=1[CH3:4])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC=[N+]=[N-]
Reactant: N#CC=Cc1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: CCOCC
Product: Cc1[nH]nc(C#N)c1-c1ccc(Cl)cc1C(=O)c1ccccc1
Reaction time: 3 h

Procedure:
A solution of diazoethane in 400 ml of ether (prepared from 16.1 g (0.1 mol) of N-ethyl-N'-nitro-N-nitrosoimino urea,) was added to a solution of 15 g (0.056 mol) of crude 3-(2-benzoyl-4-chlorophenyl)-2-propenonitrile in 100 ml of ether. After standing at room temperature for 3 hr, the excess diazoethane was destroyed by addition of glacial acetic acid. The mixture was washed with saturated sodium bicarbonate solution, was dried and evaporated, at the end azeotropically with toluene. The residue was dissolved in 400 ml of toluene and the solution was heated to reflux for 11/2 hr in presence of 60 g of activated manganese dioxide. The water was separated in a Dean Stark trap. The MnO2 was removed by filtration over Celite and the filtrate was evaporated. The residue (14 g) was chromatographed over 300 g of silica gel using 10% (v/v) of ethyl acetate in methylene chloride. The homogenous fractions were combined and evaporated to yield an oily product.
Reaction SMILES: [C:1]([C:3]1[C:4](=O)[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].P(Cl)(Cl)([Cl:16])=O.CCCCCC>C(Cl)Cl>[Cl:16][C:4]1[C:3]([C:1]#[N:2])=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cc2ccccc2[nH]c1=O
Solvent: ClCCl
Solvent: CCCCCC
Product: N#Cc1cc2ccccc2nc1Cl

Procedure:
A mixture of 50 g of 3-cyano-2(1H)-quinolinone and 250 ml of phosphoryl chloride was heated at reflux for 18 hours. Volatile material was evaporated from the mixture under reduced pressure and the resulting residue was carefully added to water. The solid which formed was separated by filtration, washed with water and dried to give crude product. This was dissolved in methylene chloride and the resulting solution was treated with silica gel and filtered to give a pale yellow solution. Hexane was added to the solution which was then placed on a steam bath until crystallization occurred. The solid was then separated by filtration to give 2-chloro-3-cyanoquinoline. This compound melts at about 163°-164° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([CH3:20])([CH3:19])[CH2:10][NH:11]C(=O)OC(C)(C)C)[CH:5]=[CH:6][CH:7]=1.[ClH:21].CCOC(C)=O>CCOC(C)=O>[ClH:21].[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([CH3:20])([CH3:19])[CH2:10][NH2:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(CNC(=O)OC(C)(C)C)Cc1cccc(Br)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(CN)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
tert-Butyl 3-(3-bromophenyl)-2,2-dimethylpropylcarbamate (72) (3.2 g, 9.35 mmol) was dissolved in EtOAc (55 mL), and a solution of HCl-EtOAc (˜4.2 M, 20 mL, 84 mmol) was added. The reaction was vented with a needle and stirred at room temperature for 2.5 h. The reaction was then diluted with hexanes and the white solid was collected on a fritted glass funnel. The mother liquor was concentrated under reduced pressure, suspended in ˜5-10% EtOAc-hexanes, and the white solid was collected and combined with the first batch. The solid was dried in a vacuum oven at room temperature overnight to give pure 3-(3-bromophenyl)-2,2-dimethylpropan-1-amine hydrochloride as a white solid. Yield (1.52 g): 1H NMR (400 MHz, CDCl3) δ 8.53 (br s, 2H), 7.37 (dq, J=1.2 and 8.0 Hz, 1H), 7.31 (t, J=1.6 Hz, 1H), 7.13 (t, J=7.7 Hz, 1H), 7.08 (dt, J=8.0, 1.6 Hz, 1H), 2.83-2.84 (m, 2H), 2.67 (s, 2H), 1.09 (s, 6H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([CH:9]=[CH2:10])[N:6]=[C:5]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.[H][H]>[Pd].C(O)C>[CH2:9]([C:7]1[N:6]=[C:5]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:13][CH2:12]2)[N:4]([CH2:3][CH2:2][OH:1])[CH:8]=1)[CH3:10]
Reactant: [H][H]
Reactant: C=Cc1cn(CCO)c(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: [Pd]
Solvent: CCO
Product: CCc1cn(CCO)c(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Reaction time: 2 h
Yield: 99.4 %

Procedure:
Add 10% palladium on carbon (2.10 g) in ethanol (50 mL). Then add a solution of tert-butyl 4-(1-(2-hydroxyethyl)-4-vinyl-1H-imidazol-2-yl)piperidine-1-carboxylate (20.00 g, 62.22 mmol) in ethanol (200 mL). Cycle through nitrogen and vacuum three times, then hydrogen and vacuum three times. Allow to stir at room temperature under 1 atmosphere hydrogen. After two hours, filter through Celite®. Wash with methanol. Concentrate the filtrate in vacuo to give a light yellow solid as the title compound (20.00 g, 99%). MS (ES) m/z=324 [M]+.
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[F:9][C:10]([F:18])([F:17])[CH:11]([OH:16])[C:12](F)(F)F>>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][CH2:12][C@@H:11]([OH:16])[C:10]([F:18])([F:17])[F:9]
Reactant: Nc1ccccc1N
Reactant: OC(C(F)(F)F)C(F)(F)F
Product: Nc1ccccc1NC[C@@H](O)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.2 %

Procedure:
Benzene-1,2-diamine (4.83 g, 44.6 mmol) was dissolved in hexafluoroisopropanol (9.37 mL, 89 mmol), (R)-trifluoromethylepoxide (0.769 mL, 8.92 mmol) was added, and the resulting reaction mixture was stirred at room temperature for 4 hours. The solution was concentrated and purified on a silica gel column with a 0-100% EtOAc/Hexanes gradient in a 100 g cartridge. (R)-3-[(2-aminophenyl)amino]-1,1,1-trifluoropropan-2-ol (1.30 g, 5.90 mmol) was obtained in 66.2% yield. 1H NMR (400 MHz, CDCl3) 83.32 (dd, J=13.4, 8.3 Hz, 1H), 3.55 (dd, J=13.5, 3.3 Hz, 1H), 3.55 (bs, 3H), 4.22 (m, 1H), 6.71 (d, J=7.7 Hz, 1H), 6.79 (m, 2H), 6.87 (d, d, J=7.7, 2.2 Hz, 1H). MS m/z=221.00
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:11]1[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]=1[Br:21])[OH:10])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CCOC(C)=O.C(O[C:32]([CH3:35])([CH3:34])[CH3:33])(=O)C>>[C:1]([O:7][CH2:8][C@H:9]([C:11]1[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]=1[Br:21])[O:10][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(=O)OC(C)(C)C
Reactant: Cc1cc([N+](=O)[O-])cc(Br)c1[C@H](O)COC(=O)C(C)(C)C
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])cc(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 85 %

Procedure:
To a solution of (S)-2-(2-bromo-6-methyl-4-nitrophenyl)-2-hydroxyethyl pivalate (65E) in t-butyl acetate at 0° C., was added HClO4 (perchloric acid) (5.45 ml) slowly, stirred at 0° C. for 5 min, then the reaction mixture was warmed up to rt and stirred for 3 hs. The mixture was diluted by EtOAc, washed by sat. NaHCO3, extracted by EtOAc, dry over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in Hexanes to give 65F (9 g, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]=1[CH3:21])=[O:4].[Br:22]N1C(=O)CCC1=O>CC#N.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]=1[CH2:21][Br:22])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)c(-c2ccccc2)nc2ccccc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Product: COC(=O)c1c(CBr)c(-c2ccccc2)nc2ccccc12
Yield: 203.5 %

Procedure:
10 g (36 mmol) of 3-methyl-2-phenyl-quinoline-4-carboxylic acid methyl ester (compound of Description 1) were dissolved in 500 ml of CH3CN; 13 g (72 mmol) of N-bromosuccinimide were added and the reaction mixture was heated to reflux. After adding 1 g (4.1 mmol) of dibenzoylperoxide; the reaction was refluxed for 24 h; then additional 4 g (22.5 mmol) of N-bromosuccinimide and 0.5 g (2.0 mmol) of dibenzoylperoxide were added and the reaction was refluxed for 4 h. The solvent was evaporated in vacuo to dryness to yield 26.1 g of crude title compound which has been used in the following reaction without further purification.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][NH:8][N:7]=1)[CH3:4].Cl[CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([O:26][CH2:27][C:28]2[N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:31][C:32]=2[CH3:33])[CH:25]=1.O>CN(C)C=O>[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[C:24]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:31][C:32]=3[CH3:33])[CH:25]=2)[N:7]=1)[CH3:4]
Reactant: Cc1oc(-c2ccccc2)nc1COc1cncc(CCl)c1
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2cncc(OCc3nc(-c4ccccc4)oc3C)c2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl)propionate (318 mg) and 3-chloromethyl-5-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (472 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-yl]propionate (616 mg, yield: 84%) as a colorless oily substance from the fraction eluted with ethyl acetate.
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].[N:6]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:11][CH2:10]N[CH2:8][CH2:7]1>O1CCOCC1>[NH2:4][S:1]([N:5]1[CH2:10][CH2:11][N:6]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:7][CH2:8]1)(=[O:3])=[O:2]
Reactant: NS(N)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(S(N)(=O)=O)CC1
Yield: 70 %

Procedure:
Sulfamide (5 eq) was added to a solution of tert-butyl piperazine-1-carboxylate in dioxane (0.12 M). The reaction was stirred at reflux overnight. The solvent was removed in vacuo, the residue taken up in EtOAc and washed with H2O, brine, before being dried (Na2SO4), filtered and concentrated in vacuo to give the crude material. Purification was by automated FC (EtOAc:PE:Et3N 40:60:0.02) to afford the title compound (70%). 1H NMR (300 MHz, DMSO-d6, 300 K) δ 1.39 (s, 9H), 2.88-2.90 (m, 4H), 3.37-3.39 (m, 4H), 6.78 (s, 2H).