Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]#[C:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19].F[B-](F)(F)F.[N:29]1(OC(N(C)C)=[N+](C)C)[C:33]2[CH:34]=[CH:35][CH:36]=CC=2N=N1.NCC1CC1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH:34]1([CH2:33][NH:29][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][CH:23]=[C:15]([C:14]#[C:13][C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])[CH:16]=2)[CH2:36][CH2:35]1
Reactant: Cc1onc(-c2ccccc2)c1C#Cc1cccc(C(=O)O)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: NCC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1C#Cc1cccc(C(=O)NCC2CC2)c1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 86.9 %

Procedure:
To a solution of 3-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-benzoic acid (250 mg; 0.82 mmol) in N,N-dimethylformamide (4.8 mL) was added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (318 mg, 0.99 mmol) at 0° C. After stirring for 15 min at this temperature, aminomethylcyclopropane (86 μl, 0.99 mmol) and N-ethyldiisopropylamine (0.85 mL, 4.94 mmol) were added and the reaction mixture was allowed to warm to ambient temperature. After 1.75 h stirring at ambient temperature, it was extracted with dichloromethane (300 mL) and aqueous sodium carbonate (2 M, 75 mL). The combined organic layers were washed with brine (75 mL), dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 0:100) afforded the title compound (254 mg, 87%) as a white solid. MS: m/e=357.1 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].N.[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[CH2:7]([S:5][CH2:4][CH2:3][NH2:2])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: NCCS
Agent: Cl
Agent: N
Solvent: CO
Product: NCCSCc1ccccc1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a suspension of 0.1 mole cysteamine hydrochloride in 20 mL methanol were added 13.6 mL of 25% ammonia solution, followed by dropwise addition of 0.12 mole benzyl bromide at room temperature. The mixture was stirred for 0.5 h, and the formed precipitate of S-dibenzylcysteamine was collected by filtration. The product was extracted with ether (3×100 mL) and the organic phase was successively washed with brine (2×100 mL), dried over MgSO4 and the solvent evaporated in vacuo. The crude product was essentially pure enough for the next step. It could, however be recrystallized from ethyl acetate. Yield 86%, of white solid. m.p. 85–6° C. NMR (CDCl3) in agreement with the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH:9]2[C:17](=[O:18])[CH:16]3[CH:11]([CH:12]4[O:19][CH:15]3[CH2:14][CH2:13]4)[C:10]2=[O:20])=[C:5]([CH3:8])[S:6][CH:7]=1)[CH3:2].[Br:21]Br>C(Cl)Cl>[Br:21][C:7]1[S:6][C:5]([CH3:8])=[C:4]([CH:9]2[C:17](=[O:18])[CH:16]3[CH:11]([CH:12]4[O:19][CH:15]3[CH2:14][CH2:13]4)[C:10]2=[O:20])[C:3]=1[CH2:1][CH3:2]
Reactant: CCc1csc(C)c1C1C(=O)C2C3CCC(O3)C2C1=O
Reactant: BrBr
Solvent: ClCCl
Product: CCc1c(Br)sc(C)c1C1C(=O)C2C3CCC(O3)C2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.6 %

Procedure:
To a suspension of 4-(4-ethyl-2-methyl-thiophen-3-yl)-10-oxa-tricyclo[5.2.1.0*2,6*]decane-3,5-dione (73 mg, 0.25 mmol) in DCM (2 ml), at 0° C., is added bromine (26 μl, 0.5 mmol) in one portion, and the reaction allowed to warm to ambient and stirred at room temperature for 3 hours. The reaction is concentrated in vacuo, re-dissolved in methanol (10 ml), potassium carbonate (250 mg) added and the resulting suspension stirred at room temperature for a further 17 hours. The reaction is quenched by the addition if 2N aqueous HCl (10 ml) and extracted with DCM (2×10 ml). The combined organics extracts are dried, filtered, concentrated in vacuo, and purified by flash chromatography on silica gel to give 4-(5-bromo-4-ethyl-2-methyl-thiophen-3-yl)-10-oxa-tricyclo[5.2.1.0*2,6*]decane-3,5-dione as a brown solid (43 mg).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17].S(Cl)(Cl)=O.[CH3:25][C@H:26]1[CH2:31][C@@H:30](O)[C@H:29]([CH:33]([CH3:35])[CH3:34])[CH2:28][CH2:27]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([O:20][C:26]1([CH3:25])[CH2:31][CH2:30][CH:29]([CH:33]([CH3:35])[CH3:34])[CH2:28][CH2:27]1)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18]
Reactant: CC(C)CCCCCCCCCCCCCCC(=O)O
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)CCCCCCCCCCCCCCC(=O)OC1(C)CCC(C(C)C)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83.1 %

Procedure:
284.5 g of isostearic acid (molecular weight: 284.49, 1.00 mol) and thionyl chloride (molecular weight: 118.97, 1.05 mol) were placed in a 1-L reaction flask equipped with a thermometer. The mixture was stirred at room temperature for 20 minutes and then, heated at an oil bath temperature of 40° C. and stirred for 1 hour. The reaction solution obtained was left under reduced pressure for removal of the dissolved gas and excess thionyl chloride. 300 ml of toluene and 156.3 g of 1-menthol (molecular weight: 156.27, 1.00 mol) were added thereto; and 121.4 g of triethylamine (molecular weight: 101.19, 1.20 mol) was added dropwise over 20 minutes. After dropwise addition, the mixture was stirred at an oil bath temperature of 60° C. for 3 hours. The reaction solution obtained was quenched in water and extracted with toluene. The toluene phase was washed with aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and condensed in rotary evaporator for removal of the solvent to give yellow oil. Distillation thereof under reduced pressure gave a desired product, isostearic acid-1-menthyl as colorless oil. Yield: 351.4 g, (molecular weight: 422.7, 831.4 mmol), purity: 99.8%, yield: 83.1%.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].Cl.C(O[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])C>C(O)C>[CH2:1]([NH:4][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])[CH:2]=[CH2:3]
Reactant: CCOc1ccncc1[N+](=O)[O-]
Reactant: C=CCN
Agent: Cl
Solvent: CCO
Product: C=CCNc1ccncc1[N+](=O)[O-]

Procedure:
40 ml of allylamine was added to a 400 ml ethanol solution of 18.0 g of 4-ethoxy-3-nitropyridine hydrochloride, and the mixture was heated under reflux for 8 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 13.6 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (1:1).
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]#[C:15][C:16]1[C:17]([O:26][CH3:27])=[CH:18][C:19]([O:24][CH3:25])=[C:20]([CH:23]=1)[CH:21]=[O:22].[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl>[CH:21]([C:20]1[C:19]([O:24][CH3:25])=[CH:18][C:17]([O:26][CH3:27])=[C:16]([C:15]#[C:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:28](=[O:30])[CH3:29])[CH:23]=1)=[O:22]
Reactant: COc1cc(OC)c(C=O)cc1C#Cc1ccccc1N
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(OC)c(C=O)cc1C#Cc1ccccc1NC(C)=O
Temperature: 0 °C
Yield: 77.7 %

Procedure:
Pyridine (453 μL, 5.61 mmol) was added to a suspension of 5-(2-amino-phenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C, 750 mg, 2.67 mmol) in anhydrous methylene chloride (20 mL) and chilled to 0° C. The reaction mixture was treated dropwise with acetyl chloride (9.25 mL, 75.1 mmol). Upon completion the reaction was quenched with IN HCl (10 mL) and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness. The crude solid was purified by silica gel chromatography (5% MeOH/CH2Cl2) to yield 671 mg (78%) of N-[2-(5-formyl-2,4-dimethoxyphenylethynyl)phenyl]acetamide as an off-white solid. 1H-NMR (300 MHz, DMSO-d6) 10.15 (s, 1H), 9.23 (br s, 1H), 7.82 (m, 2H), 7.80 (s, 1H), 7.50 (dd, 1H, J=0.9, 7.8 Hz), 7.35 (dt, 1H, J=1.8, 9.3 Hz), 7.12 (t, 1H, J=7.8 Hz), 6.82 (s, 1H), 4.00 (s, 3.99 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7](O)=[O:8])=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:4][N:3]=1.[CH3:16][N:17](C=O)C.S(Cl)(Cl)=O.CN>ClCCCl.C(O)C>[CH3:16][NH:17][C:7]([C:6]1[C:2]([CH3:1])=[N:3][O:4][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8]
Reactant: Cc1noc(-c2ccccc2)c1C(=O)O
Reactant: CN(C)C=O
Agent: CN
Solvent: CCO
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: CNC(=O)c1c(C)noc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 6.0 g (29.6 mmol) of 3-methyl-5-phenyl-isoxazole-4-carboxylic acid in 150 ml DCE is added 0.3 ml of DMF and 2.6 ml (35.5 mmol, 1.2 eq.) of thionyl chloride. The mixture is stirred for 2 h at reflux until a brown solution is formed. The solution is cooled to room temperature and then slowly added to a 8M solution of methylamine in ethanol (18 ml) at 5° C. The suspension is poured onto methylene chloride, washed with sat. NaHCO3-solution, dried over Na2SO4 and concentrated. This yields 6.7 g (quant.) of the title compound as brown solid, which is used for further reactions without purification. Mass spectrum: m/z (M+H)+: 217.2
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](/[C:10](/[C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=2)=[CH:11]/[C@@H:12]2[N:16](CC3C=CC(OC)=CC=3OC)[C:15](=[O:28])[CH2:14][CH2:13]2)=[N:6][C:7]=1[O:8][CH3:9].C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5](/[C:10](/[C:29]2[CH:30]=[CH:31][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:33][CH:34]=2)=[CH:11]/[C@@H:12]2[NH:16][C:15](=[O:28])[CH2:14][CH2:13]2)=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(N)c(OC)n2)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)ccc1N
Yield: 43.5 %

Procedure:
A solution of (5R)-5-[(E)-2-(5-amino-6-methoxypyridin-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (198 mg) in trifluoroacetic acid (4 mL) and anisole (2 mL) was stirred at 80° C. for six hours. Saturated aqueous sodium bicarbonate was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:4) to give (5R)-5-[(E)-2-(5-amino-6-methoxypyridin-2-yl)-2-(4-tert-butylphenyl)ethenyl]pyrrolidin-2-one as a light brown solid (61 mg, 44%).
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[C:4](=[N:6][OH:7])Cl.[CH2:13]([O:15][C:16](=[O:20])[C:17]#[C:18][CH3:19])[CH3:14].CCN(CC)CC>CCOCC>[CH2:13]([O:15][C:16]([C:17]1[C:4]([C:3]2[C:8]([F:12])=[CH:9][CH:10]=[CH:11][C:2]=2[I:1])=[N:6][O:7][C:18]=1[CH3:19])=[O:20])[CH3:14]
Reactant: ON=C(Cl)c1c(F)cccc1I
Reactant: CC#CC(=O)OCC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)c1c(-c2c(F)cccc2I)noc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of 2-iodo-6-fluorobenzoyl chloride oxime (26.6 mmol) and ethyl-2-butynoate (3.72 ml, 31.92 ml, 1.2 eq.) in Et2O (106 ml) under N2, stirring at 0-5° C. added dropwise a solution of Et3N (4.81 ml, 34.6 mmol, 1.3 eq) in Et2O (13 ml) over 1 h. The reaction was allowed to warm to room temperature and stirred overnight. Et2O was added and then washed with H2O, brine, dried (MgSO4), filtered, and concentrated. The crude residue was chromatographed on silica gel using ethyl acetate in hexanes (1-20%) to give the title compound (8.21 g, 82%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:34])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17](=[O:33])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1.Br[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>CN(C=O)C>[CH3:7][O:8][C:9](=[O:34])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17](=[O:33])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:30][CH:31]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)c1ccccc1NC(=O)Cc1ccc(Oc2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1NC(=O)Cc1ccc(Oc2ccc(OCC(=O)OC(C)(C)C)cc2)cc1
Yield: 60 %

Procedure:
Potassium carbonate (162 mg) was added to 221 mg of 2-(2-(4-(4-hydroxyphenyloxy)phenyl)acetylamino)benzoic acid methyl ester obtained by the Reference Example 24, the mixture was suspended in dried DMF (5 ml), t-butyl bromoacetate (130 μl) was added little by little to the suspension at room temperature, and the mixture was stirred as it is over a night at room temperature. After completing the reaction, DMF was distilled out under reduced pressure and the product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of potassium bisulfate and dried with anhydrous magnesium sulfate. After removing the solvent by distillation, the residue was purified by silica gel column chromatography (developing liquid: hexane:ethyl acetate 4:1 to 1:1) to obtain 174 mg of the subject compound. The 1H-NMR of the compound was consistent with the above structure.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[H][H].F[C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#[N:19]>CS(C)=O>[N:1]1([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: N#Cc1cccc(F)c1
Reactant: c1ccc2[nH]ccc2c1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1cccc(-n2ccc3ccccc32)c1
Reaction time: 16 h
Yield: 100 %

Procedure:
To a stirred solution, under nitrogen, of 17.6 g (0.150 mole) of indole in 100 ml of dry dimethylsulfoxide (DMSO) was added 4.5 g (0.188 mole) of sodium hydride in portions over a 1.5 hour period. When no more bubbles of hydrogen were visible (4-5 hours), there was added dropwise a solution of 22.8 g (0.188 mole) of 3-fluorobenzonitrile in 25 ml of dry DMSO. When the addition was complete (1 hour) the mixture was stirred overnight (about 16 hours) and then 3 hours at 100° C. The cooled mixture was poured into 1.5 liters of a stirred water-ice mixture to precipitate a semi-solid. The supernatent was poured off and the coagulated material was washed several times more with water. It was then dissolved in 500 ml of dichloromethane, washed twice with dilute brine, dried over Na2SO4, and concentrated in vacuo to an oil. This material weighed 32 g (100% yield). A portion was distilled yielding 3-(1-indolyl)benzonitrile (160°/0.1 mm) in 75% overall yield. The product was a soft, crystalline material at room temperature, m.p. 33°-36° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH3:24])[CH:17]=1.ClC(Cl)(O[C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[NH2:37][N:38]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29]([NH:37][N:38]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:35])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: NN1CCCCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1NC(=O)NN1CCCCCC1
Yield: 49 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methoxyaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (50 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-aminohomopiperidine (50 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to the reaction solution to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (35 mg, yield 49%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH3:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH3:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH:39][C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:31])([F:32])[F:1])=[CH:4][CH:5]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:29])=[CH:36][CH:35]=1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: Cc1ccc(CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(CNC(=O)c2cnc3cc(NC(=O)c4ccccc4-c4ccc(C(F)(F)F)cc4)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (40 mg, 0.092 mmol) was combined with 4-methylbenzylamine (17 mg, 0.14 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21 mg, 0.11 mmol), 1-hydroxybenzotriazole (14 mg, 0.10 mmol), and triethylamine (0.051 ml, 0.37 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with 4% methanol in dichloromethane. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 20 mg of the title compound as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27]1[CH:36]=[C:35]([C:37](O)=[O:38])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1>C1COCC1>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:37]([C:35]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=[C:27]([C:23]5[O:22][CH:26]=[CH:25][CH:24]=5)[CH:36]=4)=[O:38])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: O=C(O)c1cc(-c2ccco2)nc2ccccc12
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cc(-c3ccco3)nc3ccccc23)cc1-c1ccc(C(=O)NCC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (42 mg, 0.15 mmol) and 2-fur-2-ylquinoline-4-carboxylic acid (95.7 mg, 0.4 mmol) were mixed in THF (5 ml) and the mixture shaken in a varian tube for 30 min at room temperature. Carbodiimde resin (442 mg, 0.5 mmol) was added and shaking continued for 18 h. The solution was filtered off, the resin washed with THF and methanol and the combined filtrate and washings reduced to dryness under vacuum. The residue was dissolved in ethyl acetate, washed with hydrochloric acid (1M) and aqueous sodium hydrogen carbonate. The solvent was evaporated from the organic fraction under vacuum to give N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-fur-2-ylquinoline-4-carboxamide. NMR; δH [2H6]—DMSO 10.85,(1H, s), 8.62,(1H, t), 8.12-8.07,(3H, m), 7.97,(1H, m), 7.94,(2H, d), 7.82,(1H, m), 7.72,(2H, m), 7.63,(1H, m), 7.49-7.45,(3H, m), 7.34,(1H, d), 6.75,(1H, m), 3.16,(2H, t), 2.23,(3H, s), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.69 min, MH+502.
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:28])[N:14]([N:23]=[CH:24][CH:25]([CH3:27])[CH3:26])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:29]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:28])[N:14]([NH:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 228A (0.132 g, 0.32 mmol) in tetrahydrofuran (6 mL) and methanol (0.026 mL, 0.64 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.24 mL, 0.48 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water (12 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with 1:1 ethyl acetate:hexane (10 ml) and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03 (d, J=6.62 Hz, 6 H) 1.86 (m, 1 H) 2.73 (m, 2 H) 5.94 (t, J=7.35 Hz, 1 H) 7.07 (t, J=7.35 Hz, 1 H) 7.27 (m, 2 H) 7.54 (m, 2 H) 7.60 (d, J=6.99 Hz, 1 H) 7.66 (d, J=6.99 Hz, 1 H) 8.08 (d, J=8.09 Hz, 1 H) 16.27 (s, 1 H). MS (ESI−) (M−H)− m/z 411.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16](=[O:29])[N:17]([CH3:28])[C:18]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:19][CH:20]=3)=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:30][CH2:31][N:32]([CH2:35][CH3:36])[CH2:33]C.ClC(OC1C=CC=CC=1)=[O:39].N1CCCC1>C1COCC1>[CH3:28][N:17]1[C:16](=[O:29])[C:15]([C:12]2[N:13]=[CH:14][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:33]([N:32]4[CH2:35][CH2:36][CH2:30][CH2:31]4)=[O:39])[CH:7]=3)=[CH:10][CH:11]=2)=[CH:20][N:19]=[C:18]1[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCN(CC)CC
Reactant: Cn1c(Nc2ccccc2)ncc(-c2ccc(Oc3ccnc(N)c3)cn2)c1=O
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: Cn1c(Nc2ccccc2)ncc(-c2ccc(Oc3ccnc(NC(=O)N4CCCC4)c3)cn2)c1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 10.8 %

Procedure:
5-(5-(2-aminopyridin-4-yloxy)pyridin-2-yl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (128.6 mg, 0.333 mmol) was dissolved in THF (5.0 ml) and Et3N (0.10 ml, 0.72 mmol) and phenyl chloroformate (0.070 ml, 0.56 mmol) were added via syringe, and the reaction was stirred at room temperature. After about 45 minutes, pyrrolidine (0.31 ml, 3.7 mmol) was added, and the reaction was stirred at room temperature overnight. The next morning, the reaction was quenched with saturated ammonium chloride (5 ml) and extracted with DCM (3×15 ml). The organic phases were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel column (30:1->20:1 DCM/2 N ammonia in MeOH). The fractions with product collected, concentrated, washed with Et2O, and filtered. The solid collected was washed with Et2O and acetone and filtered again. The solid was collected and dried under vacuum to give the desired titled compound N-(4-(6-(1-methyl-6-oxo-2-(phenylamino)-1,6-dihydropyrimidin-5-yl)pyridin-3-yloxy)pyridin-2-yl)pyrrolidine-1-carboxamide (17.4 mg, 0.0360 mmol, 11% yield). MS (ESI pos. ion) m/z: 484 (MH+). Calc'd exact mass for C26H25N7O3: 483.