Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][N:4]1[CH:8]=[C:7]([NH2:9])[CH:6]=[N:5]1.Cl[C:13]1[N:18]=[C:17]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]2)[C:16]([Cl:33])=[CH:15][N:14]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>O1CCOCC1>[Cl:33][C:16]1[C:17]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]2)=[N:18][C:13]([NH:9][C:7]2[CH:6]=[N:5][N:4]([CH2:3][C:2]([F:1])([F:10])[F:11])[CH:8]=2)=[N:14][CH:15]=1
Reactant: Nc1cnn(CC(F)(F)F)c1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)C1(c2ccccc2CCc2nc(Nc3cnn(CC(F)(F)F)c3)ncc2Cl)CC1
Temperature: 120 °C
Yield: 26 %

Procedure:
A mixture of 1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-amine (0.160 g, 0.967 mmol), 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.101 g, 0.300 mmol) and TsOH.H2O (0.010 g, 0.051 mmol) in 1,4-dioxane (2.0 mL) was heated to 120° C. for 3 hours in the microwave. The mixture was concentrated under reduced pressure and purified using silica gel column chromatography (0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound 29 (0.036 g, 26%). LCMS-D: rt 3.402 min; m/z 465.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29])[CH2:2][CH2:3][CH3:4].[NH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:36])[CH3:35]>>[C:34]([NH:33][CH2:32][CH2:31][NH:30][C:24]([C:7]1[C:6](=[O:29])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:14]2[C:9]([C:8]=1[OH:23])=[N:10][CH:11]=[C:12]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[CH:13]=2)=[O:25])(=[O:36])[CH3:35]
Reactant: CCCCn1c(=O)c(C(=O)OCC)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Reactant: CC(=O)NCCN
Product: CCCCn1c(=O)c(C(=O)NCCNC(C)=O)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 58.7 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-butyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (30 mg, 0.075 mmol) and N-(2-aminoethyl)acetamide (27 mg, 0.264 mmol) was prepared N-[2-(acetylamino)ethyl]-1-butyl-7-[(4fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (20 mg, 59% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.41 (br s, 1 H), 8.55 (s, 1 H), 7.27 (s, 1 H), 8.17-7.13 (m, 2 H), 7.05-7.01 (m, 2 H), 6.18 (br s, 1 H), 4.13 (s, 2 H), 4.06 (m, 2 H), 3.59 (m, 2 H), 3.47 (m, 2 H), 1.97 (s, 3 H), 1.52 (m, 2 H), 1.33 (m, 2 H), 0.90 (m, 3 H); MS m/z 455 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[S:8])[NH2:7].Br[CH:10]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>C(#N)C>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([C:10]2[N:7]=[C:6]([C:2]3[NH:1][CH:5]=[CH:4][CH:3]=3)[S:8][C:11]=2[C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[CH:26][CH:25]=1
Reactant: COc1ccc(C(=O)C(Br)c2ccc(OC)cc2)cc1
Reactant: NC(=S)c1ccc[nH]1
Solvent: CC#N
Product: COc1ccc(-c2nc(-c3ccc[nH]3)sc2-c2ccc(OC)cc2)cc1
Temperature: 60 °C
Reaction time: 0.83 h
Yield: 86 %

Procedure:
Pyrrole-2-carbothioamide (cf. J. Org. Chem., 38, 667, 1973) (1.51 g, 12 mmole) and α-bromo-4,4'-dimethoxydeoxybenzoin (cf. Aust. J. Chem., 8, 385. 1955) (4.02 g, 12 mmole) are dissolved in acetonitrile (120 ml). The mixture is stirred at 60° C. for 50 minutes. After the reaction, the reaction mixture is distilled under reduced pressure to remove the solvent. To the resulting residue are added chloroform and aqueous solution of sodium carbonate, and the mixture is shaken. The chloroform layer is taken, and the aqueous layer is further extracted with chloroform. The chloroform layers are combined, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue is recrystallized from ligroin to give 4,5-bis(4-methoxyphenyl)-2-(pyrrol-2-yl)-thiazole (3.74 g, yield: 86%).
Reaction SMILES: [CH3:1][C:2]1(C)[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:39])[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([N:32]4[C:36](=[O:37])[CH2:35][NH:34][C:33]4=[O:38])[CH:29]=[CH:30][CH:31]=3)=[CH:11][C:5]=2[CH2:4][O:3]1>C(O)(=O)C.O>[C:2]([OH:7])(=[O:3])[CH3:1].[OH:39][C@H:12]([C:10]1[CH:9]=[CH:8][C:6]([OH:7])=[C:5]([CH2:4][OH:3])[CH:11]=1)[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([N:32]2[C:36](=[O:37])[CH2:35][NH:34][C:33]2=[O:38])[CH:29]=[CH:30][CH:31]=1
Reactant: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCCCc3cccc(N4C(=O)CNC4=O)c3)ccc2O1
Solvent: O
Solvent: CC(=O)O
Product: O=C1CNC(=O)N1c1cccc(CCCCOCCCCCCNC[C@H](O)c2ccc(O)c(CO)c2)c1
Yield: 135.2 %

Procedure:
A solution of 3-(3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)imidazolidine2,4-dione (414 mg) in acetic acid (20 ml) and water (5 ml) was heated to 75° C. for 30 min before evaporating to dryness. The residue was purified by chromatography on Biotage (40 g) eluting with CH2Cl2:MeOH:2M NH3 in MeOH (85:10:5). Appropriate fractions were combined and evaporated to dryness. Acetone (10 ml) was added and the mixture was re-evaporated under reduced pressure to give the title compound (290 mg). LCMS RT=2.44 min, ES+ve 514 (MH)+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:15][C:16]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[Se:18][C:17]=1[C:25]([NH2:27])=[O:26].CN(C=O)C.[OH-].[Na+]>>[C:11]([C:9]1[O:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:15][C:16]3[CH:20]=[C:19]([C:21]([CH3:24])([CH3:22])[CH3:23])[Se:18][C:17]=3[C:25]([NH2:27])=[O:26])[C:3]=2[CH:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc2c(Cl)ncnc2o1
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2c(Nc3cc(C(C)(C)C)[se]c3C(N)=O)ncnc2o1

Procedure:
The reaction of 4-chloro-6-tert-butylfuro[2,3-d]pyrimidine with 3-amino-5-tert-butylselenophene-2-carboxamide in the presence of DMF/NaOH as described in Example 1 gave title compound as an off-white color solid, mp 288-290° C. IR (KBr) vmax 3491, 3325 2964, 1593, 1388, 1354, 1314, 1287, 1149, 1119, 1089, 936, 806, 773 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.80 (1H, s, exchangeable with D2O), 8.46 (2H, s), 7.48 (2H, br s, exchangeable with D2O), 6.41 (1H, s), 1.39 (9H, s), 1.36 (9H, s); 13C NMR (100 MHz, DMSO-d6): δ 167.4, 167.1, 166.0, 164.1, 152.6, 152.3, 144.9, 121.0, 113.1, 103.3, 94.8, 36.4, 32.7, 32.2, 28.23; LC-MS (negative ion mode): m/z 417, 419 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[C:10]([Cl:15])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18]([CH3:22])[CH2:19][C:20]#[CH:21]>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:21]#[C:20][CH2:19][N:18]([CH3:22])[CH3:17])=[C:10]([Cl:15])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)c(Cl)c1
Reactant: C#CCN(C)C
Solvent: CCN(CC)CC
Product: CN(C)CC#Cc1ccc(NC(=O)OC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a deoxygenated solution of (3-chloro-4-iodo-phenyl)-carbamic acid tert-butyl ester (10.0 g) in triethylamine (120 ml) is added 1-dimethylamino-2-propyne (2.82 g), bis(triphenyl-phosphine)palladium(ll) chloride (0.4 g), and cuprous iodide (0.054 g). The mixture is stirred at room temperature under an atmosphere of argon for approximately 6 hours and is then heated briefly (ca. 10 minutes) to 60° C. The reaction mixture is then cooled, filtered through diatomaceous earth, and the solvent is removed by evaporation under reduced pressure. The residue is dissolved in ethyl acetate, washed three times with water, once with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure, and the residue is chromatographed over silica gel (80% ethyl acetate in hexanes is used as the eluant) to give the purified product as an amber oil that solidified on standing.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][C:27]1[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=O>>[CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:34]([CH3:35])[C:27]=3[CH3:26])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C=O)c1C
Reactant: Nc1cccc(-c2c(Cc3ccccc3)nnc3c(Cl)cccc23)c1
Product: Cc1cccc(CNc2cccc(-c3c(Cc4ccccc4)nnc4c(Cl)cccc34)c2)c1C

Procedure:
The title compound was prepared from [3-(3-benzyl-8-chlorocinnolin-4-yl)phenyl]amine and 2,3-dimethylbenzaldehyde according to the procedure of Step 5 Example 6. MS (ESI) m/z 464.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[NH2:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:10]=[CH:11][CH:12]=1>>[Br:1][CH2:2][CH2:3][CH2:4][NH:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:10]=[CH:11][CH:12]=1
Reactant: BrCCCBr
Reactant: COC(=O)Cc1cccc(N)c1
Product: COC(=O)Cc1cccc(NCCCBr)c1

Procedure:
Using 1,3-dibromopropane (1.7 ml) and methyl (3-aminophenyl)acetate (280 mg), the same manner to Example 2-41 step (i) was conducted to give the titled compound as a solid. Yield: 200 mg (70%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[NH:9][C:8]1=[O:18])[CH3:2].Cl[CH2:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[N:9]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:8]1=[O:18])[CH3:2]
Reactant: CCOC(=O)CCn1c(=O)[nH]c2ccc(C#N)cc21
Reactant: ClCc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)CCn1c(=O)n(Cc2cccc3ccccc23)c2ccc(C#N)cc21
Temperature: 65 °C
Reaction time: 16 h
Yield: 12.8 %

Procedure:
To a solution of 3-(6-Cyano-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid ethyl ester (0.1 g, 0.39 mmol) in DMA (3 mL) were added 1-(chloromethyl)naphthalene (0.1 g, 0.58 mmol) and K2CO3 (0.11 g, 0.81 mmol). The reaction mixture was stirred at 65° C. for 16 h. When the reaction was complete, the reaction mixture was diluted with ethyl acetate and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 98:2 CH2Cl2:MeOH as an eluent to afford 20 mg (13%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([N:39]2[CH2:44][CH2:43][N:42]([C:21]([C:20]3[CH:24]=[CH:25][CH:26]=[C:18]([C:16]4[CH:15]=[N:14][C:10]5[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]6[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=6[C:28]([F:31])([F:30])[F:29])[C:9]=5[CH:17]=4)[CH:19]=3)=[O:22])[CH2:41][CH2:40]2)=[CH:37][CH:38]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(c2ccc(Cl)cc2)CC1

Procedure:
(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(4-chlorophenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=625.95 (M+H+); retention time=1.05 minutes.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(Br)cnc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1cc(Br)cnc1N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Heat a solution of 2,5-dibromo-3-methyl-pyridine (Chontech Inc.) (12.6 g, 50.3 mmol), piperazine-1-carboxylic acid tert-butyl ester (11.7 g, 62.9 mmol) and DIEA (13.3 g, 102.0 mmol) in DMA at 130° C. for 36 h. Partition the dark brown reaction mixture between water and EtOAc. Wash the EtOAc layer with water (1×) and brine (1×), dry (Na2SO4) and concentrate under reduced pressure to give the crude product. Purify by flash chromatography, eluting with 9:1 hexanes:EtOAc, increasing to 3:1 hexanes:EtOAc to provide the title compound as a solid.
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.[NH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14]>CC(O)C.C(OCC)(=O)C>[OH:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][NH:8][C:2]1[CH2:6][S:5][C:4](=[O:7])[N:3]=1
Reactant: O=C1NC(=S)CS1
Reactant: NCCOCCO
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: O=C1N=C(NCCOCCO)CS1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-thioxo-1,3-thiazolidin-2-one (10 g) in 2-propanol (25 mL) and ethyl acetate (75 mL) was added 2-(2-aminoethoxy)ethanol (7.50 mL), and the mixture was stirred at room temperature for 2 hr and further stirred for 2 hr under ice-cooling. The precipitate was collected by filtration, and the obtained solid was washed with ethyl acetate to give the title compound (12.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[I:14](O)(=O)=O.II>C(O)(=O)C.S(=O)(=O)(O)O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: [O-][I+2]([O-])O
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Brc1ccc(-c2ccc(I)cc2)cc1
Temperature: 65 °C
Reaction time: 4.5 h
Yield: 325.1 %

Procedure:
A 4-neck one liter round bottom flask equipped with mechanical stirrer, thermometer and reflux condenser topped with nitrogen bubbler inlet was charged with 4-bromobiphenyl (23.31 g, 100 mmol) in acetic acid (400 mL), sulfuric acid (10 mL) and water (20 mL). To this stirring mixture was added iodic acid (4.84 g, 27.5 mmol) followed immediately by addition of iodine chips (11.17 g, 44.0 mmol). The reaction flask was immersed in a preheated tri(ethylene glycol) heating bath and heated at 65° C. internal temperature. After 30 min the bath temperature was increased such that the internal temperature raised to 85° C. after 20 min. Heating at this temperature was continued for 4.5 hours at which point HPLC analysis showed the reaction to be complete. After stirring overnight at room temperature the reaction mixture was vacuum filtered through a coarse fritted funnel and the solids were rinsed with water. The resulting white solid (32.1 g, 89% yield) had mp 177-179° C. and was used without further purification in the next step. NMR analysis confirmed the structure of Intermediate Compound 3,4-bromo-4′-iodobiphenyl. Purity (HPLC): >99%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[S:22][C:21]([CH2:23][CH3:24])=[N:20][C:14]=3[CH:15]=[N+:16]([O-])[C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C([N:29]=C=O)=O>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[S:22][C:21]([CH2:23][CH3:24])=[N:20][C:14]=3[C:15]([NH2:29])=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1nc2c[n+]([O-])c3cc(OCc4ccccc4)ccc3c2s1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2s1
Temperature: 25 °C
Yield: 75.5 %

Procedure:
To a vigorously stirred pale orange solution of 7-benzyloxy-2-ethylthiazolo[4,5-c]quinoline 5-oxide (15.00 g, 44.6 mmol) in dichloromethane (200 mL), at room temperature, was slowly added trichloroacetylisocyanate (1.05 eq., 5.6 ml 46.8 mmol). The solution was maintained at room temperature for 18 hours. At this time the reaction was quenched by the addition of concentrated ammonium hydroxide solution (60 ml). An off-white precipitate formed and was collected by vacuum filtration. Recrystallization from acetonitrile provided 11.3 g of 7-benzyloxy-2-ethylthiazolo[4,5-c]quinolin-4-amine as a white crystalline solid, mp 208-209° C. MS (APCI) m/z 336.1 (M+H)+; Anal. calcd for C19H17N3OS: C, 68.03; H, 5.11; N, 12.53. Found: C, 67.45; H, 4.83; N, 12.41.
Reaction SMILES: C[N:2]([CH3:19])/[CH:3]=[C:4](/[C:10](=[O:18])[C:11]1[C:16](F)=[CH:15][CH:14]=[CH:13][N:12]=1)\[C:5]([O:7][CH2:8][CH3:9])=[O:6].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:28][C:29]([F:45])([F:44])[C:30]1[CH:31]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2CN)[CH:33]=[CH:34][CH:35]=1.O>CC(N(C)C)=O>[O:18]=[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][N:12]=2)[N:2]([CH2:19][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([C:29]([F:28])([F:45])[F:44])[CH:31]=2)[CH:3]=[C:4]1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1ncccc1F
Reactant: NCc1ccccc1-c1cccc(C(F)(F)F)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccccc2-c2cccc(C(F)(F)F)c2)c2cccnc2c1=O
Temperature: 74 °C
Reaction time: 15 h
Yield: 37.1 %

Procedure:
To a brown solution of (Z)-ethyl 3-(dimethylamino)-2-(3-fluoropicolinoyl)acrylate (31) (200 mg, 0.751 mmol) in DMA (dimethylacetamide) (8 mL) in a 20 mL vial were added a solid powder of tribasic potassium phosphate (399 mg, 1.88 mmol) and (3′-(trifluoromethyl)biphenyl-2-yl)methanamine (208 mg, 0.826 mmol) at room temperature under a nitrogen atmosphere. The resulting brown suspension was heated to 74° C. and stirred for 15 h at which time LCMS analysis indicated the absence of starting material. Then, it was cooled to room temperature and poured slowly into water (100 mL), but no solids precipitated. Then, the organic compound was extracted with dichloromethane and the combined extracts were washed with water and brine solution, and dried over anhydrous MgSO4. Filtration and concentration gave the crude brown oil which was purified using ISCO (120 g) column chromatography, eluting with ethyl acetate in hexanes (0 to 100%) and then 5 to 10% methanol in dichloromethane. The desired fractions were combined and the solvent was removed under vacuum to obtain ethyl 4-oxo-1-((3′-(trifluoromethyl)biphenyl-2-yl)methyl)-1,4-dihydro-1,5-naphthyridine-3-carboxylate (32) (126 mg, 37% yield) as a light brown solid.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@H:23]([OH:32])[CH2:24][CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)([OH:8])=[O:7].[C:33](=O)([O-])O.[Na+].[C:38]([OH:43])(=[O:42])[C:39]([OH:41])=[O:40]>CO.CCOCC>[C:38]([OH:43])(=[O:42])[C:39]([OH:41])=[O:40].[CH3:33][O:7][C:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C@H:23]([OH:32])[CH2:24][CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:19][CH:20]=2)[CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: O=C(O)c1cccc(-c2ccc(OC[C@H](O)CCc3cccnc3)cc2)c1
Reactant: O=C([O-])O
Agent: O=C(O)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1cccc(-c2ccc(OC[C@H](O)CCc3cccnc3)cc2)c1
Temperature: 25 °C

Procedure:
Concentrated sulfuric acid (2.5 ml) was added to a suspension of (2R)-1-(3'-carboxybiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol (0.5 g) in methanol (50 ml). The mixture was heated at reflux for 10 hours. The mixture was cooled to room temperature and made basic by addition of aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane:methanol (19:1) to give an oil which was converted to the oxalate salt upon treatment with oxalic acid (excess) in ether to give the title compound as a solid (0.482 g).
Reaction SMILES: [I:1][C:2]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]2[CH2:6][NH:7][CH2:8][CH2:9][N:4]2[N:3]=1.[N:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[C:17]=[O:18]>C1COCC1>[C:19]([NH:16][C:17]([N:7]1[CH2:8][CH2:9][N:4]2[N:3]=[C:2]([I:1])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]2[CH2:6]1)=[O:18])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)N=C=O
Reactant: CCOC(=O)c1c(I)nn2c1CNCC2
Solvent: C1CCOC1
Product: CCOC(=O)c1c(I)nn2c1CN(C(=O)NC(C)(C)C)CC2
Reaction time: 1.5 h
Yield: 70.1 %

Procedure:
To a stirred solution of Intermediate 104F (2.4 g, 7.47 mmol) in THF (20 mL) was added 2-isocyanato-2-methylpropane (0.741 g, 7.47 mmol) and the reaction mixture was stirred for 1.5 h. The volatiles were evaporated under reduced pressure. The crude was purified by silica gel chromatography (120 g REDISEP® column, eluting with 28% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate 104G (2.2 g, 70%). MS(ES): m/z=421 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 6.25 (s, 1H), 4.72 (s, 2H), 4.25 (q, J=6.8 Hz, 2H), 4.10 (t, J=5.24 Hz, 2H), 3.75 (m, 2H), 1.30 (t, J=7.2 Hz, 3H) 1.28 (s, 9H).
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27](Cl)=[CH:28][C:29]=2[C:30]2[CH:31]=[N:32][CH:33]=[N:34][CH:35]=2)=[CH:18][C:17]=1[F:37])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(C)(C)C.[F:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:20]1[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27]([C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([F:39])[CH:45]=3)=[CH:28][C:29]=2[C:30]2[CH:31]=[N:32][CH:33]=[N:34][CH:35]=2)=[CH:18][C:17]([F:37])=[C:16]([S:13]([NH:7][C:8]2[N:9]=[CH:10][S:11][CH:12]=2)(=[O:15])=[O:14])[CH:21]=1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(Oc2cnc(Cl)cc2-c2cncnc2)cc1F
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1cscn1)c1cc(Cl)c(Oc2cnc(-c3cccc(F)c3)cc2-c2cncnc2)cc1F
Reaction time: 0.17 h
Yield: 29.9 %

Procedure:
20 mg (0.03 mmol) of tert-butyl((5-chloro-4-((6-chloro-4-(pyrimidin-5-yl)pyridin-3-yl)oxy)-2-fluorophenyl)sulfonyl)(thiazol-4-yl)carbamate was dissolved in 3 mL of N,N-dimethylformamide, and 7 mg (0.05 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 3.8 mg (10 mol %) of Pd(PPh3)4, 10.6 mg (0.10 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 10 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 5 mg (27% yield) of the title compound.