Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.[CH2:6]([NH2:8])[CH3:7].[CH:9]1([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[C:24]([C@@H:27]3[CH:32]4[O:33][C@@H:29]([CH2:30][CH2:31]4)[C@@H:28]3[CH2:34][C:35]3[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=3[CH2:42][CH2:43][C:44]([OH:46])=O)[O:25][CH:26]=2)=[O:21])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH:9]1([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[C:24]([CH:27]3[CH:28]([CH2:34][C:35]4[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=4[CH2:42][CH2:43][C:44](=[O:46])[NH:8][CH2:6][CH3:7])[CH:29]4[O:33][CH:32]3[CH2:31][CH2:30]4)[O:25][CH:26]=2)=[O:21])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCN
Reactant: O=C(O)CCc1ccc(F)cc1C[C@H]1[C@@H]2CCC(O2)[C@H]1c1nc(C(=O)NCCCCC2CCCCC2)co1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCNC(=O)CCc1ccc(F)cc1CC1C2CCC(O2)C1c1nc(C(=O)NCCCCC2CCCCC2)co1
Reaction time: 23 h
Yield: 20.8 %

Procedure:
DMF (0.22 mL) and ethyl amine (77 μL, 0.15 mmol) were added to 3-(2-{(1S,2R,3S)-3-[4-(4-Cyclohexyl-butylcarbamoyl)-oxazol-2yl]-7-oxa-bicyclo[2.2.1]hept-2-ylmethyl}-4-fluoro-phenyl)-propionic acid (1) (28 mg, 0.053 mmol), EDCI [1-(3-dimehylaminopropyl)-3-ethylcarbodiimide hydrochloride] (17 mg, 0.089 mmol) and DMAP (8 mg, 0.065 mmol). The solution was stirred for 23 h and then was diluted with 15 mL ethyl acetate and washed with HCl (1 M, 3×15 mL). The ethyl acetate solution was then dried (Na2SO4), filtered and evaporated. Flash chromatography on silica gel (ethyl acetate) gave a mixture of the starting acid and the product amide. Purification by preparative thin layer chromatography (4% methanol/dichloromethane) gave the title amide (6 mg, 0.011 mmol, 20%). 1H NMR (300 MHz, ppm) δ 8.06 (s, 1 H) 7.1–7.0 (m, 2 H) 6.8–6.7 (m, 2 H) 5.43 (br s, 1 H) 4.97 (d, J=4.4 Hz, 1 H) 4.82 (d, J=4.4 Hz, 1 H) 3.4–3.3 (m, 3 H) 3.3–3.2 (m, 2 H) 2.9–2.8 (m, 2 H) 2.6–2.5 (m, 1 H) 2.3–2.1 (m, 4 H) 1.8–0.8 (m, 24 H).
Reaction SMILES: O1C=CC=C1.Cl[C:7]1[N:8]=[C:9]2[CH:19]=[CH:18][O:17][C:10]2=[C:11]2[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]2.[F-:20]>>[F:20][C:7]1[N:8]=[C:9]2[CH2:19][CH2:18][O:17][C:10]2=[C:11]2[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]2
Reactant: [F-]
Reactant: Clc1nc2ccoc2c2ccccc12
Solvent: c1ccoc1
Product: Fc1nc2c(c3ccccc13)OCC2

Procedure:
The chloride/fluoride exchange was achieved by the method (reference 3) cited above. Thus 90 mg of 5-chloro-2,3-dihydro-1-oxa-4-aza-cyclopenta[α]naphthalene (Example 217) was suspended in 1.5 mL of Bu4PHF2 and was irradaited under microwave (Smith Reactor) to about 120° C. for 2 hours. After aqueous work up and column purification, 22 mg of fluoride product was obtained (26.9%). LC/MS rt-min (MH+): 1.91 (190) [method B]. The furan derivative (Example 218), 5-chloro-1-oxa-4-aza-cyclopenta[α]naphthalene was sufficiently reactive to be alkylated with the tripeptide directly without fluoride activation.
Reaction SMILES: [CH2:1]([C:5]1[N:6](CC2C=CC=CC=2Cl)[C:7](C=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:20][CH:1]([C:5]1[NH:6][CH:7]=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(C=O)n1Cc1ccccc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCCC(Br)c1ncc[nH]1

Procedure:
A mixture of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde and N-bromosuccinimide in carbon tetrachloride was irradiated to give the 2-(1-bromobutyl)imidazole which was dehydrobrominated by treating 1,8-diazabicyclo[4.5.0]undec-1-ene in tetrahydrofuran to give 2-(1-butenyl)-1-(2-chlorophenyl)-methyl-1H-imidazol-5-carboxyaldehyde.
Reaction SMILES: I[C:2]1[S:3][C:4]2[NH:5][C:6](=[O:15])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1.CN(C=O)C.[CH3:21][N:22]([CH3:26])[CH2:23][C:24]#[CH:25]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[CH3:21][N:22]([CH3:26])[CH2:23][C:24]#[C:25][C:2]1[S:3][C:4]2[NH:5][C:6](=[O:15])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1
Reactant: O=c1[nH]c2sc(I)nc2c2ccccc12
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CC#Cc1nc2c([nH]c(=O)c3ccccc32)s1
Yield: 68 %

Procedure:
2-Iodo-1,3-thiazolo[5,4-c]isoquinolin-5(4H)-one (0.1 g, 0.3 mmol), DMF (10 ml), 1-dimethylamino-2-propyne (0.25 g, 3.05 mmol), (Ph3P)2PdCl2 (10 mg), CuI (1 mg), and triethylamine (1.2 ml) were stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the mixture was chromatographed on SiO2 gel, eluting, with dichloromethane/methanol (98/2), to produce the title compound. Yield: 68% yield.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.CN1CCOCC1.CN(C(O[N:47]1N=[N:54][C:49]2C=CC=N[C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:48]([CH2:49][NH:54][C:3](=[O:5])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:30])([F:31])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)#[N:47]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: N#CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 46.9 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 35 mg, 0.081 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.054 mL, 0.487 mmol), 2-aminoacetonitrile, HCl (15.02 mg, 0.162 mmol), and HATU (61.7 mg, 0.162 mmol). This was stirred overnight and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention time=33.2 min) to give single enantiomer N-(cyanomethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (18.3 mg, 0.038 mmol, 46.6% yield): LCMS=470.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.15-8.23 (2 H, m), 7.65-7.76 (4 H, m), 7.53-7.64 (3 H, m), 5.21 (1 H, s), 4.19 (2 H, d, J=2.86 Hz). HPLC Peak RT=9.5 min (Analytical Method A).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:8][C:9]=1[N:10]([CH:23]([C:30]1[O:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:11]([C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([Cl:21])=[CH:16][C:15]=1[CH3:22])(=[O:13])=[O:12])=[O:4].O[Li].O>C1COCC1.CO.O>[O:34]1[C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[CH:31]=[C:30]1[CH:23]([N:10]([S:11]([C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([Cl:21])=[CH:16][C:15]=1[CH3:22])(=[O:12])=[O:13])[C:9]1[CH:8]=[C:7]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(c1ccccc1)c1cc2ccccc2o1)S(=O)(=O)c1cc(C)c(Cl)cc1C
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(S(=O)(=O)N(c2cc(-c3ccccc3)sc2C(=O)O)C(c2ccccc2)c2cc3ccccc3o2)c(C)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.9 %

Procedure:
3-[(3-Benzofuran-2-yl-benzyl)-(4-chloro-2,5-dimethyl-benzenesulfonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (20 mg, 0.031 mmol) was taken in a mixture of THF:MeOH:H2O (3:2:1, 3 mL) and then added 1N aqueous solution of LiOH.H2O (0.20 mL, 0.186 mmol). The reaction mixture was stirred at room temperature for 12 h. Solvents were removed and the residue was partitioned between water and ethyl acetate. The aqueous layer was acidified using 10% KHSO4 solution. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using dichloromethane and methanol (−9:1) to obtain 3-[(3-Benzofuran-2-yl-benzyl)-(4-chloro-2,5-dimethyl-benzene-sulfonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid (14 mg, 70%) as a white solid. 1H NMR (DMSO, 400 MHz): δ7.93 (s, 1H), 7.84 (s, 1H), 7.74 (bd, 1H), 7.65-7.22 (m, 14H), 4.95 (s, 2H), 2.33, 2.23, (2s, 6H).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([Cl:27])[CH:18]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[C:38]([C:40]1([OH:46])[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)#[CH:39]>C1(C)C=CC=CC=1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:27][C:19]1[CH:18]=[C:17]([C@@H:10]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([NH:8][C:5]2[CH:4]=[N:3][C:2]([C:39]#[C:38][C:40]3([OH:46])[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:7][N:6]=2)=[O:28])[CH:22]=[CH:21][C:20]=1[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: C#CC1(O)CCOCC1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(C#CC3(O)CCOCC3)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
A suspension of N-(5-bromo-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (prepared as in Example 6, 486 mg, 1.0 mmol) in toluene (8 mL) was treated with N,N-diisopropylethylamine (2 mL), 4-ethynyl-tetrahydropyran-4-ol (prepared as in Example 46, 252 mg, 2.0 mmol), copper(I) iodide (20 mg), and dichlorobis(triphenylphosphine)palladium(II) (40 mg). The mixture was stirred at 25° C. overnight, and an oily black precipitate was obtained. The top clear solution was decanted, and the oily precipitate was rinsed first with toluene (5 mL) and then with hexanes (5 mL). The residue was dissolved in methylene chloride and extracted with methylene chloride and a 0.2N aqueous hydrochloric acid solution. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 2/1 ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(4-hydroxy-tetrahydropyran-4-yl-ethynyl)-pyrazin-2-yl]-propionamide (474 mg, 89.30%) as a fluffy solid: (ES)+-HRMS m/e calcd for C23H30ClN3O4S (M+H)+ 532.1668, found 532.1675.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:22]=[C:21]([N:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:34]=3[N:33]=[C:32]2[CH:42]([F:44])[F:43])[N:20]=1.C(O)(=O)C>C1COCC1.O>[F:44][CH:42]([F:43])[C:32]1[N:31]([C:21]2[N:22]=[C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:24]=[C:19]([NH:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][N:3]=3)[N:20]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:34]=2[N:33]=1
Reactant: Nc1ccncn1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(Nc2ccncn2)nc(N2CCOCC2)n1
Reaction time: 0.17 h
Yield: 15.7 %

Procedure:
To 0.225 g (2.37 mmol) of 4-aminopyrimidine in THF (3 mL) was added 1.30 mL of NaHMDS (2 M solution in THF) and the mixture was stirred for 10 min. A solution of 0.320 g (0.81 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole in THF (5 mL) was added and the resulting mixture was stirred for 1 hr. The reaction mixture was neutralized with acetic acid, diluted with water and extracted with EtOAc. The organic layer was washed with water, and aq. NH3, and dried. Removal of the solvent, followed by chromatography on silica, eluting first with hexanes-EtOAc (1:1), then CH2Cl2/EtOAc (1:1) to CH2Cl2/EtOAc (1:3) gave a white powder. Recrystallization from EtOH/CH2Cl2 gave 0.058 g (16% yield) of 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(4-pyrimidinyl)-1,3,5-triazin-2-amine: mp 234-236° C.; 1H NMR (CDCl3) δ8.91 (d, J=1.0 Hz, 1H), 8.65 (d, J=5.8 Hz, 1H), 8.23 (dd, J=5.8, 1.3 Hz, 1H), 7.99 (s, 1H), 7.93 (dd, J=8.3, 0.5 Hz, 1H), 7.47 (t, JHF=53.4 Hz, 1H), 7.38 (t, J=8.2 Hz, 1H), 6.85 (d, J=7.8 Hz, 1H), 4.06 (s, 3H), 3.97-3.96 (m, 4H), 3.86-3.84 (m, 4H); Anal. Calcd. for C20H19F2N9O20.31H2O: C, 52.1; H, 4.3; N, 27.3. Found: C, 51.7; H, 4.15; N, 27.3%.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.C1(C)C=CC(S(O[CH2:32][CH2:33][O:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:43][CH3:44])(=O)=O)=CC=1>>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:32][CH2:33][O:34][CH2:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH3:44])=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: COc1ccccc1CCOCCOS(=O)(=O)c1ccc(C)cc1
Product: COc1ccccc1CCOCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1

Procedure:
Analogously to Method I, 2.80 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 3.71 g of 2-[2-(2-methoxyphenyl)ethoxy]ethyl toluene-4-sulphonate (Example 45b) are reacted. The title compound is obtained as a colourless oil. Rf=0.47 (1:1 EtOAc-heptane); Rt=5.11.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:22])=[CH:4][C:5]([F:21])=[C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])[CH:7]=1.[F:23][C:24]([F:34])([F:33])[CH:25]1[CH2:31][C:30](=[O:32])[O:29][C:27](=[O:28])[CH2:26]1>C1(C)C=CC=CC=1>[Cl:22][C:3]1[CH:4]=[C:5]([F:21])[C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[CH:7][C:2]=1[NH:1][C:30]([CH2:31][CH:25]([C:24]([F:23])([F:34])[F:33])[CH2:26][C:27]([OH:29])=[O:28])=[O:32]
Reactant: O=C1CC(C(F)(F)F)CC(=O)O1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N)c(Cl)cc2F)c1=O
Solvent: Cc1ccccc1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(NC(=O)CC(CC(=O)O)C(F)(F)F)c(Cl)cc2F)c1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A mixture of 0.50 g of 3-(5-amino-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, 0.27 g of 3-trifluoromethylglutaric anhydride and 6 ml of toluene was stirred at 100° C. for one hour. After cooling to room temperature, the solvent was removed by distillation under reduced pressure to obtain 0.7 g of the desired compound as crystal.
Reaction SMILES: Cl.[OH:2]/[N:3]=[C:4](/[C:10]1[N:11]=[C:12]([NH:15]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:13][CH:14]=1)\[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:35]1([CH2:41]Br)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>C(O)=O>[NH2:15][C:12]1[S:13][CH:14]=[C:10](/[C:4](=[N:3]/[O:2][CH2:41][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:11]=1
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: BrCC1CCCCC1
Agent: Cl
Solvent: O=CO
Product: CCOC(=O)/C(=N\OCC1CCCCC1)c1csc(N)n1
Yield: 62 %

Procedure:
Ethyl (Z)-2-(hydroxyimino)-2-(2-tritylaminothiazol-4-yl)acetate hydrochloride (3.08 g) was reacted with cyclohexylmethyl bromide as described in Example 5a. The product was deprotected with formic acid as described in Example 1a. Crystallisation from cyclohexane/hexane gave the title compound as a white solid (1.2 g, 62%), m.p. 107.0°-107.5° C. [Found: C: 54.21; H: 6.58; N: 13.31. C14H21N3O3S requires C: 54.00; H: 6.80; N: 13.49%]. νmax (CHCl3) 3400, 2920, 1730, 1600 cm-1 ; δH (CDCl3) 1.0 (2H, m), 1.2 (3H, m), 1.33 (3H, t), 1.7 (6H, m), 3.97 (2H, d), 4.35 (2H, q), 5.60 (2H, br s, exch. D2O), 6.63 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][N:3]=1.[Br:9][C:10]1[CH:11]=[CH:12][C:13]([OH:23])=[C:14]([CH:22]=1)[C:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:23][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)=[C:14]([CH:22]=1)[C:15]([N:17]([CH2:18][CH3:19])[CH2:20][CH3:21])=[O:16]
Reactant: Fc1ccnc(Cl)c1
Reactant: CCN(CC)C(=O)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCN(CC)C(=O)c1cc(Br)ccc1Oc1ccnc(Cl)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2-Chloro-4-fluoropyridine (0.242 g, 1.837 mmol) was added to a mixture of 5-bromo-N,N-diethyl-2-hydroxybenzamide (0.500 g, 1.837 mmol) and cesium carbonate (1.197 g, 3.67 mmol) in acetonitrile (10.0 mL). The mixture stirred at 100° C. for 8 h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a brown oil. This oil was purified via column chromatography on silica gel (RediSep 80 g column, gradient elution with 0-50% ethyl acetate-hexane) to afford 5-bromo-2-(2-chloropyridin-4-yloxy)-N,N-diethylbenzamide as a thick, yellow oil. MS m/z=383.0 [M+H]+. Calcd for C16H16BrClN2O2: 382.0.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][C:26]([CH3:32])([CH3:31])[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].Cl>CN(C=O)C.O>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][C:26]([CH3:32])([CH3:31])[CH2:27][C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: CC(C)(N)CC(=O)O
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(CC(=O)O)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Yield: 41 %

Procedure:
To mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.31 mmol) and 3-amino-3-methyl-butyric acid ((97 mg, 0.94 mmol) (Oakwood) in DMF (3 mL) was added NaOMe solid (68 mg, 1.25 mmol). The resultant mixture was heated in a 150-160° C. oil bath for 3 h. Reaction mixture was diluted with water (100 mL) and acidified by 1 N HCl to pH=3-4. Precipitate was collected and dried. Crude residue was purified by silica gel chromatography, eluting with 10-50% EtOAc/CH2Cl2. Fractions containing the produce were collected and concentrated. It was triturated with MeOH (2 mL). Solid was collected and dried in vacuo to provide the title compound 51 mg (0.13 mmol) in 41% yield. LC-MS ESI−: 404.06 (M−1)−.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:18]1=[O:35])[CH3:16].[H-].[Na+]>CN(C=O)C>[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:30][CH:29]=2)[C:18]1=[O:35])[CH3:16]
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(OC)cc21
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2ncc(OC)cc21
Temperature: 150 °C
Reaction time: 2 h
Yield: 15.5 %

Procedure:
To a solution of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (67 mg) and 1-ethyl-3-(4-hydroxyphenyl)-6-methoxy-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (75 mg) in DMF (3 mL) was added NaH (13 mg) at room temperature, and the mixture was stirred at 150° C. under microwave irradiation for 2 h. The mixture was partitioned between water and AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (dry charge, NH silica gel, eluted with 50%-100% AcOEt in hexane) and column chromatography (dry charge, silica gel, eluted with 50%-100% AcOEt in hexane), and recrystallized from MeOH to give 1-ethyl-6-methoxy-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (17 mg) as white crystals.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[C:8]3[S:14][CH2:13][CH2:12][N:9]32)=[CH:4][C:3]=1[F:19].[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27]C[CH2:25][CH2:24]1.[N:29]1C=CC=CC=1>>[F:19][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:29]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][OH:20])[CH2:24][CH2:25]1)[N:9]1[CH2:12][CH2:13][S:14][C:8]1=[C:7]([C:15]([OH:17])=[O:16])[C:6]2=[O:18]
Reactant: c1ccncc1
Reactant: O=C(O)c1c2n(c3cc(Cl)c(F)cc3c1=O)CCS2
Reactant: OCCN1CCCCC1
Product: O=C(O)c1c2n(c3cc(N4CCN(CCO)CC4)c(F)cc3c1=O)CCS2
Temperature: 25 °C

Procedure:
A mixture of 500 mg (1.67 mmol) of 8-chloro-7-fluoro-5-oxo-1,2-dihydro-5H-thiazolo(3,2-a)-quinoline-4-carboxylic acid and 1.09 grams (8.34 mmol) of N-(beta-hydroxyethyl)-piperidine was suspended in 20 ml of pyridine and the mixture was heated to reflux for thirty two hours. When the reaction was completed, the mixture was cooled to a room temperature, crystals separated out therefrom were collected by filtration, successively washed with pyridine, ethanol and ether, and recrystallized from dimethyl formamide to give the title compound as pale yellow powders. Yield 426.6 mg (65 percent). Melting point 256° to 256.5° C. Elementary analysis calculated as C18H20FN3O4S: C 54.95, H 5.12, N 10.68; Found: C 54.52, H 5.14, N 10.73.