Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12](=[O:25])[NH:13][CH2:14][CH2:15][N:16]1[CH2:23][CH:22]2[O:24][CH:18]([CH2:19][NH:20][CH2:21]2)[CH2:17]1)([CH3:10])([CH3:9])[CH3:8].Br[CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1.C(O)(=O)C.C(O)=O>C(#N)C>[C:32]([C:31]1[CH:34]=[CH:35][C:28]([CH2:27][N:20]2[CH2:19][CH:18]3[O:24][CH:22]([CH2:23][N:16]([CH2:15][CH2:14][NH:13][C:12](=[O:25])[O:11][C:7]([CH3:10])([CH3:8])[CH3:9])[CH2:17]3)[CH2:21]2)=[CH:29][CH:30]=1)#[N:33]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)NCCN1CC2CNCC(C1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O=CO
Product: CC(C)(C)OC(=O)NCCN1CC2CN(Cc3ccc(C#N)cc3)CC(C1)O2
Temperature: 25 °C
Yield: 99 %

Procedure:
Potassium carbonate (3.82 g, 27.6 mmol) was added to a mixture of tert-butyl[2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]carbamate (5.00 g, 18.4 mmol; see WO 02/83690 and WO 2004/035592) and 4-(bromomethyl)benzonitrile (3.61 g, 18.4 mmol) in acetonitrile (150 mL). The mixture was heated to reflux overnight, cooled to room temperature, filtered and then evaporated. The residue was dissolved in dichloromethane (100 mL), washed with water and dried over MgSO4. Purification by preparative HPLC gave 7.04 g (78%) of the title compound as a salt with one equivalent of acetic acid and one equivalent of formic acid.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[N:30]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[C:34]([F:40])[CH:33]=4)[CH:29]=[N:28][CH:27]=3)[CH2:21][C:20]2=[O:41])=[CH:11][CH:10]=1)C1C=CC=CC=1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[H][H]>CO.CCOC(C)=O.[Pd]>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[N:30]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[C:34]([F:40])[CH:33]=4)[CH:29]=[N:28][CH:27]=3)[CH2:21][C:20]2=[O:41])=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: N#Cc1ccc(Cn2cncc2CN2CCN(c3cccc4ccc(OCc5ccccc5)cc34)C(=O)C2)cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(Cn2cncc2CN2CCN(c3cccc4ccc(O)cc34)C(=O)C2)cc1F
Reaction time: 8 h

Procedure:
To a solution of the benzyl ether from Step F (1.563 g, 2.85 mmol) in 25 mL of 1:1 MeOH/EtOAc was added trifluoroacetic acid (1.0 mL) and 10% palladium on carbon (900 mg). The solution was stirred under a balloon atmosphere of hydrogen at room temperature. After 8 hours, the solution was filtered through celite, and the filter pad was rinsed with 1:1 MeOH/THF. Concentration in vacuo provided the titled product as a white foam which was used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]([Cl:33])([Cl:32])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:31])[C@@H:14]([NH:16][C:17](=[O:30])[C@@H:18]([NH:22][C:23](OC(C)(C)C)=[O:24])[CH:19]([CH3:21])[CH3:20])[CH3:15])[NH:8]1)=[O:6].FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(N(CC)C(C)C)(C)C.[OH:55][C@@H:56]([C:58]1[CH:67]=[CH:66][C:65]2[C:60](=[CH:61][C:62](/[CH:68]=[CH:69]/[C:70]([CH2:75][CH2:76][O:77][CH3:78])(C)[C:71](O)=O)=[CH:63][CH:64]=2)[N:59]=1)[CH3:57].C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>ClCCl.CN(C)C=O>[Cl:32][C:2]([Cl:33])([Cl:1])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:31])[C@@H:14]([NH:16][C:17](=[O:30])[C@@H:18]([NH:22][C:23](=[O:24])[C:70]([CH2:75][CH2:76][O:77][CH3:78])([CH3:71])/[CH:69]=[CH:68]/[C:62]2[CH:61]=[C:60]3[C:65]([CH:66]=[CH:67][C:58]([C@H:56]([OH:55])[CH3:57])=[N:59]3)=[CH:64][CH:63]=2)[CH:19]([CH3:21])[CH3:20])[CH3:15])[NH:8]1)=[O:6]
Reactant: COCCC(C)(/C=C/c1ccc2ccc([C@@H](C)O)nc2c1)C(=O)O
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCCC(C)(/C=C/c1ccc2ccc([C@@H](C)O)nc2c1)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.2 %

Procedure:
A solution of (S)-1-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (1.24 g, 2.38 mmol) in anhydrous dichloromethane (40 mL) was cooled to 0° C. before adding trimethylsilyl trifluoromethanesulfonate (660 μL, 3.62 mmol). The reaction mixture was stirred at 0° C. for 1.5 h before addition of N,N-diisopropylethylamine (1.65 mL, 9.47 mmol). The reaction mixture was then evaporated to dryness and the residue was dissolved in N,N-dimethylformamide (20 mL) and added to a stirred solution of crude (E)-4-[2-((R)-1-hydroxy-ethyl)-quinolin-7-yl]-2-(2-methoxy-ethyl)-2-methyl-but-3-enoic acid (2.43 g) and N,N-diisopropylethylamine (1.65 mL, 9.47 mmol) in N,N-dimethylformamide (50 mL). The reaction was treated with 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (1.37 g, 3.78 mmol) and stirred at room temperature for 3 h. It was evaporated then purified by silica gel chromatography eluting with iso-hexanes/dichloromethane/methanol 1:1:0 to 0:1:0 to 0:98:2 to 0:24:1 to yield the title product (1.17 g, 66%) as a pale yellow solid and as a mixture of diastereoisomers. LCMS (m/z) 742.3, 744.2, 746.2 [M+H], Tr=2.15 min.
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH3:21][O:22][C:23](=[O:27])[C:24](Cl)=[O:25].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:21][O:22][C:23](=[O:27])[C:24]([NH:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:25]
Reactant: COC(=O)C(=O)Cl
Reactant: Nc1cccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(=O)Nc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
In a round bottom flask containing 1-naphthyl amine (0.1 g, 0.68 mmol) stirring in DCM (5 mL) was added DIEA (0.18 mL, 1.02 mmol) and chloro-oxo-acetic acid methyl ester (0.068 mL, 0.748 mmol). The mixture was allowed to stir at room temperature for 1 h. The reaction mixture was poured over saturated sodium bicarbonate and the layers separated. The aqueous layer was extracted twice more with 3×15 mL DCM. The combined organics were washed with brine, dried over MgSO4 and concentrated in vacuo to afford a brown solid. The crude material was purified by flash chromatography (0-50% EtOAc:Hexanes on silica gel) to yield the desired product (0.14 g, 90%) as an off-white solid. Expected mass=229. Observed mass=230.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:13][C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[C:11]#[N:12])=[CH:6][CH:5]=1.CN(C=O)C.Cl.Cl[CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1>CCCCCC.C(OCC)(=O)C.CCOCC.O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:11]#[N:12])([CH2:13][C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[CH2:26][N:27]2[CH:31]=[N:30][CH:29]=[N:28]2)=[CH:6][CH:5]=1
Reactant: ClCn1cncn1
Reactant: N#CC(Cc1ccco1)c1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O
Product: N#CC(Cc1ccco1)(Cn1cncn1)c1ccc(Cl)cc1
Yield: 37.1 %

Procedure:
To a flask under a nitrogen atmosphere was added 1.66 g. (0.069 mole) of 60% sodium hydride, which had been washed twice with hexane to remove the mineral oil, in 40 ml. of dry DMF. To this slurry at room temperature was added with stirring 6.40 g. (27.7 mmoles) of 2-(4-chlorophenyl)-3-(2-furyl)propionitrile in 25 ml. of dry DMF. The mixture was stirred for 45 minutes and then 4.66 g. (30.47 mmoles) of 1-(chloromethyl)-1,2,4-triazole hydrochloride was added directly in two portions. The flask contents were stirred for six hours after which 1.6 g. of 60% sodium hydride which had been washed with hexane to remove the oil was added to complete the reaction. Water, 20 ml., was added dropwise followed by 100 ml. of ether and 50 ml. of ethyl acetate. The combined extracts were dried, decolorized with activated charcoal, filtered through infusorial earth, and concentrated to give a thick oil which crystallized on cooling to 3.2 g. (37.1% yield) of 1-[2-(4-chlorophenyl)-2-cyano-3-(2-furyl)propyl]-1,2,4-triazole as a light yellow solid, melting point 112°-114° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11](F)[C:12]=3[C:14]([F:17])([F:16])[F:15])[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[NH:24]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:35][NH2:36])[CH2:25]1>>[NH2:36][CH2:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH:26]1[CH2:27][CH2:28][N:24]([C:11]2[C:12]([C:14]([F:16])([F:15])[F:17])=[C:13]3[C:8]([C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:19])[CH2:25]1
Reactant: NCc1ccccc1C1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(C(F)(F)F)c(F)c(F)cc2c1=O
Product: NCc1ccccc1C1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2C(F)(F)F)C1

Procedure:
Starting from 1-cyclopropyl-6, 7-difluoro-1,4-dihydro-4-oxo-8-trifluoromethyl-3-quinolinecarboxylic acid (1.00 g, 3.0 mmol) and 2-(3-pyrrolidinyl)-benzenemethanamine, a procedure analogous to that given in Example 1 provided the title compound.
Reaction SMILES: N#N.C([O:5][C:6](=[O:20])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2([CH3:19])[O:18][CH2:17][CH2:16][O:15]2)[CH:9]=1)C.[OH-].[Na+].Cl>C1COCC1>[CH3:19][C:14]1([C:10]2[CH:9]=[C:8]([CH2:7][C:6]([OH:20])=[O:5])[CH:13]=[CH:12][CH:11]=2)[O:18][CH2:17][CH2:16][O:15]1
Reactant: CCOC(=O)Cc1cccc(C2(C)OCCO2)c1
Agent: Cl
Agent: N#N
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(c2cccc(CC(=O)O)c2)OCCO1
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [3-(2-methyl-[1,3]dioxolan-2-yl)-phenyl]-acetic acid ethyl ester (3.27 g, 13.07 mmol) in THF (131 mL) was treated at rt with 1N NaOH (64 mL, 64.00 mmol) and the reaction mixture was stirred for 1 h overnight. The reaction mixture was carefully acidified to pH 5-6 with 1N HCl and extracted twice with EA (200 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a brown solid. LC-MS-conditions 02: tR=0.79 min.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[C:3]=1[CH3:11].[Si:12]([O:19][C@@H:20]1[C@H:24]([CH3:25])[NH:23][C:22](=[O:26])[CH2:21]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[Si:12]([O:19][C@H:20]1[CH2:21][C:22](=[O:26])[N:23]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[C:3]=2[CH3:11])[C@H:24]1[CH3:25])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: Cc1c(Br)ccc(C#N)c1F
Reactant: C[C@@H]1NC(=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(N2C(=O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]2C)ccc(C#N)c1F
Yield: 18.6 %

Procedure:
To a solution of 4-bromo-2-fluoro-3-methylbenzonitrile (1.10 g), (4S,5S)-4-(tert-butyldimethylsilyloxy)-5-methylpyrrolidin-2-one (1.18 g), cesium carbonate (2.51 g), tris(dibenzylideneacetone)dipalladium(0) (235 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (297 mg) in dioxane (30 mL) was stirred under an argon atmosphere at 80° C. for 8 hr. 5 The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (yield: 347 mg, 19%).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:23]=[CH:22][C:14]2[C:15]([CH3:21])([CH3:20])[O:16][C:17](=[O:19])[NH:18][C:13]=2[CH:12]=1)(=O)=O.[C:24]1([SH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([S:30][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:23]=[CH:22][C:14]3[C:15]([CH3:20])([CH3:21])[O:16][C:17](=[O:19])[NH:18][C:13]=3[CH:12]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Sc1ccccc1
Reactant: CC1(C)OC(=O)Nc2cc(OCCCCOS(C)(=O)=O)ccc21
Product: CC1(C)OC(=O)Nc2cc(OCCCCSc3ccccc3)ccc21

Procedure:
Prepared analogously to Example 210 from 7-(4-methanesulfonyloxy-butoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and thiophenol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([Cl:26])[C:24]=1[OH:25])[NH2:21]>>[F:16][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[N:7][C:2]([NH:21][C:20]2[CH:19]=[C:18]([Cl:17])[C:24]([OH:25])=[C:23]([Cl:26])[CH:22]=2)=[N:3][CH:4]=1
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: Oc1cccc(Nc2nc(Nc3cc(Cl)c(O)c(Cl)c3)ncc2F)c1

Procedure:
In a like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 3,5-dichloro-4-hydroxyaniline were reacted to produce 5-Fluoro-N2-(3,5-dichloro-4-hydroxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.47 (bs, 1H), 9.35 (bs, 1H), 9.22 (bs, 2H), 8.09 (d, 1H, J=3.6 Hz), 7.70 (s, 2H), 7.31 (dd, 1H, J=1.2 and 9.3 Hz), 7.10 (t, 1H, J=7.5 Hz), 7.00 (bs, 1H), 6.48 (dd, 1H, J=1.2 and 6.9 Hz); LCMS: purity: 93%; MS (m/e): 382 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:24]=3[NH:23][CH:22]=[C:21]4[CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:32]1N2CCN(CC2)C1.C(=O)(OC)OC>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:24]=3[N:23]([CH3:32])[CH:22]=[C:21]4[CH2:25][CH2:26][C:27]([OH:29])=[O:28])[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C1CN2CCN1CC2
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC)c(OC)c4)n3)cccc12
Solvent: CN(C)C=O
Solvent: COC(=O)OC
Product: COc1ccc(-c2nc(-c3cccc4c(CCC(=O)O)cn(C)c34)no2)cc1OC
Temperature: 50 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
Ethyl 3-(7-{5-[3,4-bis(methyloxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate (100 mg) (D67), DABCO (27 mg) and N,N-dimethylformamide (3 mL) was added to dimethyl carbonate (10 mL) successively. The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 150° C. for 2 h. After cooling the reaction, the solvent was removed in vacuo. The residue was dissolved in tetrahydrofuran (5 mL) and methanol (5 mL), and then NaOH (48 mg) in water (5 mL) was added. The mixture was stir at 50° C. for 8 h. The organic solvent was removed and the mixture was acidified with HCl (1 M) solution to pH around 1. Extracted with EtOAc (60 mL), the organic layer was separated and the organic solvent was evaporated off. The residue was purified by Mass Directed Auto Prep to afford 3-(7-{5-[3,4-bis(methyloxy)phenyl]-1,2,4-oxadiazol-3-yl}-1-methyl-1H-indol-3-yl)propanoic acid (E44) (56 mg). δH (DMSO-d6, 400 MHz): 2.60 (2H, t), 2.96 (2H, t), 3.62 (3H, s), 3.88 (6H, s), 7.17 (1H, t), 7.19 (1H, s), 7.22 (1H, d), 7.43 (1H, dd), 7.66 (1H, d), 7.79 (1H, dd), 7.82 (1H, dd), 12.12 (1H, s). MS (ES): C22H21N3O5 requires 407; found 408.2 (M+H+).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:25]([S:33]([CH3:36])(=[O:35])=[O:34])[CH2:26][CH2:27][CH2:28]/[C:29](=[N:31]/[OH:32])/[NH2:30])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]4[NH:20][CH:21]=[CH:22][N:23]=4)[C:8]=3[CH:24]=2)[CH2:3][CH2:2]1.[C:37](N1C=CN=C1)([N:39]1[CH:43]=[CH:42][N:41]=[CH:40]1)=[S:38].C(OCC)(=O)C>O1CCCC1>[N:39]1([C:37]([O:32]/[N:31]=[C:29](\[NH2:30])/[CH2:28][CH2:27][CH2:26][N:25]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:24][C:8]3[C:9]([C:19]4[NH:20][CH:21]=[CH:22][N:23]=4)=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[O:11][C:7]=3[CH:6]=2)[S:33]([CH3:36])(=[O:35])=[O:34])=[S:38])[CH:43]=[CH:42][N:41]=[CH:40]1
Reactant: CS(=O)(=O)N(CCC/C(N)=N/O)c1cc2oc(-c3ccc(F)cc3)c(-c3ncc[nH]3)c2cc1C1CC1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N(CCC/C(N)=N/OC(=S)n1ccnc1)c1cc2oc(-c3ccc(F)cc3)c(-c3ncc[nH]3)c2cc1C1CC1
Yield: 100 %

Procedure:
A solution of Example 176 (69.3 mg, 0.135 mmol) and 1,1′-thiocarbonyldiimidazole (38.1 mg, 0.203 mmol) in anhydrous tetrahydrofuran (1.3 mL) was stirred under nitrogen at 25° C. for 1.5 hours. Ethyl acetate (25 mL) was added, the mixture was washed with H2O (2×10 mL) and brine (10 mL), dried over anhydrous MgSO4, filtered, and concentrated by rotary evaporation to provide the title compound as a yellow foam (84 mg, 0.135 mmol, 100%).
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[CH:5][C:4]([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]3[N:19]=[N:20][NH:21][CH:22]=3)=[C:9]([O:23]C)[C:8]2=[S:25])=[CH:3][CH:2]=1.B(Br)(Br)Br>C(Cl)Cl>[C:1]1([CH3:26])[CH:6]=[CH:5][C:4]([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]3[N:19]=[N:20][NH:21][CH:22]=3)=[C:9]([OH:23])[C:8]2=[S:25])=[CH:3][CH:2]=1
Reactant: COc1c(CCCCCc2c[nH]nn2)ccn(-c2ccc(C)cc2)c1=S
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc(-n2ccc(CCCCCc3c[nH]nn3)c(O)c2=S)cc1
Yield: 58.4 %

Procedure:
Reaction of 165a (0.075 g, 0.203 mmol) and 1M BBr3 (0.24 mL) in CH2Cl2 (8 mL) within 48 h as described for the synthesis of 148a gave compound 167a (0.042 g, 62%) as olive green solid. 1H NMR (400 MHz, CD3OD) δ 8.18 (s, 1H), 7.66 (d, J=8.0 Hz, 2H), 7.55 (d, J=5.7 Hz, 1H), 7.20 (d, J=7.7 Hz, 2H), 6.97 (d, J=6.7 Hz, 1H), 4.55 (m, 2H), 4.43 (t, J=6.7 Hz, 2H), 2.34 (s, 3H), 2.01 (m, 4H), 1.39 (t, J=22.5 Hz, 2H). 13C NMR (100 MHz, CD3OD) δ 149.25, 139.68, 130.93, 129.13, 127.01, 122.27, 51.41, 30.95, 24.51, 21.83. HRMS (EI) calcd for C19H22N4OS [M]+ 354.151. found 354.1512.
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.[Cl:15][C:16]1[CH:17]=[C:18]2[N:24]([CH2:25][CH3:26])[C:23](=[O:27])[N:22]([C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=3)[C:19]2=[N:20][CH:21]=1.[H-].[Na+]>CN(C=O)C.CO>[Cl:15][C:16]1[CH:17]=[C:18]2[N:24]([CH2:25][CH3:26])[C:23](=[O:27])[N:22]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:3]4[N:2]([CH3:1])[C:6]5=[N:7][CH:8]=[CH:9][CH:10]=[C:5]5[N:4]=4)=[CH:30][CH:29]=3)[C:19]2=[N:20][CH:21]=1
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(Cl)cc21
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2ncc(Cl)cc21
Temperature: 180 °C
Yield: 22.3 %

Procedure:
3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (90 mg) was added to a solution of 6-chloro-1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (127 mg) and NaH (18.74 mg) in DMF (2 mL) at room temperature. The mixture was heated at 180° C. for 30 min under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 6-chloro-1-ethyl-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 (40 mg) as colorless crystals.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:25]=[CH:24][C:8]2[N:9]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=4)[N:12]=[C:10]3[S:11][C:7]=2[CH:6]=1.[H][H]>CO.C1COCC1.[Pd]>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:25]=[CH:24][C:8]2[N:9]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=4)[N:12]=[C:10]3[S:11][C:7]=2[CH:6]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(-c2cn3c(n2)sc2cc(OCCCl)ccc23)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(-c2cn3c(n2)sc2cc(OCCCl)ccc23)cc1
Temperature: 25 °C

Procedure:
A mixture of 7-(2-chloro-ethoxy)-2-(4-nitro-phenyl)-benzo[d]imidazo[2,1-b]thiazole (1 equivalent) and 10% Pd/C (0.05-0.1 equivalents) in a mixture of MeOH and THF under 1 atmosphere of hydrogen gas is stirred at rt until the reaction is substantially complete as monitored by LCMS or TLC. The mixture is filtered through Celite and concentrated under reduced pressure. The residue is purified by silica gel flash chromatography to afford 7-(2-chloro-ethoxy)-2-(4-amino-phenyl)-benzo[d]imidazo[2,1-b]thiazole.
Reaction SMILES: C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[F:17][C:18]([F:25])([F:24])[CH:19]([OH:23])[C:20]([OH:22])=[O:21].[C:26](Cl)(=[O:30])[C:27]([CH3:29])=[CH2:28].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C1COCC1>[F:17][C:18]([F:25])([F:24])[CH:19]([O:23][C:26](=[O:30])[C:27]([CH3:29])=[CH2:28])[C:20]([OH:22])=[O:21]
Reactant: O=C(O)C(O)C(F)(F)F
Reactant: C=C(C)C(=O)Cl
Agent: CN(C)c1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC(C(=O)O)C(F)(F)F
Reaction time: 2 h
Yield: 35 %

Procedure:
Under a nitrogen atmosphere, 50 mL of dehydrated THF, 5.56 g (55.0 mmol) of triethylamine and 305 mg (2.5 mmol) of dimethylaminopyridine were added to 7.20 g (50.0 mmol) of 3,3,3-trifluorolactic acid at a room temperature. Thereafter, 5.75 g (55.0 mmol) of methacrylic acid chloride was added dropwise over 10 min, and then the mixture was stirred for 2 hrs. After disappearance of the raw material was confirmed by TLC, an aqueous sodium bicarbonate solution was added to stop the reaction. Thereafter, ethyl acetate was added to the reaction liquid and extraction was carried out three times. The organic layer thus obtained was washed with water, saturated brine each once, and dried by adding anhydrous sodium sulfate. Thereafter, the solvent was distilled off under a reduced pressure, and the resulting product was purified by column chromatography to give 3.71 g of 3,3,3-trifluoro-2-(methacryloyloxy)propionic acid represented by the following formula in the form of pale yellow oil (yield: 35%).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4]1.[N+:18]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br)([O-:20])=[O:19]>CN(C)C=O>[N+:18]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4]1)([O-:20])=[O:19]
Reactant: O=C(O)CCCc1c[nH]c2ccccc12
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CCCc1cn(Cc2cccc([N+](=O)[O-])c2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil) (0.59 g) in N,N-dimethylformamide (10 ml) was added a solution of 4-(3-indolyl)butyric acid (1.0 g) in N,N-dimethylformamide (5 ml). The mixture was stirred at room temperature for 30 minutes and cooled at -40° C. To the mixture was added a solution of 3-nitrobenzyl bromide (1.06 g) in N,N-dimethylformamide (5 ml). The mixture was stirred at -40° C. for 20 minutes and partitioned between ethyl acetate and 7% hydrochloric acid. The organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was washed with diisopropyl ether to give 4-[1-(3-nitrobenzyl)indol-3-yl]butyric acid as a white powder (1.20 g).