Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:21])([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])C(OCC)=O)=[O:5])[CH3:2].[OH-].[Na+].Cl>C(O)C>[N+:28]([C:25]1[CH:24]=[CH:23][C:22]([C:20](=[O:21])[CH2:19][CH:6]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:27][CH:26]=1)([O-:30])=[O:29]
Reactant: CCOC(=O)CCC(CC(=O)c1ccc([N+](=O)[O-])cc1)(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CCC(CC(=O)c1ccc([N+](=O)[O-])cc1)C(=O)OCC
Yield: 71.9 %

Procedure:
A solution of diethyl 2-ethoxycarbonyl-2-(2-(4-nitrophenyl)-2-oxoethyl)glutarate (2.5 g, 5.9 mmol) in ethanol:1N NaOH (2:1, 105 ml) was stirred 20 hours at room temperature and then acidified to pH 1.5 with concentrated HCl and concentrated in vacuo. The residue was dissolved in diglyme (50 ml) and the solution stirred at reflux for 20 minutes and then concentrated in vacuo. The residue was then dissolved in ethanol (50 ml). HCl gas was bubbled into the solution for 30 seconds, and the solution was stirred at room temperature over the weekend and then concentrated in vacuo. The product was taken up in diethyl ether (100 ml), washed with saturated sodium bicarbonate solution (35 ml), dried (MgSO4), and concentrated in vacuo. Purification by chromatography on silica gel eluting with ethyl acetate:hexane (1:4) gave diethyl (RS)-2-(2-(4-nitrophenyl)-2-oxoethyl)glutarate (1.49 g) as an oil 1H NMR (DMSO-d6, 200 MHz) δ: 1.13 (t, J=7 Hz, 3H, CH3), 1.19 (t, J=7 Hz, 3H, CH3), 1.74-1.93 (m, 2H, CH2), 2.35-2.45 (m, 2H, CH2CO2), 2.82-3.00 (m, 1H, CH), 3.24-3.67 (m, 2H, COCH2), 4.03 (q, J=7 Hz, 2H, ester CH2), 4.04 (q, J=7 Hz, 2H, ester CH2), 8.20 (d, J=9 Hz, 2H, Ar), 8.33 (d, J=9 Hz, 2H, Ar). Anal. Calculated for C17H21NO7.1/4H2O: C, 57.38; H, 6.09; N, 3.94. Found: C, 57.35; H, 6.11; N, 3.89.
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[Cl:11][C:12]1[N:20]=[C:19]2[C:15]([NH:16][CH:17]=[N:18]2)=[C:14](Cl)[N:13]=1.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][NH:18]2)=[C:14]([NH:1][C@@H:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)[N:13]=1
Reactant: N[C@H]1CCc2ccccc21
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Clc1nc(N[C@H]2CCc3ccccc32)c2nc[nH]c2n1
Yield: 79.6 %

Procedure:
(S)-(+)-1-Aminoindane (266.0 mg, 2.0 mmol), 2,6-dichloropurine (380 mg, 2.0 mmol) and N,N-diisopropylethylamine (380 μL, 2.2 mmol), were dissolved in Ethanol (4.0 mL) and reacted in a microwave at 120° C. for 600 s. A yellow solid formed which was filtered, washed with ethanol (20 mL) and dried to give the title compound 0.455 g, 80% yield.
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]2[C:13]([C:14](Br)=[C:15]3[C:20]=1[CH:19]=[CH:18][CH:17]=[CH:16]3)=[CH:12][CH:11]=[CH:10][CH:9]=2.[CH:28]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)=[CH2:29]>>[C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]2[C:13]([C:14]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([CH:28]=[CH2:29])[CH:35]=3)=[C:15]3[C:20]=1[CH:19]=[CH:18][CH:17]=[CH:16]3)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: C=Cc1cccc(B(O)O)c1
Reactant: Brc1c2ccccc2c(-c2ccccc2-c2ccccc2)c2ccccc12
Product: C=Cc1cccc(-c2c3ccccc3c(-c3ccccc3-c3ccccc3)c3ccccc23)c1
Yield: 63 %

Procedure:
A run was carried out as in Example 1 aside from using 9-biphenyl-2-yl-10-bromoanthracene and 3-vinylphenylboronic acid. There was obtained 9-biphenyl-2-yl-10-(3-vinylphenyl)anthracene in a yield of 63%. From this monomer, a polymer was prepared in a yield of 78% and had a weight average molecular weight of 21,000. An organic EL device was fabricated as in Example 1. This device produced blue light emission from tetraphenylbutadiene and showed a current efficiency of 4.0 cd/A upon constant current driving at 10 mA/cm2. The luminance half-life at 10 mA/cm2 was 580 hours.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:24]([CH3:25])[C:13]2=[N:14][CH:15]=[C:16]([CH:18](O)[C:19]([F:22])([F:21])[F:20])[CH:17]=[C:12]2[N:11]=1)[CH3:2].C1(C)C=CC=CC=1.S(Cl)([Cl:35])=O.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[Cl:35][CH:18]([C:16]1[CH:17]=[C:12]2[N:11]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[S:3][CH2:1][CH3:2])[N:24]([CH3:25])[C:13]2=[N:14][CH:15]=1)[C:19]([F:22])([F:21])[F:20]
Reactant: O=S(Cl)Cl
Reactant: CCSc1ccccc1-c1nc2cc(C(O)C(F)(F)F)cnc2n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCSc1ccccc1-c1nc2cc(C(Cl)C(F)(F)F)cnc2n1C
Temperature: 50 °C

Procedure:
To a mixture of 1-[2-(2-ethylsulfanyl-phenyl)-3-methyl-3H-imidazo[4,5-b]pyridin-6-yl]-2,2,2-trifluoro-ethanol (98 mg), toluene (10 ml), and pyridine (50 μl), thionyl chloride (1 ml) was added. The mixture was stirred with heating at 50° C. for 5 hours, and then saturated aqueous sodium hydrogen carbonate solution was poured, and extracted with ethyl acetate. The combined organic layer was dried over sodium, sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 66 mg of 6-(1-chloro-2,2,2-trifluoro-ethyl)-2-(2-ethylsulfanyl-phenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 266).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]2=[O:26])(=O)=O)=CC=1.C(N(C(C)C)CC)(C)C.[CH3:36][O:37][C:38](=[O:45])[CH2:39][CH:40]1[CH2:44][CH2:43][NH:42][CH2:41]1>CN(C=O)C>[O:26]=[C:21]1[CH2:22][CH2:23][CH2:24][CH2:25][N:20]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][CH2:12][N:42]1[CH2:43][CH2:44][CH:40]([CH2:39][C:38]([O:37][CH3:36])=[O:45])[CH2:41]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccccc2N2CCCCC2=O)cc1
Reactant: COC(=O)CC1CCNC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC1CCN(CCc2ccccc2N2CCCCC2=O)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution of 2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl 4-methylbenzenesulfonate a2-3 (2.85 g, 7.65 mmol, 1 eq) in DMF (10 ml) at room temperature are added diisopropylethylamine (2.65 ml, 15.30 mmol, 2 eq) and methylpyrrolidin-3-ylacetate a13-0 (1.08 g, 7.65 mmol, 1 eq). The mixture is stirred at 80° C. overnight. The solvent is removed under vacuum. The residue obtained is purified by chromatography over silicagel (eluent: CH2Cl2/EtOH 95/5) to afford 1.05 g of methyl (1-{2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl}pyrrolidin-3-yl)acetate a13-1 as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH:10]([OH:13])[N:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CCO>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH:10]([O:13][CH2:21][CH3:22])[N:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(O)N1C(=O)OC(C)(C)C
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CCOC1CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 5062.5 %

Procedure:
A solution of 12.1 g of 207 (42.1 mmol) in 100 ml of anhydrous EtOH was added with 200 mg of PPTS (0.80 mmol, 1.9 mole %) and stirred at RT overnight. Thereafter, the solvent was completely removed under vacuum, and the residue was taken up in 250 ml of a 1:2 mixture of EE/CH. After filtration over a short silica gel column, the eluate was concentrated to obtain 12.8 g of α-methoxycarbamate 45 (40.5 mmol, 96%) as a slightly yellowish oil. An analytical sample was obtained by column chromatography over silica gel (EE/CH 1:2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])[C:10]([Cl:17])=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:12]=2)=[C:4]([Cl:26])[CH:3]=1.[CH3:27][S:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29].C([O-])([O-])=O.[K+].[K+]>>[Cl:17][C:10]1[N:9]([C:18]2[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:25])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([S:28]([CH3:27])(=[O:30])=[O:29])[CH:36]=3)=[CH:3][C:4]=2[Cl:26])=[N:12][C:11]=1[C:13]([OH:16])([CH3:15])[CH3:14]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC(C)(O)c1nc(-c2ccc(Br)cc2Cl)n(-c2c(Cl)cccc2Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(O)c1nc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2Cl)n(-c2c(Cl)cccc2Cl)c1Cl
Temperature: 60 °C
Reaction time: 1.17 h
Yield: 78.2 %

Procedure:
A mixture of 2-[2-(4-bromo-2-chlorophenyl)-5-chloro-1-(2,6-dichlorophenyl)-1H-imidazol-4-yl]-propan-2-ol (184 mg, 0.37 mmol), 3-methanesulfonyl-phenylboronic acid (90 mg, 0.45 mmol), K2CO3 (0.15 g, 1.1 mmol), Cl2Pd(dppf).DCM (15 mg, 5 mol %) and H2O (0.2 mL) in DME (2 mL) was sparged with Argon for 5 min and then heated at 60° C. as a sealed flask. After 70 min the reaction mixture was allowed to cool to ambient temperature, filtered (Celite™) and the filter agent rinsed with EtOAc. The combined filtrates were concentrated under reduced pressure and purified by chromatography (silica, EtOAc/Hex, 20:80 to 60:40) to give the title compound (165 mg, 78%) as a white solid. 1H-NMR (DCM-d2): δ 8.08 (m, 1H), 7.93 (m, 1H), 7.84 (m, 1H), 7.73 (d, 1H), 7.67 (m, 1H), 7.33-7.47 (m, 5H), 3.42 (br s, 1H), 3.06 (s, 3H), 1.68 (s, 61-1); MS (ES): 591, 593, 595 [M+Na]+.
Reaction SMILES: C([O:9][CH2:10][C@@H:11]1[C:15]([O:17]C(=O)C)([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:28]=[CH:27][C:26](=[O:29])[NH:25][C:24]2=[O:30])[O:12]1)(=O)C1C=CC=CC=1.CO>N>[F:22][C:14]1([CH3:21])[C@@:15]([OH:17])([CH3:16])[CH:11]([CH2:10][OH:9])[O:12][C@H:13]1[N:23]1[CH:28]=[CH:27][C:26](=[O:29])[NH:25][C:24]1=[O:30]
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2ccc(=O)[nH]c2=O)[C@]1(C)F
Agent: N
Solvent: CO
Product: CC1(F)[C@H](n2ccc(=O)[nH]c2=O)OC(CO)[C@@]1(C)O
Yield: 55 %

Procedure:
A solution of ((2R,4R)-3-acetoxy-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.25 g, 0.59 mmol) in methanolic ammonia (25% w/w 10 ml) was stirred at room temperature for overnight. Completion of the reaction mixture monitored by thin-layer chromatography and methanol was removed under reduced pressure. Water added to the crude and extracted with ethyl acetate and the organic layer was dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 5% methanol in dichloromethane to elude title compound (0.09 g). Yield: 55%; 1H-NMR: 1H NMR (300 MHz, CDCl3): δ 8.57 (bs, 1H), 7.38-7.33 (m, 1H), 6.44 (d, 1H, J=22.2 Hz), 5.73 (d, 1H, J=8.1 Hz), 4.65 (bs, 1H), 4.19-4.09 (m, 3H), 2.86 (bs, 1H), 1.48 (s, 3H), 1.35 (d, 3H, J=2.6 Hz); ES Mass: [M+Na]+: 297 (20%), [M+1]+ 275 (20%); IR cm−: 3430 2928, 2864, 2273, 1707, 1385, 1270, 1052, 821, 567; HPLC: 93.2%.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][S:29]([C:32]1[S:36][C:35]([C:37](O)=[O:38])=[CH:34][CH:33]=1)(=[O:31])=[O:30]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:37]([C:35]5[S:36][C:32]([S:29]([CH3:28])(=[O:31])=[O:30])=[CH:33][CH:34]=5)=[O:38])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)s1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CS(=O)(=O)c1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5c4CCO5)CC3)CC2)s1

Procedure:
The title compound, off-white solid (98 mg, 76%), MS (ISP) m/z=519.2 [(M+H)+], mp 229° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 5-methanesulfonyl-thiophene-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:28])[CH2:18][CH2:17][C:16]([CH2:26][NH2:27])([C:19]2[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:27][CH2:26][C:16]1([C:19]2[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:17][CH2:18][C:13]([F:12])([F:28])[CH2:14][CH2:15]1)=[O:6]
Reactant: O=C(O)c1c(F)cccc1Cl
Reactant: NCC1(c2ccc(F)nc2)CCC(F)(F)CC1
Product: O=C(NCC1(c2ccc(F)nc2)CCC(F)(F)CC1)c1c(F)cccc1Cl

Procedure:
From 2-chloro-6-fluorobenzoic acid and C-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=401.1, tR (minutes, Method C)=1.07
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:15]([C@H:17]1[O:19][CH2:18]1)[Cl:16]>>[Cl:16][CH2:15][C@@H:17]([OH:19])[CH2:18][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: ClC[C@@H]1CO1
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=[N+]([O-])c1nccn1C[C@H](O)CCl

Procedure:
Alternatively, reaction of 2-nitroimidazole, anhydrous potassium carbonate, and (S)-(+)-epichlorohydrin as described in Example 1(a) gives the product.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>O>[CH2:6]1[O:5][C:4]2[C:8](=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[C:2]([CH:3]=2)[C:1]([OH:12])=[O:11])[O:7]1
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc2c(c1)OCO2
Solvent: O
Product: O=C(O)c1cc2c(cc1[N+](=O)[O-])OCO2
Temperature: 50 °C

Procedure:
30 g (0.18 mole) of piperonylic acid are added with care to 200 ml of nitric acid (d=1.42). After a first addition of 5 g, the reaction is started by heating and by vigorously stirring the reaction mixture at 50° C. The addition of the remaining 25 g is carried out in small fractions. At the end of the addition, the reaction mixture is left stirring for 2 hours. Then 200 ml of water are added, the insoluble reaction product is spun, washed with 100 ml of water and then dissolved in a saturated aqueous solution of sodium bicarbonate. The insoluble compounds are removed. The filtrate is acidified at 0° C. and the precipitate is collected and then spun, washed with water and dried.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=2)[N:4]=[C:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)(=[O:24])=[O:23])[CH:17]=1>CO.O1CCCC1>[CH3:1][C:2]1([CH3:30])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)(=[O:24])=[O:23])[CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)N3CCCC3)c1)=N2
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)N3CCCC3)c1)N2
Yield: 78.9 %

Procedure:
A mixture of methyl 3,3-dimethyl-2-(3-(pyrrolidin-1-ylsulfonyl)phenyl)-3,4-dihydroquinoline-6-carboxylate (140 mg, 0.328 mmol) in methanol/tetrahydrofuran (6 mL/6 mL) was treated with H2 at room temperature overnight. C-MS showed the reaction was complete. The mixture was separated by filtration and the filtrate was concentrate in vacuo to give 110.9 mg of methyl 3,3-dimethyl-2-(3-(pyrrolidin-1-ylsulfonyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate, yield: 78.9%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([OH:32])=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)=[CH:18][C:17]=2[F:33])=[CH:12][N:11]=1>>[NH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([O:32][C:23]2[CH:24]=[C:25]([C:28]([F:29])([F:30])[F:31])[CH:26]=[CH:27][C:22]=2[C:19]2[CH:20]=[CH:21][C:16]([C:13]3[CH:12]=[N:11][C:10]([NH2:9])=[N:15][CH:14]=3)=[C:17]([F:33])[CH:18]=2)[N:7]=1
Reactant: Nc1ccnc(Cl)n1
Reactant: Nc1ncc(-c2ccc(-c3ccc(C(F)(F)F)cc3O)cc2F)cn1
Product: Nc1ccnc(Oc2cc(C(F)(F)F)ccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)n1

Procedure:
The title compound was prepared in a manner similar to that described in Example 555 using 2-chloropyrimidin-4-amine and 4′-(2-aminopyrimidin-5-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-ol. MS (ESI): mass calcd. for C21H14F4N6O, 442.12; m/z found, 443.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.46 (s, 2H), 7.80-7.74 (m, 1H), 7.74-7.67 (m, 1H), 7.67-7.62 (m, 1H), 7.52 (s, 1H), 7.51-7.44 (m, 1H), 7.44-7.31 (dd, J=17.9, 10.0, 2H), 6.20-6.08 (dd, J=6.0, 1.4, 1H).
Reaction SMILES: [CH2:1]([C:3]1[C:10]([C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=3)=[N:13][CH:12]=2)=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O)[CH3:2].[NH:30]1[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:1]([C:3]1[C:10]([C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[C:18]([C:26]([F:28])([F:29])[F:27])[CH:17]=3)=[N:13][CH:12]=2)=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][N:30]1[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]1)[CH3:2]
Reactant: CCc1c(C=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Reactant: O=C(O)C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1c(CN2CC(C(=O)O)C2)cccc1-c1cnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.4 %

Procedure:
To a solution of 2-ethyl-3-{2-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}benzaldehyde (D72) (60 mg), 3-azetidinecarboxylic acid (28.9 mg) and acetic acid (0.1 mL) in dichloromethane (DCM) (3 mL) stirred under nitrogen at room temperature for 1 h was added sodium triacetoxyborohydride (60.6 mg) in one charge. The reaction was stirred at room temperature overnight. The mixture was partitioned with DCM and water, washed with saturated brine and the organic phase was dried and evaporated, the residue was purified by Mass Directed AutoPrep to afford 1-[(2-ethyl-3-{2-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}phenyl)methyl]-3-azetidinecarboxylic acid (E31) (14 mg). δH (DMSO-d6, 400 MHz): 1.06 (3H, t), 1.33 (6H, d), 2.73 (2H, m), 3.22 (5H, m), 3.63 (2H, s), 4.89 (1H, m), 7.26 (2H, m), 7.39 (1H, d), 7.45 (1H, d), 7.84 (1H, s), 8.15 (2H, m). δF (DMSO-d6, 376 MHz): −61.3. MS (ES): C26H27F3N2O3S requires 504. found 505.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([S:17][CH3:18])=[N:15]3)=[CH:10][CH:9]=2)=[C:4]([N+:19]([O-])=O)[CH:3]=1.[Cl-].[NH4+].C(O)C.O>[Fe]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([S:17][CH3:18])=[N:15]3)=[CH:10][CH:9]=2)=[C:4]([NH2:19])[CH:3]=1
Reactant: CSc1ncc2ccc(-c3ccc(C)cc3[N+](=O)[O-])n2n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CSc1ncc2ccc(-c3ccc(C)cc3N)n2n1
Temperature: 100 °C
Yield: 86.5 %

Procedure:
A mixture of 7-(4-Methyl-2-nitro-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (620 mg, 2.1 mmol), iron (346 mg, 6.19 mmol), ammonium chloride (55.2 mg, 1.03 mmol) in ethanol (12.0 mL, 206 mmol) and water (8 mL, 400 mmol) was heated at 100° C. The mixture was cooled, solvent was evaporated and was diluted with water and EtOAc. It was filtered through a pad of celite, extracted from EtOAc, combined organic was washed with brine. After drying, solvent was evaporated to give 5-Methyl-2-(2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenylamine as a solid (491 mg, 88%). LCMS (E/I+) 271. The product was taken to the next step without further purification.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:35]([CH3:36])=[CH:34][C:14]2[N:15]=[C:16]([N:18]3[CH2:22][CH:21]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([CH3:32])[N:27]=[CH:26]5)[CH2:20][C:19]3=[O:33])[S:17][C:13]=2[C:12]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-:44].[Na+].Cl>C1COCC1.CO>[C:1]([O:5][C@H:6]([C:7]([OH:9])=[O:8])[C:11]1[C:35]([CH3:36])=[CH:34][C:14]2[N:15]=[C:16]([NH:18][CH2:22][CH:21]([C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[N:28]([CH3:32])[N:27]=[CH:26]4)[CH2:20][C:19]([OH:33])=[O:44])[S:17][C:13]=2[C:12]=1[C:37]1[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [OH-]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CC(c4ccc5c(cnn5C)c4)CC3=O)sc2c1-c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2nc(NCC(CC(=O)O)c3ccc4c(cnn4C)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(4-(1-methyl-1H-indazol-5-yl)-2-oxopyrrolidin-1-yl)benzo[d]thiazol-6-yl)acetate (5 mg) in THF/MeOH (0.5 mL/0.5 mL) was added sodium hydroxide solution (1.0 N, 0.5 mL). The mixture was stirred at 25° C. for 2 hours and heated at 50° C. for 16 hours. The mixture was cooled and neutralized with 0.1 N hydrochloric acid until pH=5. The reaction mixture was freeze-dried and used for next step without further purification. LCMS-ESI+: calc'd for C32H33ClN4O5S: 621.2 (M+H+); Found: 621.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[Cl:16].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1.C(=O)([O-])O.[Na+]>C(#N)C.[I-].[Na+]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:11][CH2:12][N:13]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:34])([C:26]([F:27])([F:28])[F:29])[C:30]([F:31])([F:32])[F:33])=[CH:23][CH:24]=3)[CH2:14][CH2:15]2)=[O:9])=[CH:4][C:3]=1[Cl:16]
Reactant: Nc1ccc(C(=O)N2CCNCC2)cc1Cl
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1Cl
Reaction time: 24 h
Yield: 50.2 %

Procedure:
A mixture of (4-amino-3-chlorophenyl)(piperazin-1-yl)methanone (6.67 mmol, 1.6 g), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (6.67 mmol, 2.250 g), sodium hydrogencarbonate (20.02 mmol, 1.682 g) and sodium iodide (0.334 mmol, 0.050 g) in acetonitrile (50 mL) was stirred for 24 hours. The reaction was concentrated under reduced pressure and dichloromethane was added. The mixture was filtered and the filtrate was chromatographed on silica eluting with dichloromethane to dichloromethane/ethyl acetate to give the title compound (1.66 g).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]1([O:13][C:14]2[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Br[C:24]1[C:25]([NH2:31])=[N:26][CH:27]=[C:28]([Cl:30])[CH:29]=1>COCCOC.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:30][C:28]1[CH:29]=[C:24]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]3)=[CH:15][CH:16]=2)[C:25]([NH2:31])=[N:26][CH:27]=1
Reactant: Nc1ncc(Cl)cc1Br
Reactant: OB(O)c1ccc(OC2CCCCC2)cc1
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: COCCOC
Product: Nc1ncc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 48.4 %

Procedure:
A mixture of sodium carbonate (307 mg), tetrakis(triphenylphosphine)palladium(0) (50.1 mg), 4-(cyclohexyloxy)phenylboronic acid (414 mg) and 3-bromo-5-chloropyridin-2-amine (300 mg) in DME (15 mL) and water (3 mL) was stirred at 80° C. for 5 hr. Silica gel was added and the mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (212 mg) as a yellow gum.