Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12]([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][N:23]([C:26](=[O:28])[CH3:27])[CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH2:29])=[CH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:54]([C:56]1[N:57]=[C:58]([C:69](O)=[O:70])[N:59]([CH2:61][O:62][CH2:63][CH2:64][Si:65]([CH3:68])([CH3:67])[CH3:66])[CH:60]=1)#[N:55].[K+].C(C1N=C(C([O-])=O)N(COCC[Si](C)(C)C)C=1)#N.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][C:12]([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:21][CH2:22][N:23]([C:26](=[O:28])[CH3:27])[CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[NH:29][C:69]([C:58]2[N:59]([CH2:61][O:62][CH2:63][CH2:64][Si:65]([CH3:68])([CH3:67])[CH3:66])[CH:60]=[C:56]([C:54]#[N:55])[N:57]=2)=[O:70])=[CH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)O
Reactant: CC(=O)N1CCC(c2ccc(N)c(C3=CCCN(C(=O)OC(C)(C)C)C3)c2)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCN(C(=O)OC(C)(C)C)C3)c2)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A solution of 5-[5-(1-acetyl-piperidin-4-yl)-2-amino-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (as prepared in the previous step, 0.25 g, 0.63 mmol) in CH2Cl2 was treated with PyBroP (0.44 g, 0.94 mmol) and 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid, potassium salt (as prepared in Example 3, step (d), 0.21 g, 0.69 mmol). The resulting slurry was cooled to 0° C. and treated with DIEA (0.33 mL, 1.88 mmol). The ice bath was removed and the mixture stirred at room temperature for 18 h. The reaction was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated in vacuo. Silica gel chromatography (25-45% EtOAc in hexanes then 100% EtOAc) afforded the title compound (399 mg, 98%) as a white solid. LC-MS (ESI, m/z): Calcd. for C34H48N6O5Si 649.4 (M+H), found 649.9.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].P.C(O)(CC)(C)C.[CH3:16][S:17]([NH2:20])(=[O:19])=[O:18].S(C(C(C(C(F)(F)F)(F)F)(F)F)(F)F)(O)(=O)=O.[CH3:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl.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]>[C:39]1([CH3:38])[CH:44]=[CH:43][C:42]([NH:20][S:17]([CH3:16])(=[O:19])=[O:18])=[CH:41][CH:40]=1
Reactant: Cc1ccccc1
Reactant: CS(N)(=O)=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCC(C)(C)O
Product: Cc1ccc(NS(C)(=O)=O)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
In a nitrogen-atmosphere glovebox, a microwave vial equipped with a magnetic stir bar was charged with potassium phosphate (71.6 mg, 0.337 mmol, 1.1 equivalents), tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3) (2.8 mg, 0.00307 mmol, 0.01 equivalents) and phosphine ligand (0.00736 mmol, 0.024 equivalents). t-Amyl alcohol (1.1 mL) was syringed into the vial and the mixture was stirred for 30 minutes at 80° C. After cooling to room temperature, methanesulfonamide (35.0 mg, 0.368 mmol, 1.2 equivalents) and p-methylbenzene nonaflate (100 mg, 0.307 mmol, 1 equivalent) were added to the reaction solution. The vial was sealed with a crimp top and placed in a heating block at 80° C. After 16 hours, the reaction was cooled to room temperature and brought out of the glovebox. The reaction solution was diluted with CH2Cl2 (2 mL) and filtered through a pad of diatomaceous earth. The vial was rinsed with CH2Cl2 (2×2 mL), then the filter cake was washed with CH2Cl2 (2×2 mL). The filtrate was transferred to a tared flask and concentrated on a rotary evaporator to furnish an orange oil. The crude concentrate was sampled for a wt % analysis. Purified material could be isolated as an off-white solid by silica gel flash column chromatography (30 g silica gel, gradient from 85:15 to 70:30 heptane:ethyl acetate) (literature reference: Shekhar S, et al. J. Org. Chem. 2011; 76: 4552-4563.). 1H NMR (400 MHz, CDCl3) δ ppm 7.22-7.07 (m, 4H), 6.57 (br s, 1H), 2.99 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: CN([CH:4]=[C:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12]2[C:13]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[N:14][CH:15]=[CH:16][C:17]=2[CH3:18])[CH2:6]1)C.C(=O)(O)O.[NH2:33][C:34]([NH2:36])=[NH:35].O.O.O.C([O-])(=O)C.[Na+]>CO>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:19][C:13]2[C:12]([N:7]3[CH2:8][CH2:9][C:10]4[N:35]=[C:34]([NH2:36])[N:33]=[CH:4][C:5]=4[CH2:6]3)=[C:17]([CH3:18])[CH:16]=[CH:15][N:14]=2)=[CH:22][CH:23]=1
Reactant: N=C(N)N
Reactant: COc1ccc(COc2nccc(C)c2N2CCC(=O)C(=CN(C)C)C2)cc1
Agent: CC(=O)[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(COc2nccc(C)c2N2CCc3nc(N)ncc3C2)cc1
Reaction time: 8 h
Yield: 37 %

Procedure:
A solution of 3-dimethylaminomethylene-2′-(4-methoxybenzyloxy)-4′-methyl-2,3,5,6-tetrahydro[1,3′]bipyridinyl-4-one (5.21 g, 13.66 mmol) in methanol (340 ml) was treated with guanidine carbonate (9.84 g, 54.63 mmol), followed by addition of sodium acetate trihydrate (14.87 g, 109.28 mmol) and the reaction mixture was refluxed for 3 hours. The solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The separated organic layer was dried (MgSO4), filtered, and concentrated to a red oil. The oil was taken up in a minimal volume of EtOAc and allowed to stand overnight at room temperature. The resulting yellow, crystalline solid was collected, washed with EtOAc, and dried to give the title compound (1.91 g). The mother liquor was concentrated and the residue was eluted through a flash column (silica gel 60, 230-400 mesh, EtOAc) to obtain an additional lot of the title compound (1.05 g) The total amount 2.96 g, 57%). HPLC analysis showed the compound has a purity of 98%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[N:6][CH:7]=1.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].C1(C)C=CC=CC=1>C(Cl)Cl>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:28]=[CH:27][CH:26]=[C:11]([CH:12]=[C:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[CH:10]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(Br)cn3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Brc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reaction time: 2 h

Procedure:
tert-Butyl 4-(3-(5-bromopyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (1.36 g, 3.05 mmol) from Step 4 was dissolved in CH2Cl2 (15 mL) and treated with trifluoroacetic acid (6 mL). After 2 h, toluene was added and the reaction was concentrated in vacuo. After evaporating again from toluene, the residue was dried in vacuo to afford the title compound (2.08 g, quantitative yield based on 3 eq trifluoroacetic acid) as an orange oil. This material was dissolved in acetonitrile (0.33 mmol/mL) and used in the next step.
Reaction SMILES: [OH:1][CH:2]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][CH2:22][CH3:23])[CH:16]=[C:15]2[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][C:26]=1[O:35][CH3:36])[CH:3]([C:6](=[O:11])[NH:7][CH2:8][CH2:9][CH3:10])[CH2:4][CH3:5].[C:37](OC(=O)C)(=[O:39])[CH3:38].C(N(CC)CC)C.C(Cl)Cl>C(OCC)(=O)C>[C:37]([O:1][CH:2]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][CH2:22][CH3:23])[CH:16]=[C:15]2[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][C:26]=1[O:35][CH3:36])[CH:3]([C:6](=[O:11])[NH:7][CH2:8][CH2:9][CH3:10])[CH2:4][CH3:5])(=[O:39])[CH3:38]
Reactant: CCCNC(=O)C(CC)C(O)c1ccc2c(c1)c(Cc1ccc(C(=O)OC)cc1OC)cn2CCC
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCNC(=O)C(CC)C(OC(C)=O)c1ccc2c(c1)c(Cc1ccc(C(=O)OC)cc1OC)cn2CCC

Procedure:
Methyl 4-[5-[1-hydroxy-2-(propylcarbamoyl)butyl]-1-propylindol-3-ylmethyl]-3-methoxybenzoate (0.75 g, as a mixture of diastereomers) was combined with acetic anhydride (0.31 g), triethylamine (0.152 g), and methylene chloride (20 ml), under a nitrogen atmosphere, and the mixture heated under reflux for 20 hr. The cooled mixture was diluted with ethyl acetate, washed (1M hydrochloric acid (twice), water, brine), dried (MgSO4) and evaporated to give a dark oil. The product was purified by flash chromatography, eluting with 8:2 methylene chloride:ethyl acetate, to give methyl 4-[5-[1-acetoxy-2-(propylcarbamoyl)butyl]-1-propylindol-3-ylmethyl]-3-methoxybenzoate (0.69 g, 85%, as a mixture of diastereomers) as an oil: partial NMR (300 MHz, DMSO-d6): 0.40(t, 3H, CH3, one isomer), 0.66(t, 3H, CH3, other isomer), 0.79(m, 12H, 2×CH3, one isomer, 2×CH3, other isomer), 1.84(s, 3H, OCOCH3, one isomer), 1.97(s, 3H, OCOCH3, other isomer), 5.66 (d, 1H, CHOCOCH3, one isomer), 5.79(d, 1H, CHOCOCH3, other isomer), 7.67(br t, 1H, NH, one isomer), 8.04(br t, 1H, NH, other isomer).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.CN1CCOCC1.[Br:25][C:26]1[C:31]([F:32])=[CH:30][C:29]([S:33](Cl)(=[O:35])=[O:34])=[C:28]([F:37])[CH:27]=1>ClCCl>[Br:25][C:26]1[C:31]([F:32])=[CH:30][C:29]([S:33]([NH:14][C:13]2[CH:15]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[CH:10]=[CH:11][C:12]=2[O:16][CH3:17])(=[O:34])=[O:35])=[C:28]([F:37])[CH:27]=1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1N
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1cc(F)c(Br)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)aniline (D4) (500 mg, 2.12 mmol) in dichloromethane (30 ml) was treated with morpholinomethyl-polystyrene HL resin (1 g, 4 mmol/g loading, 4.24 mmol) followed by 4-bromo-2,5-difluorobenzene sulfonyl chloride (930 mg, 3.2 mmol). The resulting solution was stirred room temperature for 18 hours and was then filtered, washing with dichloromethane, and the filtrate concentrated in vacuo. The residue was then purified using an SCX ion exchange cartridge (Varian bond-elute) eluting with methanol followed by ammonia (0.5M to 2M in methanol). The appropriate fractions were combined and reduced in vacuo to afford a crude product which was purified further by trituration with methanol to afford the desired product D37. MS (ES+) m/e 490/492 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[S:5][CH:6]=1.C(N(CC)CC)C.C(NC1C=CC(S([N:33]=[N+:34]=[N-])(=O)=O)=CC=1)(=O)C>C(#N)C>[N+:33](=[C:7]([C:4]1[S:5][CH:6]=[C:2]([CH3:1])[N:3]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N-:34]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CCOC(=O)Cc1nc(C)cs1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=[N+]=[N-])c1nc(C)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
A solution of ethyl (4-methyl-1,3-thiazol-2-yl)acetate (ENAMINE, 300 mg, 1.619 mmol) in acetonitrile (ACN) (12 mL) was treated with triethylamine (FLUKA, 0.339 mL, 2.429 mmol) at 0° C. After 20 minutes 4-acetamidobenzenesulfonyl azide (ALDRICH, 389 mg, 1.619 mmol) was added and the mixture was allowed to reach room temperature overnight. Then, 4-acetamidobenzenesulfonyl azide (ALDRICH, 94 mg, 0.391 mmol) was added and continued stirring at room temperature for 2 h. Reaction mixture was concentrated and residue was triturated with a mixture 1:1 Et2O-hexane and filtered. Solid was washed several times with the same mixture. The filtrate was concentrated to give 310 mg of crude. It was purified on a 10 g silica cartridge and eluted manually with linear gradient 0-50% hexane-ethyl acetate to yield the title compound (200 mg, 0.947 mmol, 58.5% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.49 (d, 1H), 4.34 (q, 2H), 2.60 (s, 3H), 1.32 (t, 3H). [ES+MS] m/z 212 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[C:43]([F:45])[CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([F:31])=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:45][C:43]1[CH:42]=[C:4]([CH:3]=[C:2]([F:1])[CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([F:31])=[C:24]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(-c4ccc(F)c(NS(C)(=O)=O)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CS(=O)(=O)Nc1cc(-c2cnc3[nH]cc(-c4cnn(Cc5cc(F)cc(F)c5)c4)c3c2)ccc1F
Yield: 37.1 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-fluorophenyl)methane sulfonamide (53 mg, 0.184 mmol) was hydrolyzed by lithium hydroxide (18 mg, 0.407 mmol) in THF/methanol/water (15/5/5 ml) to yield 34 mg (85% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.44-8.43 (d, 1H), 8.35-8.34 (d, 1H), 8.23 (s, 1H), 7.953-7.951 (d, 1H), 7.80-7.77 (dd, 1H), 7.66 (s, 1H), 7.59-7.55 (m, 1H), 7.34-7.29 (m, 1H), 6.90-6.86 (m, 2H), 5.43 (s, 2H), 305 (s, 3H). MS: m/z=498.1 (M+1), HPLC: 93.19% in method B.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.F[C:14]1[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][C:15]=1[C:16]#[N:17]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1)[O:12][C:14]1[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: Oc1cc(F)cc(C(F)(F)F)c1
Product: N#Cc1cc(C=O)ccc1Oc1cc(F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D30 starting from 3-fluoro-5-(trifluoromethyl)phenol and 2-fluoro-5-formylbenzonitrile.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[Cl:11].B(O)(O)[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[F:19].C(=O)([O-])[O-].[Na+].[Na+]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].COCCOC.O>[Cl:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[F:19]
Reactant: OB(O)c1ccncc1F
Reactant: O=[N+]([O-])c1ccc(Cl)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)c(-c2ccncc2F)c1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of DME:H2O (3:1) was degassed with N2 for one half hour. 2-bromo-1-chloro-4-nitrobenzene (1 eq) added and degassed for another 10 minutes. 1,1′-bis(diphenylphosphino)ferrocene palladium(II)chloride (0.05 eq), 3-fluoropyridin-4-yl-4-boronic acid (1 eq), and sodium carbonate (3 eq) were then added and stirred at 100° C. for 16 hours. Reaction then concentrated and partitioned between ethyl acetate and water. Organic layer washed with brine, dried over sodium sulfate and concentrated. Purification on silica gel, 10% ethyl acetate in hexanes to yield 4-(2-chloro-5-nitrophenyl)-3-fluoropyridine. HPLC=4.57 min; MS: MH+=253.
Reaction SMILES: [N+:1]([C:4]1[N:5]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][N:8]=1)([O-])=O.[BH4-].[Na+]>CO.O.[Pd]>[O:14]1[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][N:5]2[CH:6]=[CH:7][N:8]=[C:4]2[NH2:1])[CH2:12][CH2:13]1
Reactant: O=[N+]([O-])c1nccn1CCN1CCOCC1
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1nccn1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.2 %

Procedure:
The product from Step 1 (0.64 g, 2.81 mmol) is suspended in methanol (20 mL) and water (2 mL). Palladium on carbon (0.065 g, 0.281 mmol) is added and the mixture is degassed with nitrogen for 10 min before sodium borohydride (0.15 g, 3.93 mmol) is added portion-wise. The reaction is cooled with an ice bath and after 30 mins warmed to room temperature and stirred for 16 h at room temperature. The palladium is filtered through celite and washed with methanol (3×30 mL). The filtrate is concentrated in vacuo and the residue partitioned between dichloromethane (100 mL) and water (10 mL). The aqueous layer is extracted with dichloromethane (5×50 mL+1 mL MeOH). The organic layers are combined, dried (MgSO4) and solvent removed in vacuo to give an orange oil (0.42 g, 77%). NMR (400 MHz, CDCl3) =2.47-2.60 (m, 4H), 2.64-2.66 (m, 2H), 3.62-3.72 (m, 4H), 3.77-3.83 (m, 2H), 4.76 (brs, 2H), 6.49 (s, H), 6.61 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:12][CH3:13])=[CH:5][C:6]=1[C:7](OCC)=[O:8].[CH:14]([NH2:16])=O>O>[CH2:12]([C:4]1[S:3][C:2]2[N:1]=[CH:14][N:16]=[C:7]([OH:8])[C:6]=2[CH:5]=1)[CH3:13]
Reactant: CCOC(=O)c1cc(CC)sc1N
Reactant: NC=O
Solvent: O
Product: CCc1cc2c(O)ncnc2s1
Yield: 57 %

Procedure:
A solution of ethyl 2-amino-5-ethylthiophene-3-carboxylate (5 g, 25.09 mmol, 1.00 equiv) in formamide (60 mL) was stirred for 4 h at 180° C. in an oil bath. The reaction mixture was cooled and diluted with 200 mL of water. The solids were collected by filtration and dried in an oven under reduced pressure to give 2.6 g (57%) of 6-ethylthieno[2,3-d]pyrimidin-4-ol as a black solid. MS: m/z 181 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[S:23][C:24]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:25][C:5]=2[C:4](=[O:31])[NH:3]1.[CH:32]1([CH:38]2[CH2:40][O:39]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[CH:32]1([C:38](=[O:39])[CH2:40][N:3]2[C:4](=[O:31])[C:5]3[CH:25]=[C:24]([CH2:26][C:27]([F:30])([F:29])[F:28])[S:23][C:6]=3[N:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:13][CH:14]=3)[C:2]2=[O:1])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: C1CCC(C2CO2)CC1
Reactant: N#Cc1ccccc1-c1ccc(Cn2c(=O)[nH]c(=O)c3cc(CC(F)(F)F)sc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccccc1-c1ccc(Cn2c(=O)n(CC(=O)C3CCCCC3)c(=O)c3cc(CC(F)(F)F)sc32)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 22.6 %

Procedure:
To a mixture of 4′-{[2,4-dioxo-6-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (1.0 g), 2-cyclohexyloxirane (0.98 g) and N,N-dimethylformamide (7 mL) was added potassium carbonate (0.63 g), and the mixture was stirred at 80° C. for 24 hr. To the reaction mixture was added ethyl acetate and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. A mixture of the obtained residue, tetrapropylammonium perruthenate (0.011 g), 4-methylmorpholine-N-oxide (0.15 g), molecular sieves 4A (0.12 g) and methylene chloride (3 mL) was stirred at room temperature for 24 hr. The reaction mixture was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.29 g, 79%).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH2:16])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[C:23]([C:24](O)=[O:25])=[C:22]([F:27])[C:21]([CH2:28][NH:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:20][CH:19]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH:16][C:24](=[O:25])[C:23]3[C:18]([Cl:17])=[CH:19][CH:20]=[C:21]([CH2:28][NH:29][C:30](=[O:35])[C:31]([CH3:32])([CH3:33])[CH3:34])[C:22]=3[F:27])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Nc1ncnc2c(N)cccc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)Nc1ncnc2c(NC(=O)c3c(Cl)ccc(CNC(=O)C(C)(C)C)c3F)cccc12
Yield: 13.4 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(tert-butyl)quinazoline-4,8-diamine (Intermediate-55, 100 mg, 0.46 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 146 mg, 0.51 mmol), oxalyl chloride (126 mg, 0.99 mmol), DMF (1 drop) and DIPEA (132 mg, 1.03 mmol) in CH2Cl2 (3 mL) to afford 30 mg of the title product. 1H NMR (400 MHz, DMSO-d6): δ 10.39 (s, 1H), 8.69-8.67 (d, J=7.4 Hz, 1H), 8.51 (s, 1H), 8.18-8.16 (m, 2H), 7.54-7.50 (t, J=8.0 Hz, 1H), 7.44-7.40 (m, 2H), 7.37-7.33 (t, J=8.0 Hz, 1H), 4.32-4.30 (d, J=6.0 Hz, 2H), 1.56 (s, 9H), 1.14 (s, 9H); MS (m/z): 486.25 (M+H)+.
Reaction SMILES: Cl.[CH3:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH:20]3[S:26][C:24](=[O:25])[NH:23][C:21]3=[O:22])=[CH:17][CH:18]=2)=[N:8][CH:9]=1.C(=O)(O)[O-:28].[Na+].ClC1C=CC=C(C(OO)=O)C=1>CN(C)C=O.O.C(Cl)Cl>[O:25]=[C:24]1[NH:23][C:21](=[O:22])[CH:20]([CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][CH2:10][C:7]3[CH:6]=[CH:5][C:4]([CH2:3][CH3:2])=[CH:9][N+:8]=3[O-:28])=[CH:14][CH:15]=2)[S:26]1
Reactant: CCc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Reactant: O=C([O-])O
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)[n+]([O-])c1
Temperature: 10 °C
Reaction time: 48 h
Yield: 46.2 %

Procedure:
The hydrochloric acid salt of pioglitazone (3 g, 7.64 mmol) was dissolved in N,N-dimethylformamide (DMF, 50 mL) and neutralized by addition of an aqueous solution of sodium bicarbonate (NaHCO3, 0.641 g, 7.64 mmol in 6 mL water). The reaction mixture was diluted with water and the white solid was filtered off. It was rinsed with water and dried under vacuum. The resulting solid was resuspended in dichloromethane (CH2Cl2), and meta-chloroperbenzoic acid (m-CPBA, 50% by weight, 2.64 g, 7.64 mmol) was added to the mixture while maintaining the temperature at about 10° C. The reaction mixture was stirred at room temperature for 2 days, and then one more equivalent of m-CPBA (2.64 g, 7.64 mmol) was added. The reaction mixture was stirred for 2 h, then diluted with CH2Cl2 (50 mL). The organic layer was washed with 10% Na2S2O3 in water/water (2:1 v:v), then with 1:1 v:v 10% NaHCO3 in water/water (1:1 v:v). The resulting organic mixture was dried over sodium sulfate, filtered and solvent evaporated to give the crude N-oxide, which was further purified by flash chromatography on silica gel (gradient elution: CH2Cl2/10% MeOH in CH2Cl2 from 9:1 to 1:1). Fractions containing the pure N-oxide were pooled and evaporated to give the title compound (1.313 g, 3.53 mmol, 46.2% yield). LC/MS: 373 (M+1)