Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([NH:9][C:10]2[S:11][C:12]([C:15](=[O:29])[NH:16][C:17]3[S:18][CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)[N:21]=3)=[CH:13][N:14]=2)=[O:8])=[CH:5][N:6]=1>C(N)CC>[CH2:5]([NH:6][C:2]1[S:3][C:4]([C:7]([NH:9][C:10]2[S:11][C:12]([C:15](=[O:29])[NH:16][C:17]3[S:18][CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)[N:21]=3)=[CH:13][N:14]=2)=[O:8])=[CH:5][N:6]=1)[CH2:4][CH3:7]
Reactant: Cc1ccc(-c2csc(NC(=O)c3cnc(NC(=O)c4cnc(Br)s4)s3)n2)cc1
Solvent: CCCN
Product: CCCNc1ncc(C(=O)Nc2ncc(C(=O)Nc3nc(-c4ccc(C)cc4)cs3)s2)s1
Yield: 206.3 %

Procedure:
A solution of 2-bromo-N-(5-(4-p-tolylthiazol-2-ylcarbamoyl)thiazol-2-yl)thiazole-5-carboxamide (15 mg, 0.03 mmol) in neat propylamine (0.5 mL) was stirred at reflux for 24 hrs. The solvent was evaporated and the crude product was purified by column chromatography (0%-5% MeOH/AcOEt) yielding 2-(propylamino)-N-(5-(4-p-tolylthiazol-2-ylcarbamoyl)-thiazol-2-yl)thiazole-5-carboxamide (15 mg, 17%).
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3].[ClH:10]>CC(C)=O>[CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].[ClH:10]
Reactant: CN(C)C(=N)NC(=N)N
Agent: Cl
Solvent: CC(C)=O
Product: CN(C)C(=N)N=C(N)N
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
500 mg of metformin free base was dissolved in 30 Ml of acetone, and then 280 Ml of concentrated hydrochloric acid was added, and stirred for 2 hours at room temperature. The resulting crystal was filtered and washed with acetone, and then dried with heated air at 70° C. to obtain 490 mg of metformin hydrochloride (yield: 76.4%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[C:8]([Br:10])[N:7]=[C:6]([CH3:11])[N:5]=1.Cl[C:13]1[S:14][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][N:17]=1.Cl>C1COCC1>[Br:10][C:8]1[N:7]=[C:6]([CH3:11])[N:5]=[C:4]([NH:3][C:13]2[S:14][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][N:17]=2)[CH:9]=1
Reactant: Cc1nc(N)cc(Br)n1
Reactant: COC(=O)c1cnc(Cl)s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cnc(Nc2cc(Br)nc(C)n2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
60% sodium hydride (12.0 g, 0.30 mol) was suspended in THF (300 mL) and cooled down to 0° C. 4-amino-6-bromo-2-methylpyrimidine (Compound 9) (18.7 g, 0.1 mol) was then added in batches and stirred for 30 min. After methyl 2-chlorothiazole-5-formate (Compound 10) (17.7 g, 0.1 mol) was added in batches, the reactants were heated and reacted by refluxing for 4 h, and then cooled down to room temperature for reaction overnight. When controlling the temperature between 0° C. and 5° C., hydrochloric acid (2N) was added for neutralization reaction. After adding keep heat and stirred to grow grains for 1 h. Filtrate and wash the cake with water, and then dry to give target Compound 11 (25.8 g, yield is 78.4%).
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH2:29]O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:19](=[O:20])[C:18]3[CH:21]=[CH:22][C:23]([N+:24]([O-:26])=[O:25])=[C:16]4[C:17]=3[C:12](=[CH:13][CH:14]=[CH:15]4)[C:11]2=[O:27])=[CH:6][CH:5]=1)[CH3:2].P(Br)(Br)[Br:32]>C(Cl)(Cl)Cl>[Br:32][CH2:29][CH2:28][N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:19](=[O:20])[C:18]3[CH:21]=[CH:22][C:23]([N+:24]([O-:26])=[O:25])=[C:16]4[C:17]=3[C:12](=[CH:13][CH:14]=[CH:15]4)[C:11]2=[O:27])=[CH:6][CH:5]=1
Reactant: CCN(CCO)c1ccc(N2C(=O)c3cccc4c([N+](=O)[O-])ccc(c34)C2=O)cc1
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Product: CCN(CCBr)c1ccc(N2C(=O)c3cccc4c([N+](=O)[O-])ccc(c34)C2=O)cc1

Procedure:
1.5 g (3.7 mmol) of 2-{4-[ethyl(2-hydroxyethyl)amino]phenyl}-6-nitro-1H-benzo[de]isoquinolin-1,3(2H)-dione was dissolved in 80 mL of chloroform and heated to a boil. Then, 10.7 mL (11.1 mmol) of phosphorus tribromide was added dropwise within 20 minutes, and the solution was heated at reflux for an additional 2 hours. The mixture was then poured onto ice, and the aqueous phase was extracted with chloroform. The combined organic phases were dried over magnesium sulfate. The purification was performed by column chromatography on silica gel with toluene as the developing solvent. Yield: 0.90 g (52% of the theoretical), dark-red powder. 1H-NMR (d6DMSO/300 MHz): δ=1.12 (t, J=8.1 Hz, 3H), 1.86 (q, 2H), 3.58 (t, J=6.9 Hz, 2H), 4.01 (t, J=6.9 Hz, 2H), 6.96 (d, J=4.2 Hz, 2H, phenyl), 7.83 (d, J=7.6 Hz, 1H, naphthalene), 7.95 (d, J=4.4 Hz, 2H, phenyl), 8.33 (d, J=8.1 Hz, 1H, naphthalene), 8.52 (d, J=8.8 Hz, 1H, naphthalene), 8.67 (d, J=8.0 Hz, 1H, naphthalene), 9.13 (d, J=8.6 Hz, 1H, naphthalene).
Reaction SMILES: [Cl-:1].Br[C:3]1[C:12]2[CH2:11][CH2:10][N:9]([CH3:13])[CH2:8][CH:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[S:5][CH:4]=1>CN(C)C=O.[Cu]>[Cl:1][C:3]1[C:12]2[CH2:11][CH2:10][N:9]([CH3:13])[CH2:8][CH:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[S:5][CH:4]=1
Reactant: [Cl-]
Reactant: CN1CCc2c(Br)csc2C(c2ccccc2)C1
Agent: [Cu]
Solvent: CN(C)C=O
Product: CN1CCc2c(Cl)csc2C(c2ccccc2)C1

Procedure:
Anhydrous copper I chloride (0.68 g) was added to a stirred solution of 3-bromo-6-methyl-8-phenyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine (1.0 g) in dry dimethylformamide under nitrogen. The mixture was heated to 120° for 5 hours, evaporated, water added and extracted with dichloromethane. The extracts were dried, filtered and evaporated and the residue chromatographed on silica, eluting with 1% methanol in dichloromethane, to give a crude product which contained 10% of the starting bromo- compound. Further purification using preparative reverse phase high pressure liquid chromatographed gave the pure title product, m.p. 67° C.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=1)([O-])=O.CO>[Pd].CCOC(C)=O>[NH2:1][C:4]1[CH:14]=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=1
Reactant: O=C1COc2cc([N+](=O)[O-])ccc2N1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)OCC(=O)N2
Yield: 92.3 %

Procedure:
7-Nitro-4H-benzo[1,4]oxazin-3-one (0.65 g, 3.3 mmol) and 10% palladium on carbon (0.13 g) were combined in EtOAc (15 mL) and MeOH (15 mL) and hydrogenated for 2 h at atmospheric pressure. The catalyst was removed by filtration through celite and the filtrate reduced in vacuo to yield the title compound as a colourless oil (0.50 g, 91%). δH (DMSO-d6) 4.42 (2H, s), 4.89 (2H, br s), 6.13-6.20 (2H, m), 6.56 (1H, d, J 8.1 Hz), 10.27 (1H, br s).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:12]([C:15]([N:17]3[CH2:22][C@@H:21]4[CH2:23][C@H:18]3[CH2:19][O:20]4)=[O:16])=[CH:13][N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>COCCOC>[CH3:24][N:25]1[CH:29]=[C:28]([C:2]2[C:3]3[N:4]([C:12]([C:15]([N:17]4[CH2:22][C@@H:21]5[CH2:23][C@H:18]4[CH2:19][O:20]5)=[O:16])=[CH:13][N:14]=3)[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=2)[CH:27]=[N:26]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(c1cnc2c(Br)cc(C(F)(F)F)cn12)N1C[C@@H]2C[C@H]1CO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: Cn1cc(-c2cc(C(F)(F)F)cn3c(C(=O)N4C[C@@H]5C[C@H]4CO5)cnc23)cn1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
A mixture of (8-bromo-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methanone (50.0 mg), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (40.0 mg), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (10.5 mg) and cesium carbonate (125 mg) in DME (2.5 mL) was stirred with microwave irradiation at 120° C. for 30 min. To the reaction mixture was added 0.1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (15.6 mg).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Cl:25][C:26]1[CH:31]=[C:30]([NH:32][NH2:33])[N:29]=[CH:28][N:27]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O.CO.C(Cl)Cl>[F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:33][NH:32][C:30]3[CH:31]=[C:26]([Cl:25])[N:27]=[CH:28][N:29]=3)=[O:22])[N:14]=2)[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: NNc1cc(Cl)ncn1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NNc1cc(Cl)ncn1
Temperature: -40 °C
Yield: 37.8 %

Procedure:
A 25-mL, 3-necked, round-bottomed flask was charged with a solution of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.5 g) and 4-chloro-6-hydrazinopyrimidine (0.20 g, 1.0 eq.) in EtOAc (5.0 mL). The mixture was cooled at −40° C. and treated with T3P (2.3 mL, 2.5 eq.) and DIPEA (0.98 mL, 4.0 eq.). TLC analysis (using 5% MeOH—CH2Cl2 as eluent) showed that the starting material was consumed after 30 min. The reaction mixture was then diluted with CH2Cl2, washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure (25° C., 20 mmHg) to afford crude material that was subjected to preparative TLC purification using 5% MeOH—CH2Cl2 with as the mobile phase. This afforded 250 mg (yield: 36.74%) (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(6-chloropyrimidin-4-yl-)acrylohydrazide. 1H NMR (400 MHz, DMSO-d6), δ=10.59 (br s, exchangeable, 1H), 9.85 (br s, exchangeable, 1H), 9.52 (s, 1H), 8.50 (s, 2H), 8.38 (s, 1H), 8.27 (s, 1H), 7.52-7.55 (d, 1H, J=10.4 Hz), 6.69 (s, 1H), 6.05-6.08 (d, 1H, J=10.4 Hz); LCMS: Calculated for C17H11ClF6N7O (M+H)+ 478.76. found: 478.09 (RT 2.79 min, purity: 97.51%).
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:23]([O:25][CH2:26][CH:27]([O:40][C:41](=[O:59])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH:28]=[CH:29][C:30]([O:32]CC1C=CC=CC=1)=[O:31])=[O:24])[CH:20]([CH3:22])[CH3:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]>C(OCC)(=O)C.[Pd]>[C:1]([NH:18][C@H:19]([C:23]([O:25][CH2:26][CH:27]([O:40][C:41](=[O:59])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:24])[CH:20]([CH3:22])[CH3:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC(C=CC(=O)OCc1ccccc1)COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCC(=O)OC(CCC(=O)O)COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C

Procedure:
A solution of benzyl 5-(N-FMOC-L-valyloxy)-4-stearoyloxy-2-pentenoate (3.8 g, 4.69 mmole) in 50 ml ethyl acetate was hydrogenated with 10% palladium on charcoal (0.5 g) at normal pressure for five hours at room temperature. The catalyst was filtered and washed with ethyl acetate and 1,4-dioxane. The solution was evaporated under reduced pressure Yield: 3.3 g=99%
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17]/[C:18](=[N:25]\[O:26][CH3:27])/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:12]([O:28][CH3:29])[CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:30][CH2:31][C:32]([OH:34])=[O:33].[OH-].[Na+:36]>>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17]/[C:18](=[N:25]\[O:26][CH3:27])/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:12]([O:28][CH3:29])[CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:30][CH2:31][C:32]([O-:34])=[O:33].[Na+:36]
Reactant: CO/N=C(\COc1ccc(COc2ccc(CCC(=O)O)c(F)c2)cc1OC)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CO/N=C(\COc1ccc(COc2ccc(CCC(=O)[O-])c(F)c2)cc1OC)c1ccccc1
Yield: 30 %

Procedure:
Compound 56 was synthesized from 3-{2-fluoro-4-[(3-methoxy-4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}benzyl)oxy]phenyl}propanoic acid (0.3 g, 0.6 mmol) and sodium hydroxide (0.072 g, 1.8 mmol) by following the procedure described in scheme 12 (0.085 g, yield: 30.00%); Purity: 90.03%.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:33])[CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:17][CH:16]=1)C1C=CC=CC=1>[Pd].CO>[C:29]([O:28][C:26](=[O:27])[NH:25][CH2:24][CH2:23][C:22](=[O:33])[NH:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH2:10])=[CH:16][CH:17]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)NCCC(=O)Nc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1ccc(CCCCN)cc1
Reaction time: 4 h
Yield: 58.2 %

Procedure:
To a degassed solution of {4-[4-(3-tert-butoxycarbonylaminopropionylamino)phenyl]-butyl}carbamic acid benzyl ester 330 (1.78 g, 3.79 mmol) and methanol (50 mL) was added 10% palladium on activated carbon (0.5 g, 50% wet). The mixture was hydrogenated for 4 hours under atmospheric hydrogen. The catalyst was filtered through a pad of Celite and the solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 6:1:0.1, v/v chloroform/methanol/concentrated ammonium hydroxide) to provide 340 (0.74 g, 58%). 1H NMR (300 MHz, CH3OD) δ 1.44 (s, 9H), 1.50 (m, 2H), 1.66 (m, 2H), 2.60 (m, 6H), 3.38 (m, 2H), 7.14 (d, 2H), 7.44 (d, 2H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][C:13]1[CH:36]=[CH:35][C:16]([CH2:17][O:18][CH:19]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:14]=1.I[CH2:38][C:39]#[C:40][CH2:41][CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45]>C1COCC1>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][O:18][CH:19]([C:25]2[CH:26]=[CH:27][C:28]([N:31]([CH2:38][C:39]#[C:40][CH2:41][CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])[C:32](=[O:34])[CH3:33])=[CH:29][CH:30]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:35][CH:36]=1
Reactant: CCCCCC(OCc1ccc(OC)cc1)c1ccc(NC(C)=O)cc1
Reactant: COC(=O)CCCC#CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCC(OCc1ccc(OC)cc1)c1ccc(N(CC#CCCCC(=O)OC)C(C)=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.1 %

Procedure:
Sodium bis(trimethylsilyl)amide (0.31 ml of a 1.0 M solution in THF, 0.31 mmol) was added to a solution of the aryl amide 103 (100 mg, 0.282 mmol) in THF (1.3 mL) at 0° C. After 15 min a solution of the methyl 7-iodohept-5-ynoate (90 mg, 0.338 mmol) in THF (0.3 mL) was added and the reaction was warmed room temperature. After stirring for 16 h the reaction was the quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic portion was washed with brine, dried (MgSO4), filtered and the filtrate was concentrated in vacuo. Purification by FCC (silica gel, 3:2 hex/EtOAc) gave 35 mg (25%) of ester 104.
Reaction SMILES: [OH-].[Na+].O.[CH3:4]/[C:5](/[CH:11]=[CH:12]/[C:13](/[F:26])=[C:14](\[CH3:25])/[CH:15]=[CH:16]/[C:17]1[C:21]([CH3:22])=[C:20]([CH3:23])[S:19][C:18]=1[CH3:24])=[CH:6]\[C:7]([O:9]C)=[O:8].Cl>C(O)C>[CH3:4]/[C:5](/[CH:11]=[CH:12]/[C:13](/[F:26])=[C:14](\[CH3:25])/[CH:15]=[CH:16]/[C:17]1[C:21]([CH3:22])=[C:20]([CH3:23])[S:19][C:18]=1[CH3:24])=[CH:6]\[C:7]([OH:9])=[O:8]
Reactant: COC(=O)/C=C(C)/C=C/C(F)=C(C)/C=C/c1c(C)sc(C)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(/C=C/c1c(C)sc(C)c1C)=C(F)\C=C\C(C)=C\C(=O)O
Temperature: 45 °C
Reaction time: 4 h

Procedure:
A solution of 0.5 g. (12.5 mmol) of sodium hydroxide in 4 ml. of water was added to a solution of 1.0 g. (3 mmole) of methyl 2E,4E,6Z,8E-3,7-dimethyl-6-fluoro-9-(2,4,5-trimethyl-3-thienyl)-2,4,6,8-nonatetraenoate in 10 ml. of absolute ethanol. The mixture was stirred at 45° C. for 4 hours. The solution was cooled to room temperature, acidified with 3 N hydrochloric acid and filtered. The crude orange solid was purified by silica gel chromatography, euted with hexane-ethyl acetate (3:5 parts by volume) and crystallized from hexane-ethyl acetate (1:1 parts by volume) to give 600 mg. (62% yield) of 2E,4E,6Z,8E-3,7-dimethyl-6-fluoro-9-(2,4,5-trimethyl-3-thienyl)-2,4,6,8-nonatetraenoic acid orange crystals, m.p. 217°-223° C.
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:12]([CH3:25])[CH:11]=2)[N:4]=1.[CH2:27]([O:34][CH2:35][CH:36]1[CH:40]([CH2:41][N:42]2[CH:46]=[C:45](Br)[CH:44]=[N:43]2)[O:39][C:38](=[O:48])[NH:37]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH2:27]([O:34][CH2:35][CH:36]1[CH:40]([CH2:41][N:42]2[CH:46]=[C:45]([C:14]3[CH:13]=[C:12]([CH3:25])[CH:11]=[C:10]([NH:9][C:5]4[N:4]=[C:3]([CH:2]([F:1])[F:26])[CH:8]=[CH:7][N:6]=4)[CH:15]=3)[CH:44]=[N:43]2)[O:39][C:38](=[O:48])[NH:37]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1cc(Nc2nccc(C(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=C1NC(COCc2ccccc2)C(Cn2cc(Br)cn2)O1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CC3OC(=O)NC3COCc3ccccc3)c2)c1
Temperature: 110 °C

Procedure:
A mixture of 4-(difluoromethyl)-N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine (111 mg, 0.307 mmol), 4-[(benzyloxy)methyl]-5-[(4-bromo-1H-pyrazol-1-yl)methyl]-1,3-oxazolidin-2-one (109 mg, 0.298 mmol), potassium phosphate tribasic (239 mg, 1.13 mmol), and Pd(dbpf)Cl2 (4 mg, 0.006 mmol) in dioxane (2 mL) was stirred and heated to 110° C. in a microwave reactor for 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by prep-TLC (ethyl acetate/petroleum ether) to give 4-[(benzyloxy)methyl]-5-{[4-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)-1H-pyrazol-1-yl]methyl}-1,3-oxazolidin-2-one. MS ESI calc'd. for C27H27F2N6O3 [M+H]+ 521. found 521. 1H NMR (400 MHz, CD3OD) δ 8.60 (d, J=4.8 Hz, 1H), 7.99 (s, 1H), 7.84 (s, 1H), 7.77 (s, 1H), 7.40 (s, 1H), 7.38-7.26 (m, 5H), 7.15 (s, 1H), 7.05 (d, J=4.8 Hz, 1H), 6.56 (t, J=54.4 Hz, 1H), 4.88-4.76 (m, 1H), 4.54 (s, 2H), 4.48-4.46 (m, 2H), 3.94-3.92 (m, 1H), 3.48-3.46 (m, 2H), 2.35 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:25]=2)(=[O:23])=[O:22])[C:5]([C:8]([C:10]2[C:18]3[O:17][C:16](=[O:19])[NH:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[O:9])=[N:6][CH:7]=1.[BH4-].[Na+].CCOC(C)=O>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([C:31]([F:34])([F:32])[F:33])[CH:25]=2)(=[O:23])=[O:22])[C:5]([CH:8]([OH:9])[C:10]2[C:18]3[O:17][C:16](=[O:19])[NH:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2cccc3[nH]c(=O)oc23)cc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(O)c2cccc3[nH]c(=O)oc23)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-[5-chloro-2-(2-oxo-2,3-dihydro-benzooxazole-7-carbonyl)-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamide (41 mg) in THF (1 mL) and H2O (0.1 mL) was added NaBH4 (10 mg). The mixture was stirred at room temperature for 1 h, diluted by EtOAc (3 mL) and quenched by saturated aqueous NH4Cl solution (1 mL). The organic layer was separated, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by flash chromatography (silica) to afford the title compound as a white powder. MS (M+H)+: 514.0.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])[CH:6]=[CH:7][CH:8]=1)=O.[S:19]1[CH2:23][C:22](=[O:24])[NH:21][C:20]1=[O:25].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1.O>[F:16][C:15]([F:18])([F:17])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH:1]=[C:23]1[S:19][C:20](=[O:25])[NH:21][C:22]1=[O:24]
Reactant: O=Cc1cccc(-c2ccccc2C(F)(F)F)c1
Reactant: O=C1CSC(=O)N1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: O
Product: O=C1NC(=O)C(=Cc2cccc(-c3ccccc3C(F)(F)F)c2)S1

Procedure:
To a solution of 3-formyl-(2′-trifluoromethyl-1,1′-biphenyl) (0.334 g, 1.34 mmol) and 2,4-thiazolidinedione (0.19 g, 1.6 mmol) in toluene (20 mL) were added piperidine (0.017 mL, 0.174 mmol) and benzoic acid (0.025 mg, 0.2 mmol), and the reaction was refluxed for 3 h with continuous removal of water. The solvent was then distilled off and the residue was crystallized from ether-pet ether to yield titled product as a solid.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]3=[N:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24][N:19]3[CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C1COCC1.CO.[Pt](=O)=O>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:20]3=[N:21][S:22](=[O:25])(=[O:26])[CH2:23][CH2:24][N:19]3[CH2:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCCN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.6 %

Procedure:
Platinum(IV) oxide (2.0 g) was added to a solution of 9-(4-((tert-butyl(dimethyl)silyl)oxy)phenyl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (20.0 g) in THF (dry) (500 mL) and MeOH (300 mL) and the mixture was stirred at room temperature under H2 for 4 hr. The mixture was passed through NH silica gel cartridge with Celite (eluted with THF). The filtrate was concentrated in vacuo. The residual solid was recrystallized from THF (100 mL)-IPE (300 mL) to give the title compound (17.3 g).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[NH:7][C:6]=1[C:15]([C:17]1[N:18]([CH3:22])[CH:19]=[CH:20][CH:21]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+]>CO.O>[Cl:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:15]([C:17]1[N:18]([CH3:22])[CH:19]=[CH:20][CH:21]=1)=[O:16])=[C:5]2[CH2:4][C:3]([OH:23])=[O:2]
Reactant: COC(=O)Cc1c(C(=O)c2cccn2C)[nH]c2ccc(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cn1cccc1C(=O)c1[nH]c2ccc(Cl)cc2c1CC(=O)O
Temperature: 25 °C
Yield: 16 %

Procedure:
A mixture of methyl[5-chloro-2-(1-methylpyrrole-2-carbonyl)-1H-indol-3-yl]acetate (Example 251, 250 mg, 0.79 mmol) and potassium carbonate (900 mg, 6.4 mmol) in methanol-water (1:1, 40 ml) was heated at reflux temperature for 1 h. After cooling to room temperature, the mixture was concentrated. The residue was neutralized with 2N aqueous HCl and extracted with ethyl acetate (50 ml×2) The combined extracts were dried (MgSO4) and concentrated. The residual solids were recrystallized from ethyl acetate/hexane to afford 40 mg (23%) of the title compound as pale yellow solids.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[CH:15][C:14]([OH:22])=[CH:13][CH:12]=3)=[O:5])[CH3:2].Br[C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][N:25]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[CH:15][C:14]([O:22][C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][N:25]=1)=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: Brc1ccc(Br)nc1
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(O)cc3c2c1COC
Product: CCOC(=O)c1ncc2[nH]c3ccc(Oc4ccc(Br)cn4)cc3c2c1COC

Procedure:
In analogy to Example 8 from 6-hydroxy-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester with 2,5-dibromopyridine, mp 210°-212° C.