Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=NNC(N)=O)[CH2:7][C@H:8]([NH:11][C:12](=[O:37])[CH2:13][N:14]([C:22](=[O:36])[C@@H:23]([NH:27][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:24]([CH3:26])[CH3:25])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:9]=[O:10])(C)(C)C.C(O)(C(F)(F)F)=[O:44]>C(Cl)Cl>[C:28]([NH:27][C@@H:23]([CH:24]([CH3:26])[CH3:25])[C:22]([N:14]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:13][C:12]([NH:11][C@H:8]([CH:9]=[O:10])[CH2:7][C:6]([OH:5])=[O:44])=[O:37])=[O:36])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C)Cc1ccccc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@H](C=O)CC(=O)O)Cc1ccccc1
Reaction time: 4 h

Procedure:
To a suspension of compound 705 (600 mg, 1.04 mmol) in CH2Cl2 (10 mL) was added TFA (4.0 mL) and the reaction allowed to stir for 4 hr. The reaction was concentrated in vacuo and the residue co-concentrated with toluene (3×). The residue was dissolved in MeOH (10 mL) and treated with HOAc (2.0 mL) followed by formaldehyde (2.0 mL). After stirring for 3 hr at rt, the reaction was concentrated in vacuo. Prep-HPLC provided 89 mg of compound 706: 1H NMR (500 MHz, CD3OD) 68.34-8.21 (m), 7.80-7.69 (m), 7.51-7.02 (m), 4.99-4.81 (m), 4.73-4.59 (m), 4.57-4.56 (m), 4.35-4.12 (m), 4.07-3.96 (m), 3.93-3.84 (m), 2.64-2.51 (m), 2.49-2.31 (m), 2.29-2.13 (m), 1.02-0.80 (m). ##STR85##
Reaction SMILES: O=[C:2]([C:8]1[S:9][C:10]2[CH2:16][CH2:15][CH2:14][CH2:13][C:11]=2[CH:12]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])(=O)C.[Na+].Cl.[NH2:23][OH:24]>C(O)C>[OH:24][N:23]=[C:2]([C:8]1[S:9][C:10]2[CH2:16][CH2:15][CH2:14][CH2:13][C:11]=2[CH:12]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(=O)c1cc2c(s1)CCCC2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=NO)c1cc2c(s1)CCCC2
Yield: 98.8 %

Procedure:
A solution of 14.0 g of ethyl α-oxo-α-(4,5,6,7-tetrahydro-2-benzothienyl)acetate in 300 ml of ethanol containing 5.31 g of sodium acetate and 6.50 g of hydroxylamine hydrochloride was heated at reflux for three hours. The reaction mixture was cooled and the solvent was removed by evaporation under reduced pressure to provide 14.7 g of ethyl α-hydroxyimino-α-(4,5,6,7-tetrahydro-2-benzothienyl)acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[N:27][CH:28]=[C:29]([CH:33]=2)[C:30](O)=[O:31])[N:21]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:30](=[O:31])[C:29]3[CH:33]=[C:25]([C:22]4[N:21]=[C:20]([C:19]([F:35])([F:34])[F:18])[O:24][N:23]=4)[CH:26]=[N:27][CH:28]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(CN)c1coc(-c2ccc(F)cc2)n1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Product: CC(C)(CNC(=O)c1cncc(-c2noc(C(F)(F)F)n2)c1)c1coc(-c2ccc(F)cc2)n1
Yield: 13 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and 5-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)-nicotinic acid as described in example 8 step 6 (19 mg, yield 13%). 1H NMR (400 MHz, MeOD) δ 9.38 (d, J=1.5 Hz, 1H), 9.17 (d, J=1.8 Hz, 1H), 8.84 (d, J=1.8 Hz, 1H), 8.09-8.05 (m, 2H), 7.78 (s, 1H), 7.25-7.20 (m, 2H), 3.68 (s, 2H), 1.42 (s, 6H). MS (ESI) m/z: Calculated for C22H17F4N5O3: 475.13. found: 476.2 (M+H)+.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:8][C@@H:7]([N:20]2[CH:27]=[C:26]([F:28])[C:24](N)=[N:23][C:21]2=[O:22])[C@H:6]1[F:29])(=[O:3])[CH3:2].C(O)(=[O:32])C>>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:8][C@@H:7]([N:20]2[CH:27]=[C:26]([F:28])[C:24](=[O:32])[NH:23][C:21]2=[O:22])[C@H:6]1[F:29])(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(=O)O[C@H]1[C@H](F)[C@H](n2cc(F)c(N)nc2=O)O[C@@H]1COC(=O)c1ccccc1
Product: CC(=O)O[C@H]1[C@H](F)[C@H](n2cc(F)c(=O)[nH]c2=O)O[C@@H]1COC(=O)c1ccccc1

Procedure:
A mixture of 1-(3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-fluorocytosine (650 mg) in 80% acetic acid (50 ml) is heated under reflux for 48 hours. After removal of the solvent in vacuo the residue is chromatographed over a column of silica gel G60 (22×2 cm) using CHCl3 :MeOH (30:1 v/v as the eluent. Each fraction is checked by tlc and the appropriate fractions are collected and evaporated in vacuo, and the residue is crystallized from ethanol to give pure 1-(3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-fluorouracil, 300 mg, m.p. 177°-179°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)/[CH:5]=[C:6]1/[C:7](=[O:23])[C:8]2[C:13]([CH2:14]/1)=[CH:12][C:11]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[C:10]([O:21][CH3:22])[CH:9]=2>CO.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=1)[CH2:5][CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:21][CH3:22])=[C:11]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[CH:12]=2)[C:7]1=[O:23]
Reactant: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cc(Cl)cc(C(F)(F)F)c1)C2=O
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1N1CCOCC1)CC(Cc1cc(Cl)cc(C(F)(F)F)c1)C2=O
Reaction time: 6 h

Procedure:
The 49 (30 mg, 0.068 mmol) was dissolved in methanol 20 mL, Pd/C 10 mg added and stirred under hydrogen balloon for 6 h. The reaction was filtered through celite bed and washed with excess methanol. The organic layer was concentrated to get the crude compound 50. The crude 50 was purified by flash chromatography using 100-200 mesh silica gel. The compound 2-(3-chloro-5-(trifluoromethyl)benzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 50 was eluted at 28% ethyl acetate in hexane as half white coloured solid. 1HNMR (400 MHz, CDCl3) δ ppm 7.43 (m, 3H), 7.18 (s, 1H), 6.82 (s, 1H), 3.90 (m, 3H), 3.87 (m, 4H), 3.37 (m, 1H), 3.17 (m, 4H), 3.09 (m, 1H), 2.96 (m, 1H), 2.70 (m, 2H); MS (ESI) m/z 440.0 (M+H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1.[OH:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46][C:47](=[O:49])[CH3:48])=[CH:42][CH:41]=1.[C:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][CH:60](O)[CH2:59][CH2:58]1)=[O:56])([CH3:53])([CH3:52])[CH3:51]>O1CCCC1>[C:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][CH:60]([O:39][C:40]2[CH:41]=[CH:42][C:43]([CH2:46][C:47](=[O:49])[CH3:48])=[CH:44][CH:45]=2)[CH2:59][CH2:58]1)=[O:56])([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(=O)Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)Cc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
A solution of triphenylphosphine (18.5 g, 70.6 mmol) and 40% DEAD in toluene (12.3 g, 70.6 mmol) in 125.0 mL of tetrahydrofuran was cooled to 0° C. under N2 as a solution of 1-(4-hydroxy-phenyl)-propan-2-one (6.54 g, 43.6 mmol) and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (10.7 g, 53.2 mmol) in 125.0 mL of tetrahydrofuran was added dropwise via addition funnel. After stirred at rt overnight, the solvent was evaporated. The residue was stirred in hexane/EtOAc, the solid formed was filtered. The hexane/EtOAC solution was concentrated and purified by ISCO graduate chromatography (hexane-20% EtOAc in hexane) to give 4-[4-[2-oxo-propyl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (8.52 g, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:13]C)[C:10]([CH3:12])([CH3:11])O2)=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:13])[C:10]([CH3:11])([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH3:12])=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: COC1(c2ccc(Cl)cc2)OC1(C)C
Product: CC(C)(C(=O)c1ccc(Cl)cc1)N1CCOCC1

Procedure:
85.1 g (0.4 mol) of 2-(4-chlorophenyl)-3,3-dimethyl-2-methoxyoxirane and 139.4 g (1.6 mols) of morpholine are combined and warmed to reflux temperature. After 22 hours the mixture is cooled and morpholine is removed by distillation. The residue is taken up in ether, and the solution is extracted with dilute hydrochloric acid. The hydrochloric acid solution is rendered alkaline and extracted with ether. The ether solution is dried with Na2SO4 and concentrated. The residue is recrystallised from ethanol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:31])C(=O)C1>C(#N)C>[C:1]([O:5][C:6](=[O:23])[CH2:7][N:8]([C:9]1[CH:14]=[CH:13][C:12]([Br:31])=[C:11]([CH3:15])[N:10]=1)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1cccc(N(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cc1nc(N(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc1Br
Temperature: 40 °C
Reaction time: 3 h
Yield: 95.1 %

Procedure:
To a solution of tert-butyl[tert-butoxycarbonyl(6-methylpyridin-2-yl)amino]-acetate (477 mg, 1.48 mmol) obtained in Reference Example 1-(a) in acetonitrile (3 ml) was added NBS (398 mg, 2.24 mmol), followed by stirring at 40° C. for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=20:1→5:1 (V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (565 mg) as a white solid. (Yield: 95%)
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH3:25])[C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]=2)=[CH:5][CH:4]=1)=O.[S:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32].C(O)(=O)C.N1CCCCC1.C1(C)C=CC=CC=1>O>[O:32]=[C:27]1[NH:28][C:29](=[O:31])[C:30](=[CH:1][C:3]2[CH:4]=[CH:5][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH3:25])[C:17](=[O:24])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:10]=3)=[CH:7][CH:8]=2)[S:26]1
Reactant: CN(Cc1cccc(-c2ccc(C=O)cc2)c1)C(=O)c1ccccc1
Reactant: O=C1CSC(=O)N1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CN(Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)C(=O)c1ccccc1

Procedure:
1.6 g (4.6 mmol) of N-(4′-Formylbiphenyl-3-ylmethyl)-N-methylbenzamide, 610 mg (4.6 mmol) of 2,4-thiazolidine dione, 137 mg of piperidine acetate and 60 ml of toluene are introduced into a round-bottomed flask under a stream of nitrogen. The mixture is refluxed for five hours and the water formed is separated out using Dean-Stark apparatus. The reaction medium is cooled and the precipitate formed is filtered off and purified on a column of silica with an fluent mixture of heptane and ethyl acetate (70/30). After evaporation of the solvents, 1.4 g (70%) of the expected product are collected.
Reaction SMILES: [K+].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:14]=[C:15]([C:19]([C:21]3[C:29]4[CH:28]=[N:27][CH:26]=[N:25][C:24]=4[N:23]([CH2:30][C:31]([O-])=[O:32])[CH:22]=3)=[O:20])[CH:16]=[N:17][CH:18]=2)=[O:11])=[CH:5][CH:4]=1.Cl.[CH3:35][NH:36][CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>N1C=CC=CC=1.C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:14]=[C:15]([C:19]([C:21]3[C:29]4[CH:28]=[N:27][CH:26]=[N:25][C:24]=4[N:23]([CH2:30][C:31]([N:36]([CH3:37])[CH3:35])=[O:32])[CH:22]=3)=[O:20])[CH:16]=[N:17][CH:18]=2)=[O:11])=[CH:5][CH:4]=1
Reactant: CNC
Reactant: O=C([O-])Cn1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)C(=O)Cn1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncnc21
Temperature: 25 °C
Yield: 55 %

Procedure:
{5-[(5-{[(4-chlorophenyl)acetyl]amino}pyridin-3-yl)carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}acetic acid potassium salt (Example 307, 50 mg, 0.102 mmol) was added to a stirred solution of dimethyl amine HCl (12.5 mg, 0.153 mmol) and HATU (58.2 mg, 0.153 mmol) in pyridine (2 mL) and the resultant solution was stirred at 50° C. (reactivial) for 14 hours. The reaction was cooled to 25° C., diluted with DCM (5 mL) then quenched with saturated NaHCO3 (aq) (5 mL) and extracted with further DCM (3×5 mL). The organics were combined, washed with saturated brine (5 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. Purification by preparative HPLC gave the title compound in 55% yield, 26.6 mg.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[C:18]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13]([CH2:25][NH3+:26])=[CH:14]2.[Cl-].[C:28]1([N:34]2[C:38]([CH2:39][CH2:40][CH3:41])=[C:37]([C:42](Cl)=[O:43])[CH:36]=[N:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[CH3:24][O:23][C:21](=[O:22])[CH2:20][O:19][C:18]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:25][NH:26][C:42]([C:37]3[CH:36]=[N:35][N:34]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:38]=3[CH2:39][CH2:40][CH3:41])=[O:43])[CH:14]=2)[C:9]=1[Br:8]
Reactant: CCCc1c(C(=O)Cl)cnn1-c1ccccc1
Reactant: COC(=O)COc1ccc2cc(C[NH3+])ccc2c1Br
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1c(C(=O)NCc2ccc3c(Br)c(OCC(=O)OC)ccc3c2)cnn1-c1ccccc1
Reaction time: 17 h
Yield: 95 %

Procedure:
Triethylamine (0.192 mL, 1.38 mmol) was added under nitrogen to a mixture of 5-bromo-6-methoxycarbonylmethoxy-naphthalen-2-ylmethyl-ammonium; chloride (0.25 g, 0.69 mmol), prepared in the previous step, and 1-phenyl-5-propyl-1H-pyrazole-4-carbonyl chloride (0.17 g, 0.69 mmol) in 20 mL of methylene chloride at room temperature. The reaction stirred under nitrogen for 17 h. The reaction was diluted with methylene chloride, extracted two times with water, two times with 5% sodium bicarbonate, dried (MgSO4) and the solvent removed under reduced pressure to give (1-Bromo-6-{[(1-phenyl-5-propyl-1H-pyrazole-4-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-acetic acid methyl ester (0.347 g, 95%) as a white solid, mp 144-146° C.
Reaction SMILES: Br[C:2]1[C:3](=[O:13])[N:4]([CH2:8][CH2:9][CH2:10][CH2:11][Cl:12])[CH:5]=[CH:6][CH:7]=1.[CH3:14][C:15]1[N:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.N#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:12][CH2:11][CH2:10][CH2:9][CH2:8][N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:18]2[CH:19]=[N:20][C:15]([CH3:14])=[CH:16][CH:17]=2)[C:3]1=[O:13]
Reactant: O=c1c(Br)cccn1CCCCCl
Reactant: Cc1ccc(B(O)O)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: C1COCCO1
Product: Cc1ccc(-c2cccn(CCCCCl)c2=O)cn1
Reaction time: 18 h
Yield: 67 %

Procedure:
3-Bromo-1-(4-chlorobutyl)-2(1H)-pyridinone (400 mg, 1.51 mmol and then 627 mg, 4.54 mmol) was added to a solution of (6-methyl-3-pyridinyl)boronic acid (commercial Synchem OHG product list) (311 mg, 2.27 mmol) in dioxane (5K2CO3 ml). The mixture was degassed bubbling with N2 for 10′ and then triphenylphosphine (120 mg, 0.45 mmol) and palladium(II)acetate (34 mg, 0.15 mmol) were added. The reaction mixture was stirred at reflux for 5 h and then at room temperature for 18 hours. Further (6-methyl-3-pyridinyl)boronic acid (Synchem OHG product list) (60 mg, 0.43 mmol), triphenylphosphine (78 mg, 0.3 mmol) and palladium(II)acetate (22 mg, 0.1 mmol) were added and the reaction was stirred for additional 4 hours at 80° C. The reaction was cooled and concentrated by removing the solvent under reduced pressure. Water was added to the crude and the organic layers were extracted with DCM. The organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with a gradient of methanol in DCM (from 0 to 5%) to afford the title compound (280 mg, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([NH:13]CC2C=CC(OC)=CC=2)[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1>C(O)(C(F)(F)F)=O>[NH2:13][C:11]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=[C:2]([Cl:1])[CH:12]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1NCc1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cnc(Cl)cc1N
Temperature: 25 °C
Yield: 76 %

Procedure:
Heat a mixture of ethyl 6-chloro-4-(4-methoxybenzylamino)nicotinate (21 g, 65.6 mmol) and TFA (150 mL) at 50° C. overnight. Cool the mixture to RT, concentrate to dryness, dissolve the residue in EtOAc, wash with satd. NaHCO3 (2×), then brine (1×), dry over MgSO4, concentrate and purify via silica gel chromatography to give the title compound (10 g, 76%). 1H NMR (400 MHz, DMSO-d6): δ 8.49 (s, 1H), 7.47 (s, 2H), 6.76 (s, 1H), 4.29 (q, J=7.2 Hz, 2H), 1.31 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([OH:6])(=O)/[CH:2]=[CH:3]/[CH3:4].[C:7]1([NH:13][NH2:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCOCC>[CH3:4][CH:3]1[CH2:2][C:1](=[O:6])[N:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:14]1
Reactant: C/C=C/C(=O)O
Reactant: NNc1ccccc1
Solvent: CCOCC
Product: CC1CC(=O)N(c2ccccc2)N1
Temperature: 155 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
17.2 g of crotonic acid (MW 86.09, 0.2 mol) was added to 21.6 g of phenylhydrazine (MW 108.14, 0.2 mol), and the mixture was stirred for one hour while heating at 150-160° C. The reaction solution was dissolved in 500 ml of ether. The solution was washed twice with 100 ml of 10% aqueous solution of sodium hydroxide and once with 100 ml of water, followed by evaporation of the ether. The resulting solid was dried under reduced pressure and recrystallized from toluene to obtain 20.31 g of 3-methyl-1-phenyl-5-pyrazolidone (MW 176.0, 0.126 mol, 58%).
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH2:13][S:14][C:15]2[N:20]3[CH:21]=[CH:22][N:23]=[C:19]3[CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([N:7]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH2:13][S:14][C:15]1[N:20]2[CH:21]=[CH:22][N:23]=[C:19]2[CH:18]=[CH:17][CH:16]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: c1ccc(NCCOCCCSc2cccc3nccn23)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(CCOCCCSc1cccc2nccn12)c1ccccc1
Yield: 1.2 %

Procedure:
To a solution of 5-[3-[2-(phenylamino)ethyloxy]propylthio]imidazo[1,2-a]pyridine (1.034 g, 3.158 mmoles) and triethylamine (0.88 ml, 6.3 mmoles) in methylene chloride (30 ml) was added methanesulfonyl chloride (0.37 ml, 4.7 mmoles) with stirring under ice-cooling and the mixture was further stirred under ice-cooling for 10 minutes. The reaction mixture was washed with water and the aqueous layer was extracted with methylene chloride (30 ml×3). The methylene chloride layers were combined and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 16 mg of the desired product (brown oily product)
Reaction SMILES: C(OC(=O)NC1(C2C=CC(C3C(=O)[C:26]4[C:21](=[CH:22][C:23]([C:29]5[NH:30]N=CC=5)=CC=4)OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C.[C:41]([O:45][C:46](=[O:76])[NH:47][C:48]1([C:52]2[CH:57]=[CH:56][C:55]([C:58]3[C:67](=[O:68])[C:66]4[C:61](=[C:62](Br)[CH:63]=[CH:64][CH:65]=4)[O:60][C:59]=3[C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)=[CH:54][CH:53]=2)[CH2:51][CH2:50][CH2:49]1)([CH3:44])([CH3:43])[CH3:42].N1C=CC=C(B(O)O)C=1>CCOC(C)=O>[C:41]([O:45][C:46](=[O:76])[NH:47][C:48]1([C:52]2[CH:57]=[CH:56][C:55]([C:58]3[C:67](=[O:68])[C:66]4[C:61](=[C:62]([C:23]5[CH:29]=[N:30][CH:26]=[CH:21][CH:22]=5)[CH:63]=[CH:64][CH:65]=4)[O:60][C:59]=3[C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)=[CH:54][CH:53]=2)[CH2:51][CH2:50][CH2:49]1)([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Br)cccc4c3=O)cc2)CCC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(-c5ccn[nH]5)ccc4c3=O)cc2)CCC1
Agent: OB(O)c1cccnc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-c5cccnc5)cccc4c3=O)cc2)CCC1
Yield: 59 %

Procedure:
Following the procedure used to prepare (1-{4-[4-oxo-2-phenyl-7-(2H-pyrazol-3-yl)-4H-chromen-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester, {1-[4-(8-bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted with pyridine-3-boronic acid to give a crude residue which was insoluble in the EtOAc/aqueous work-up mixture. The solid was collected by filtration and air dried to give the title compound as a tan solid (44 mg, 59%). LCMS (Method B): RT=4.74 min, [M+H]+=545.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Br:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8]Br.Cl>C1C=CC=CC=1>[Br:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][N:2]([CH3:3])[CH3:1]
Reactant: BrCc1cccc(Br)c1
Reactant: CNC
Agent: Cl
Solvent: c1ccccc1
Product: CN(C)Cc1cccc(Br)c1
Yield: 79.9 %

Procedure:
Dimethylamine (51.4 g, 1.14 mol) was reacted with 3-bromobenzyl bromide (95 g, 0.38 mol) in benzene at 5° and the mixtue was acidified with hydrochloric acid and the mixture was extracted with aqueous 3N hydrochloric acid. The aqueous extracts were made alkaline with aqueous potassium hydroxide and the oil which separated out was distilled to give 3-bromo-N,N-dimethylbenzylamine (65 g, 80%) b.p. 118°/20 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[C:5]([N:7]([CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:11][CH:12]=C)[CH3:8])=[O:6].C[N+]1([O-])CC[O:29]CC1.OS([O-])=O.[Na+].I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.C(O)(C)(C)C.O.O=[Os](=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[C:5]([N:7]([CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:11][CH:12]=[O:29])[CH3:8])=[O:6]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(Cl)cc(Cl)c1)c1ccc(F)cc1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CC(C)=O
Solvent: O
Product: CN(C[C@@H](CC=O)c1ccc(F)cc1)C(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
3,5-Dichloro-N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methylbenzamide (210 mg, 0.57 mmol) was dissolved in a mixture of acetone (4 mL), t-butyl alcohol (2 mL) and water (1 mL). OsO4 (2.5% in t-butyl alcohol, 0.080 mL, 0.006 mmol) was added together with 4-methylmorpholine-4-oxide (296 mg, 2.52 mmol). The solution was stirred under nitrogen at room temperature overnight and then an aqueous solution of NaHSO3 (39%, 6 mL) was added. The mixture was stirred for 30 min, diluted with water (25 mL) and then extracted twice with CH2Cl2. The organic solution was dried over Na2SO4 and then the solvent was evaporated. The residue (256 mg) was dissolved in a mixture of THF (3 mL) and water (1 mL) and to the resultant solution was added sodium periodate (135 mg, 0.63 mmol). The mixture was stirred at room temperature overnight, diluted with water (25 mL) and then extracted twice CH2Cl2. The combined organic solutions were dried over Na2SO4 and then the solvent was evaporated. There was obtained 146 mg (69%) of 3,5-dichloro-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methylbenzamide as an oil. 1H NMR (400 MHz, CDCl3): 2.6-3.9 (cm, 8H), 6.4-7.4 (cm, 7H), 9.8 (s, 1H); LCMS: m/z 369 (M+1)+.