Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C:10]1[CH:30]=[CH:29][C:13]([C:14]([NH:16][C@H:17]([C:19]2[NH:23][C:22]3[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:21]=3[N:20]=2)[CH3:18])=[O:15])=[CH:12][C:11]=1[Cl:31])=[O:9].[CH2:32]([N:34]=[C:35]=[O:36])[CH3:33].C(N(CC)CC)C>O1CCCC1>[Cl:31][C:11]1[CH:12]=[C:13]([CH:29]=[CH:30][C:10]=1[C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[CH2:2][NH:1][C:35]([NH:34][CH2:32][CH3:33])=[O:36])=[O:9])[C:14]([NH:16][C@H:17]([C:19]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:21]=2[N:20]=1)[CH3:18])=[O:15]
Reactant: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@@H]2CN)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)NC[C@H]1CCCN1C(=O)c1ccc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
200 mg (0.3 mmol) of 4-[(2R)-2-aminomethylpyrrolidin-1-ylcarbonyl]-3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]benzamide, 26 mg (0.36 mmol) of ethyl isocyanate, and 0.2 mL (1.2 mmol) of triethylamine are stirred for 16 hours at ambient temperature in 20 mL of tetrahydrofuran. Then the solvent is distilled off and the residue is chromatographed on silica gel, eluting with dichloromethane/ethanol (9:1). Yield: 140 mg (86%); Rf value: 0.38 (silica gel; dichloromethane/ethanol=9:1); C25H28Cl2N6O3 (531.44); mass spectrum: (M+H)+=531/533 (chlorine isotope) and (M−H)−=529/531 (chlorine isotope).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH:18]=[CH:17][C:7]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])=[C:6]([F:19])[CH:5]=1)[CH3:3].Cl[C:21]1[N:26]=[C:25]([N:27]2[C@@H:31]([CH:32]([CH3:34])[CH3:33])[CH2:30][O:29][C:28]2=[O:35])[CH:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH:11]1([NH:10][C:8](=[O:9])[C:7]2[CH:17]=[CH:18][C:4]([C@@H:2]([NH:1][C:21]3[N:26]=[C:25]([N:27]4[C@@H:31]([CH:32]([CH3:33])[CH3:34])[CH2:30][O:29][C:28]4=[O:35])[CH:24]=[CH:23][N:22]=3)[CH3:3])=[CH:5][C:6]=2[F:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Reactant: C[C@H](N)c1ccc(C(=O)NC2CCCCC2)c(F)c1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(C(=O)NC3CCCCC3)c(F)c2)n1
Temperature: 125 °C
Yield: 19.6 %

Procedure:
To (S)-4-(1-aminoethyl)-N-cyclohexyl-2-fluorobenzamide (16 mg, 0.061 mmol) was added (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (29.3 mg, 0.121 mmol), NMP (0.5 ml) and Hunig's Base (0.032 ml, 0.182 mmol). The reaction was heated at 125° C. for 4 hours or until done by LCMS. The reaction was let cool, 0.5 ml of NMP added, filtered, purified by prep LC and lyophilized to give 5.6 mg of N-cyclohexyl-2-fluoro-4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzamide as the TFA Salt. LCMS m/z 470.2 (M+H)+, Rt 0.83 min.
Reaction SMILES: [I:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7](Cl)=[O:8].CCN(C(C)C)C(C)C.[F:19][C:20]([F:24])([F:23])[CH2:21][NH2:22]>O1CCCC1>[I:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]([NH:22][CH2:21][C:20]([F:24])([F:23])[F:19])=[O:8]
Reactant: NCC(F)(F)F
Reactant: O=C(Cl)c1ccoc1I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NCC(F)(F)F)c1ccoc1I
Reaction time: 1 h
Yield: 52.6 %

Procedure:
To a stirred solution of 2-iodofuran-3-carbonyl chloride (6.69 g, 26.1 mmol) in anhydrous tetrahydrofuran (120 ml) was added DIPEA (9.11 ml, 52.2 mmol) followed by 2,2,2-trifluoroethanamine (2.08 ml, 26.1 mmol) and the solution stirred for 1 h. The mixture was concentrated in vacuo. The residue was partitioned between 2M hydrochloric acid (aq) solution (100 ml) and dichloromethane (100 ml). The aqueous layer was separated and extracted with dichloromethane (2×100 ml). The combined organic layers were dried (phase separator) and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (gradient 0-50% ethyl acetate in cyclohexane) to afford the title compound (4.38 g, 53%). LCMS RT=0.98 min, M+H+=319.9.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:37][O:38][C:39]1[CH:45]=[C:44]([N:46]2[CH2:51][CH2:50][CH:49]([N:52]3[CH2:57][CH2:56][N:55]([S:58]([CH3:61])(=[O:60])=[O:59])[CH2:54][CH2:53]3)[CH2:48][CH2:47]2)[CH:43]=[CH:42][C:40]=1[NH2:41].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:41][C:40]3[CH:42]=[CH:43][C:44]([N:46]4[CH2:51][CH2:50][CH:49]([N:52]5[CH2:57][CH2:56][N:55]([S:58]([CH3:61])(=[O:60])=[O:59])[CH2:54][CH2:53]5)[CH2:48][CH2:47]4)=[CH:45][C:39]=3[O:38][CH3:37])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Nc3ccc(N4CCC(N5CCN(S(C)(=O)=O)CC5)CC4)cc3OC)n2)cc1C(=O)Nc1c(F)cccc1F
Temperature: 175 °C
Yield: 39.4 %

Procedure:
A mixture of 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (0.10 g, 0.20 mmol), 2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (Example 58, Step B) (0.073 g, 0.20 mmol) and para-toluenesulfonic acid (0.090 g, 0.47 mmol) in i-PrOH (5 mL) was heated in a microwave at 175° C. for 25 min. The reaction mixture was concentrated onto silica gel and purified by flash chromatography. Recrystallization from DCM and diethyl ether afforded N-(2,6-difluorophenyl)-2-(ethyloxy)-5-(3-{2-[(2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}-imidazo[1,2-a]pyridin-2-yl)benzamide (0.066 g, 40%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.76 (s, 1H), 9.37 (br. s., 1H), 8.45 (s, 1H), 8.21 (d, J=5.2 Hz, 1H), 8.06 (d, J=1.5 Hz, 1H), 7.65-7.81 (m, 2H), 7.35-7.50 (m, 3H), 7.28 (d, J=8.6 Hz, 1H), 7.16-7.25 (m, 2H), 6.88-7.02 (m, 1H), 6.69 (d, J=2.3 Hz, 1H), 6.46-6.61 (m, 2H), 4.22-4.33 (m, 2H), 3.81 (s, 3H), 3.71-3.79 (m, 2H), 3.03-3.15 (m, 4H), 2.87 (s, 3H), 2.64-2.73 (m, 2H), 2.58-2.64 (m, 4H), 2.38-2.46 (m, 1H), 1.80-1.89 (m, 2H), 1.50-1.62 (m, 2H), 1.44 (t, J=6.9 Hz, 3H). MS (M+H, ES+) 838.
Reaction SMILES: [NH2:1][NH2:2].[CH2:3]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)[CH2:4][CH:5]=[CH2:6].ClCCl>CO>[CH2:3]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[N:1][N:2]=[CH:11][C:10]2[CH:13]=[CH:14][C:7]([CH2:3][CH2:4][CH:5]=[CH2:6])=[CH:8][CH:9]=2)=[CH:9][CH:8]=1)[CH2:4][CH:5]=[CH2:6]
Reactant: NN
Reactant: C=CCCc1ccc(C=O)cc1
Solvent: CO
Solvent: ClCCl
Product: C=CCCc1ccc(C=NN=Cc2ccc(CCC=C)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8.4 g of a monohydrate of hydrazine and 45 g of 4-(3-butenyl)benzaldehyde were dissolved in 80 ml of methanol. The mixture was stirred at room temperature for 2 hours. To the mixture was then added 150 ml of dichloromethane. The mixture was then washed with saturated aqueous solution of sodium bicarbonate twice. The mixture was then dehydrated and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The resulting crude reaction product was purified through basic alumina column chromatography, and then recrystallized from methanol to obtain 42 g of 1,2-bis[4-(3-butenyl)benzylidene]hydrazine. The compound thus obtained had a melting point of 57° C. and exhibited nematic phase up to 116° C.
Reaction SMILES: [CH2:1]([C:5]1[C:13]([C:14]([C:16]2[CH:23]=[CH:22]C=C[C:17]=2[C:18]#N)=[O:15])=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)O.[C:29]([OH:32])(=[O:31])[CH3:30]>O>[CH2:1]([C:5]1[C:13]([C:14]([C:16]2[CH:23]=[CH:22][C:30]([C:29]([OH:32])=[O:31])=[CH:18][CH:17]=2)=[O:15])=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn2ccccc2c1C(=O)c1ccccc1C#N
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCc1nn2ccccc2c1C(=O)c1ccc(C(=O)O)cc1

Procedure:
A mixture of 845 mg of the product of Example 2 and 15 ml of a mixture in equal proportions of sulfuric acid, acetic acid and water was refluxed for 2 hours and the mixture was cooled down, taken up in water, filtered, washed with water and dried at 80° C. under reduced pressure.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C@H:15]1[CH2:20][CH2:19][C@@H:18]([CH2:21][N:22]2[C:26]3=[N:27][C:28]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([S:39](=[O:42])(=[O:41])[NH2:40])[CH:33]=4)=[N:29][CH:30]=[C:25]3[CH:24]=[N:23]2)[CH2:17][CH2:16]1)(C)(C)C>C(Cl)Cl>[NH2:14][C@@H:15]1[CH2:16][CH2:17][C@H:18]([CH2:21][N:22]2[C:26]3=[N:27][C:28]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([S:39]([NH2:40])(=[O:42])=[O:41])[CH:33]=4)=[N:29][CH:30]=[C:25]3[CH:24]=[N:23]2)[CH2:19][CH2:20]1
Reactant: Cc1ccc(Nc2ncc3cnn(C[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c3n2)cc1S(N)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(Nc2ncc3cnn(C[C@H]4CC[C@@H](N)CC4)c3n2)cc1S(N)(=O)=O
Reaction time: 2 h

Procedure:
TFA (1.0 mL, 13 mmol) was added drop-wise over about 1 min to a 100 mL round-bottomed flask containing a solution of tert-butyl-cis-4-((6-(4-methyl-3-sulfamoylphenylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate (0.55 g, 1.1 mmol, Example #B.1.1) in DCM (5 mL) at ambient temperature. The reaction mixture was allowed to stir for about 2 h then concentrated under reduced pressure. The crude product was purified by RP-HPLC (Table 2, Method b) to give 5-(1-((cis-4-aminocyclohexyl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-2-methylbenzenesulfonamide (0.435 g. 95%) as a white solid. LC/MS (Table 2, Method a) Rt=1.39 min; MS m/z: 414 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:8]2[CH2:7][CH2:6][O:5][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:21]([C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[F:18])=[O:22])=[N:15][CH:16]=2)=[CH:9][C:8]2[CH2:7][CH2:6][O:5][C:4]=2[CH:3]=1
Reactant: O=C(Cl)c1ccccc1F
Reactant: Nc1ccc(-c2cc3c(cc2Cl)OCC3)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(-c2cc3c(cc2Cl)OCC3)cn1)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
To a solution of 5-(6-chloro-2,3-dihydrobenzo[3,4-b]furan-5-yl)-2-pyridylamine (144) (19 mg, 0.045 mmol) in 1 ml DCM was added 2-fluorobenzoyl chloride (16 μl, 3 eq) followed by addition of DIEA (39 μl). The resulting solution was stirred at r.t. for overnight. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (100 μl) at r.t. for 2 h and before worked up with EA/aq. NaHCO3. Prep HPLC purification furnished N-[5-(6-chloro(2,3-dihydrobenzo[3,4-b]furan-5-yl))(2-pyridyl)](2-fluorophenyl)carboxamide (146) (7.6 mg, yield: 45.8%, purity>95%) as white solid.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]2)=[N:6][CH:7]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[CH:28])=[N:25][CH:26]=2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[C:28][C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]4)=[N:6][CH:7]=3)=[N:25][CH:26]=2)=[CH:19][CH:20]=1
Reactant: O[C@@H]1CCN(c2ccc(I)cn2)C1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: O[C@@H]1CCN(c2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cn2)C1

Procedure:
Prepared according to general working method I from (R)-1-(5-iodo-pyridin-2-yl)-pyrrolidin-3-ol (1.30 g, 4.48 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (957 mg, 4.48 mmol).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.C(O)(C)C.C(=O)=O.[CH2:14]([O:21][C:22]([O:24][CH:25]1[CH2:34][CH2:33][C:32]2[N:31]=[CH:30][C:29]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:28](O)[C:27]=2[CH2:26]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:14]([O:21][C:22]([O:24][CH:25]1[CH2:34][CH2:33][C:32]2[N:31]=[CH:30][C:29]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:28]([Cl:4])[C:27]=2[CH2:26]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1cnc2c(c1O)CC(OC(=O)OCc1ccccc1)CC2
Agent: O=C=O
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: CCOC(=O)c1cnc2c(c1Cl)CC(OC(=O)OCc1ccccc1)CC2
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (1.82 g) is added to 100 mL of DMF dropwise under stirring and cooling (isopropanol-dry ice) maintaining the temperature below -20°. Stirring is continued for 30 minutes at the same temperature. To the mixture, 2.66 g of ethyl 6-benzyloxycarbonyloxy-4-hydroxy-5,6,7,8-tetrahydroquinoline-3-carboxylate is added in one portion, and stirring is continued for 2 hours at -30° to -20°, then at room temperature overnight. The reaction mixture is evaporated to dryness and the residue is taken up in CH2Cl2, washed with saturated NaHCO3, dried (MgSO4) and evaporated to leave an oil which is purified by flash chromatography on a silica gel column obtaining ethyl 6-benzyloxycarbonyloxy-4-chloro-5,6,7,8-tetrahydroquinoline-3-carboxylate.
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7](=[O:11])[NH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].Br[CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17]>CN(C=O)C>[Br:1][C:2]1[C:6]2[C:7](=[O:11])[NH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:3]=1
Reactant: CCC(Br)CC
Reactant: O=c1[nH]ccc2[nH]cc(Br)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(CC)n1cc(Br)c2c(=O)[nH]ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.8 %

Procedure:
To a solution of 3-bromo-1,5-dihydro-4H-pyrrolo[3,2-c]pyridin-4-one (1.00 g) in DMF (30 mL) was added sodium hydride (60% dispersion in mineral oil, 0.207 g), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 3-bromopentane (0.851 g), and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate to ethyl acetate) to give the title compound (90.5 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5](Br)[C:6]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])=O)[CH3:2].[C:19]([NH2:22])(=[S:21])[CH3:20]>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH3:16])=[C:8]([C:6]2[N:22]=[C:19]([CH3:20])[S:21][C:5]=2[C:4]([O:3][CH2:1][CH3:2])=[O:18])[CH:13]=1
Reactant: CC(N)=S
Reactant: CCOC(=O)C(Br)C(=O)c1cc(Cl)ccc1OC
Product: CCOC(=O)c1sc(C)nc1-c1cc(Cl)ccc1OC

Procedure:
Using 2-bromo-3-(5-chloro-2-methoxy-phenyl)-3-oxo-propionic acid ethyl ester and thioacetamide, the title compound was prepared following the synthetic procedures described for ethyl 2-amino-4-(5-chloro-2-methoxyphenyl)thiazole-5-carboxylate with additional purification by flash chromatography on silica gel (50 to 100% DCM in cyclohexane) to give ethyl 4-(5-chloro-2-methoxyphenyl)-2-methylthiazole-5-carboxylate. LCMS (ESI) m+H=321.4; 1H NMR (400 MHz, CDCl3): δ 7.38 (d, 1H); 7.33 (dd, 1H); 6.87 (d, 1H); 4.20 (q, 2H); 3.75 (s, 3H); 2.76 (s, 3H); 1.20 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[Br:10][CH:11]([CH2:17][Br:18])[C:12]([N:14]=[C:15]=[O:16])=[O:13]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:15]([NH:14][C:12](=[O:13])[CH:11]([Br:10])[CH2:17][Br:18])=[O:16])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C=NC(=O)C(Br)CBr
Solvent: c1ccccc1
Product: O=C(NC(=O)C(Br)CBr)Nc1ccc(Cl)c(Cl)c1
Temperature: 5 °C

Procedure:
16 g of 3,4-dichloroaniline are dissolved in 200 ml of dry benzene and a solution of 26.0 g of 2,3-dibromopropionyl isocyanate in 50 ml of benzene is added dropwise with cooling at 5° C. The urea formed is immediately precipitated in crystalline form. After stirring for 3 hours at 20° C., the reaction mixture is diluted with the same volume of petroleum ether, filtered and dried. Yield: 39.0 g, m.p: 174° - 175° C.
Reaction SMILES: [C:1](/[C:3](/[CH3:11])=[C:4](\[O-])/[C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:2].[K+].FC(F)(F)C(O)=O.Cl.Cl.[CH2:22]([O:24][C:25]1[CH:33]=[C:32]([F:34])[C:28]([CH2:29][NH:30][NH2:31])=[C:27]([F:35])[CH:26]=1)[CH3:23]>O1CCOCC1>[NH2:2][C:1]1[N:30]([CH2:29][C:28]2[C:27]([F:35])=[CH:26][C:25]([O:24][CH2:22][CH3:23])=[CH:33][C:32]=2[F:34])[N:31]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]=1[CH3:11]
Reactant: CCOc1cc(F)c(CNN)c(F)c1
Reactant: CCOC(=O)/C([O-])=C(\C)C#N
Agent: Cl
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CCOC(=O)c1nn(Cc2c(F)cc(OCC)cc2F)c(N)c1C
Reaction time: 0.17 h

Procedure:
2.01 g potassium (2Z)-3-cyano-1-ethoxy-1-oxobut-2-en-2-olate (10.9 mmol, 1.0 eq.) were dissolved in dioxane at rt and 1.34 mL trifluoroacetic acid (17.4 mmol, 1.6 eq.) were added within 2 minutes. The slurry was stirred for 10 minutes and 3.00 g (4-ethoxy-2,6-difluorobenzyl)hydrazine dihydrochloride (10.9 mmol, 1.0 eq.) were added. The reaction mixture was stirred at 130° C. for 3 hours. The resulting solid was filtered off and washed rinsed with dioxane. The filtrate was partitioned between ethyl acetate and water. The aqueous phase was washed with ethyl acetate three times. The collected organic solutions were washed with brine, dried over a silicon filter, concentrated in vacuo and purified by flash chromatography: 1.10 g (2.42 mmol, 22%) of a 71% pure target compound.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]3[CH2:27][CH2:26][CH2:25][O:24]3)=[CH:17][N:16]=1)=[O:14])[CH2:6]2)=C.C[CH:29]([OH:31])C.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O>[CH:29]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]3[CH2:27][CH2:26][CH2:25][O:24]3)=[CH:17][N:16]=1)=[O:14])[CH2:6]2)=[O:31]
Reactant: C=Cc1ccc2c(c1)C[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cn1)C2
Reactant: CC(C)O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: O=Cc1ccc2c(c1)C[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cn1)C2
Reaction time: 3 h

Procedure:
A mixture of N-((R)-5-vinylindan-2-yl)-5-[(S)-1-(tetrahydrofuran-2-yl)methoxy]pyridine-2-carboxamide (0.60 g) and 2-propanol (5 ml) was admixed with a mixture of sodium periodate (0.775 g) and water (3 ml). Osmium(VIII) oxide (solution in tert-butanol; 16.7 mg) was added and the mixture was stirred vigorously for 3 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. This afforded the product with the molecular weight of 366.42 (C21H22N2O4); MS (ESI): 367 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH:25]1[C:30]([OH:31])=[CH:29][CH:28]=[C:27]([CH3:32])[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:5]2[N:6]([C:8]3[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=3)[CH:7]=[C:3]([CH2:2][O:31][C:30]3[CH:25]=[CH:26][C:27]([CH3:32])=[CH:28][CH:29]=3)[N:4]=2)=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)c1ccc(-n2cc(CCl)nc2-c2ccc(Cl)cc2)cc1
Reactant: Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2cn(-c3ccc(S(C)(=O)=O)cc3)c(-c3ccc(Cl)cc3)n2)cc1
Reaction time: 6 h
Yield: 81.4 %

Procedure:
A mixture of 122 mg (0.32 mmole) of 4-chloromethyl-2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole (Step 1), p-cresol (69 mg, 0.64 mmole), and potassium carbonate (110 mg, 0.8 mmole) in 5 ml of dimethylformamide was stirred at 85–90° C. for 6 hours. After cooling, the mixture was partitioned between ethyl acetate and aqueous sodium chloride, and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue over silica gel using mixtures of ethyl acetate and hexane gave 2-(4-chlorophenyl)-4-[(4-methylphenoxy)methyl]-1-[4-(methylsulfonyl)phenyl]-1H-imidazole as a pure white solid (118 mg): m.p. (DSC) 193° C. Anal. Calc'd. for C24H21ClN2O3S (Mw 452.96): C, 63.64; H, 4.67; N, 6.18. Found: C, 63.42; H, 4.64; N, 5.79.
Reaction SMILES: [C:1]1([C:6]2[O:7][C:8]3[C:9](=[C:11]([C:23]#[N:24])[C:12]([CH3:22])=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:14]=3F)[N:10]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1.C(N(CC)CC)C.[CH3:32][N:33]([CH3:39])[C@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1>CS(C)=O>[C:1]1([C:6]2[O:7][C:8]3[C:9](=[C:11]([C:23]#[N:24])[C:12]([CH3:22])=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:14]=3[N:36]3[CH2:37][CH2:38][C@H:34]([N:33]([CH3:39])[CH3:32])[CH2:35]3)[N:10]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C3=CCCC3)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(C3=CCCC3)nc2c1C#N
Temperature: 95 °C
Reaction time: 4 h
Yield: 17.9 %

Procedure:
2-(Cyclopent-1-en-1-yl)-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-214) (145 mg, 0.46 mmol) was dissolved in dimethyl sulfoxide (5 ml), then triethylamine (130 μl, 0.91 mmol) and (3S)-3-(dimethylamino)pyrrolidine (121 μl, 0.96 mmol) were added, followed by stirring at 95° C. for 4 hours. After cooled, this was concentrated under reduced pressure, diluted with chloroform, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was subjected to preparative silica gel column chromatography. The eluate with chloroform/methanol (5:1, y/v) gave the entitled compound (34 mg, 18%) as a pale yellow amorphous substance.
Reaction SMILES: [O:1]=[C:2]1[O:6][CH:5]([C:7]([OH:9])=O)[CH2:4][CH2:3]1.S(Cl)([Cl:12])=O>>[O:1]=[C:2]1[O:6][CH:5]([C:7]([Cl:12])=[O:9])[CH2:4][CH2:3]1
Reactant: O=C1CCC(C(=O)O)O1
Reactant: O=S(Cl)Cl
Product: O=C1CCC(C(=O)Cl)O1

Procedure:
A mixture of 4.9 g of 5-oxotetrahydrofuran-2-carboxylic acid and 5.5 ml of thionyl chloride was subjected to reflux for 2 hours. Thionyl chloride was then distilled off under reduced pressure to leave 5-oxotetrahydrofuran-2-carbonyl chloride. This product was mixed with 5.0 g of 2-aminobenzophenone, 200 ml of ethyl acetate and 200 ml of a saturated aqueous solution of sodium hydrogencarbonate, which was stirred for one hour at room temperature. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (eluent, hexane:ethyl acetate=2:1) to give 2-(5-oxotetrahydrofuran-2-carbonyl)aminobenzophenone (6.5 g) as needles, m.p. 100° C.-102° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5]Br.[CH2:11]([O:13][P:14]([O:18]CC)[O:15][CH2:16][CH3:17])[CH3:12]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][P:14](=[O:18])([O:15][CH2:16][CH3:17])[O:13][CH2:11][CH3:12]
Reactant: CCOP(OCC)OCC
Reactant: Fc1cc(F)cc(CBr)c1
Product: CCOP(=O)(Cc1cc(F)cc(F)c1)OCC
Temperature: 135 °C
Reaction time: 8 h

Procedure:
3,5-difluorobenzyl bromide (3.0 mL, 23.2 mmol) was combined with triethylphosphite (9.1 mL, 53.3 mmol) and the mixture heated and stirred at 135° C. overnight. The mixture was put under hi-vacuum and heated to 70° C. for 12 hours. The final product was a clear oil (5.78 g, 94% yield). 1H NMR (400.14 MHz, CDCl3) δ 6.83 (m, 2H), 6.71 (dt, J=9.00, 2.28 Hz), 4.06 (m, 4H), 3.12 (d, J=21.94 Hz, 2H), 1.28 (t, J=7.09 Hz, 6H). 31P{1H} NMR (161.97 MHz, CDCl3): δ 25.22.