Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:10]=[N:11][CH:12]=[N:13][CH:14]=2)[CH:5]=[N:6][CH:7]=1.[C:15](=[O:22])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[NH2:16].CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[N:11]1[CH:10]=[C:9]([O:8][C:4]2[CH:3]=[C:2]([NH:16][C:15](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:7]=[N:6][CH:5]=2)[CH:14]=[N:13][CH:12]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: Brc1cncc(Oc2cncnc2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1cncc(Oc2cncnc2)c1
Yield: 95.4 %

Procedure:
Compound 5 (1.0 g, 4.0 mmol, 1.0 eq), tert-Butyl carbamate (560 mg, 4.78 mmol, 1.20 eq), tris(dibenzylideneacetone) dipalladium-chloroform adduct (120 mg, 0.116 mmol, 0.0300 eq), sodium tert-butoxide (530 mg, 5.52 mmol, 1.40 eq), and 2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (180 mg, 0.424 mmol, 0.0900 eq) stirred in toluene (15 mL) at rt overnight. The mixture was filtered through celite and washed with 5% MeOH in CH2Cl2. The filtrate was collected and concentrated in vacuo to afford 1.1 g (100%) of the title compound as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 9.05 (s, 1H), 8.72 (s, 2H), 8.45 (d, J=1.7 Hz, 1H), 8.10 (t, J=2.5 Hz, 1H), 7.69 (s, 1H), 1.45 (s, 9H); ES-MS [M+1]+: 289.1.
Reaction SMILES: S1(CCCC1)(=O)=O.C[C:9]([O:11][CH2:12][C:13]1[CH2:22][S:21][C@@H:16]2[C@H:17]([NH2:20])[C:18](=[O:19])[N:15]2[C:14]=1[C:23]([OH:25])=[O:24])=O.S(=O)(=O)(O)O>CO>[NH2:20][CH:17]1[C:18](=[O:19])[N:15]2[C:14]([C:23]([OH:25])=[O:24])=[C:13]([CH2:12][O:11][CH3:9])[CH2:22][S:21][C@H:16]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=S(=O)(O)O
Solvent: O=S1(=O)CCCC1
Solvent: CO
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 30 °C

Procedure:
To 10 ml of sulfolane were added 1.41 g of 7-ACA, 1.96 g of ferric chloride, 0.29 ml of concentrated sulfuric acid and 0.45 ml of methanol. The mixture was heated at 30° C. for 2 hours to advance a reaction. After completion of the reaction, substantially the same procedure as in Example 1 was repeated, to thereby obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.71 g. The yield of the desired product was 56%.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[CH2:6]([C:13]1([OH:19])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>C(OCC)C.C(Cl)Cl>[CH2:6]([C:13]1([OH:19])[CH2:18][CH2:17][N:16]([CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: ClCC1CO1
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: OC(CCl)CN1CCC(O)(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.4 %

Procedure:
(rac)-Epichlorohydrin (2.5 ml, 31 mmol) dissolved in diethylether (10 ml) was added at room temperature to a suspension of 4-benzyl-4-hydroxy-piperidine (6.0 g, 31 mmol) in diethylether (40 ml) and CH2Cl2 (40 ml). The mixture was stirred overnight at room temperature, water (50 ml) and CH2Cl2 (50 ml) were added and the organic phase was separated. The water phase was extracted with CH2Cl2, the organic phases were pooled, dried with Na2SO4 and the solvents evaporated. The residue was chromatographed over silica gel (ethyl acetate-MeOH, 9:1) to give 4-benzyl-1-(3-chloro-2-hydroxy-propyl)-piperidin-4-ol (1.0 g, 13%) as a colorless solid, m.p. 194°-195° C. and MS: m/e=(M+H+).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:15]([OH:17])=O)[CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14])(=[O:3])[CH3:2]>C1(C)C(C)=CC=CC=1>[C:1]([NH:4][CH:5]1[C:15](=[O:17])[NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H](CSc1ccccc1N)C(=O)O
Solvent: Cc1ccccc1C
Product: CC(=O)NC1CSc2ccccc2NC1=O
Yield: 71.7 %

Procedure:
1.2 g of N-acetyl-S-(2-aminophenyl)cysteine was dissolved in 20 ml of xylene and the resulting solution was heated under reflux for 2 hours. After cooling, the precipitated crystals were separated and washed with methanol to obtain 0.8 g of the desired compound, or 3-acetylamino-2,3-dihydro-1,5-benzothiazepin-4(5H)-one. Its melting point was 283°-286° C.
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=C(C2C=CC(C)=CC=2)O[C:7]=1[C:8]1[CH:13]=CC=C[CH:9]=1.CC(C)C(=O)C(=NO)C.[F:30][C:31]([F:41])([F:40])[C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][CH:33]=1>>[I:1][CH2:2][C:3]1[N:4]=[C:36]([C:35]2[CH:38]=[CH:39][C:32]([C:31]([F:40])([F:41])[F:30])=[CH:33][CH:34]=2)[O:37][C:7]=1[CH:8]([CH3:13])[CH3:9]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Agent: CC(=NO)C(=O)C(C)C
Product: CC(C)c1oc(-c2ccc(C(F)(F)F)cc2)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, 4-methylpentane-2,3-dione-2-oxime and 4-trifluoromethylbenzaldehyde gave 4-iodomethyl-5-isopropyl-2-(4-trifluoromethylphenyl)-oxazole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:21][CH:20]([CH3:22])[N:11]2[C:12]3[C:13](Br)=[CH:14][CH:15]=[CH:16][C:17]=3[CH:18]=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cu][C:24]#[N:25]>[C-]#N.C([N+](CC)(CC)CC)C.O1CCOCC1.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].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]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]2[C:12]3[C:17]([CH2:18][C:24]#[N:25])=[CH:16][CH:15]=[CH:14][C:13]=3[CH:22]=[C:20]2[CH2:21]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC1CN(C(=O)OC(C)(C)C)Cc2cc3cccc(Br)c3n21
Reactant: N#C[Cu]
Agent: [Fe+2]
Agent: [Pd]
Agent: CC[N+](CC)(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCn2c(cc3cccc(CC#N)c32)C1

Procedure:
A suspension of 0.30 g (0.82 mmol) 6-bromo-4-methyl-3,4-dihydro-1H-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester, 0.29 g (3.3 mmol) copper(I)cyanide, 34.0 mg (0.030 mmol) tris(dibenzylideneacetone)dipalladium(0), 72.9 mg (0.013 mmol) 1,1′-bis(diphenylphosphino)ferrocene and 128.3 mg (0.82 mmol) tetraethylammonium cyanide in 6 ml dioxane was heated under reflux for 18 h. The reaction mixture was filtered, diluted with ethyl acetate and extracted with 10% aqueous citric acid, 10% aqueous sodium bicarbonate solution and brine. After drying over magnesium sulfate and filtration, the solvent was removed at a rotary evaporator and the residue was purified by chromatography on silica gel (0.032-0.063 mm) with n-hexane:ethyl acetate (9:1) as eluant to give the product as a light yellow foam. ISP-MS: m/e 312.2 ([M+H+]).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13][C:12]([C:22](O)=[O:23])=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:26][C@H:27]([C:36]([NH2:38])=[O:37])[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(NC(C)C)(C)C>CN(C)C=O>[C:36]([CH:27]([NH:26][C:22]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[C:15]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:23])[CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)(=[O:37])[NH2:38]
Reactant: O=C(O)c1ccc2[nH]c(-c3ccccc3)c(-c3ccccc3)c2c1
Reactant: NC(=O)[C@@H](N)CCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: NC(=O)C(CCc1ccccc1)NC(=O)c1ccc2[nH]c(-c3ccccc3)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
0.16 g (0.5 mmol) of 2,3-diphenyl-1H-indole-5-carboxylic acid (see process variant A) was dissolved at RT in 10 ml of dry dimethylformamide (DMF) and admixed successively with 0.11 g (0.5 mmol) of L-homophenyl-alaninamide hydrochloride, 0.16 g of TOTU (O-[(cyano(ethoxycarbonyl)-methylidene)amino-1,1,3,3-tetramethyl]uronium tetrafluoroborate) and 0.14 ml (1 mmol) of diisopropylamine. The reaction mixture was stirred at RT for 6 h and then concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The organic phase was washed successively with water, saturated sodium carbonate solution, water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. This gave N-(1-carbamoyl-3-phenylpropyl)-2,3-diphenyl-1H-indole-5-carboxamide of melting point 120° C. to 125° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.[F:10][C:11]1[C:16](B(O)O)=[CH:15][C:14]([Br:20])=[CH:13][N:12]=1>C(#N)C.[F-].[K+]>[Br:20][C:14]1[CH:15]=[C:16]([C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[CH:6][C:5]=2[NH2:8])[C:11]([F:10])=[N:12][CH:13]=1
Reactant: Nc1cnc(Cl)cc1I
Reactant: OB(O)c1cc(Br)cnc1F
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: Nc1cnc(Cl)cc1-c1cc(Br)cnc1F
Temperature: 80 °C
Yield: 48.6 %

Procedure:
A mixture of 6-chloro-4-iodo-pyridin-3-ylamine (2.37 g, 9.31 mmol), 2-fluoro-5-bromopyridine-3-boronic acid (2.64 g, 12.0 mmol) and 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.76 g, 0.93 mmol) in acetonitrile (35 mL) and 1N aqueous potassium fluoride solution (35 mL) was degassed with nitrogen for 20 minutes. The reaction mixture was heated at 80° C. for 3 h, allowed to cool to ambient temperature then partitioned between ethyl acetate (100 mL) and water (75 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The resultant solid residue was triturated using 1:1 DCM/methanol, collected by filtration, washed with diethyl ether and ethyl acetate to afford the title compound as a tan solid (1.37 g, 49%). The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (silica, 80 g column, ISCO, 0-40% ethyl acetate in pentane) to afford further title compound as a brown solid (0.73 g, 26%). 1H NMR (DMSO-Do, 300 MHz): 8.46 (dd, J=2.5, 1.3 Hz, 1H), 8.24 (dd, J=8.3, 2.5 Hz, 1H), 7.88 (s, 1H), 7.19 (s, 1H), 5.57 (s, 2H). LCMS (Method B): RT=3.21 min, M+H+=304.
Reaction SMILES: [CH3:1][N:2](C)[C:3]1[O:4][CH:5]([CH:9]([C:11]2[C:19]3[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH3:10])[C:6](=[O:8])[N:7]=1.CN>>[F:20][C:16]1[CH:15]=[C:14]2[C:19]([C:11]([CH:9]([CH:5]3[O:4][C:3]([NH:2][CH3:1])=[N:7][C:6]3=[O:8])[CH3:10])=[CH:12][NH:13]2)=[CH:18][CH:17]=1
Reactant: CC(c1c[nH]c2cc(F)ccc12)C1OC(N(C)C)=NC1=O
Agent: CN
Product: CNC1=NC(=O)C(C(C)c2c[nH]c3cc(F)ccc23)O1
Reaction time: 3 h
Yield: 78.5 %

Procedure:
2-Dimethylamino-5-[1-(6-fluoroindol-3-yl)ethyl]-2-oxazolin-4-one (340 mg) was dissolved into methylamine (5 ml) at −10° C. The mixture was stirred for 3 hours at the same temperature. The mixture was concentrated to give a residue, which was subjected to column chromatography. Elution with hexane-acetone (1:1) provided the titled compound (254 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:31])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]2[N:23]=[C:22]([NH2:24])[N:21]=[C:20]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:19]=2)=[CH:12][CH:11]=1>CO.[Pd]>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:31])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]2[N:23]=[C:22]([NH2:24])[N:21]=[C:20]([N:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)[N:19]=2)=[CH:12][CH:11]=1
Reactant: Nc1nc(C=Cc2ccc(C(=O)Nc3ccccc3N)cc2)nc(N2CCCCC2)n1
Agent: [Pd]
Solvent: CO
Product: Nc1nc(CCc2ccc(C(=O)Nc3ccccc3N)cc2)nc(N2CCCCC2)n1
Reaction time: 16 h
Yield: 55.8 %

Procedure:
To a solution of 223 (18 mg, 0.043 mmol) in MeOH (5 mL) was added 10% Pd/C (10 mg, 0.021 mmol). The reaction mixture was shaked under a pressure of H2 (40 psi) at room temperature for 16 h using an hydrogenation apparatus. Then, the reaction mixture was purged with N2, filtered through celite, and concentrated. The crude residue was then purified by flash chromatography on silica gel (MeOH/CH2Cl2: 2/98→4/96) to afford the title compound 224 (10 mg, 0.024 mmol, 56% yield). 1H NMR (300 MHz, CDCl3—CD3OD) δ (ppm): 7.82 (d, J=8.1 Hz, 2H), 7.35 (d, J=8.1 Hz, 2H), 7.08 (t, J=7.0 Hz, 1H), 6.89-6.79 (m, 2H), 7.80-6.90 (m, 1H), 3.76 (s, 4H), 3.13 (t, J=8.1 Hz, 2H), 2.88 (t, J=8.1 Hz, 2H), 1.90-1.40 (m, 10H).
Reaction SMILES: [OH-].[Na+].O.BrBr.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][C:12](C(N)=O)=[CH:11]2.[N:21]1C=CC=CC=1>>[NH2:21][C:12]1[CH:13]=[N:14][C:15]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:7][CH3:6])=[CH:17][CH:16]=2
Reactant: COc1ccc2ncc(C(N)=O)cc2c1
Reactant: c1ccncc1
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2ncc(N)cc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
104 kg of a 32% sodium hydroxide solution are added to 341 kg of water. The solution is cooled to 0° C. and 22.0 kg of bromine are introduced over 1.5 hours while maintaining the temperature at 0° C. The solution is stirred at this temperature for 1 hour, and then 409 kg of pyridine are introduced over 3 hours at 0° C. 26.5 kg of 6-methoxy-quinoline-3-carboxamide are then added over 50 minutes at 0° C. The reaction medium is kept at this temperature for 2 hours and then gradually heated to 60° C. over 1 hour. After maintaining the temperature at 60° C. for 6 hours, the reaction mass is cooled to 20° C. and separated by settling out. The aqueous phase (172 kg) is washed with pyridine (60 liters). The organic phases are pooled (820 kg) and concentrated to dryness under reduced pressure (100-150 mbar) at a maximum of 84° C. The residue is then taken up with 425 l of water and 43 l of ethanol. The suspension obtained is refluxed for 1 hour and then cooled. The product begins to precipitate at a temperature of 65° C. The medium is then cooled to 0-5° C., and kept at this temperature for 2 hours. The precipitate is filtered off, washed with cold water, and then dried at 50-55° C. under reduced pressure. 16.5 kg (72.3%) of 3-amino-6-methoxyquinoline are obtained in the form of a brown solid (HPLC titer=99.1%), having a melting point of 108-110° C. A second crop of 3.7 kg (13.1%) is obtained from the mother liquors (HPLC titer=98%).
Reaction SMILES: COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.CC([O-])(C)C.[Na+].[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH2:42].Cl[C:44]1[CH:63]=[CH:62][C:47]([O:48][C:49]2[C:54]([C:55]3[CH:60]=[CH:59][N:58]=[C:57]([CH3:61])[CH:56]=3)=[CH:53][CH:52]=[CH:51][N:50]=2)=[CH:46][CH:45]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:61][C:57]1[CH:56]=[C:55]([C:54]2[C:49]([O:48][C:47]3[CH:62]=[CH:63][C:44]([NH:42][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=4)=[CH:45][CH:46]=3)=[N:50][CH:51]=[CH:52][CH:53]=2)[CH:60]=[CH:59][N:58]=1
Reactant: Nc1ccccn1
Reactant: Cc1cc(-c2cccnc2Oc2ccc(Cl)cc2)ccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: Cc1cc(-c2cccnc2Oc2ccc(Nc3ccccn3)cc2)ccn1
Temperature: 100 °C

Procedure:
To a sealed tube, under nitrogen, was added Pd2(dba)3 (0.19 g, 0.21 mmol), S-phos (0.36 g, 0.84 mmol), sodium 2-methylpropan-2-olate (2.0 g, 21 mmol), pyridin-2-amine (0.95 g, 10 mmol), 2-(4-chlorophenoxy)-3-(2-methylpyridin-4-yl)pyridine (2.5 g, 8.4 mmol), and toluene (18 mL). Reaction mixture was heated to 100° C. overnight. The reaction mixture was directly purified by silica gel chromatography (0-100% EtOAc/hexane). Solid precipitate formed upon rotovap of rich cut. The solid was collected and rinsed with EtOAc to afford N-(4-(3-(2-methylpyridin-4-yl)pyridin-2-yloxy)phenyl)pyridin-2-amine. MS (ESI, pos. ion) m/z: 355.1 (M+1). IC50 (uM) 0.003343.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:24][CH2:25][CH3:26])=[C:6]([CH:13]([OH:23])[CH2:14][NH:15][C:16](=O)[O:17]C(C)(C)C)[C:7]([C:11]#[N:12])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].Cl.C(N(CC)C(C)C)(C)C.C1N=CN(C(N2C=NC=C2)=O)C=1>O1CCOCC1>[C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([C:11]#[N:12])=[C:6]([CH:13]2[O:23][C:16](=[O:17])[NH:15][CH2:14]2)[C:5]=1[O:24][CH2:25][CH3:26])(=[O:3])[CH3:2]
Reactant: CCOc1c(C(C)=O)cc(Cl)c(C#N)c1C(O)CNC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOc1c(C(C)=O)cc(Cl)c(C#N)c1C1CNC(=O)O1
Temperature: 70 °C

Procedure:
tert-Butyl [2-(3-acetyl-5-chloro-6-cyano-2-ethoxyphenyl)-2-hydroxyethyl]carbamate (290 mg, 0.76 mmol) (racemic mixture from step 2) was treated with 4.0 M hydrogen chloride in 1,4-dioxane (6.1 mL) for 15 minutes and the mixture was evaporated. The residue was dissolved in tetrahydrofuran (2.3 mL) and N,N-diisopropylethylamine (0.66 mL, 3.8 mmol). N,N-carbonyldiimidazole (250 mg, 1.5 mmol) was added and the reaction mixture was refluxed at 70° C. overnight. The reaction mixture was evaporated. Purification on silica gel using ethyl acetate in hexane (0-100%) gave the desired compound as a racemic mixture, 110 mg, 47%. LCMS calculated for C14H14ClN2O4(M+H)+: m/z=309.1; found: 309.1. 1H NMR (400 MHz, DMSO-d6): δ 8.00 (br s, 1 H), 7.93 (s, 1 H), 5.99 (m, 1 H), 3.89 (m, 1 H), 3.81 (m, 2 H), 3.52 (m, 1 H), 2.58 (s, 3 H), 1.23 (m, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[C:4]([CH3:11])[CH:3]=1.[NH2:12][C:13]1[O:14][CH:15]=[C:16]([CH3:18])[N:17]=1.C(Cl)Cl.CO>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:12][C:13]2[O:14][CH:15]=[C:16]([CH3:18])[N:17]=2)=[S:10])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1coc(N)n1
Reactant: Cc1cc(Cl)ccc1N=C=S
Solvent: ClCCl
Solvent: CC#N
Solvent: CO
Product: Cc1coc(NC(=S)Nc2ccc(Cl)cc2C)n1

Procedure:
Prepared using Method A from 4.04 g (22 mmol) of 4-chloro-2-methyl-phenyl isothiocyanate and 2.16 g (22 mmol) of 2-amino-4-methyloxazole to give 4.5 g of crude title compound. Pure title compound was obtained by flash chromatography (silica Merck 60, CH2Cl2—CH3OH, 19:1) and crystallization from CH3CN to give 2.12 g of the title compound as a yellow solid (72.5% yield, m.p. 214° C. with decomposition).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:10]2[N:14]=[CH:13][N:12]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[N:11]=2)=[C:5]([Br:9])[C:6]=1[C:7]#[N:8].C[Sn](C)(C)[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:33])[O:31][CH3:32])[CH:24]=1.[Cl-].[Li+]>O1CCOCC1.CN(C=O)C.C(Cl)Cl.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:9][C:5]1[C:6]([C:7]#[N:8])=[C:2]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:33])[O:31][CH3:32])[CH:24]=2)[S:3][C:4]=1[C:10]1[N:14]=[CH:13][N:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[N:11]=1
Reactant: COC(=O)Nc1cc([Sn](C)(C)C)ccn1
Reactant: N#Cc1c(Br)sc(-c2ncn(C3CCCCO3)n2)c1Br
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COC(=O)Nc1cc(-c2sc(-c3ncn(C4CCCCO4)n3)c(Br)c2C#N)ccn1
Temperature: 100 °C
Yield: 77.7 %

Procedure:
A mixture of 2,4-dibromo-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]thiophene-3-carbonitrile (1.27 g, 3.05 mmol), methyl [4-(trimethylstannyl)pyridin-2-yl]carbamate (0.960 g, 3.05 mmol), lithium chloride (0.388 g, 9.14 mmol), copper(I) iodide (0.174 g, 0.914 mmol) and tetrakis(triphenylphosphine)platinum (0) (0.190 g, 0.152 mmol) in anhydrous 1,4-dioxane (45 mL) was degassed by evacuation in vacuum and backfilling with N2 4 times, then heated to 100° C. under N2 for 8 hours, then cooled to room temperature. The suspension was filtered and washed with dioxane. The solid was suspended in 20% MeOH in DCM (300 mL), and washed with water (2×). The organic suspension was concentrated in a rotavapor to give a solid residue. The residue was stirred in DMF/DCM (10 mL/10 mL) at room temperature for 20 min, filtered and washed with DCM to give a solid product (1.16 g, yield 77.8%). LC/MS: (FA) ES+ 489, 491. 1H NMR (400 MHz, d4-MeOH/d-chloroform) δ 8.26-8.35 (m, 3H), 7.34 (m, 1H), 5.48 (m, 1H), 4.00 (m, 1H), 3.73 (s, 3H), 3.64-3.69 (m, 1H), 1.97-2.14 (m, 3H), 1.58-1.68 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])C(=O)[NH:6]2.[OH-:13].[Na+].OO>>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[C:3]=1[C:4]([OH:12])=[O:13]
Reactant: [OH-]
Reactant: O=C1Nc2cccc(Br)c2C1=O
Agent: OO
Agent: [Na+]
Product: Nc1cccc(Br)c1C(=O)O
Temperature: 80 °C
Reaction time: 1 h
Yield: 107.3 %

Procedure:
To 4-bromoindoline-2,3-dione (8.94 g, 39.6 mmol) was added 1.0 M sodium hydroxide (40 mL, 120 mmol) to give a dark brown mixture. The mixture was heated to 80° C. then 20% hydrogen peroxide (9 mL, 88 mmol) was added slowly over 15 min (caution: a strong exotherm was observed upon reagent addition). The mixture was then stirred at 80° C. for 1 h. After this time, the mixture was cooled in an ice bath to ˜10° C. and then concentrated to a residue. HCl was added cautiously to the residue until the pH of the mixture was 4-5. Once at the prescribed pH, the mixture was then concentrated to dryness and MeOH (150 ml) was added. The resulting suspension stirred for 15 min and then filtered. The filtrate was concentrated to dryness and dried under vacuum for 14 h to yield 2-amino-6-bromobenzoic acid (9.18 g) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.72 (1H, t, J=7.91 Hz), 6.60 (1H, dd, J=7.78, 1.00 Hz), 6.52 (1H, dd, J=7.91, 1.13 Hz). LCMS Method D: retention time 0.68 min, [M+1] 200.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[O:23]1[CH2:26][C:25](=O)[CH2:24]1.C([BH3-])#N.[Na+].C(Cl)Cl.C(OCC)C.CO>CO.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH:25]4[CH2:26][O:23][CH2:24]4)[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Nc2ccc(C3CCNCC3)cn2)c1=O
Reactant: O=C1COC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: Cn1cc(Br)cc(Nc2ccc(C3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 48 °C
Yield: 30.5 %

Procedure:
Following Example 214b, 264b (450 mg, 1.25 mmol), oxetan-3-one (800 mg, 11.1 mmol) in methanol (10 mL) were mixed. Sodium cyanoborohydride (236 mg, 3.75 mmol) and zinc chloride (256 mg, 1.88 mmol) in methanol (10 mL) was added, and the reaction was heated at 48° C. for 12 hours. Work-up and flash column chromatography (silica, 60:35:5 methylene chloride/diethyl ether/methanol) afford a 30% yield (160 mg) of 264c as a light green solid: MS (ESI+) m/z 421.1 (M+H).
Reaction SMILES: [C:1](Cl)(=O)C.[CH:5]1[CH:9]=[C:8]([CH:10]([NH2:14])[C:11]([OH:13])=[O:12])[S:7][CH:6]=1>CO>[NH2:14][CH:10]([C:8]1[S:7][CH:6]=[CH:5][CH:9]=1)[C:11]([O:13][CH3:1])=[O:12]
Reactant: NC(C(=O)O)c1cccs1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)C(N)c1cccs1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 111.8 %

Procedure:
To dry MeOH (1000 mL) stirring at room temperature was added acetyl chloride (40.3 g, 513 mmol) over a 5 minute period. A mild exothermic reaction resulted. The mixture was stirred for 10 minutes and DL-α-amino-2-thiopheneacetic acid (40.5 g, 257 mmol) was added. The brown mixture was heated to reflux and stirred overnight. After cooling to room temperature, the mixture was concentrated to a volume of 400 mL and poured into Et2O (1500 mL). The precipitated white solid was collected and dried in vacuo to afford 49.2 g (92%) of the title compound as its hydrochloride salt. The 1H NMR spectrum was consistent for the title compound. An analytical sampie was recrystallized from EtOAc-hexane. Mpt.=182° C.