Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[CH:6][C:3]=1[CH:4]=[O:5].S(=O)(=O)([OH:15])N.CCOC(C)=O.[Cl:24]([O-:26])=[O:25].[Na+:27]>O>[Cl:24]([O-:26])=[O:25].[Na+:27].[Br:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[CH:6][C:3]=1[C:4]([OH:15])=[O:5]
Reactant: COc1cc(Br)c(C=O)cc1O
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(Br)c(C(=O)O)cc1O
Temperature: 5 °C
Yield: 89 %

Procedure:
1 Kg of 2-bromo-5-hydroxy-4-methoxy benzaldehyde (B2) and 1.255 Kg of sulfamic acid were added with stirring into a mixture of 4.473 Kg of EtOAc and 8 L of water. The reaction mixture was stirred until all of the solid had dissolved. The reaction mixture was cooled to between −10 and 0° C. An aqueous solution of sodium chlorite was prepared by dissolving 505 g of sodium chlorite in 3 L of water. The sodium chlorite solution was added to the pre-cooled B2 solution at a rate that maintained the reaction temperature under 5° C. After the complete addition of sodium chlorite solution, the reaction mixture was stirred for another hour at 0° C. and was then allowed to warm up to room temperature. The reaction was monitored by TLC. After the TLC analysis showed completion of the reaction, the aqueous layer was separated. The aqueous layer was extracted with EtOAc (1.789 Kg) and the combined organic layer was transferred to another flask and EtOAc was removed by vacuum distillation at 40° C. 6.92 Kg of toluene was added at between 30 to 40° C., the slurry was cooled to between −10 to 0° C. and the precipitate was collected by filtration to give about 950 g (89% (yield) of 2-bromo-5-hydroxy-4-methoxy benzoic acid (B13). 1H NMR (CDCl3) δ 3.95 (3H, s, CH3), 7.22 (1H, s, CH), 7.46 (1H, s, CH).
Reaction SMILES: CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+].[NH2:11][CH:12]([CH2:17][C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=1[F:26])[CH2:13][C:14](O)=[O:15]>C(#N)C>[F:26][C:19]1[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:18]=1[CH2:17][CH:12]1[NH:11][C:14](=[O:15])[CH2:13]1
Reactant: NC(CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=C1CC(Cc2cc(F)c(F)cc2F)N1
Temperature: 80 °C
Reaction time: 16 h
Yield: 96.9 %

Procedure:
To the rapidly stirred 80° C. suspension of methanesulfonyl chloride (0.88 g, 7.72 mmol) and sodium bicarbonate (3.24 g, 38.6 mmol) in acetonitrile (400 mL), 3-amino-4-(2,4,5-trifluorophenyl)butanoic acid ((±)-Ia, 1.5 g, 6.43 mmol) is added over period of 2 h. The resulting suspension was further stirred for 16 h at 80° C., after which time the fine suspension was cooled to 0° C. and filtered. The filtrate was evaporated under reduced pressure to afford 1.34 g (96% yield) of racemic 4-(2,4,5-trifluorobenzyl)azetidin-2-one ((±)-IIa) as pale yellow crystalline solid.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][N:17]1[C:25]2[C:20](=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=2)[CH:19]=[N:18]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:20]=2[CH:19]=[N:18][N:17]3[CH3:16])[C:11]=1[CH3:12]
Reactant: Cn1ncc2c(B(O)O)cccc21
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2cccc3c2cnn3C)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 1-methyl-1H-indazol-4-ylboronic acid (0.53 g, 3.02 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 17 h to give 4-chloro-5,7-difluoro-3-methyl-2-(1-methyl-1H-indazol-4-yl)quinoline as a yellow solid. Mass Spectrum (ESI) m/e=344.0 (M+1).
Reaction SMILES: C(OC(=O)N(C(C(=O)[NH:12][C:13]1[CH:18]=[C:17]([C:19]2[C:20]3[N:27]([CH3:28])[N:26]=[C:25]([CH3:29])[C:21]=3[N:22]=[CH:23][N:24]=2)[CH:16]=[C:15]([C:30]#[C:31][C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[C:38]([CH3:42])=[N:37][CH:36]=[CH:35]3)[N:14]=1)C)C)(C)(C)C.[H][H].[OH-].[K+]>>[CH3:28][N:27]1[C:20]2[C:19]([C:17]3[CH:16]=[C:15]([C:30]#[C:31][C:32]4[CH:33]=[C:34]5[C:39](=[CH:40][CH:41]=4)[C:38]([CH3:42])=[N:37][CH:36]=[CH:35]5)[N:14]=[C:13]([NH2:12])[CH:18]=3)=[N:24][CH:23]=[N:22][C:21]=2[C:25]([CH3:29])=[N:26]1
Reactant: [H][H]
Reactant: Cc1nccc2cc(C#Cc3cc(-c4ncnc5c(C)nn(C)c45)cc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)n3)ccc12
Agent: [K+]
Agent: [OH-]
Product: Cc1nccc2cc(C#Cc3cc(-c4ncnc5c(C)nn(C)c45)cc(N)n3)ccc12
Temperature: 60 °C
Reaction time: 48 h

Procedure:
A mixture of tert-butyl-N-{1-[(4-{1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl}-6-[2-(1-methylisoquinolin-6-yl)ethynyl]pyridin-2-yl)carbamoyl]ethyl}-N-methylcarbamate H2 (150 mg, 0.31 mmol) and potassium hydroxide (1 mol/l solution in MeOH:water=2:1, 3 ml, 3 mmol) is stirred at 60° C. for 2 days. The precipitate is collected and purified by NP chromatography to yield 4-{1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl}-6-[2-(1-methylisoquinolin-6-yl)ethynyl]pyridin-2-amine. Yield: 110 mg (89%). HPLC-MS: M+H=406; tR=1.07 min (METHOD—1).
Reaction SMILES: CC([O:4][CH2:5][C@H:6]1[O:11][C@H:10]([O:12][C@:13]2([CH2:22][Cl:23])[O:17][C@H:16]([CH2:18][Cl:19])[C@@H:15]([OH:20])[C@@H:14]2[OH:21])[C@H:9]([OH:24])[C@@H:8]([OH:25])[C@H:7]1[Cl:26])=O.[OH-].[K+]>CO>[CH2:5]([OH:4])[C@@H:6]1[O:11][C@H:10]([O:12][C@:13]2([CH2:22][Cl:23])[O:17][C@H:16]([CH2:18][Cl:19])[C@@H:15]([OH:20])[C@@H:14]2[OH:21])[C@@H:9]([OH:24])[C@@H:8]([OH:25])[C@H:7]1[Cl:26]
Reactant: CC(=O)OC[C@H]1O[C@H](O[C@]2(CCl)O[C@H](CCl)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@H]1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: OC[C@@H]1O[C@H](O[C@]2(CCl)O[C@H](CCl)[C@@H](O)[C@@H]2O)[C@@H](O)[C@@H](O)[C@H]1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
20 g Sucralose-6-acetate was dissolved in 150 ml methanol, and the pH value of the solution was adjusted into 11 with KOH. The reaction was kept at 45° C. for 4 hours, then decolored with activated carbon, filtered and the filtrate was concentrated. 6 ml Water was added to the concentrate in 70° C. The resulting solution was Cooled gradually to room temperature and kept standing, then Filtered to obtain the product sucralose, 12.3 g. It was verified that the purity was over 99%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[Cl:26][C:27]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=1[S:34]([N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]([CH:46]=O)=[CH:38]1)(=[O:36])=[O:35].N1CCCCC1>CO>[Cl:26][C:27]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=1[S:34]([N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39](/[CH:46]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[CH:38]1)(=[O:36])=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1cn(S(=O)(=O)c2cccc(Cl)c2Cl)c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2cn(S(=O)(=O)c4cccc(Cl)c4Cl)c4ccccc24)C3=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.287 mmol) obtained in Example A16, Step 1 in methanol (1.2 mL) was added with 1-(2,3-dichlorophenylsulfonyl)-1H-indole-3-carboxaldehyde (0.102 g, 0.287 mmol) and piperidine (0.00244 g, 0.0287 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with methanol (2 mL), and the solid was suspended in methanol and thereby washed to obtain tert-butyl (Z)-4-[(2-{[1-(2,3-dichlorophenylsulfonyl)-1H-indol-3-yl]methylene}-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.159 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:31])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][C:11]=2[NH:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]2)=[N:6][CH:7]=1.O1CCCC1.[OH-].[Li+].Cl>O>[ClH:1].[C:16]([C:13]1[CH:14]=[CH:15][C:10]([C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:31])=[C:11]([NH:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]2)[CH:12]=1)([OH:18])=[O:17]
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(NCC2CCN(C(C)C)CC2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N1CCC(CNc2cc(C(=O)O)ccc2C(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 17 h
Yield: 60.9 %

Procedure:
A solution of N-(5-chloropyridin-2-yl)-2-(1-isopropylpiperidin-4-ylmethylamino)-4-methoxycarbonylbenzamide (100 mg, 0.225 mmol) in 4:1 tetrahydrofuran:water (2.5 mL) was treated with lithium hydroxide (20 mg, 0.90 mmol). After 17 h, the pH of the mixture was adjusted to 2-3 by addition of 1 N HCl. The mixture was then concentrated and the residue purified by RPHPLC affording 32 mg (30%) of the title compound as a hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:18]1([CH3:27])[CH:23]=[CH:22][CH:21]=[C:20]([N:24]=[C:25]=[O:26])[CH:19]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:25]([NH:24][C:20]4[CH:21]=[CH:22][CH:23]=[C:18]([CH3:27])[CH:19]=4)=[O:26])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: Cc1cccc(N=C=O)c1
Solvent: ClCCl
Product: Cc1cccc(NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)c1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (62 mg, 0.25 mmol) and m-tolyl isocyanate (32 μL, 0.25 mmol) in CH2Cl2 (5 mL) are reacted according to method C yielding the title product as colorless solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[N:18]=3)[C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[N:12]=2)[CH2:3]1.C[O:28][C:29]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1)=[O:30].CCN=C=NCCCN(C)C.C(N(CC)CC)C.CN1C=CN=C1>ClCCl>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:9]2[C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[N:12]=[C:7]([N:4]3[CH2:5][CH2:6][CH:2]([NH:1][C:35]([C:34]4[CH:38]=[CH:39][C:31]([C:29]([OH:30])=[O:28])=[CH:32][CH:33]=4)=[O:36])[CH2:3]3)[CH:8]=2)=[N:18][C:19]=1[O:25][CH3:26]
Reactant: COc1ccc(Nc2cc(N3CCC(N)C3)nn3ccnc23)nc1OC
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Nc2cc(N3CCC(NC(=O)c4ccc(C(=O)O)cc4)C3)nn3ccnc23)nc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.9 %

Procedure:
A mixture of 6-(3-aminopyrrolidin-1-yl)-N-(5,6-dimethoxypyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (180 mg, 0.51 mmol), 4-(methoxycarbonyl)benzoic acid (92 mg, 0.51 mmol), EDCI (389 mg, 2.0 mmol), triethylamine (103 mg, 1.02 mmol) and 1-methyl-1H-imidazole (167 mg, 2.0 mmol) in dichloromethane (10 mL) was stirred at room temperature for 16 h. The residue was concentrated and purified by chromatography (silica gel, 200-300 mesh, dichloromethane:MeOH=20:1) to give 4-(1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-ylcarbamoyl)benzoic acid (100 mg, 38%) as a brown liquid. LC-MS: 518 [M+1]+, tR=1.327 min.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])=[CH2:2]>[Pd].CO>[CH2:1]([C:3]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])[CH3:2]
Reactant: C=Cc1cc(C)ccc1C(=O)OC
Agent: [Pd]
Solvent: CO
Product: CCc1cc(C)ccc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
Charged compound methyl 2-ethenyl-4-methylbenzoate (773 mg, 4.42 mmol), Pd/C (100 mg) and methanol (14 mL) to a flask, the mixture was then purged with H2, and stirred at room temperature overnight. It was then filtered, filtrated concentrated to give the title compound (646 mg, 83%). 1H NMR (300 MHz, CDCl3): δ 1.22 (3H, t, J=7.5 Hz), 2.36 (3H, s), 2.95 (2H, q, J=7.5 Hz), 3.87 (3H, s), 7.04 (1H, d, J=8.1 Hz), 7.07 (1H, s), 7.78 (1H, d, J=8.1 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:9]=3[C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[C:19](Cl)(=[O:21])[CH3:20]>N1C=CC=CC=1>[Cl:16][C:13]1[CH:14]=[CH:15][C:9]2[C:8](=[O:17])[NH:7][C:6]3[CH:18]=[C:2]([NH:1][C:19](=[O:21])[CH3:20])[CH:3]=[CH:4][C:5]=3[NH:11][C:10]=2[CH:12]=1
Reactant: Nc1ccc2c(c1)NC(=O)c1ccc(Cl)cc1N2
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)NC(=O)c1ccc(Cl)cc1N2
Reaction time: 8 h
Yield: 55.8 %

Procedure:
A solution of Example 7C (100 mg, 0.38 mmol) in pyridine (10 mL) at 0° C. was treated with acetyl chloride (32 mg, 0.40 mmol), stirred overnight, and concentrated. The residue was purified by flash column chromatography on silica gel with ethyl acetate to provide 64 mg (56%) of the desired product. MS (DCI) m/e 302 (M+H)+, 319 (M+NH4)+; 1H NMR (500 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.81 (s, 1H), 7.93 (s, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.25 (d, J=1.9 Hz, 1H), 7.16 (dd, J=8.4, 2.2 Hz, 1H), 7.05 (d, J=1.9 Hz, 1H), 6.90 (dd, J=8.4, 1.9 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 1.99 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH:29]([CH3:33])[CH2:30][CH2:31][OH:32])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[N:11][N:12]=1.[CH3:34]N(C)CCC(S(C1C=CC(C2N=C(C3OC(C4C=CC=CC=4F)=NN=3)C(N)=NC=2)=CC=1)(=O)=O)C.FC1C=CC=CC=1C1OC(C2C(N)=NC=C(C3C=CC(S(C4CCOC4)(=O)=O)=CC=3)N=2)=NN=1>>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10]1[O:9][C:8]([C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH:29]4[CH2:33][CH2:34][O:32][CH2:31][CH2:30]4)(=[O:28])=[O:27])=[CH:22][CH:21]=3)[N:6]=2)=[N:12][N:11]=1
Reactant: CC(CCN(C)C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccccc4F)o3)n2)cc1
Reactant: CC(CCO)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccccc4F)o3)n2)cc1
Agent: Nc1ncc(-c2ccc(S(=O)(=O)C3CCOC3)cc2)nc1-c1nnc(-c2ccccc2F)o1
Product: Nc1ncc(-c2ccc(S(=O)(=O)C3CCOCC3)cc2)nc1-c1nnc(-c2ccccc2F)o1

Procedure:
Compound IA-339 3-[4-[5-amino-6-[5-(2-fluorophenyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]phenyl]sulfonylbutan-1-ol 1H NMR (400.0 MHz, DMSO) d 1.20 (d, 3H), 1.37-1.46 (m, 1H), 1.99-2.02 (m, 1H), 3.38-3.43 (m, 2H), 3.52 (s, 1H), 4.66 (t, 1H), 7.50-7.59 (m, 2H), 7.77 (d, 1H), 7.97 (d, 2H), 8.20 (s, 1H), 8.37 (d, 2H) and 9.08 (s, 1H) ppm; MS (ES+) 470 Compound IA-343 5-[4-[3-(dimethylamino)-1-methyl-propyl]sulfonylphenyl]-3-[5-(2-fluorophenyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-amine 1H NMR (400.0 MHz, DMSO) d 1.20 (d, 3H), 1.76-1.82 (m, 1H), 2.14-2.20 (m, 1H), 2.79 (s, 6H), 3.21 (s, 2H), 3.47-3.55 (m, 1H), 7.50-7.59 (m, 2H), 7.75-7.81 (m, 1H), 8.01 (d, 2H), 8.19 (m, 1H), 8.40 (d, 2H), 9.10 (s, 1H) and 9.58 (s, 1H) ppm; MS (ES+) 497 Compound IA-349 3-[5-(2-fluorophenyl)-1,3,4-oxadiazol-2-yl]-5-(4-tetrahydrofuran-3-ylsulfonylphenyl)pyrazin-2-amine 1H NMR (400.0 MHz, DMSO) d 2.13-2.19 (m, 2H), 3.65 (m, 1H), 3.74-3.80 (m, 1H), 3.86 (dd, 1H), 4.04 (dd, 1H), 4.22-4.28 (m, 1H), 7.50-7.60 (m, 2H), 7.75-7.80 (m, 1H), 8.04 (d, 2H), 8.20 (m, 1H), 8.38 (d, 2H) and 9.09 (s, 1H) ppm; MS (ES+) 468
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=O.NC1C=CC(C)=C(C(C2C=CC(OC)=CC=2)=O)C=1.NC1C=CC(C)=C(C(C2C=CC(OC)=CC=2)O)C=1>C(OCC)(=O)C.[Pd]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([CH2:11][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:4]=1
Reactant: COc1ccc(C(=O)c2cc([N+](=O)[O-])ccc2C)cc1
Agent: [Pd]
Agent: COc1ccc(C(=O)c2cc(N)ccc2C)cc1
Agent: COc1ccc(C(O)c2cc(N)ccc2C)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(Cc2cc(N)ccc2C)cc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A mixture of (2-methyl-5-nitro-phenyl)-(4-methoxy-phenyl)-methanone (5.8 g) and 10% Pd on carbon (1.0 g) in ethyl acetate (200 mL) is shaken under hydrogen atmosphere (7 bar) at ambient temperature for 4.5 h. The solution is separated from the palladium catalyst by filtration and the filtrate is concentrated in vacuo to give a mixture of the title compound, (5-amino-2-methyl-phenyl)-(4-methoxy-phenyl)-methanone and (5-amino-2-methyl-phenyl)-(4-methoxy-phenyl)-methanol. This compound mixture is dissolved in a mixture of acetonitrile (12 mL) and dichloromethane (8 mL) and the resulting solution is cooled in an ice-bath. Triethylsilane (20 mL) is added followed by the slow addition of boron trifluoride diethyl etherate (16 mL). The solution is stirred for 0.5 h at 5° C. and then quenched by the addition of aqueous sodium hydroxide solution (2 mol/L). The organic phase is separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with brine, dried (sodium sulphate) and concentrated in vacuo. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 9:1->2:1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([O:20][CH2:21][CH3:22])[C:18]=1I)[CH2:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)[CH3:2].[NH2:23][C:24]1[CH:25]=[C:26]([B])[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(O)C>[NH2:23][C:24]1[CH:29]=[C:28]([C:18]2[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]([CH2:7][C:8]3[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=3)=[CH:16][C:17]=2[O:20][CH2:21][CH3:22])[CH:27]=[CH:26][CH:25]=1
Reactant: [B]c1cccc(N)c1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1cccc(N)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Tetrakis-triphenylphosphine-palladium (555 mg; 0.48 mmol) is suspended in dimethoxyethane (7 ml) while gassing with argon, and 5-(3,5-diethoxy-4-iodo-benzyl)-pyrimidine-2,4-diamine (example 1) (4.14 g; 10 mmol) in dimethoxyethane (60 ml) is added. After stirring for 15 minutes at room temperature, 3-amino-phenylboron acid monnohydrate (2.37 g; 15 mmol) in ethanol (17 ml) is added, the mixture is stirred at room temperature for a further 10 minutes, aqueous 2 M sodium carbonate solution (44 ml) is added and the mixture is then boiled under reflux for 4 hours. The reaction mixture is concentrated and the residue is stirred with water and filtered off with suction. The filter cake is stirred with MeOH (230 ml) and filtered off with suction. The filtrate is concentrated and the residue is chromatographed over silica gel (225 g) with methylene chloride/methanol/ammonia (19/1/0.05, later 90/10/1). The pure fractions are combined and concentrated and the residue is dried under a high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([CH:20]3[O:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]3)=[O:19])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]>FC(F)(F)C(O)=O.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([CH:20]3[O:25][CH2:24][CH2:23][NH:22][CH2:21]3)=[O:19])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C(=O)C2CNCCO2)CC1
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
Trifluoroacetic acid/dichloromethane (1:1, 10 ml) was added to tert-butyl 2-[(4-{[(3,4-dichlorophenyl)amino]carbonyl}piperazin-1-yl)carbonyl]morpholine-4-carboxylate (900 mg, impure) followed by stirring for 30 min. The solvent was removed under reduced pressure then taken up in 1M. NaOH (aq.) (30 ml) and extracted with ethyl acetate (3×30 ml). The combined organic layers were dried (MgSO4), filtered and evaporated to form the title compound (700 mg) as a white foam which was used without further purification.
Reaction SMILES: N[C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]([F:14])([F:13])[CH2:11][OH:12].CS(O)(=O)=O.S([O-])([O-])(=O)=O.[Mg+2].N(OC(C)(C)C)=O.C(=O)(O)[O-].[Na+]>>[Cl:8][C:3]1[C:2]([O:12][CH2:11][C:10]([F:14])([F:13])[F:9])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: OCC(F)(F)F
Reactant: Nc1cccnc1Cl
Agent: CC(C)(C)ON=O
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Product: FC(F)(F)COc1cccnc1Cl
Yield: 70.1 %

Procedure:
A reactor vessel is charged with 3-amino-2-chloropyridine (2.7 g, 21 mmol), 2,2,2-trifluoroethanol (15 g, 150 mmol), methanesulfonic acid (2.02 g, 21 mmol), and magnesium sulfate (3 g). The solution is cooled to the range 0° C. to 5° C. and then the reagent t-butyl nitrite (2.51 g of a 96% solution, 23.4 mmol) is added drop-wise to the vessel maintaining the temperature in the range 0° C. to 5° C. After stirring a few minutes the solution is transferred drop-wise to a reactor vessel containing 2,2,2-trifluoroethanol (20 g, 200 mmol) maintained at 65° C. to 70° C. After cooling the solution it is neutralized with aqueous saturated sodium bicarbonate solution and then extracted with MTBE. The solvent is removed by evaporation to obtain 2-chloro-3-(2,2,2-trifluoroethoxy)pyridine as a crude oil (4.4 g) with an actual yield of 70.1%.
Reaction SMILES: [CH3:1][C:2]([NH:14]C(=O)C)([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[N:5]=1)[CH3:3].[OH-].[Na+]>Cl>[CH3:3][C:2]([NH2:14])([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([F:11])([F:13])[F:12])[N:5]=1)[CH3:1]
Reactant: CC(=O)NC(C)(C)c1ccnc(C(F)(F)F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(N)c1ccnc(C(F)(F)F)n1
Temperature: 25 °C
Yield: 56.6 %

Procedure:
Heat a solution of N-[1-methyl-1-(2-trifluoromethyl-pyrimidin-4-yl)-ethyl]-acetamide (15.4 g, 62 mmol) and aqueous 5N HCl (150 mL) to 100° C. for 20 hours then cool to room temperature. Extract the reaction with diethyl ether (2×) then make the aqueous layer alkaline with aqueous 5N NaOH. Extract the aqueous layer with diethyl ether (3×), dry the combined organic layers over sodium sulfate, filter, and concentrate under reduced pressure to give 1-methyl-1-(2-trifluoromethyl-pyrimidin-4-yl)-ethylamine (7.2 g, 56%) as a brown oil. 1H NMR (400 MHz, CDCl3): δ 8.80 (d, J=5.3 Hz, 1H), 7.68 (d, J=5.3 Hz, 1H), 1.76 (br s, 2H), 1.49 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH:10]C(CC3C=CC=CC=3)=O)[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([O-:22])=[O:21].[K+].CC1(C)S[C@@H]2[C@H](NC(CC3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O>P([O-])([O-])([O-])=O>[CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH2:10])[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([OH:22])=[O:21]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O

Procedure:
The enzymatic activity of the penicillin amidase-support complex obtained is determined by contacting 0.5 g. of complex with 40 ml. of a 20 g./l. penicillin G solution in 0.1 M phosphate buffer, of pH 7.5, at 30° C., for 30 minutes. The complex is then removed by filtration and the 6-amino-penicillanic acid (6-APA) formed determined in the filtrate. The enzymatic activity of the complex is 50 U/g. (the unit "U" is the amount of complex which hydrolyzes 1 mircomol of penicillin G per minute).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][C:5]([O:10][CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8].[F:18][C:19]1[C:24]2[B:25]([OH:28])[O:26][CH2:27][C:23]=2[CH:22]=[C:21]([OH:29])[CH:20]=1>>[Cl:1][C:2]1[C:3]([O:29][C:21]2[CH:20]=[C:19]([F:18])[C:24]3[B:25]([OH:28])[O:26][CH2:27][C:23]=3[CH:22]=2)=[N:4][C:5]([O:10][CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: OB1OCc2cc(O)cc(F)c21
Reactant: CC(=O)CCCOc1nc(Cl)c(Cl)cc1C#N
Product: CC(=O)CCCOc1nc(Oc2cc(F)c3c(c2)COB3O)c(Cl)cc1C#N

Procedure:
This compound was prepared from 5,6-dichloro-2-(4-oxopentyloxy)nicotinonitrile and 7-fluorobenzo[c][1,2]oxaborole-1,5(3H)-diol in a similar manner to that of D230. 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 1.72-1.75 (m, 2H), 2.05 (s, 3H), 2.38 (t, J=5.4 Hz, 2H), 4.03 (t, J=5.4 Hz, 2H), 5.03 (s, 2H), 7.13 (d, J=7.8 Hz, 1H), 7.2 (s, 1H), 8.61 (s, 1H), 9.36 (s, 1H).