Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[S:9][C:10]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[C:11]([C:13]([NH2:15])=[O:14])[N:12]=2)[CH2:3]1.CN(C)C=O.C(N(C(C)C)CC)(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>O1CCCC1>[CH3:37][S:38]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[S:9][C:10]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[C:11]([C:13]([NH2:15])=[O:14])[N:12]=2)[CH2:3]1)(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: NC(=O)c1nc(N2CCC[C@@H](N)C2)sc1Nc1ccccn1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N[C@@H]1CCCN(c2nc(C(N)=O)c(Nc3ccccn3)s2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-((R)-3-amino-piperidin-1-yl)-5-(pyridin-2-ylamino)-thiazole-4-carboxylic acid amide (prepared as described in example 4) (5.6 mg, 171 μmol) in tetrahydrofuran (1 mL) was added N,N-dimethylformamide (0.5 mL) to form a clear solution. Diisopropylethylamine (59.9 μL, 343 μmol) was added followed by methanesulfonyl chloride (20 μL, 257 μmol) and the mixture left to stir overnight at ambient temperature under argon. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride solution (2 mL), poured into water (5 mL) and extracted with ethyl acetate (5×2 mL), the combined organic extracts were washed with brine (2×2 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography using a C-18 column gradient eluted from 10% acetonitrile in water to 100% acetonitrile. The product containing fractions were combined and concentrated in vacuo. The residue was lyophilized from water/ethanol to give (R)-2-(3-(methylsulfonamido)piperidin-1-yl)-5-(pyridin-2-ylamino)thiazole-4-carboxamide as an off-white lyophilized powder (41 mg, 60%).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([C:7]1[CH:20]=[CH:19][C:10]2[N:11]=[C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[S:13][C:9]=2[CH:8]=1)[CH3:6])C.[OH-].[Na+].C(O)(=O)C>C1COCC1.O>[CH3:18][S:15]([NH:14][C:12]1[S:13][C:9]2[CH:8]=[C:7]([CH:5]([CH3:6])[C:4]([OH:21])=[O:3])[CH:20]=[CH:19][C:10]=2[N:11]=1)(=[O:16])=[O:17]
Reactant: CCOC(=O)C(C)c1ccc2nc(NS(C)(=O)=O)sc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc2nc(NS(C)(=O)=O)sc2c1
Temperature: 25 °C

Procedure:
A mixture of 5 (156 mg, 1 mmol) in THF (10 ml) and H2O (10 ml) is stirred at room temperature. Sodium hydroxide (50 mg, 2.5 mmol) is added to the mixture. The reaction mixture is stirred for 15 h at room temperature. The reaction mixture is acidified to pH 3˜4 with acetic acid. Water is added to the mixture and extracted with dichloromethane. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Yield: quantitative.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]#[N:11])=[N:2]1.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]#[N:11])=[N:2]2)=[CH:15][CH:16]=1
Reactant: COc1ccc(CBr)cc1
Reactant: N#Cc1n[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(C#N)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6.47 g of 1H-indazole-3-carbonitrile (45.2 mmol, 1 eq.) were dissolved in 65 ml of dry DMF. 10 g of 1-(bromomethyl)-4-methoxybenzene (49.7 mmol, 1.1 eq.) and 17.7 g of cesium carbonate (54.2 mmol, 1.2 eq.) were added. The mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. Then the reaction mixture was partitioned between water and tert-butyl methyl ether. The separated aqueous layer was extracted twice with tert-butyl methyl ether. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The crystallization from methanol provided 9.25 g (35.1 mmol, 77.7%) of analytically pure target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O>C1(OC2C=CC=CC=2)C=CC=CC=1.C1(=O)CCCCC1>[O:6]=[C:4]1[C:3]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:2]=2[NH:1][C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2
Reactant: Nc1cc(C(=O)O)ccc1C(=O)O
Solvent: O=C1CCCCC1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=C(O)c1ccc2c(=O)c3c([nH]c2c1)CCCC3
Temperature: 250 °C

Procedure:
To a suspension of 2-amino terephthalic acid (12 g, 6.6 mmols) in diphenyl ether (120 mL), cyclohexanone (25 mL) was added and the reaction mixture was heated to 250° C. for 10 min. Reaction completion was monitored by LC/MS (75% starting material and 25% Product formation was observed). Cyclohexanone (25 mL) was added and the reaction mixture was heated to 250° C. for another 10 min. (LC/MS showed 50% product formation). The above process was repeated till LC/MS showed complete product formation (Starting material <2%). The reaction mixture was cooled to 25° C., product was filtered, washed with hexane (100 mL) and dried under vacuum to get 15.8 g of (Via) (98%) as a yellow solid.
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][O:4][CH:3]([C:7](OC)=[O:8])[CH2:2]1.[BH4-].[Li+].O>O1CCCC1>[OH:8][CH2:7][CH:3]1[O:4][CH2:5][CH2:6][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:2]1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOC(CO)C1
Reaction time: 1 h

Procedure:
The crude product from step (i) (62.6 mmol) was dissolved in dry tetrahydrofuran (THF) (100 ml) and added dropwise at 0° C. to a suspension of lithium borohydride (2.50 g, 115 mmol) in dry THF (100 ml). The mixture was allowed to attain room temperature over night. Water (10 ml) was added and after stirring for 1 h the mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic phase was washed with 0.5 M hydrochloric acid, saturated sodium hydrogen carbonate and water. Drying over magnesium sulfate and concentration gave the title compound as a crude product (13.3 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH2:11][CH:12]=[CH2:13])[C:5]=1[OH:14])([O-:3])=[O:2].CI.[C:17](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH2:11][CH:12]=[CH2:13])[C:5]=1[O:14][CH3:17])([O-:3])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: C=CCc1cc(Cl)cc([N+](=O)[O-])c1O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: C=CCc1cc(Cl)cc([N+](=O)[O-])c1OC
Temperature: 25 °C
Yield: 93.4 %

Procedure:
A mixture of 2-nitro-4-chloro-6-allylphenol (21.7 g), methyl iodide (28.28 g), and potassium carbonate (16.6 g) in acetone (300 ml) was refluxed for 16 hours. After cooling to room temperature and filtration, the filtrate was concentrated in vacuo to give a residue. The residue was extracted with dichloromethane. The organic layer was washed with water, dried over MgSO4, and concentrated to give crude 2-nitro-4-chloro-6-allylanisole (21.6 g, 96%) which was used in the next step without purification. 1H NMR (300 MHz, CDCl3) δ7.69 (d, J=2.6 Hz, 1 H), 7.41 (d, J=2.6 Hz, 1 H), 5.97-5.89 (m, 1 H), 5.20-5.10 (m, 2 H), 3.88 (s, 3 H), 3.48 (d, J=6.65 Hz, 2 H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([NH2:6])=[N:2]1.O=[C:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1.C([BH3-])#N.[Na+].O>C(O)(=O)C>[N:1]1[N:2]=[C:3]([NH:6][CH:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]2)[NH:4][CH:5]=1
Reactant: Nc1nc[nH]n1
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C1CCC(Nc2nnc[nH]2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.7 %

Procedure:
To a solution (200 mL) of 1H-1,2,4-triazol-3-amine (11 g) and ethyl 4-oxocyclohexanecarboxylate (28 g) in acetic acid was added sodium cyanoborohydride (35 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (13 g, 40%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:25][C@@H:26]2[CH2:30][CH2:29][O:28][CH2:27]2)=[N:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH:22]3[CH2:24][O:23]3)[CH:15]=2)=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[CH3:31][NH2:32]>CO>[CH3:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][C:5]([C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[O:20][CH2:21][CH:22]([OH:23])[CH2:24][NH:32][CH3:31])=[N:4][C:3]=1[NH:25][C@@H:26]1[CH2:30][CH2:29][O:28][CH2:27]1
Reactant: Cc1c(N[C@@H]2CCOC2)nc(-c2cccc(OCC3CO3)c2)nc1N1CCOCC1
Reactant: CN
Solvent: CO
Product: CNCC(O)COc1cccc(-c2nc(N[C@@H]3CCOC3)c(C)c(N3CCOCC3)n2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 37 %

Procedure:
5-Methyl-6-morpholino-2-(3-(oxiran-2-ylmethoxy)phenyl)-N—((R)-tetra-hydrofuran-3-yl)pyrimidin-4-amine (20 mg, 0.05 mmol) was dissolved in a 2N MeNH2 solution in methanol, (10 mL) and the mixture was stirred at room temperature for 14 h., concentrated under vacuum and the residue was purified by preparative HPLC to obtain the 1-(3-(5-methyl-4-morpholino-6-((R)-tetrahydrofuran-3-ylamino)pyrimidin-2-yl)phenoxy)-3-(methyl-amino)propan-2-ol (8 mg, 37% yield) as a white solid. 1H NMR (500 MHz, CD3OD) δ ppm: 8.02-7.96 (m, 2H), 7.34 (t, J=8.0 Hz, 1H), 7.05-7.00 (m, 1H), 4.85-4.80 (m, 1H), 4.20-4.14 (m, 2H), 4.07-4.01 (m, 3H), 3.93-3.84 (m, 5H), 3.78-3.74 (m, 1H), 2.96-2.92 (m, 1H), 2.88-2.82 (m, 1H), 2.53 (s, 3H), 2.42-2.35 (m, 1H), 2.11-2.04 (m, 4H); ESI-LCMS (m/z): 444.3 [M+1]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:27])([F:26])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[NH:22][N:21]=[C:20]([C:23]([OH:25])=O)[CH:19]=2)=[CH:14][CH:13]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:51][CH2:52][C:53]([N:55]1[CH2:60][CH2:59][CH:58]([O:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=2[Cl:68])[CH2:57][CH2:56]1)=[O:54]>CN(C=O)C.O>[Cl:68][C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][C:62]=1[O:61][CH:58]1[CH2:57][CH2:56][N:55]([C:53](=[O:54])[CH2:52][NH:51][C:23]([C:20]2[CH:19]=[C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:11]([F:10])([F:27])[F:26])=[CH:17][CH:16]=3)[NH:22][N:21]=2)=[O:25])[CH2:60][CH2:59]1
Reactant: O=C(O)c1cc(-c2ccc(C(F)(F)F)cc2)[nH]n1
Reactant: NCC(=O)N1CCC(Oc2ccccc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)CC1)c1cc(-c2ccc(C(F)(F)F)cc2)[nH]n1
Reaction time: 8 h
Yield: 48.2 %

Procedure:
DIPEA (150 mg, 1.15 mmol) was added to a stirred solution of 5-(4-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid (84 mg, 0.33 mmol) (prepared by the method used for the synthesis of Intermediate 29, starting from (p-trifluoromethyl)acetophenone) in DMF (2 mL) followed by HOBt (46 mg, 0.34 mmol) and EDCI.HCl (66 mg, 0.34 mmol). After 2 minutes 2-amino-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (100 mg, 0.33 mmol) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to afford the residue. The residue was purified by washing with mixture of ethyl acetate and methanol to afford 80 mg (48.2% Yield) of 5-(4-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 507, 92.02%. 1H NMR (300 MHz, DMSO-d6): δ13.7 (d, 1H), 8.0 (m, 3H), 7.8 (m, 2H), 7.44 (d, 1H), 7.24 (m, 3H), 6.96 (m, 1H), 4.7 (m, 1H), 4.2 (d, 2H), 3.7 (m, 2H), 3.4 (m, 2H), 1.9 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: BrC1C=C(NC2C=CC([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:19][CH2:18]3)=CN=2)C(=O)N(C)C=1.[Br:27][C:28]1[CH:29]=[C:30]([NH:36][C:37]2[CH:45]=C3CNCCN3[N:38]=2)[C:31](=[O:35])[N:32]([CH3:34])[CH:33]=1.O1CC(=O)C1.C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-].C(Cl)Cl.C(OCC)C.CO>[Br:27][C:28]1[CH:29]=[C:30]([NH:36][C:37]2[CH:45]=[C:22]3[CH2:21][N:20]([CH:23]4[CH2:24][O:25][CH2:26]4)[CH2:19][CH2:18][N:17]3[N:38]=2)[C:31](=[O:35])[N:32]([CH3:34])[CH:33]=1
Reactant: Cn1cc(Br)cc(Nc2cc3n(n2)CCNC3)c1=O
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: O=C1COC1
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1cc(Br)cc(Nc2cc3n(n2)CCN(C2COC2)C3)c1=O
Temperature: 48 °C
Yield: 34 %

Procedure:
Compound 125i was synthesized using the same procedure as 101k, where 5-bromo-1-methyl-3-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridin-2(1H)-one (125h) (250 mg, 0.78 mmol), and oxetan-3-one (600 mg, 8.3 mmol) in methanol (8 mL) were mixed. Sodium cyanoborohydride (148 mg, 3 mmol) and zinc chloride (165 mg, 1.5 mmol) in methanol (8 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 34% yield (100 mg) of 5-bromo-1-methyl-3-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridin-2(1H)-one (125i) as a light green solid: MS (ESI+) m/z 382.1 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1>C1(C)C=CC=CC=1.C(O)C.C([O-])([O-])=O.[Na+].[Na+].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:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2ccccc2Br)cc1
Yield: 82.5 %

Procedure:
Under nitrogen, 1.2 g (1.0 mmol) of Pd(PPh3)4 was added to a stirred solution of 9.9 g (42 mmol) of 1,2-dibromobenzene (Aldrich) and 3.0 g (21 mmol) of 4-fluorophenylboronic acid in 42 mL of toluene, 42 mL of ethanol and 42 mL of 2M Na2CO3. After vigorous stirring at reflux for 3 hours, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate. The resulting solution was washed with water and dried over MgSO4. Purification by silica gel chromatography (Waters Prep-500A) with hexane gave 4.35 g (81%) of 1-bromo-2-(4-fluorophenyl)benzene as a colorless oil: NMR (CDCl3) δ 7.07-7.26 (m, 3H), 7.27-7.44 (m, 4H), 7.67(d, J=8 Hz, 1H).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9](=[O:23])[CH2:10][C:11]1[C:12]([CH3:22])=[N:13][NH:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.[N:24]1[CH:29]=[C:28](B(O)O)[CH:27]=[N:26][CH:25]=1.Cl.S(=O)(=O)(O)O>ClCCl.CO.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O>[CH3:7][O:8][C:9](=[O:23])[CH2:10][C:11]1[C:12]([CH3:22])=[N:13][N:14]([C:28]2[CH:29]=[N:24][CH:25]=[N:26][CH:27]=2)[C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: COC(=O)Cc1c(C)n[nH]c1-c1ccccn1
Reactant: OB(O)c1cncnc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: c1ccncc1
Product: COC(=O)Cc1c(C)nn(-c2cncnc2)c1-c1ccccn1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
1.767 g (9.73 mmol) of copper(II) acetate and 1.049 ml (12.973 mmol) of pyridine were added to 1.5 g (6.486 mmol) of methyl[3-methyl-5-(pyridin-2-yl)-1H-pyrazol-4-yl]acetate in 20 ml of dichloromethane. 1.607 g (12.973 mmol) of 5-pyrimidinylboronic acid were then added, and the mixture was stirred at 20° C. for 48 h. The mixture was poured into 1-molar aqueous HCl (10 ml) and extracted with dichloromethane. The combined organic phases were dried with magnesium sulfate, filtrered and concentrated. The crude product was purified by preparative HPLC. This gave a mixture of ester and acid which was heated at reflux in methanol with a drop of sulfuric acid for 4 h. The reaction mixture was poured into water (20 ml), neutralized and extracted with dichloromethane. The combined organic phases were dried with magnesium sulfate and concentrated. This gave 0.031 g of product (1.47% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([C:18]#[N:19])[C:15]([S:20][C:21]([F:24])([F:23])[F:22])=[C:14]1[NH2:25].C1C=C[NH+]=CC=1.[Br:32][Br-]Br>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([Br:32])=[C:16]([C:18]#[N:19])[C:15]([S:20][C:21]([F:24])([F:22])[F:23])=[C:14]1[NH2:25]
Reactant: N#Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Agent: c1cc[nH+]cc1
Product: N#Cc1c(SC(F)(F)F)c(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1Br
Yield: 375 %

Procedure:
To a cold (0° C.) solution of 1.53 g (3.60 mmoles) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-2-amino-3-trifluoromethylthio-4-cyanopyrrole (made according to the process described in EXAMPLE 13, melting point about 182° C.) in 15 ml of pyridine was added, under inert atmosphere, a solution of 1.46 g (3.6 mmoles) of 80% pyridinium bromide perbromide in 15 ml of pyridine. After 30 minutes, the reaction mixture was poured into cold (0° C.) ethyl ether and a precipitate which formed was removed by filtration. The filtrate was washed with aqueous HCl, aqueous NaOH and water. The organic layer was dried over anhydrous magnesium sulfate and evaporated to yield 1.34 g of a brown solid. This was combined with 230 mg of product from an earlier reaction of 300 mg (0.7 mmole) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-2-amino-3-trifluoromethylthio-4-cyanopyrrole and 0.29 g of 80% pyridinium bromide perbromide. The consolidated products were chromatographed on silica gel eluting with 4:1 v/v hexane-ethyl acetate to give 1.31 g (73%) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-2-amino-3-trifluoromethylthio-4-cyano-5-bromopyrrole (EXAMPLE 12) as a white solid. Recrystallization from hexane/ethyl acetate furnished 910 mg of this product as colorless needles, melting point about 160° C.
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[S:7][C:8]([CH:11]([OH:14])[CH2:12][OH:13])=[CH:9][N:10]=1.O.[C:16]1(C)[CH:21]=CC(S([O-])(=O)=O)=C[CH:17]=1.[NH+]1C=CC=CC=1>CC(C)=O>[CH3:17][C:16]1([CH3:21])[O:14][CH:11]([C:8]2[S:7][C:6]([CH:2]=[O:3])=[N:10][CH:9]=2)[CH2:12][O:13]1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: OCC(O)c1cnc(C2OCCO2)s1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)OCC(c2cnc(C=O)s2)O1
Yield: 113.3 %

Procedure:
To a solution of 1-[2-(1,3-dioxolan-2-yl)-1,3-thiazol-5-yl]ethane-1,2-diol (1.50 g) in acetone (10 mL) were added water (1 mL) and pyridinium p-toluenesulfonate (0.52 g) and the mixture was stirred with heating under reflux overnight. The reaction mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give a crude product (1.20 g). To a solution of the obtained crude product (1.20 g) in acetone (80 mL) was added pyridinium p-toluenesulfonate (1.80 g), and the mixture was stirred with heating under reflux overnight. The reaction mixture was concentrated, the residue was dissolved in ethyl acetate, and the solution was washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (0.50 g, yield 34%) was obtained as a yellow oil from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). MS: 214 (MH+).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:21])[CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:7][CH:6]=1.[N+:22]([C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=O)([O-:24])=[O:23].[BH3-]C#N.[Na+]>CO.CC(O)=O>[N+:22]([C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH:1][C@@H:2]([CH3:21])[CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])=[CH:7][CH:6]=1)([O-:24])=[O:23]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: C[C@H](N)COc1ccc(C(=O)OCc2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H](COc1ccc(C(=O)OCc2ccccc2)cc1)NCc1ccccc1[N+](=O)[O-]
Yield: 42.1 %

Procedure:
To a stirred and cooled (0° C.) solution of benzyl (S)-4-(2-amino-1-propoxy)benzoate (1.50 g, 5.26 mmol) and 2-nitrobenzaldehyde (0.87 g, 5.76 mmol) in MeOH—AcOH (16 mL, 15:1, v/v) was added NaBH3CN (1.65 g, 26.3 mmol), and the resulting mixture was stirred at room temp overnight. The mixture was quenched by sat. NaHCO3 and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3 to 5% MeOH in CHCl3 as eluent to give 931 mg (42%) benzyl (S)-4-[2-(2-nitrobenzylamino)-1-propoxy]benzoate as a yellow oil. 1H-NMR (CDCl3) δ 1.21 (d, 3 H, J=6.4 Hz), 3.13–3.18 (m, 1 H), 3.88–3.97 (m, 2 H), 4.06–4.20 (m, 2 H), 5.34 (s, 2 H), 6.89–6.94 (m, 2 H), 7.29–7.65 (m, 8 H), 7.94–8.03 (m, 3 H); MS (FAB) m/z 421 (M++1).
Reaction SMILES: C([O:5][CH:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])N(C)C)(C)(C)C.[F:15][C:16]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([F:27])[C:17]=1C(O)=O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[C:11]([O:10][C:6](=[O:5])[C:17]1[C:16]([F:15])=[CH:24][C:23]([O:25][CH3:26])=[CH:22][C:21]=1[F:27])([CH3:12])([CH3:13])[CH3:14]
Reactant: COc1cc(F)c(C(=O)O)c(F)c1
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(F)c(C(=O)OC(C)(C)C)c(F)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
N,N-dimethylformamide di-tert-butyl acetal (75 ml, 0.31 mol) in toluene (60 ml) was added dropwise over 1.5 hours to 2,6-difluoro-4-methoxy-benzoic acid (15 g, 80 mmol)(Mol. Cryst. Liq. Cryst. 1989, 172) in toluene (120 ml) at 80° C. under a nitrogen atmosphere. The mixture was stirred at 80° C. for 30 minutes and then cooled to room temperature. Ethyl acetate (100 ml) was added and the organic solution was washed with saturated sodium hydrogen carbonate solution (2×150 ml), brine (150 ml), dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using diethyl ether in pentane as eluant (10:90) to give the title compound as an oil (17.91 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[OH-].[K+].[N+:11]([CH2:13][C:14]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:15])#[C-:12]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[O:8][CH:12]=[N:11][C@H:13]2[C:14]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[O:15])[CH:2]=1
Reactant: O=Cc1cccnc1
Reactant: [C-]#[N+]CC(=O)N1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([C@@H]1N=CO[C@H]1c1cccnc1)N1CCOCC1
Temperature: 0 °C
Reaction time: 20 h
Yield: 72.5 %

Procedure:
SLA 09050A was prepared in accordance with method D using pyridine-3-carbaldehyde (0.65 mL, 4.86 mmol), KOH (0.273 mg, 4.86 mmol) in methanol (10 mL) and 2-isocyano-1-morpholinoethanone SLA 07118 (0.75 g, 4.86 mmol). The solution was stirred for 20 h at 0° C. After work-up (without any further purification), evaporation and drying trans-(4,5-dihydro-5-(pyridin-3-yl)oxazol-4-yl)(morpholino)methanone SLA 09050A was obtained as a yellow solid (0.92 g, 72.5% yield).