Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(O[C:6](=O)[N:7]([CH2:9][CH2:10][NH:11][C:12]1[N:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=1)C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Br:18][C:15]1[CH:16]=[N:17][C:12]([NH:11][CH2:10][CH2:9][NH:7][CH3:6])=[N:13][CH:14]=1
Reactant: CN(CCNc1ncc(Br)cn1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCNc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
An ice-cooled solution of [2-(5-bromo-pyrimidin-2-ylamino)-ethyl]-methyl-carbamic acid dimethyl-ethyl ester, D10 (2.32 g, 7.0 mol) in dichloromethane (90 ml) was treated with trifluoroacetic acid (10 ml). The reaction mixture was stirred for 2 h at room temperature, under argon then poured onto K2CO3 (excess)/ice. The aqueous layer was separated, washed with dichloromethane (3×) and the combined organics dried (MgSO4) and the solvent removed in vacuo to afford the title compound (1.00 g, 61%).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:14][C:15]4[CH:21]=[C:20]([C:22]([OH:24])=O)[CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:25]1([NH2:32])[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1>>[C:25]1([NH:32][C:22]([C:20]2[CH:19]=[CH:18][C:16]3[NH:17][C:13]([C:10]4[CH:9]=[CH:8][C:7]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[CH:12][CH:11]=4)=[N:14][C:15]=3[CH:21]=2)=[O:24])[CH:30]=[CH:29][C:28]([NH:31][C:22]([C:20]2[CH:19]=[CH:18][C:16]3[NH:17][C:13]([C:10]4[CH:9]=[CH:8][C:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[CH:12][CH:11]=4)=[N:14][C:15]=3[CH:21]=2)=[O:24])=[CH:27][CH:26]=1
Reactant: Nc1ccc(N)cc1
Reactant: O=C(O)c1ccc2nc(-c3ccc(N4CCOCC4)cc3)[nH]c2c1
Product: O=C(Nc1ccc(NC(=O)c2ccc3[nH]c(-c4ccc(N5CCOCC5)cc4)nc3c2)cc1)c1ccc2[nH]c(-c3ccc(N4CCOCC4)cc3)nc2c1

Procedure:
Compound 280 was prepared according to the procedure similar to that described in Scheme V from 2-(4-morpholinylphenyl)benzimidazole-5-carboxylic acid and 1,4-phenylenediamine. [M+H]+ calcd for C42H38N8O4: 719.30; found: 719.12.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.Br[CH:12]([CH3:21])[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14]>CN(C=O)C>[OH:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([NH:1][CH:12]([CH3:21])[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:3][CH:4]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: CC(Br)C(=O)c1ccccc1
Solvent: CN(C)C=O
Product: CC(Nc1ccc(CCO)cc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 4-aminophenethyl alcohol (690 mg, 5.0 mmol), 2-bromopropiophenone (2.1 g, 10 mmol) potassium carbonate (690 mg, 5.0 mmol) in DMF (50 mL) was stirred at ambient temperature for 3 days. The mixture was partitioned between ethyl acetate and water. The combined organic phase was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (2:1) to afford the title compound quantitatively as yellow oil: 1H-NMR (CDCl3) δ 1.49 (2H, d, J=6.9 Hz), 2.74 (2H, t, J=6.4 Hz), 3.79 (2H, t, J=6.4 Hz), 4.65 (1H, br), 5.11 (1H, m), 6.65 (2H, d, J=8.4 Hz), 7.05 (2H, d, J=8.6 Hz), 7.48-7.65 (3H, m), 8.03 (2H, d, J=7.2 Hz).
Reaction SMILES: [I:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][NH2:14])=[O:12])=[CH:10][C:5]2=[N:4][CH:3]=1.[CH2:15](C(CC)(CC)C([O-])([O-])[O-])[CH3:16]>OS(O)(=O)=O>[I:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3[O:12][C:15]([CH3:16])=[N:14][N:13]=3)=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: NNC(=O)c1ccn2c(I)cnc2c1
Agent: O=S(=O)(O)O
Product: Cc1nnc(-c2ccn3c(I)cnc3c2)o1
Temperature: 80 °C

Procedure:
3-Iodo-imidazo[1,2-a]pyridine-7-carboxylic acid hydrazide (0.18 g, 0.59 mmol) was treated with triethylorthoacetate (3 ml) and concentrated H2SO4 (1 drop). The mixture was heated at 80° C. o/n, allowed to cool, solid was filtered off and washed with EtOH and dried to afford 0.165 g of product. MS: [M+H]+ 327
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH:19]=O)[CH:6]=1.[NH2:22][C@@H:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][NH:22][C@@H:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24]2)[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2C=O)c1
Reactant: N[C@H]1CCc2ccccc21
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN[C@H]2CCc3ccccc32)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 2, using the following starting materials: [3-(4-bromo-2-formyl-phenoxy)-phenyl]-acetic acid methyl ester and (S)-(+)-1-aminoindan.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH:7]2[C:12]1[N:13]=[CH:14][NH:15][CH:16]=1>C(O)C.[Pd]>[CH:7]1([C:12]2[N:13]=[CH:14][NH:15][CH:16]=2)[C:8]2[C:3](=[CH:2][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][CH2:6]1
Reactant: Clc1cccc2c1CCCC2c1c[nH]cn1
Agent: [Pd]
Solvent: CCO
Product: c1ccc2c(c1)CCCC2c1c[nH]cn1

Procedure:
4-(5-Chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-imidazole (300 mg) is dissolved in ethanol (15 ml). The reaction solution is hydrogenated at 50° C. with 10% palladium on carbon as catalyst for 8 hours. The mixture is filtered to remove the catalyst, and the filtrate is evaporated under reduced pressure. The residue is dissolved in water and is made alkaline with sodium hydroxide solution. The product is extracted into methylene chloride which is washed with water, dried with sodium sulfate and evaporated under reduced pressure. The crude product is recrystallized from ethyl acetate. The yield is 169 mg, m.p. 105-110° C.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CC[OH:28])C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCOCC1>[C:14]1([P:7](=[O:28])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: OCCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1COCCO1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triphenylphosphine (1.2 g, 5.4 mmol) and 2-phenylethanol (0.65 g, 5.4 mmol) were sequentially added to a solution of tri-N2,1,2′-O-acetyl-L-biopterin (1.5 g, 4.21 mmol) in 1,4-dioxane (7 ml). To this mixture diisopropylazodicarboxylate (1.05 ml, 5.4 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 18 h. Evaporation and column chromatography on silica gel eluting with AcOEt (1:2) followed by AcOEt gave the expected product together with triphenylphosphine oxide.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH:14]([CH3:16])[CH3:15])[CH:5]=1.[OH-].[Li+]>CO>[CH:14]([O:13][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[N+:10]([O-:12])=[O:11])[C:3]([OH:17])=[O:2])([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OC(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Oc1cc(C(=O)O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To a solution of 1.0 g (4.2 mole) of 3-isopropoxy-4-nitro-benzoic acid methyl ester in 20 mL of methanol was added 8.4 mL (8.4 mole) of 1M lithium hydroxide. The mixture was stirred at room temperature for 2 hours. The mixture was partially concentrated under reduced pressure and then acidified to by addition of 1 M of hydrochloric acid. The solid, which formed, was collected by filtration, washed with water and dried under vacuum to give 0.93 g of 3-isopropoxy-4-nitro-benzoic acid as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=O)=[N:6][CH:7]=1.Cl.[O:28]([NH2:30])[CH3:29]>CCO>[CH3:29][O:28][N:30]=[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=1)[C:10]1[N:19]=[C:18]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: CON
Reactant: Cc1cc(Nc2nc(C(=O)c3ccc(F)cn3)nc3ccccc23)n[nH]1
Agent: Cl
Solvent: CCO
Product: CON=C(c1ccc(F)cn1)c1nc(Nc2cc(C)[nH]n2)c2ccccc2n1
Temperature: 60 °C

Procedure:
To a 0.3 M solution of (5-fluoropyridin-2-yl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone from Example 1 in EtOH is added methoxylamine hydrochloride (2 equiv) and the mixture is heated to 60° C. for 30 min or until the reaction is substantially complete. The mixture is concentrated under reduced pressure and the residue is purified by chromatography to afford (5-fluoropyridin-2-yl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone O-methyl oxime. LC-MS (ESI) m/z 377 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH:24][C@H:25]4[CH2:30][CH2:29][CH2:28][C@H:27]([OH:31])[CH2:26]4)=[N:21][CH:20]=[N:19][C:18]=3[O:17][C:16]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:11][CH:10]=1.[C:38](#[N:41])[CH:39]=[CH2:40]>C1COCC1.ClCCl>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:23]3[C:22]([NH:24][C@H:25]4[CH2:30][CH2:29][CH2:28][C@H:27]([O:31][CH2:40][CH2:39][C:38]#[N:41])[CH2:26]4)=[N:21][CH:20]=[N:19][C:18]=3[O:17][C:16]=2[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(N[C@H]4CCC[C@H](O)C4)c23)cc1
Reactant: C=CC#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(N[C@H]4CCC[C@H](OCCC#N)C4)c23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add a solution of approx. 2 mg of potassium tert-butoxide in 0.2 ml of THF dropwise to a solution of 34.4 mg (0.059 mmol) of (+/−)-trans-3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}cyclohexanol in 0.23 ml of acrylonitrile. Stir the reaction mixture with exclusion of light at RT for approx. 2 h. After diluting with dichloromethane, wash successively with 1N hydrochloric acid, satd. sodium hydrogencarbonate solution and satd. sodium chloride solution, and concentrate the organic phase under reduced pressure. After the residue has been purified by means of preparative RP-HPLC (eluent: acetonitrile/water gradient), 33.6 mg of the target product are obtained (86.6% of theory).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH:5]([C:10]1[CH:11]=[C:12]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH:18]([C:22]([F:25])([F:24])[F:23])[NH:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[CH3:37][O:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br-]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CCN(C(C)C)C(C)C>[CH2:1]([O:3][C:4](=[O:36])[CH:5]([C:10]1[CH:11]=[C:12]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:31]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH:18]([C:22]([F:23])([F:24])[F:25])[N:17]2[CH2:43][C:42]2[CH:45]=[CH:46][C:39]([O:38][CH3:37])=[CH:40][CH:41]=2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: COc1ccc(CBr)cc1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCC(C(F)(F)F)N2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCC(C(F)(F)F)N2Cc2ccc(OC)cc2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-Methyl-2-[4′-trifluoromethyl-5-(6-trifluoromethyl-piperidin-2-yl)-biphenyl-3-yl]-pentanoic acid ethyl ester, compound 7b (47 mg, 0.092 mmol), 4-Methoxybenzyl bromide (66 μl, 0.46 mmol), DIEA (160 μl, 0.919), and tetrabutylammonium iodide (TBAI)(36 mg, 0.096 mmol) were combined and heated to 80° C. After overnight, no product was formed. Cesium carbonate (30 mg, 0.46 mmol) was added and after 5.5 hours ˜30% product was obtained. Additional Cesium carbonate (30 mg), bromide (66 ml) and TBAI were added and the reaction continued 72 hours. Little change in product formation. Reaction was purified directly by silica gel chromatography to give 21.3 mg, 36% as a clear oil. (M+H) 635.38, Found 636.4.
Reaction SMILES: C([N:8]([CH2:26][C@H:27]([OH:49])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([O:36]CC2C=CC=CC=2)=[C:32]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])[CH:31]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:25]=[CH:24][C:18]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)C1C=CC=CC=1>O1CCCC1.C(O)C.[Pd]>[OH:49][C@H:27]([CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])[CH:31]=1)[CH2:26][NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]2[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:24][CH:25]=2)[CH2:13][CH2:14]1
Reactant: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(OCC(=O)O)cc3)CC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN[C@H]2CC[C@H](c3ccc(OCC(=O)O)cc3)CC2)ccc1O
Reaction time: 4 h

Procedure:
A mixture of 0.3 g of trans-(4-{4-[benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)amino]cyclohexyl}phenoxy)acetic acid (0.44 mmol) and of 0.20 g of 10% palladium-on-charcoal (50% in water) in a mixture of tetrahydrofuran (5 ml) and ethanol (5 ml) is placed under a hydrogen atmosphere and stirred for 4 h. The reaction mixture is filtered through celite. The solvents are evaporated under reduced pressure and trans-(4-{4-[((2S)-2-hydroxy-3-{4-hydroxy-3-[(methylsulfonyl)amino]phenoxy}propyl)amino]cyclohexyl}-phenoxy)acetic acid is obtained in the form of a white solid (0.07 g, 32%) after purification on C18-grafted silica (eluent: water/acetonitrile, 95/5 to 5/95 gradient in 15 min).
Reaction SMILES: [CH:1]1([N:7]([C@H:29]2[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]2)[C:8](=[O:28])[NH:9][C:10]2[S:11][C:12]([S:15]([N:18](C)[CH2:19][C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])(=[O:17])=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N([C@H]2CC[C@H](C)CC2)C(=O)NC2SC(S(NCC(O)=O)(=O)=O)=CN=2)CCCCC1.C(NCC)C>>[CH:1]1([N:7]([C@H:29]2[CH2:30][CH2:31][C@H:32]([CH3:35])[CH2:33][CH2:34]2)[C:8](=[O:28])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18][CH2:19][C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])(=[O:16])=[O:17])=[CH:13][N:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCN(CC)C(=O)CN(C)S(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](C)CC2)s1
Agent: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(S(=O)(=O)NCC(=O)O)s2)C2CCCCC2)CC1
Solvent: CCNCC
Product: CCN(CC)C(=O)CNS(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](C)CC2)s1

Procedure:
The title compound was prepared in a similar manner to 2-({2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-methyl-amino)-N,N-diethyl-acetamide using {2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonylamino}-acetic acid and diethylamine.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[N:7]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][CH:8]=1.O>C1(C)C=CC=CC=1>[N:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:9][CH:8]=1
Reactant: Nc1nccs1
Reactant: O=Cc1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: c1cc(CNc2nccs2)ccn1
Reaction time: 3 h
Yield: 73.2 %

Procedure:
A mixture of 2-aminothiazole (3 g, 30 mmol) and 4-pyridinecarboxaldehyde (3.21 g, 30 mmol) in toluene (50 ml) was refluxed with a Dean-Stark water separator for 3 h. Solvent was removed under reduced pressure and the resulting yellow solid was dissolved in CH3OH (80 ml). The solution was carefully treated with sodium borohydride (1.8 g) and was stirred for 20 minutes. The reaction mixture was quenched with 1N NaOH and evaporated to dryness. The residue was dissolved in EtOAc, washed with brine and dried (MgSO4). Solvent was evaporated to give the crude intermediate N-(pyridin-4ylmethyl)-1,3-thiazol-2-amine as a brown solid (4.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([C:16]2([C:23]#[N:24])[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)=[CH:5][CH:4]=1.CO[CH:27](OC)[N:28]([CH3:30])[CH3:29]>C1C=CC=CC=1>[CH3:27][N:28](/[CH:30]=[C:20]1\[CH2:21][C:16]([C:6]2[C:7]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[O:9][C:8]=3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)([C:23]#[N:24])[CH2:17][CH2:18][C:19]\1=[O:22])[CH3:29]
Reactant: COc1ccc(C2(C#N)CCC(=O)CC2)c2c1oc1ccccc12
Reactant: COC(OC)N(C)C
Solvent: c1ccccc1
Product: COc1ccc(C2(C#N)CCC(=O)/C(=C/N(C)C)C2)c2c1oc1ccccc12

Procedure:
A solution of the compound obtained in example 2 (200 mg, 0.626 mmol), dimethylformamide dimethylacetal (447 mg, 3.76 mmol) and a catalytic amount of tetraethyl amine in benzene (15 ml) were distilled over a period of 3 hrs to about one half the original volume. Benzene (15 ml) was added to the reaction mixture and the distillation was continued. The process was repeated until the reaction showed absence of the ketone starting material. After all starting material was consumed, the solvent was completely evaporated under vacuum and residue was purified by column chromatography to give 174 mg (74.5% yields) of an off-yellow solid product. Melting point (MP)-decomposes at 300° C.
Reaction SMILES: C1C2C(CO[C:16]([N:18](C)[C@H:19]([C:23]([NH:25][C@H:26]([C:30]([N:32]([C@@H:34]([C@@H:67]([CH3:70])[CH2:68][CH3:69])[C@H:35]([O:65][CH3:66])[CH2:36][C:37]([N:39]3[CH2:43][CH2:42][CH2:41][C@H:40]3[C@H:44]([O:63][CH3:64])[C@@H:45]([CH3:62])[C:46]([NH:48][C@H:49]([C:57]3[S:58][CH:59]=[CH:60][N:61]=3)[CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[S:47])=[O:38])[CH3:33])=[O:31])[CH:27]([CH3:29])[CH3:28])=[O:24])[CH:20]([CH3:22])[CH3:21])=O)C3C(=CC=CC=3)C=2C=CC=1.C(OCC)C.CCCCCCC>ClCCl.C(NCC)C>[CH3:16][NH:18][C@H:19]([C:23]([NH:25][C@H:26]([C:30]([N:32]([C@@H:34]([C@@H:67]([CH3:70])[CH2:68][CH3:69])[C@H:35]([O:65][CH3:66])[CH2:36][C:37]([N:39]1[CH2:43][CH2:42][CH2:41][C@H:40]1[C@H:44]([O:63][CH3:64])[C@@H:45]([CH3:62])[C:46]([NH:48][C@H:49]([C:57]1[S:58][CH:59]=[CH:60][N:61]=1)[CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[S:47])=[O:38])[CH3:33])=[O:31])[CH:27]([CH3:29])[CH3:28])=[O:24])[CH:20]([CH3:22])[CH3:21]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: ClCCl
Solvent: CCNCC
Solvent: CCOCC
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Yield: 91.7 %

Procedure:
According to general procedure A, from #25 (701 mg, 0.694 mmol) in dichloromethane (10 mL, 0.07 M) and diethylamine (10 mL) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0% to 10% methanol in dichloromethane) to give a glass-like solid. Diethyl ether and heptane were added and the mixture was concentrated in vacuo, producing #26 (501 mg, 92%) as a white solid. HPLC (Protocol A): m/z 787.4 [M+H+], retention time=7.229 minutes, (purity >97%); 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [10.54 (br d, J=8 Hz) and 10.81 (br d, J=8. Hz), total 1H], [7.99 (br d, J=9 Hz) and 8.00 (br d, J=9 Hz), total 1H], [7.80 (d, J=3.3 Hz) and 7.83 (d, J=3.3 Hz), total 1H], [7.65 (d, J=3.2 Hz) and 7.69 (d, J=3.3 Hz), total 1H], 7.29-7.34 (m, 2H), 7.19-7.28 (m, 2H), 7.13-7.19 (m, 1H), [6.31 (ddd, J=11, 8, 4.5 Hz) and 6.45 (ddd, J=11.5, 8, 4.5 Hz), total 1H], [4.57 (dd, J=8.9, 8.7 Hz) and 4.63 (dd, J=8.7, 8.7 Hz), total 1H], 3.16, 3.21, 3.24 and 3.25 (4 s, total 6H), 2.96 and 3.03 (2 br s, total 3H), [1.14 (d, J=6.6 Hz) and 1.17 (d, J=6.4 Hz), total 3H].
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[N:12]=[C:13]2[N:18]([CH:19]=1)[CH2:17][CH2:16][C@H:15]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=1)[O:14]2)([O-:10])=[O:9].[CH:34]([O:36][CH2:37][CH2:38]Cl)=[O:35].Cl>C(Cl)Cl>[CH2:37]([O:36][C:34]([N:31]1[CH2:32][CH2:33][N:28]([C:25]2[CH:26]=[CH:27][C:22]([O:21][CH2:20][C@@H:15]3[O:14][C:13]4=[N:12][C:11]([N+:8]([O-:10])=[O:9])=[CH:19][N:18]4[CH2:17][CH2:16]3)=[CH:23][CH:24]=2)[CH2:29][CH2:30]1)=[O:35])[CH3:38]
Reactant: O=[N+]([O-])c1cn2c(n1)O[C@@H](COc1ccc(N3CCNCC3)cc1)CC2
Reactant: O=COCCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(c2ccc(OC[C@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Reaction time: 14 h

Procedure:
Triethylamine (0.31 ml) was added to a methylene chloride suspension (6 ml) of (R)-2-nitro-7-(4-piperazin-1-ylphenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (0.40 g). Subsequently, chloroethyl formate (0.11 ml) was added thereto dropwise under ice cooling, and the mixture was stirred for 14 hours while it gradually returned to room temperature. A 0.5 N hydrochloric acid aqueous solution was then added to the reaction mixture, followed by extraction with methylene chloride. After washing the organic layer with water and a saturated sodium chloride aqueous solution, the organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (methylene chloride:methanol=90:10) and recrystallized from acetone-water to afford the title compound as a pale yellow powder (0.36 g).
Reaction SMILES: [C:1]1(=[N:7]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1(=[O:16])N[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C1(=NO)CCCCCCCCCCC1>>[C:9]1(=[O:16])[NH:7][CH2:1][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C1CCCCCN1
Reactant: ON=C1CCCCC1
Agent: ON=C1CCCCCCCCCCC1
Product: O=C1CCCCCCCCCCCN1

Procedure:
An oxime can be converted into an amide compound by Beckmann rearrangement reaction, particularly an oxime derived from a cyclic ketone can be converted into a lactam. For example, cyclohexanone oxime gives ε-caprolactam which is a starting material for Nylon 6 and cyclododecanone oxime gives laurolactam which is a starting material for Nylon 12.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Br[CH:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39]>CN(C)C=O>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39]
Reactant: COC(=O)C(C)Br
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3O)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 83.3 %

Procedure:
Into 6 ml of N,N-dimethylformamide was dissolved 0.23 g of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenol. After adding 0.22 g of anhydrous potassium carbonate, 0.13 g of methyl 2-bromopropionate was added at room temperature with stirring and then the mixture was stirred at 80° C. for 3 hours. After cooling the reaction solution to room temperature, the reaction solution was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica-gel column chromatography to give 0.23 g of methyl 2-[2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl) -1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]propionate [Compound A-3].